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FTR #1131 Bio-Psy-Op Apocalypse Now, Part 7: Moderna Uber Alles

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FTR #1131 This pro­gram was record­ed in one, 60-minute seg­ment

Intro­duc­tion: This pro­gram con­tin­ues dis­cus­sion of Mod­er­na from FTR #1130. The fir­m’s mRNA (mes­sen­ger RNA) vac­cine that was high­light­ed in that pro­gram is a major top­ic of dis­cus­sion in this one as well.

Do note that DARPA sup­port for Mod­er­na and their work on “gene dri­ving” tech­nol­o­gy in the con­text of that vac­cine.

Intro­duc­ing the top­ic of Mod­er­na’s SARS Cov‑2 vac­cine as a mon­ey mak­er for both Mod­er­na and as a dri­ver for the mar­ket as a whole, we note last Mon­day’s announce­ment which gen­er­at­ed a major boost in the val­ue of Mod­er­na’s stock and a strong, gen­er­al ral­ly. The lat­ter appar­ent­ly stems from opti­mism that a suc­cess­ful vac­cine will alle­vi­ate the eco­nom­ic dam­age from Covid-19.

A Mar­ket­Watch piece about the rapid fluc­tu­a­tion of Mod­er­na’s stock under­scores the sig­nif­i­cance of the tim­ing of an announce­ment cast­ing Mod­er­na’s vac­cine tri­al in over­ly opti­mistic light:

  1. Mod­er­na’s CEO (Stephen Ban­cel) and CFO (Lorence Kim) both sold stock on Fri­day, in accor­dance with pre­arranged trans­ac­tions. Bear in mind, that (as dis­cussed in FTR #1130), Mod­er­na’s stock was trad­ing at $23.46 at the begin­ning of the year, and the company–which has nev­er mar­ket­ed a vaccine–was the ben­e­fi­cia­ry of $483 mil­lion dol­lars in fed­er­al fund­ing ear­li­er in the year.) ” . . . . On Fri­day, Ban­cel sold 11,046 shares at a weight­ed aver­age price of $65.56 for about $724,200, as part of a pre­de­ter­mined trad­ing plan adopt­ed Dec. 28, 2018, accord­ing to a Form 4 fil­ing with the Secu­ri­ties and Exchange Com­mis­sion. He also dis­posed of 1,577 shares as part of a ‘bona fide’ gift. . . . Also, on Fri­day, Kim sold 20,000 shares at a weight­ed aver­age price of $65.53 for about $1.31 mil­lion, as part of a pre­de­ter­mined trad­ing plan. . . .”
  2. Kim also simul­ta­ne­ous­ly bought and sold shares of his firm for a net prof­it of $16.79 mil­lion on Mon­day, the day of an over­ly opti­mistic announce­ment by Mod­er­na. The for­tu­itous­ly timed Mod­er­na announce­ment made the fir­m’s CFO rough­ly $4 mil­lion: ” . . . . On Mon­day, he [Kim] exer­cised options to buy 241,000 shares at a weight­ed aver­age price of $12.45 for about $3 mil­lion, also as part of a pre­de­ter­mined plan. At the same time, Kim exe­cut­ed sales of 241,000 shares, at a weight­ed aver­age price of $82.12 for about $19.79 mil­lion. That means Kim net­ted about $16.79 mil­lion on the simul­ta­ne­ous buy and sale of shares. . . . with Monday’s stock price surge fol­low­ing the announce­ment of ear­ly data on its vac­cine can­di­date poten­tial­ly adding $4 mil­lion to Kim’s cof­fers. . . .”
  3. The above-ref­er­enced announce­ment by Mod­er­na led to a dra­mat­ic increase in Mod­er­na’s stock and boost­ed the mar­ket as a whole. Mod­er­na announced that evening that it would sell $1.34 bil­lion in stock to help its vac­cine oper­a­tion: ” . . . . Shares of Mod­er­na closed at a record high of $80.00 on Mon­day after the com­pa­ny released a slice of pos­i­tive inter­im clin­i­cal data from the first phase of its COVID-19 vac­cine tri­al. That night it announced it would sell $1.34 bil­lion in stock to help fund man­u­fac­tur­ing costs asso­ci­at­ed with the exper­i­men­tal COVID-19 vac­cine. . . .”
  4. Mod­er­na’s stock nose­dived at the end of the trad­ing day on Tues­day, due to a crit­i­cal arti­cle from Stat News” . . . . The stock took a nose dive on Tues­day, clos­ing at $71.67, like­ly due in some degree to a Stat News sto­ry that ques­tioned a lack of clin­i­cal clar­i­ty in the data it pro­vid­ed to investors. . . .”
  5. Mod­er­na’s announce­ment was crit­i­cal­ly assessed by Stat News, which point­ed out that the results were incom­plete at best: ” . . . . In a clin­i­cal-tri­al data dis­clo­sure on Mon­day, Mod­er­na shared that eight out of 45 par­tic­i­pants in its COVID-19 vac­cine study devel­oped neu­tral­iz­ing anti­bod­ies, a deci­sion that Stat’s Helen Bran­swell described as a ‘rea­son for cau­tion.’ It didn’t share infor­ma­tion about the immune response to the exper­i­men­tal vac­cine in the remain­ing 37 par­tic­i­pants. . . .”
  6. Nonethe­less, Mod­er­na’s stock–bolstered by gov­ern­ment investment–has been on a dra­mat­ic upward swing: ” . . . . The company’s stock was up 3.8% in trad­ing on Wednes­day. Year-to-date, it has soared 270.2%, even though the com­pa­ny has no approved prod­ucts. . . .”

There are seri­ous ques­tions about the sub­stance of Mod­er­na’s state­ment:

  1. Moderna’s much tout­ed report on its vaccine—which trig­gered an upsurge in the mar­kets on Monday—appears to have been incom­plete, at best, and pur­pose­ful­ly decep­tive, at worst. “ . . . . While Mod­er­na blitzed the media, it revealed very lit­tle infor­ma­tion — and most of what it did dis­close were words, not data.. . . . If you ask sci­en­tists to read a jour­nal arti­cle, they will scour data tables, not cor­po­rate state­ments. With sci­ence, num­bers speak much loud­er than words. Even the fig­ures the com­pa­ny did release don’t mean much on their own, because crit­i­cal infor­ma­tion — effec­tive­ly the key to inter­pret­ing them — was with­held. . . .
  2. Part of the rea­son for alarm and skep­ti­cism con­cerns the behav­ior of the NIAID—whose direc­tor is Antho­ny Fau­ci: “ . . . . The Nation­al Insti­tute for Aller­gy and Infec­tious Dis­eases has part­nered with Mod­er­na on this vac­cine. Sci­en­tists at NIAID made the vaccine’s con­struct, or pro­to­type, and the agency is run­ning the Phase 1 tri­al. This week’s Mod­er­na read­out came from the ear­li­est of data from the NIAID-led Phase 1. NIAID doesn’t hide its light under a bushel. The insti­tute gen­er­al­ly trum­pets its find­ings, often offer­ing direc­tor Antho­ny Fau­ci . . . or oth­er senior per­son­nel for inter­views. But NIAID did not put out a press release Mon­day and declined to pro­vide com­ment on Moderna’s announce­ment. . . .”
  3. To begin with, Moderna’s announce­ment was only sta­tis­ti­cal­ly sub­stan­tive for 8 of the 45 vol­un­teer sub­jects: “ . . . . The company’s state­ment led with the fact that all 45 sub­jects (in this analy­sis) who received dos­es of 25 micro­grams (two dos­es each), 100 micro­grams (two dos­es each), or a 250 micro­grams (one dose) devel­oped bind­ing anti­bod­ies. Lat­er, the state­ment indi­cat­ed that eight vol­un­teers — four each from the 25-micro­gram and 100-micro­gram arms — devel­oped neu­tral­iz­ing anti­bod­ies. Of the two types, these are the ones you’d real­ly want to see. We don’t know results from the oth­er 37 tri­al par­tic­i­pants. . . .”
  4. It is pos­si­ble that neu­tral­iz­ing anti­bod­ies may have been devel­oped in the 37 test sub­jects whose data was not released because the test­ing process is exact­ing. Still the state­ment war­rants cau­tion, at the least. “ . . . . This doesn’t mean that they didn’t devel­op neu­tral­iz­ing anti­bod­ies.Test­ing for neu­tral­iz­ing anti­bod­ies is more time-con­sum­ing than oth­er anti­body tests and must be done in a biose­cu­ri­ty lev­el 3 lab­o­ra­to­ry. Mod­er­na dis­closed the find­ings from eight sub­jects because that’s all it had at that point. Still, it’s a rea­son for cau­tion . . . .”
  5. In addi­tion, the age of the sub­jects was not released and that is rel­e­vant. “ . . . . Sep­a­rate­ly, while the Phase 1 tri­al includ­ed healthy vol­un­teers ages 18 to 55 years, the exact ages of these eight peo­ple are unknown. If, by chance, they most­ly clus­tered around the younger end of the age spec­trum, you might expect a bet­ter response to the vac­cine than if they were most­ly from the senior end of it. And giv­en who is at high­est risk from the SARS-CoV­‑2 coro­n­avirus, pro­tect­ing old­er adults is what Covid-19 vac­cines need to do. . . .”
  6. In addi­tion, there was no data released as to the dura­bil­i­ty of the neu­tral­iz­ing anti­bod­ies. If, for the sake of argu­ment, they are not long-last­ing, the util­i­ty of the vac­cine is neg­li­gi­ble. “ . . . . The report of neu­tral­iz­ing anti­bod­ies in sub­jects who were vac­ci­nat­ed comes from blood drawn two weeks after they received their sec­ond dose of vac­cine. Two weeks. ‘That’s very ear­ly. We don’t know if those anti­bod­ies are durable,’ said Anna Durbin, a vac­cine researcher at Johns Hop­kins Uni­ver­si­ty. . . .”
  7. Still anoth­er point of contention/alarm con­cerns the vari­abil­i­ty in neu­tral­iz­ing anti­bod­ies among recov­ered patients: “ . . . . But stud­ies have shown anti­body lev­els among peo­ple who have recov­ered from the ill­ness vary enor­mous­ly; the range that may be influ­enced by the sever­i­ty of a person’s dis­ease. John ‘Jack’ Rose, a vac­cine researcher from Yale Uni­ver­si­ty, point­ed STAT to a study from Chi­na that showed that, among 175 recov­ered Covid-19 patients stud­ied, 10 had no detectable neu­tral­iz­ing anti­bod­ies. Recov­ered patients at the oth­er end of the spec­trum had real­ly high anti­body lev­els. So though the com­pa­ny said the anti­body lev­els induced by vac­cine were as good as those gen­er­at­ed by infec­tion, there’s no real way to know what that com­par­i­son means. . . .”
  8. It is less than encour­ag­ing that Mod­er­na dis­closed that more rel­e­vant data will be dis­closed in a report to be released in con­junc­tion with NIAID: “ . . . . STAT asked Mod­er­na for infor­ma­tion on the anti­body lev­els it used as a com­para­tor. The response: That will be dis­closed in an even­tu­al jour­nal arti­cle from NIAID, which is part of the Nation­al Insti­tutes of Health. . . .”
  9. Ann Durbin was struck by the word­ing of Moderna’s release: “ . . . . Durbin was struck by the word­ing of the company’s state­ment, point­ing to this sen­tence: ‘The lev­els of neu­tral­iz­ing anti­bod­ies at day 43 were at or above lev­els gen­er­al­ly seen in con­va­les­cent sera.’ ‘I thought: Gen­er­al­ly? What does that mean?’ Durbin said. Her ques­tion, for the time being, can’t be answered. . . .”
  10. Jack Rose com­ment­ed on the opaque nature of Moderna’s release: “. . . . Rose said the com­pa­ny should dis­close the infor­ma­tion. ‘When a com­pa­ny like Mod­er­na with such incred­i­bly vast resources says they have gen­er­at­ed SARS‑2 neu­tral­iz­ing anti­bod­ies in a human tri­al, I would real­ly like to see num­bers from what­ev­er assay they are using,’ he said. . . .”
  11. To date, Mod­er­na issues press releas­es, not papers that can be vet­ted by the sci­en­tif­ic com­mu­ni­ty: “ . . . . It doesn’t pub­lish on its work in sci­en­tif­ic jour­nals. What is known has been dis­closed through press releas­es. That’s not enough to gen­er­ate con­fi­dence with­in the sci­en­tif­ic com­mu­ni­ty. ‘My guess is that their num­bers are mar­gin­al or they would say more,’ Rose said about the company’s SARS‑2 vac­cine, echo­ing a sus­pi­cion that oth­ers have about some of the company’s oth­er work. ‘I do think it’s a bit of a con­cern that they haven’t pub­lished the results of any of their ongo­ing tri­als that they men­tion in their press release. They have not pub­lished any of that,’ Durbin not­ed. . . .”

After sum­ma­riz­ing a high­ly tech­ni­cal arti­cle warn­ing that of the pos­si­ble con­se­quences of intro­duc­ing a SARS Cov‑2 vac­cine that gen­er­ates inad­e­quate­ly high lev­els of anti­bod­ies, we detail a 2016 STAT News arti­cle about Mod­er­na high­lights a num­ber of areas of con­cern, giv­en the speed and rel­a­tive­ly opaque nature of the poten­tial intro­duc­tion of its Covid-19 vac­cine.

The financ­ing of the com­pa­ny by DARPA, and Mon­cef Slaoui’s join­ing with Four Star Gen­er­al Per­na (ele­vat­ed by the Chair­man of the Joint Chiefs of Staff, Gen­er­al Mark A. Mil­ley) are of addi­tion­al con­cern.

  1. As of 2016, Mod­er­na had the largest val­u­a­tion of any pri­vate biotech firm and for­mer employ­ees felt that Mod­er­na prized mon­ey over sci­ence. Note that, as will be reviewed lat­er in the pro­gram, its stock has risen expo­nen­tial­ly as a result of the injec­tion of hun­dreds of mil­lions of dol­lars. Bear in mind that Mod­er­na has also been under­writ­ten by DARPA. “ . . . . Mod­er­na is worth more than any oth­er pri­vate biotech in the US, and for­mer employ­ees said they felt that Ban­cel prized the company’s ever-increas­ing val­u­a­tion, now approach­ing $5 bil­lion, over its sci­ence. . . .”
  2. Mod­er­na has main­tained a cul­ture of secre­cy, which in 2016, applied to the first two prod­ucts under­go­ing phase 1 tri­als: “ . . . . Mod­er­na just moved its first two poten­tial treat­ments — both vac­cines — into human tri­als. In keep­ing with the cul­ture of secre­cy, though, exec­u­tives won’t say which dis­eases the vac­cines tar­get, and they have not list­ed the stud­ies on the pub­lic fed­er­al reg­istry, ClinicalTrials.gov. List­ing is option­al for Phase 1 tri­als, which are meant to deter­mine if a drug is safe, but most com­pa­nies vol­un­tar­i­ly dis­close their work. . . .”
  3. Pro­tein ther­a­py has been a dri­ving eco­nom­ic and ther­a­peu­tic fac­tor in the phar­ma­ceu­ti­cal busi­ness: “ . . . . For decades, com­pa­nies have endeav­ored to craft bet­ter and bet­ter pro­tein ther­a­pies, lead­ing to new treat­ments for can­cer, autoim­mune dis­or­ders, and rare dis­eases. Such ther­a­pies are cost­ly to pro­duce and have many lim­i­ta­tions, but they’ve giv­en rise to a multi­bil­lion-dol­lar indus­try. The anti-inflam­ma­to­ry Humi­ra, the world’s top drug at $14 bil­lion in sales a year, is a shin­ing exam­ple of pro­tein ther­a­py. . . .”
  4. Mod­er­na aims at doing an end run around that tech­nol­o­gy with the injec­tion of mRNA (mes­sen­ger RNA) or DNA. This is a risky tech­nol­o­gy: “ . . . . Moderna’s tech­nol­o­gy promised to sub­vert the whole field, cre­at­ing ther­a­peu­tic pro­teins inside the body instead of in man­u­fac­tur­ing plants. The key: har­ness­ing mes­sen­ger RNA, or mRNA. . . . . It’s high­ly risky. Big phar­ma com­pa­nies had tried sim­i­lar work and aban­doned it because it’s exceed­ing­ly hard to get RNA into cells with­out trig­ger­ing nasty side effects. . . . .”
  5. CEO Ban­cel has main­tained the company’s opaque pro­fes­sion­al cul­ture, mixed with high-pro­file media pro­mo­tion: “ . . . . Under Ban­cel, Mod­er­na has been loath to pub­lish its work in Sci­ence or Nature, but enthu­si­as­tic to her­ald its poten­tial on CNBC and CNN, tak­ing part in seg­ments on the world’s most dis­rup­tive com­pa­niesand the poten­tial ‘cure for can­cer.’ . . .”
  6. Mod­er­na had dra­con­ian atti­tude toward employ­ees from its incep­tion: “ . . . . From the begin­ning, Ban­cel made clear that Moderna’s sci­ence sim­ply had to work. And that any­one who couldn’t make it work didn’t belong. The ear­ly Mod­er­na was a chaot­ic, unpre­dictable work­place, accord­ing to for­mer employ­ees. One recalls find­ing him­self out of a job when a quick-turn­around exper­i­ment failed to pan out. Anoth­er helped train a group of new hires only to real­ize they were his replace­ments. . . .”
  7. Joe Bolen exem­pli­fied the treat­ment Mod­er­na met­ed out: “ . . . . Most stun­ning to employ­ees was the abrupt depar­ture of Joseph Bolen, who came aboard in 2013 to lead Moderna’s R&D efforts. Bolen was a big-name hire in biotech cir­cles, an expe­ri­enced chief sci­en­tif­ic offi­cer who had guid­ed Mil­len­ni­um Phar­ma­ceu­ti­cals to FDA approval for a block­buster can­cer drug. . . ‘No sci­en­tist in his right mind would leave that job unless there was some­thing wrong with the sci­ence or the per­son­nel,’ said a per­son close to the com­pa­ny at the time.’ . . .”
  8. Bolen had com­pa­ny: “ . . . . Bolen wasn’t alone. Chief Infor­ma­tion Offi­cer John Reyn­ders joined in 2013 to make Mod­er­na what he called the world’s ‘first ful­ly dig­i­tal biotech,‘only to step down a year lat­er. Michael Morin, brought in to lead Moderna’s sci­en­tif­ic efforts in can­cer in 2014, last­ed less than 18 months. As did Greg Licholai, hired in 2015 to direct the company’s projects in rare dis­eases. The lat­ter two key lead­er­ship posi­tions remain unfilled. . . .”
  9. The expla­na­tion of CFO Lorence Kim is less than reas­sur­ing from the stand­point of prod­uct safe­ty and reli­a­bil­i­ty: “ . . . . ‘We force every­one to grow with the com­pa­ny at unprece­dent­ed speed,’ Mod­er­na Chief Finan­cial Offi­cer Lorence Kim said. ‘Some peo­ple grow with the com­pa­ny; oth­ers don’t.’ . . .”
  10. Begin­ning in 2013, Mod­er­na part­nered with a series of phar­ma­ceu­ti­cal giants, includ­ing AstraZeneca, which has been select­ed to devel­op a Covid-19 vac­cine: “ . . . . That’s when Mod­er­na — which had just 25 employ­ees — signed a stag­ger­ing $240 mil­lion part­ner­ship with UK phar­ma­ceu­ti­cal giant AstraZeneca. It was the most mon­ey phar­ma had ever spent on drugs that had not yet been test­ed in humans. . . .”
  11. The firm has been lav­ish­ly cap­i­tal­ized: “ . . . . In ear­ly 2015, Mod­er­na dis­closed a $450 mil­lion financ­ing round, the largest ever for a pri­vate biotech com­pa­ny. This month, the com­pa­ny broke its own record, rais­ing anoth­er $474 mil­lion. . . . Though it has yet to reveal data from a sin­gle clin­i­cal tri­al, Mod­er­na is now val­ued at $4.7 bil­lion, accord­ing to Pitch­book. . . .”
  12. Ini­tial­ly, Mod­er­na aimed at devel­op­ing prod­ucts that would be admin­is­tered for a peri­od of years: “ . . . . From the start, Mod­er­na her­ald­ed its abil­i­ty to pro­duce pro­teins with­in cells, which could open up a world of ther­a­peu­tic tar­gets unreach­able by con­ven­tion­al drugs. The most rev­o­lu­tion­ary treat­ments, which could chal­lenge the multi­bil­lion-dol­lar mar­ket for pro­tein ther­a­py, would involve repeat­ed dos­es of mRNA over many years, so a patient’s body con­tin­ued to pro­duce pro­teins to keep dis­ease at bay. . . .”
  13. Instead of pro­duc­ing treat­ments that would be admin­is­tered over a peri­od of years, the com­pa­ny focused on vac­cines: “ . . . . But Moderna’s first human tri­als aren’t so ambi­tious, focus­ing instead on the crowd­ed field of vac­cines, where the com­pa­ny has only been work­ing since 2014. . . . The choice to pri­or­i­tize vac­cines came as a dis­ap­point­ment to many in the com­pa­ny, accord­ing to a for­mer man­ag­er. The plan had been to rad­i­cal­ly dis­rupt the biotech indus­try, the man­ag­er said, so ‘why would you start with a clin­i­cal pro­gram that has very lim­it­ed upside and lots of com­pe­ti­tion?’” . . . .”
  14. The answer to Moderna’s focus on vac­cines may be due to issues of prod­uct safe­ty: “ . . . Deliv­ery — actu­al­ly get­ting RNA into cells — has long bedev­iled the whole field. On their own, RNA mol­e­cules have a hard time reach­ing their tar­gets. They work bet­ter if they’re wrapped up in a deliv­ery mech­a­nism, such as nanopar­ti­cles made of lipids. But those nanopar­ti­cles can lead to dan­ger­ous side effects, espe­cial­ly if a patient has to take repeat­ed dos­es over months or years. . . .”
  15. Vac­cines will only admin­is­ter mRNA at the time of vac­ci­na­tion, rather than over a long peri­od of time: “ . . . . ‘I would say that mRNA is bet­ter suit­ed for dis­eases where treat­ment for short dura­tion is suf­fi­cient­ly cura­tive, so the tox­i­c­i­ties caused by deliv­ery mate­ri­als are less like­ly to occur,’ said Katal­in Karikó, a pio­neer in the field who serves as a vice pres­i­dent at BioN­Tech. . . That makes vac­cines the low­est hang­ing fruit in mRNA, said Franz-Wern­er Haas, CureVac’s chief cor­po­rate offi­cer. ‘From our point of view, it’s obvi­ous why [Mod­er­na] start­ed there,’ he said.’ . . .”
  16. Moderna’s expla­na­tion for its focus on vac­cines is not reassuring—the speed with which it can pro­ceed to human tri­als. The firm’s secre­cy has gen­er­at­ed alarm: “ . . . . Mod­er­na said it pri­or­i­tized vac­cines because they pre­sent­ed the fastest path to human tri­als, not because of set­backs with oth­er projects. ‘The notion that [Mod­er­na] ran into dif­fi­cul­ties isn’t borne in real­i­ty,’ said [Chair­man of the board Noubar] Afeyan. But this is where Moderna’s secre­cy comes into play: Until there’s pub­lished data, only the com­pa­ny and its part­ners know what the data show. Every­one out­side is left guess­ing — and, in some cas­es, wor­ry­ing that Mod­er­na won’t live up to its hype. . . .”
  17. Mod­er­na applies soft­ware and a busi­ness mod­el derived from Tes­la, Ama­zon and Uber: “ . . . . Mod­er­na has pio­neered an auto­mat­ed sys­tem mod­eled on the soft­ware Tes­la uses to man­age orders, Ban­cel said: Sci­en­tists sim­ply enter the pro­tein they want a cell to express, and testable mRNA arrives with­in weeks. . . . That has always been part of the plan, for­mer employ­ees said, point­ing to Bancel’s fas­ci­na­tion with the tech indus­try. Uber and Ama­zon were not the first to come up with their respec­tive busi­ness ideas, but they were the ones that built enough scale to ward off com­pe­ti­tion. And Mod­er­na is posi­tion­ing itself to do the same in mRNA. . . .”

Mon­cef Slaoui

Mon­cef Slaoui’s  opti­mistic state­ment on the Fri­day before the Mon­day announce­ment, presents impor­tant con­text for Moderna’s Mon­day announce­ment. That announce­ment moved mar­kets based on inad­e­quate data. “Oper­a­tion Warp Speed” (head­ed by Slaoui) sug­gests that can­di­date Trump  is very inter­est­ed in those pre­lim­i­nary results as well. 

Eliz­a­beth War­ren scored Slaoui’s con­flict of interest–a con­sid­er­a­tion that will be dis­cussed at length: ” . . . . Fol­low­ing Mon­cef Slaoui’s Fri­day appoint­ment as a co-leader of the Warp Speed pro­gram, he’s set to sell about 155,000 shares in Mod­er­na, accord­ing to press reports. They were worth an esti­mat­ed $10 mil­lion Fri­day, but after Monday’s stock run-up on pos­i­tive ear­ly data, they’re now val­ued at about $12.4 mil­lion. . . . Fol­low­ing Slaoui’s selec­tion, Sen. Eliz­a­beth War­ren tweet­ed that it’s a ‘huge con­flict of inter­est’ for him to keep the Mod­er­na stock as he assumes the new role. She said he should ‘divest imme­di­ate­ly.’ In a now-delet­ed tweet, Slaoui respond­ed that there ‘is no con­flict of inter­est, and there nev­er has been,’ Busi­ness Insid­er reports. . . .”

Even after agree­ing to sell his Mod­er­na stock, Slaoui’s invest­ments raise alarm­ing ques­tions–note that he is a “ven­ture cap­i­tal­ist” and a long­time for­mer exec­u­tive at Glaxo-Smithk­line:

  1. The cir­cum­stances of his appoint­ment will per­mit him to avoid scruti­ny: ” . . . . In agree­ing to accept the posi­tion, Dr. Slaoui did not come on board as a gov­ern­ment employ­ee. Instead, he is on a con­tract, receiv­ing $1 for his ser­vice. That leaves him exempt from fed­er­al dis­clo­sure rules that would require him to list his out­side posi­tions, stock hold­ings and oth­er poten­tial con­flicts. And the con­tract posi­tion is not sub­ject to the same con­flict-of-inter­est laws and reg­u­la­tions that exec­u­tive branch employ­ees must fol­low. . . .”
  2. He will retain a great deal of Glaxo-Smithk­line stock: ” . . . . He did not say how much his GSK shares were worth. When he left the com­pa­ny in 2017, he held about [500,000 in West­ern Print Edi­tion] 240,000 shares and share equiv­a­lents, accord­ing to the drug company’s annu­al report and an analy­sis by the exec­u­tive com­pen­sa­tion firm Equi­lar. . . .”
  3. Fur­ther analy­sis of Slaoui’s posi­tion deep­ens con­cern about the integri­ty of the process: ” . . . . ‘This is basi­cal­ly absurd,’ said Vir­ginia Can­ter, who is chief ethics coun­sel for Cit­i­zens for Respon­si­bil­i­ty and Ethics in Wash­ing­ton. ‘It allows for no pub­lic scruti­ny of his con­flicts of inter­est.’ Ms. Can­ter also said fed­er­al law barred gov­ern­ment con­trac­tors from super­vis­ing gov­ern­ment employ­ees. . . . Ms. Can­ter, a for­mer ethics lawyer in the Oba­ma and Clin­ton admin­is­tra­tions, the Secu­ri­ties and Exchange Com­mis­sion and oth­er agen­cies, point­ed out that GSK’s vac­cine can­di­date with Sanofi could wind up com­pet­ing with oth­er man­u­fac­tur­ers vying for gov­ern­ment approval and sup­port. ‘If he retains stock in com­pa­nies that are invest­ing in the devel­op­ment of a vac­cine, and he’s involved in over­see­ing this process to select the safest vac­cine to com­bat Covid-19, regard­less of how won­der­ful a per­son he is, we can’t be con­fi­dent of the integri­ty of any process in which he is involved,’ Ms. Can­ter said. In addi­tion, his affil­i­a­tion with Medicxi could com­pli­cate mat­ters: Two of its investors are GSK and a divi­sion of John­son & John­son, which is also devel­op­ing a poten­tial vac­cine. . . .”

Mod­er­na stands to make bil­lions of dol­lars if their vac­cine goes to mar­ket:

  1. ” . . . . What investors are bet­ting on, for Mod­er­na and oth­ers devel­op­ing vac­cines against the SARS-CoV­‑2 virus, is that a third of the devel­oped world’s pop­u­la­tion will get vac­ci­nat­ed every year. That could amount to a $10 bil­lion annu­al busi­ness, at an esti­mat­ed price of $30 per vac­ci­na­tion. . . .”
  2. ” . . . . Mor­gan Stan­ley ana­lysts this past week­end sug­gest­ed that pric­ing might start at $5 to $10 a dose dur­ing this first pan­dem­ic cri­sis, then rise to a range of $13 to $30 for pre­ven­tive dos­es in future years. But at BMO Cap­i­tal Mar­kets, ana­lyst George Farmer spec­u­lat­ed that Mod­er­na could start charg­ing $125 per treat­ment in the U.S. mar­ket and raise that price over time to $200. . . . ”

We close the pro­gram with a reminder of the extent to which fed­er­al fund­ing dri­ves the val­ue of Mod­er­na: ” . . . . ‘Instead of wait­ing for the data and then scal­ing up with man­u­fac­tur­ing process … we can make as many dos­es as we can. We are doing both in par­al­lel,’ he said. The com­pa­ny plans to hire up to 150 peo­ple to sup­port the effort. Ban­cel said the com­pa­ny ‘couldn’t have done this’ with­out the fund­ing com­mit­ment from the Bio­med­ical Advanced Research and Devel­op­ment Author­i­ty, which is part of the Depart­ment of Health and Human Ser­vices. . . .”

1a. We begin by Intro­duc­ing the top­ic of Mod­er­na’s SARS Cov‑2 vac­cine as a mon­ey mak­er for both Mod­er­na and as a dri­ver for the mar­ket as a whole, we note last Mon­day’s announce­ment which gen­er­at­ed a major boost in the val­ue of Mod­er­na’s stock and a strong, gen­er­al ral­ly. The lat­ter appar­ent­ly stems from opti­mism that a sucess­ful vac­cine will alle­vi­ate the eco­nom­ic dam­age from Covid-19:

“Vaccine’s Ear­ly Test Result Ele­vates Hopes and Stocks” by Denise Grady; The New York Times; 5/19/2020; pp. A1-A9 [West­ern Edi­tion].

. . . . The promis­ing ear­ly news sent Moderna’s stock soar­ing by more than 25 per­cent on Mon­day after­noon and helped dri­ve Wall Street to its best day in six weeks. . . . Trad­ing on Mon­day had all of the char­ac­ter­is­tics of a ral­ly focused on prospects for a return to nor­mal: The S&P 500 rose more than 3 per­cent; stock bench­marks in Europe were 4 per­cent to 6 per­cent high­er; and oil prices also jumped. Among the best per­form­ers in the S&P 500 were trav­el-relat­ed com­pa­nies, like Unit­ed Air­lines, Expe­dia Group and Mar­riott Inter­na­tion­al. . . .

1b. A Mar­ket­Watch piece about the rapid fluc­tu­a­tion of Mod­er­na’s stock under­scores the sig­nif­i­cance of the tim­ing of an announce­ment cast­ing Mod­er­na’s vac­cine tri­al in over­ly opti­mistic light:

  1. Mod­er­na’s CEO (Stephen Ban­cel) and CFO (Lorence Kim) both sold stock on Fri­day, in accor­dance with pre­arranged trans­ac­tions. Bear in mind, that (as dis­cussed in FTR #1130), Mod­er­na’s stock was trad­ing at $23.46 at the begin­ning of the year, and the company–which has nev­er mar­ket­ed a vaccine–was the ben­e­fi­cia­ry of $483 mil­lion dol­lars in fed­er­al fund­ing ear­li­er in the year.) ” . . . . On Fri­day, Ban­cel sold 11,046 shares at a weight­ed aver­age price of $65.56 for about $724,200, as part of a pre­de­ter­mined trad­ing plan adopt­ed Dec. 28, 2018, accord­ing to a Form 4 fil­ing with the Secu­ri­ties and Exchange Com­mis­sion. He also dis­posed of 1,577 shares as part of a ‘bona fide’ gift. . . . Also, on Fri­day, Kim sold 20,000 shares at a weight­ed aver­age price of $65.53 for about $1.31 mil­lion, as part of a pre­de­ter­mined trad­ing plan. . . .”
  2. Kim also simul­ta­ne­ous­ly bought and sold shares of his firm for a net prof­it of $16.79 mil­lion on Mon­day, the day of an over­ly opti­mistic announce­ment by Mod­er­na. The for­tu­itous­ly timed Mod­er­na announce­ment made the fir­m’s CFO rough­ly $4 mil­lion: ” . . . . On Mon­day, he [Kim] exer­cised options to buy 241,000 shares at a weight­ed aver­age price of $12.45 for about $3 mil­lion, also as part of a pre­de­ter­mined plan. At the same time, Kim exe­cut­ed sales of 241,000 shares, at a weight­ed aver­age price of $82.12 for about $19.79 mil­lion. That means Kim net­ted about $16.79 mil­lion on the simul­ta­ne­ous buy and sale of shares. . . . with Monday’s stock price surge fol­low­ing the announce­ment of ear­ly data on its vac­cine can­di­date poten­tial­ly adding $4 mil­lion to Kim’s cof­fers. . . .”
  3. The above-ref­er­enced announce­ment by Mod­er­na led to a dra­mat­ic increase in Mod­er­na’s stock and boost­ed the mar­ket as a whole. Mod­er­na announced that evening that it would sell $1.34 bil­lion in stock to help its vac­cine oper­a­tion: ” . . . . Shares of Mod­er­na closed at a record high of $80.00 on Mon­day after the com­pa­ny released a slice of pos­i­tive inter­im clin­i­cal data from the first phase of its COVID-19 vac­cine tri­al. That night it announced it would sell $1.34 bil­lion in stock to help fund man­u­fac­tur­ing costs asso­ci­at­ed with the exper­i­men­tal COVID-19 vac­cine. . . .”
  4. Mod­er­na’s stock nose­dived at the end of the trad­ing day on Tues­day, due to a crit­i­cal arti­cle from Stat News” . . . . The stock took a nose dive on Tues­day, clos­ing at $71.67, like­ly due in some degree to a Stat News sto­ry that ques­tioned a lack of clin­i­cal clar­i­ty in the data it pro­vid­ed to investors. . . .”
  5. Mod­er­na’s announce­ment was crit­i­cal­ly assessed by Stat News, which point­ed out that the results were incom­plete at best: ” . . . . In a clin­i­cal-tri­al data dis­clo­sure on Mon­day, Mod­er­na shared that eight out of 45 par­tic­i­pants in its COVID-19 vac­cine study devel­oped neu­tral­iz­ing anti­bod­ies, a deci­sion that Stat’s Helen Bran­swell described as a ‘rea­son for cau­tion.’ It didn’t share infor­ma­tion about the immune response to the exper­i­men­tal vac­cine in the remain­ing 37 par­tic­i­pants. . . .”
  6. Nonethe­less, Mod­er­na’s stock–bolstered by gov­ern­ment investment–has been on a dra­mat­ic upward swing: ” . . . . The company’s stock was up 3.8% in trad­ing on Wednes­day. Year-to-date, it has soared 270.2%, even though the com­pa­ny has no approved prod­ucts. . . .”

“Moderna’s stock soars, then dips, after ques­tions arise around the lim­it­ed data shared about its COVID-19 vac­cine” by Tomi Kil­go­re and Jaimy Lee; Mar­ket­Watch; 05/20/2020

Wall Street ana­lysts large­ly view the clin­i­cal-tri­al data released by Mod­er­na, how­ev­er lim­it­ed, as a pos­i­tive

Investors in Mod­er­na Inc., the pre­clin­i­cal biotech­nol­o­gy com­pa­ny devel­op­ing one of the front-run­ning COVID-19 vac­cine can­di­dates in the U.S., may be fac­ing a volatile ride through the clin­i­cal tri­al process.

Shares of Mod­er­na closed at a record high of $80.00 on Mon­day after the com­pa­ny released a slice of pos­i­tive inter­im clin­i­cal data from the first phase of its COVID-19 vac­cine tri­al. That night it announced it would sell $1.34 bil­lion in stock to help fund man­u­fac­tur­ing costs asso­ci­at­ed with the exper­i­men­tal COVID-19 vac­cine. The stock took a nose dive on Tues­day, clos­ing at $71.67, like­ly due in some degree to a Stat News sto­ry that ques­tioned a lack of clin­i­cal clar­i­ty in the data it pro­vid­ed to investors.

The company’s stock was up 3.8% in trad­ing on Wednes­day. Year-to-date, it has soared 270.2%, even though the com­pa­ny has no approved prod­ucts. In 2019, it had $60 mil­lion in rev­enue that came from col­lab­o­ra­tions and grants.

In a clin­i­cal-tri­al data dis­clo­sure on Mon­day, Mod­er­na shared that eight out of 45 par­tic­i­pants in its COVID-19 vac­cine study devel­oped neu­tral­iz­ing anti­bod­ies, a deci­sion that Stat’s Helen Bran­swell described as a “rea­son for cau­tion.” It didn’t share infor­ma­tion about the immune response to the exper­i­men­tal vac­cine in the remain­ing 37 par­tic­i­pants.

Mod­er­na, how­ev­er, said that the full data from the tri­al will be pub­lished by the Nation­al Insti­tute for Aller­gy and Infec­tious Dis­eases (NIAID), its spon­sor for the study.

The com­pa­ny had also already dis­closed that the Food and Drug Admin­is­tra­tion (FDA) has giv­en the go-ahead for the com­pa­ny to pro­ceed with the sec­ond phase of the clin­i­cal tri­al for its mRNA vac­cine can­di­date, set to begin before the end of June.

Despite the crit­ics cit­ed in the Stat News arti­cle, Wall Street ana­lysts large­ly view the clin­i­cal-tri­al data released by Mod­er­na, how­ev­er lim­it­ed, as a pos­i­tive.

“While sam­ples are not yet avail­able for remain­ing par­tic­i­pants, and we lack specifics on the exact lev­els of bind­ing anti­bod­ies, we view this data as demon­stra­tive of ear­ly signs of effi­ca­cy,” Gold­man Sachs ana­lysts wrote in an investor note on Mon­day.

Med­ical experts and ana­lysts have also raised ques­tions about the lack of com­plete data from Gilead Sci­ences Inc.’s late-stage study for remde­sivir, which was also con­duct­ed with the NIAID.) So far, only the topline results from that tri­al have been shared pub­licly, though that was enough to inform the emer­gency use autho­riza­tion grant­ed by the FDA ear­li­er this month, at least accord­ing to the FDA’s let­ter announc­ing the EUA.

“We need to see all that data, the pub­li­ca­tion,” Dr. Eric Topol, a car­di­ol­o­gist and direc­tor of the Scripps Research Trans­la­tion­al Insti­tute, said by email on May 1. “But I do believe the drug has effi­ca­cy based on what we now know, it’s just not that potent.”

Beyond lin­ger­ing ques­tions about access to the com­plete Phase 1 clin­i­cal tri­al data set for the inves­ti­ga­tion­al vac­cine, Moderna’s splashy offer­ing on Mon­day night aim­ing to sell about $1.3 bil­lion in stock may also have con­tributed to the dive on Tues­day.

The com­pa­ny dis­closed late Tues­day that Chief Exec­u­tive Stéphane Ban­cel and Chief Finan­cial Offi­cer Lorence Kim sold stock recent­ly, with Monday’s stock price surge fol­low­ing the announce­ment of ear­ly data on its vac­cine can­di­date poten­tial­ly adding $4 mil­lion to Kim’s cof­fers.

On Fri­day, Ban­cel sold 11,046 shares at a weight­ed aver­age price of $65.56 for about $724,200, as part of a pre­de­ter­mined trad­ing plan adopt­ed Dec. 28, 2018, accord­ing to a Form 4 fil­ing with the Secu­ri­ties and Exchange Com­mis­sion. He also dis­posed of 1,577 shares as part of a “bona fide” gift.

Also, on Fri­day, Kim sold 20,000 shares at a weight­ed aver­age price of $65.53 for about $1.31 mil­lion, as part of a pre­de­ter­mined trad­ing planOn Mon­day, he exer­cised options to buy 241,000 shares at a weight­ed aver­age price of $12.45 for about $3 mil­lion, also as part of a pre­de­ter­mined plan. At the same time, Kim exe­cut­ed sales of 241,000 shares, at a weight­ed aver­age price of $82.12 for about $19.79 mil­lion. That means Kim net­ted about $16.79 mil­lion on the simul­ta­ne­ous buy and sale of shares.

If Kim had exe­cut­ed Monday’s trades on Fri­day, before the coro­n­avirus vac­cine-relat­ed stock ral­ly, he might have net­ted $12.79 mil­lion, or about $4 mil­lion less.

Mor­gan Stan­ley ana­lysts on Wednes­day set a price tar­get of $90.00 for Mod­er­na, not­ing that they expect the com­pa­ny will sell an esti­mat­ed 1.5 bil­lion dos­es dur­ing the pan­dem­ic and about 150 mil­lion dos­es each year after that. “We are pos­i­tive on the ear­ly data,” they wrote.

Moderna’s mar­ket cap­i­tal­iza­tion is rough­ly $27.4 bil­lion, up from about $6.4 bil­lion on Jan. 2.

The S&P 500 is down 9.3% year-to-date.

2a. There are seri­ous ques­tions about the sub­stance of Mod­er­na’s state­ment:

  1. Moderna’s much tout­ed report on its vaccine—which trig­gered an upsurge in the mar­kets on Monday—appears to have been incom­plete, at best, and pur­pose­ful­ly decep­tive, at worst. “ . . . . While Mod­er­na blitzed the media, it revealed very lit­tle infor­ma­tion — and most of what it did dis­close were words, not data.. . . . If you ask sci­en­tists to read a jour­nal arti­cle, they will scour data tables, not cor­po­rate state­ments. With sci­ence, num­bers speak much loud­er than words. Even the fig­ures the com­pa­ny did release don’t mean much on their own, because crit­i­cal infor­ma­tion — effec­tive­ly the key to inter­pret­ing them — was with­held. . . .
  2. Part of the rea­son for alarm and skep­ti­cism con­cerns the behav­ior of the NIAID—whose direc­tor is Antho­ny Fau­ci: “ . . . . The Nation­al Insti­tute for Aller­gy and Infec­tious Dis­eases has part­nered with Mod­er­na on this vac­cine. Sci­en­tists at NIAID made the vaccine’s con­struct, or pro­to­type, and the agency is run­ning the Phase 1 tri­al. This week’s Mod­er­na read­out came from the ear­li­est of data from the NIAID-led Phase 1. NIAID doesn’t hide its light under a bushel. The insti­tute gen­er­al­ly trum­pets its find­ings, often offer­ing direc­tor Antho­ny Fau­ci . . . or oth­er senior per­son­nel for inter­views. But NIAID did not put out a press release Mon­day and declined to pro­vide com­ment on Moderna’s announce­ment. . . .”
  3. To begin with, Moderna’s announce­ment was only sta­tis­ti­cal­ly sub­stan­tive for 8 of the 45 vol­un­teer sub­jects: “ . . . . The company’s state­ment led with the fact that all 45 sub­jects (in this analy­sis) who received dos­es of 25 micro­grams (two dos­es each), 100 micro­grams (two dos­es each), or a 250 micro­grams (one dose) devel­oped bind­ing anti­bod­ies. Lat­er, the state­ment indi­cat­ed that eight vol­un­teers — four each from the 25-micro­gram and 100-micro­gram arms — devel­oped neu­tral­iz­ing anti­bod­ies. Of the two types, these are the ones you’d real­ly want to see. We don’t know results from the oth­er 37 tri­al par­tic­i­pants. . . .”
  4. It is pos­si­ble that neu­tral­iz­ing anti­bod­ies may have been devel­oped in the 37 test sub­jects whose data was not released because the test­ing process is exact­ing. Still the state­ment war­rants cau­tion, at the least. “ . . . . This doesn’t mean that they didn’t devel­op neu­tral­iz­ing anti­bod­ies.Test­ing for neu­tral­iz­ing anti­bod­ies is more time-con­sum­ing than oth­er anti­body tests and must be done in a biose­cu­ri­ty lev­el 3 lab­o­ra­to­ry. Mod­er­na dis­closed the find­ings from eight sub­jects because that’s all it had at that point. Still, it’s a rea­son for cau­tion . . . .”
  5. In addi­tion, the age of the sub­jects was not released and that is rel­e­vant. “ . . . . Sep­a­rate­ly, while the Phase 1 tri­al includ­ed healthy vol­un­teers ages 18 to 55 years, the exact ages of these eight peo­ple are unknown. If, by chance, they most­ly clus­tered around the younger end of the age spec­trum, you might expect a bet­ter response to the vac­cine than if they were most­ly from the senior end of it. And giv­en who is at high­est risk from the SARS-CoV­‑2 coro­n­avirus, pro­tect­ing old­er adults is what Covid-19 vac­cines need to do. . . .”
  6. In addi­tion, there was no data released as to the dura­bil­i­ty of the neu­tral­iz­ing anti­bod­ies. If, for the sake of argu­ment, they are not long-last­ing, the util­i­ty of the vac­cine is neg­li­gi­ble. “ . . . . The report of neu­tral­iz­ing anti­bod­ies in sub­jects who were vac­ci­nat­ed comes from blood drawn two weeks after they received their sec­ond dose of vac­cine. Two weeks. ‘That’s very ear­ly. We don’t know if those anti­bod­ies are durable,’ said Anna Durbin, a vac­cine researcher at Johns Hop­kins Uni­ver­si­ty. . . .”
  7. Still anoth­er point of contention/alarm con­cerns the vari­abil­i­ty in neu­tral­iz­ing anti­bod­ies among recov­ered patients: “ . . . . But stud­ies have shown anti­body lev­els among peo­ple who have recov­ered from the ill­ness vary enor­mous­ly; the range that may be influ­enced by the sever­i­ty of a person’s dis­ease. John ‘Jack’ Rose, a vac­cine researcher from Yale Uni­ver­si­ty, point­ed STAT to a study from Chi­na that showed that, among 175 recov­ered Covid-19 patients stud­ied, 10 had no detectable neu­tral­iz­ing anti­bod­ies. Recov­ered patients at the oth­er end of the spec­trum had real­ly high anti­body lev­els. So though the com­pa­ny said the anti­body lev­els induced by vac­cine were as good as those gen­er­at­ed by infec­tion, there’s no real way to know what that com­par­i­son means. . . .”
  8. It is less than encour­ag­ing that Mod­er­na dis­closed that more rel­e­vant data will be dis­closed in a report to be released in con­junc­tion with NIAID: “ . . . . STAT asked Mod­er­na for infor­ma­tion on the anti­body lev­els it used as a com­para­tor. The response: That will be dis­closed in an even­tu­al jour­nal arti­cle from NIAID, which is part of the Nation­al Insti­tutes of Health. . . .”
  9. Ann Durbin was struck by the word­ing of Moderna’s release: “ . . . . Durbin was struck by the word­ing of the company’s state­ment, point­ing to this sen­tence: ‘The lev­els of neu­tral­iz­ing anti­bod­ies at day 43 were at or above lev­els gen­er­al­ly seen in con­va­les­cent sera.’ ‘I thought: Gen­er­al­ly? What does that mean?’ Durbin said. Her ques­tion, for the time being, can’t be answered. . . .”
  10. Jack Rose com­ment­ed on the opaque nature of Moderna’s release: “. . . . Rose said the com­pa­ny should dis­close the infor­ma­tion. ‘When a com­pa­ny like Mod­er­na with such incred­i­bly vast resources says they have gen­er­at­ed SARS‑2 neu­tral­iz­ing anti­bod­ies in a human tri­al, I would real­ly like to see num­bers from what­ev­er assay they are using,’ he said. . . .”
  11. To date, Mod­er­na issues press releas­es, not papers that can be vet­ted by the sci­en­tif­ic com­mu­ni­ty: “ . . . . It doesn’t pub­lish on its work in sci­en­tif­ic jour­nals. What is known has been dis­closed through press releas­es. That’s not enough to gen­er­ate con­fi­dence with­in the sci­en­tif­ic com­mu­ni­ty. ‘My guess is that their num­bers are mar­gin­al or they would say more,’ Rose said about the company’s SARS‑2 vac­cine, echo­ing a sus­pi­cion that oth­ers have about some of the company’s oth­er work. ‘I do think it’s a bit of a con­cern that they haven’t pub­lished the results of any of their ongo­ing tri­als that they men­tion in their press release. They have not pub­lished any of that,’ Durbin not­ed. . . .”

“Vac­cine experts say Mod­er­na didn’t pro­duce data crit­i­cal to assess­ing Covid-19 vac­cine” by Helen Bran­swell; Stat News; 05/19/2020

Heavy hearts soared Mon­day with news that Moderna’s Covid-19 vac­cine can­di­date — the fron­trun­ner in the Amer­i­can mar­ket — seemed to be gen­er­at­ing an immune response in Phase 1 tri­al sub­jects. The company’s stock val­u­a­tion also surged, hit­ting $29 bil­lion, an aston­ish­ing feat for a com­pa­ny that cur­rent­ly sells zero prod­ucts.

But was there good rea­son for so much enthu­si­asm? Sev­er­al vac­cine experts asked by STAT con­clud­ed that, based on the infor­ma­tion made avail­able by the Cam­bridge, Mass.-based com­pa­ny, there’s real­ly no way to know how impres­sive — or not — the vac­cine may be.

While Mod­er­na blitzed the media, it revealed very lit­tle infor­ma­tion — and most of what it did dis­close were words, not data. That’s impor­tant: If you ask sci­en­tists to read a jour­nal arti­cle, they will scour data tables, not cor­po­rate state­ments. With sci­ence, num­bers speak much loud­er than words.

Even the fig­ures the com­pa­ny did release don’t mean much on their own, because crit­i­cal infor­ma­tion — effec­tive­ly the key to inter­pret­ing them — was with­held.

The silence of the NIAID

The Nation­al Insti­tute for Aller­gy and Infec­tious Dis­eases has part­nered with Mod­er­na on this vac­cine. Sci­en­tists at NIAID made the vaccine’s con­struct, or pro­to­type, and the agency is run­ning the Phase 1 tri­al. This week’s Mod­er­na read­out came from the ear­li­est of data from the NIAID-led Phase 1.

NIAID doesn’t hide its light under a bushel. The insti­tute gen­er­al­ly trum­pets its find­ings, often offer­ing direc­tor Antho­ny Fau­ci — who, fair enough, is pret­ty busy these days — or oth­er senior per­son­nel for inter­views.

But NIAID did not put out a press release Mon­day and declined to pro­vide com­ment on Moderna’s announce­ment.

The n = 8 thing

The company’s state­ment led with the fact that all 45 sub­jects (in this analy­sis) who received dos­es of 25 micro­grams (two dos­es each), 100 micro­grams (two dos­es each), or a 250 micro­grams (one dose) devel­oped bind­ing anti­bod­ies.

Lat­er, the state­ment indi­cat­ed that eight vol­un­teers — four each from the 25-micro­gram and 100-micro­gram arms — devel­oped neu­tral­iz­ing anti­bod­ies. Of the two types, these are the ones you’d real­ly want to see.

We don’t know results from the oth­er 37 tri­al par­tic­i­pants. This doesn’t mean that they didn’t devel­op neu­tral­iz­ing anti­bod­ies. Test­ing for neu­tral­iz­ing anti­bod­ies is more time-con­sum­ing than oth­er anti­body tests and must be done in a biose­cu­ri­ty lev­el 3 lab­o­ra­to­ry. Mod­er­na dis­closed the find­ings from eight sub­jects because that’s all it had at that point. Still, it’s a rea­son for cau­tion.

Sep­a­rate­ly, while the Phase 1 tri­al includ­ed healthy vol­un­teers ages 18 to 55 years, the exact ages of these eight peo­ple are unknown. If, by chance, they most­ly clus­tered around the younger end of the age spec­trum, you might expect a bet­ter response to the vac­cine than if they were most­ly from the senior end of it. And giv­en who is at high­est risk from the SARS-CoV­‑2 coro­n­avirus, pro­tect­ing old­er adults is what Covid-19 vac­cines need to do.

There’s no way to know how durable the response will be

The report of neu­tral­iz­ing anti­bod­ies in sub­jects who were vac­ci­nat­ed comes from blood drawn two weeks after they received their sec­ond dose of vac­cine.

Two weeks.

“That’s very ear­ly. We don’t know if those anti­bod­ies are durable,” said Anna Durbin, a vac­cine researcher at Johns Hop­kins Uni­ver­si­ty.

There’s no real way to con­tex­tu­al­ize the find­ings

Mod­er­na stat­ed that the anti­body lev­els seen were on a par with — or greater than, in the case of the 100-micro­gram dose — those seen in peo­ple who have recov­ered from Covid-19 infec­tion.

But stud­ies have shown anti­body lev­els among peo­ple who have recov­ered from the ill­ness vary enor­mous­ly; the range that may be influ­enced by the sever­i­ty of a person’s dis­ease. John “Jack” Rose, a vac­cine researcher from Yale Uni­ver­si­ty, point­ed STAT to a study from Chi­na that showed that, among 175 recov­ered Covid-19 patients stud­ied, 10 had no detectable neu­tral­iz­ing anti­bod­ies. Recov­ered patients at the oth­er end of the spec­trum had real­ly high anti­body lev­els.

So though the com­pa­ny said the anti­body lev­els induced by vac­cine were as good as those gen­er­at­ed by infec­tion, there’s no real way to know what that com­par­i­son means.

STAT asked Mod­er­na for infor­ma­tion on the anti­body lev­els it used as a com­para­tor. The response: That will be dis­closed in an even­tu­al jour­nal arti­cle from NIAID, which is part of the Nation­al Insti­tutes of Health.

“The con­va­les­cent sera lev­els are not being detailed in our data read­out, but would be expect­ed in a down­stream full data expo­si­tion with NIH and its aca­d­e­m­ic col­lab­o­ra­tors,” Colleen Hussey, the company’s senior man­ag­er for cor­po­rate com­mu­ni­ca­tions, said in an email.

Durbin was struck by the word­ing of the company’s state­ment, point­ing to this sen­tence: “The lev­els of neu­tral­iz­ing anti­bod­ies at day 43 were at or above lev­els gen­er­al­ly seen in con­va­les­cent sera.”

“I thought: Gen­er­al­ly? What does that mean?” Durbin said. Her ques­tion, for the time being, can’t be answered.

Rose said the com­pa­ny should dis­close the infor­ma­tion. “When a com­pa­ny like Mod­er­na with such incred­i­bly vast resources says they have gen­er­at­ed SARS‑2 neu­tral­iz­ing anti­bod­ies in a human tri­al, I would real­ly like to see num­bers from what­ev­er assay they are using,” he said.

Moderna’s approach to dis­clo­sure

The com­pa­ny has not yet brought a vac­cine to mar­ket, but it has a vari­ety of vac­cines for infec­tious dis­eases in its pipeline. It doesn’t pub­lish on its work in sci­en­tif­ic jour­nals. What is known has been dis­closed through press releas­es. That’s not enough to gen­er­ate con­fi­dence with­in the sci­en­tif­ic com­mu­ni­ty.

“My guess is that their num­bers are mar­gin­al or they would say more,” Rose said about the company’s SARS‑2 vac­cine, echo­ing a sus­pi­cion that oth­ers have about some of the company’s oth­er work.

“I do think it’s a bit of a con­cern that they haven’t pub­lished the results of any of their ongo­ing tri­als that they men­tion in their press release. They have not pub­lished any of that,” Durbin not­ed.

Still, she char­ac­ter­ized her­self as “cau­tious­ly opti­mistic” based on what the com­pa­ny has said so far.

“I would like to see the data to make my own inter­pre­ta­tion of the data. But I think it is at least encour­ag­ing that we’ve seen immune respons­es with this RNA vac­cine that we haven’t seen with pre­vi­ous RNA vac­cines for oth­er pathogens. Whether it’s going to be enough, we don’t know,” Durbin said.

Mod­er­na has been more forth­com­ing with data on at least one of its oth­er vac­cine can­di­dates. In a state­ment issued in Jan­u­ary about a Phase 1 tri­al for its cytomegalovirus (CMV) vac­cine, it quan­ti­fied how far over base­line mea­sures anti­body lev­els rose in vac­cines.

2a. The fol­low­ing arti­cle from Nature Reviews Immunol­o­gy warns us of a poten­tial safe­ty issue with the SARS-CoV­‑2 vac­cine: In the orig­i­nal SARS out­break, we learned that if some­one devel­ops antibodies–but not at a high enough lev­el to neu­tral­ize the infec­tion–that can actu­al­ly make that infec­tion more severe. This process is known as anti­body-depen­dent enhance­ment (ADE). This only hap­pens when the neu­tral­iz­ing anti­body lev­els are below some thresh­old.

If a vac­cine induced an immune response that isn’t high enough it could actu­al­ly make the even­tu­al infec­tions even worse. This has been demon­strat­ed in Mice with SARS vac­cines. As the authors also note, there’s some evi­dence aged ani­mals might have a hard­er time gen­er­at­ing the required lev­els of anti­bod­ies after vac­ci­na­tion. So it’s pos­si­ble to have a vac­cine that pro­tects the young and actu­al­ly makes the elder­ly more vul­ner­a­ble:

“The poten­tial dan­ger of sub­op­ti­mal anti­body respons­es in COVID-19” by Akiko Iwasa­ki & Yex­in Yang; Nature Reviews Immunol­o­gy; 04/21/2020

There is a des­per­ate need for effec­tive ther­a­pies and vac­cines for SARS-CoV­‑2 to mit­i­gate the grow­ing eco­nom­ic cri­sis that has ensued from soci­etal lock­down. Vac­cines are being devel­oped at an unprece­dent­ed speed and are already in clin­i­cal tri­als, with­out pre­clin­i­cal test­ing for safe­ty and effi­ca­cy. Yet, safe­ty eval­u­a­tion of can­di­date vac­cines must not be over­looked.

The qual­i­ty and quan­ti­ty of the anti­body response dic­tates func­tion­al out­comes. High-affin­i­ty anti­bod­ies can elic­it neu­tral­iza­tion by rec­og­niz­ing spe­cif­ic viral epi­topes (Fig.1a). Neu­tral­iz­ing anti­bod­ies are defined in vit­ro by their abil­i­ty to block viral entry, fusion or egress. In vivo, neu­tral­iz­ing anti­bod­ies can func­tion with­out addi­tion­al medi­a­tors, although the Fc region is required for neu­tral­iza­tion of influen­za virus2. In the case of SARS-CoV, viral dock­ing on ACE2 on host cells is blocked when neu­tral­iz­ing anti­bod­ies, for exam­ple, rec­og­nize the recep­tor-bind­ing domain (RBD) on the spike (S) pro­tein3. S pro­tein-medi­at­ed viral fusion can be blocked by neu­tral­iz­ing anti­bod­ies tar­get­ing the hep­tad repeat 2 (HR2) domain3. In addi­tion, neu­tral­iz­ing anti­bod­ies can inter­act with oth­er immune com­po­nents, includ­ing com­ple­ment, phago­cytes and nat­ur­al killer cells. These effec­tor respons­es can aid in pathogen clear­ance, with engage­ment of phago­cytes shown to enhance anti­body-medi­at­ed clear­ance of SARS-CoV4How­ev­er, in rare cas­es, pathogen-spe­cif­ic anti­bod­ies can pro­mote pathol­o­gy, result­ing in a phe­nom­e­non known as anti­body-depen­dent enhance­ment (ADE).

Fig. 1: Poten­tial out­comes of anti­body response to coro­n­avirus.

Anti­body-depen­dent enhance­ment

Although anti­bod­ies are gen­er­al­ly pro­tec­tive and ben­e­fi­cial, the ADE phe­nom­e­non is doc­u­ment­ed for dengue virus and oth­er virus­es. In SARS-CoV infec­tion, ADE is medi­at­ed by the engage­ment of Fc recep­tors (FcRs) expressed on dif­fer­ent immune cells, includ­ing mono­cytes, macrophages and B cells5,6Pre-exist­ing SARS-CoV-spe­cif­ic anti­bod­ies may thus pro­mote viral entry into FcR-express­ing cells (Fig. 1b). This process is inde­pen­dent of ACE2 expres­sion and endo­so­mal pH and pro­teas­es, sug­gest­ing dis­tinct cel­lu­lar path­ways of ACE2-medi­at­ed and FcR-medi­at­ed viral entry6There is no evi­dence that ADE facil­i­tates the spread of SARS-CoV in infect­ed hosts. In fact, infec­tion of macrophages through ADE does not result in pro­duc­tive viral repli­ca­tion and shed­ding7Instead, inter­nal­iza­tion of virus–antibody immune com­plex­es can pro­mote inflam­ma­tion and tis­sue injury by acti­vat­ing myeloid cells via FcRs5. Virus intro­duced into the endo­some through this path­way will like­ly engage the RNA-sens­ing Toll-like recep­tors (TLRs) TLR3, TLR7 and TLR8 (Fig. 1c). Uptake of SARS-CoV through ADE in macrophages led to ele­vat­ed pro­duc­tion of TNF and IL‑6 (ref.5). In mice infect­ed with SARS-CoV, ADE was asso­ci­at­ed with decreased lev­els of the anti-inflam­ma­to­ry cytokines IL-10 and TGFß and increased lev­els of the pro-inflam­ma­to­ry chemokines CCL2 and CCL3 (ref.8). Fur­ther­more, immu­niza­tion of non-human pri­mates with a mod­i­fied vac­cinia Ankara (MVA) virus encod­ing the full-length S pro­tein of SARS-CoV pro­mot­ed acti­va­tion of alve­o­lar macrophages, lead­ing to acute lung injury9.

Pro­tec­tive ver­sus path­o­gen­ic anti­bod­ies

Mul­ti­ple fac­tors deter­mine whether an anti­body neu­tral­izes a virus and pro­tects the host or caus­es ADE and acute inflam­ma­tion. These include the speci­fici­ty, con­cen­tra­tion, affin­i­ty and iso­type of the anti­body. Viral vec­tor vac­cines encod­ing SARS-CoV S pro­tein and nucle­o­cap­sid (N) pro­tein pro­voke anti‑S and anti‑N IgG in immu­nized mice, respec­tive­ly, to a sim­i­lar extent. How­ev­er, upon re-chal­lenge, N pro­tein-immu­nized mice show sig­nif­i­cant upreg­u­la­tion of pro-inflam­ma­to­ry cytokine secre­tion, increased neu­trophil and eosinophil lung infil­tra­tion, and more severe lung pathol­o­gy8Sim­i­lar­ly, anti­bod­ies tar­get­ing dif­fer­ent epi­topes on the S pro­tein may vary in their poten­tial to induce neu­tral­iza­tion or ADE. For exam­ple, anti­bod­ies reac­tive to the RBD domain or the HR2 domain of the S pro­tein induce bet­ter pro­tec­tive anti­body respons­es in non-human pri­mates, where­as anti­bod­ies spe­cif­ic for oth­er S pro­tein epi­topes can induce ADE10In vit­ro data sug­gest that for cells express­ing FcRs, ADE occurs when anti­body is present at a low con­cen­tra­tion but damp­ens at the high-con­cen­tra­tion range. Mean­while, increas­ing anti­body con­cen­tra­tions pro­motes SARS-CoV neu­tral­iza­tion by block­ing viral entry into host cells6. For oth­er virus­es, high-affin­i­ty anti­bod­ies capa­ble of block­ing recep­tor bind­ing tend to not induce ADE.

In the ‘mul­ti­ple hit’ mod­el of neu­tral­iza­tion, the virus-block­ing effect cor­re­lates with the num­ber of anti­bod­ies coat­ing the viri­on, which is col­lec­tive­ly affect­ed by anti­body con­cen­tra­tion and affin­i­ty11. Mon­o­clon­al anti­bod­ies with high­er affin­i­ty for the enve­lope (E) pro­tein of West Nile Virus (WNV) induced bet­ter pro­tec­tion in mice receiv­ing a lethal dose of WNV11. For a giv­en con­cen­tra­tion of anti­body and a spe­cif­ic tar­get­ing domain, the sto­i­chiom­e­try of anti­body engage­ment on a viri­on is depen­dent on the strength of inter­ac­tion between anti­body and anti­gen. ADE is induced when the sto­i­chiom­e­try is below the thresh­old for neu­tral­iza­tion. There­fore, high­er affin­i­ty anti­bod­ies can reach that thresh­old at a low­er con­cen­tra­tion and medi­ate bet­ter pro­tec­tion11.

Anti­body iso­types con­trol their effec­tor func­tions. IgM is con­sid­ered more pro-inflam­ma­to­ry as it acti­vates com­ple­ment effi­cient­ly. IgG sub­class­es mod­u­late immune respons­es via the engage­ment of dif­fer­ent FcRs. Most FcγRs sig­nal through ITA­Ms, but FcγRI­Ib con­tains an ITIM on its cyto­plas­mic tail that medi­ates an anti-inflam­ma­to­ry response. Ectopic expres­sion of FcγRI­Ia and FcγRI­Ib, but not of FcγRI or FcγRI­I­Ia, induced ADE of SARS-CoV infec­tion6. Allel­ic poly­mor­phisms in FcγRI­Ia are asso­ci­at­ed with SARS pathol­o­gy, and indi­vid­u­als with an FcγRI­Ia iso­form that binds to both IgG1 and IgG2 were found to devel­op more severe dis­ease than indi­vid­u­als with Fcγthat only binds to IgG2 (ref.12).

Vac­cine approach­es

It is cru­cial to deter­mine which vac­cines and adju­vants can elic­it pro­tec­tive anti­body respons­es to SARS-CoV­‑2. Pre­vi­ous stud­ies have shown that the immu­niza­tion of mice with inac­ti­vat­ed whole SARS-CoV13, the immu­niza­tion of rhe­sus macaques9 with MVA-encod­ed S pro­tein and the immu­niza­tion of mice with DNA vac­cine encod­ing full-length S pro­tein14 could induce ADE or eosinophil-medi­at­ed immunopathol­o­gy to some extent, pos­si­bly owing to low qual­i­ty and quan­ti­ty of anti­body pro­duc­tion. Addi­tion­al­ly, we need to con­sid­er whether a vac­cine is safe and effec­tive in aged hosts. For instance, dou­ble-inac­ti­vat­ed SARS-CoV vac­cine failed to induce neu­tral­iz­ing anti­body respons­es in aged mice13. Fur­ther­more, although an alum-adju­vant­ed dou­ble-inac­ti­vat­ed SARS-CoV vac­cine elicit­ed high­er anti­body titres in aged mice, it skewed the IgG sub­class toward IgG1 instead of IgG2, which was asso­ci­at­ed with a T helper 2 (TH2)-type immune response, enhanced eosinophil­ia and lung pathol­o­gy13. By con­trast, stud­ies in mice showed that sub­unit or pep­tide vac­cines that focus the anti­body response against spe­cif­ic epi­topes with­in the RBD of the S pro­tein con­ferred pro­tec­tive anti­body respons­es3. In addi­tion, live atten­u­at­ed SARS-CoV vac­cine induced pro­tec­tive immune respons­es in aged mice15. Routes of vac­cine admin­is­tra­tion can fur­ther affect vac­cine effi­ca­cy. Com­pared with the intra­mus­cu­lar route, intranasal admin­is­tra­tion of a recom­bi­nant ade­no-asso­ci­at­ed virus vac­cine encod­ing SARS-CoV RBD induced sig­nif­i­cant­ly high­er titres of mucos­al IgA in the lung and reduced lung pathol­o­gy upon chal­lenge with SARS-CoV3.

Con­clud­ing remarks

There are now mul­ti­ple vac­cine can­di­dates (includ­ing nucle­ic acid vac­cines, viral vec­tor vac­cines and sub­unit vac­cines) in the pre­clin­i­cal and clin­i­cal tri­al stages as researchers and insti­tutes from all over the world come togeth­er to accel­er­ate the devel­op­ment of a SARS-CoV­‑2 vac­cine. Recent stud­ies of anti­body respons­es in patients with COVID-19 have asso­ci­at­ed high­er titres of anti‑N IgM and IgG at all time points fol­low­ing the onset of symp­toms with a worse dis­ease out­come16. More­over, high­er titres of anti‑S and anti‑N IgG and IgM cor­re­late with worse clin­i­cal read­outs and old­er age17, sug­gest­ing poten­tial­ly detri­men­tal effects of anti­bod­ies in some patients. How­ev­er, 70% of patients who recov­ered from mild COVID-19 had mea­sur­able neu­tral­iz­ing anti­bod­ies that per­sist­ed upon revis­it to the hospital18. Thus, insights gained from study­ing the anti­body fea­tures that cor­re­late with recov­ery as opposed to wors­en­ing of dis­ease will inform the type of anti­bod­ies to assess in vac­cine stud­ies. We argue that ADE should be giv­en full con­sid­er­a­tion in the safe­ty eval­u­a­tion of emerg­ing can­di­date vac­cines for SARS-CoV­‑2. In addi­tion to vac­cine approach­es, mon­o­clon­al anti­bod­ies could be used to tack­le this virus. Unlike vac­cine-induced anti­bod­ies, mon­o­clon­al anti­bod­ies can be engi­neered with mol­e­c­u­lar pre­ci­sion. Safe and effec­tive neu­tral­iz­ing anti­bod­ies could be pro­duced on a mass-scale for deliv­ery to pop­u­la­tions across the world in the com­ing months. . . .

3. A 2016 STAT News arti­cle about Mod­er­na high­lights a num­ber of areas of con­cern, giv­en the speed and rel­a­tive­ly opaque nature of the poten­tial intro­duc­tion of its Covid-19 vac­cine. The financ­ing of the com­pa­ny by DARPA, and Mon­cef Slaoui’s join­ing with Four Star Gen­er­al Per­na (ele­vat­ed by the Chair­man of the Joint Chiefs of Staff, Gen­er­al Mark A. Mil­ley) are of addi­tion­al con­cern.

  1. As of 2016, Mod­er­na had the largest val­u­a­tion of any pri­vate biotech firm and for­mer employ­ees felt that Mod­er­na prized mon­ey over sci­ence. Note that, as will be reviewed lat­er in the pro­gram, its stock has risen expo­nen­tial­ly as a result of the injec­tion of hun­dreds of mil­lions of dol­lars. Bear in mind that Mod­er­na has also been under­writ­ten by DARPA. “ . . . . Mod­er­na is worth more than any oth­er pri­vate biotech in the US, and for­mer employ­ees said they felt that Ban­cel prized the company’s ever-increas­ing val­u­a­tion, now approach­ing $5 bil­lion, over its sci­ence. . . .”
  2. Mod­er­na has main­tained a cul­ture of secre­cy, which in 2016, applied to the first two prod­ucts under­go­ing phase 1 tri­als: “ . . . . Mod­er­na just moved its first two poten­tial treat­ments — both vac­cines — into human tri­als. In keep­ing with the cul­ture of secre­cy, though, exec­u­tives won’t say which dis­eases the vac­cines tar­get, and they have not list­ed the stud­ies on the pub­lic fed­er­al reg­istry, ClinicalTrials.gov. List­ing is option­al for Phase 1 tri­als, which are meant to deter­mine if a drug is safe, but most com­pa­nies vol­un­tar­i­ly dis­close their work. . . .”
  3. Pro­tein ther­a­py has been a dri­ving eco­nom­ic and ther­a­peu­tic fac­tor in the phar­ma­ceu­ti­cal busi­ness: “ . . . . For decades, com­pa­nies have endeav­ored to craft bet­ter and bet­ter pro­tein ther­a­pies, lead­ing to new treat­ments for can­cer, autoim­mune dis­or­ders, and rare dis­eases. Such ther­a­pies are cost­ly to pro­duce and have many lim­i­ta­tions, but they’ve giv­en rise to a multi­bil­lion-dol­lar indus­try. The anti-inflam­ma­to­ry Humi­ra, the world’s top drug at $14 bil­lion in sales a year, is a shin­ing exam­ple of pro­tein ther­a­py. . . .”
  4. Mod­er­na aims at doing an end run around that tech­nol­o­gy with the injec­tion of mRNA (mes­sen­ger RNA) or DNA. This is a risky tech­nol­o­gy: “ . . . . Moderna’s tech­nol­o­gy promised to sub­vert the whole field, cre­at­ing ther­a­peu­tic pro­teins inside the body instead of in man­u­fac­tur­ing plants. The key: har­ness­ing mes­sen­ger RNA, or mRNA. . . . . It’s high­ly risky. Big phar­ma com­pa­nies had tried sim­i­lar work and aban­doned it because it’s exceed­ing­ly hard to get RNA into cells with­out trig­ger­ing nasty side effects. . . . .”
  5. CEO Ban­cel has main­tained the company’s opaque pro­fes­sion­al cul­ture, mixed with high-pro­file media pro­mo­tion: “ . . . . Under Ban­cel, Mod­er­na has been loath to pub­lish its work in Sci­ence or Nature, but enthu­si­as­tic to her­ald its poten­tial on CNBC and CNN, tak­ing part in seg­ments on the world’s most dis­rup­tive com­pa­niesand the poten­tial ‘cure for can­cer.’. . .”
  6. Mod­er­na had dra­con­ian atti­tude toward employ­ees from its incep­tion: “ . . . . From the begin­ning, Ban­cel made clear that Moderna’s sci­ence sim­ply had to work. And that any­one who couldn’t make it work didn’t belong. The ear­ly Mod­er­na was a chaot­ic, unpre­dictable work­place, accord­ing to for­mer employ­ees. One recalls find­ing him­self out of a job when a quick-turn­around exper­i­ment failed to pan out. Anoth­er helped train a group of new hires only to real­ize they were his replace­ments. . . .”
  7. Joe Bolen exem­pli­fied the treat­ment Mod­er­na met­ed out: “ . . . . Most stun­ning to employ­ees was the abrupt depar­ture of Joseph Bolen, who came aboard in 2013 to lead Moderna’s R&D efforts. Bolen was a big-name hire in biotech cir­cles, an expe­ri­enced chief sci­en­tif­ic offi­cer who had guid­ed Mil­len­ni­um Phar­ma­ceu­ti­cals to FDA approval for a block­buster can­cer drug. . . ‘No sci­en­tist in his right mind would leave that job unless there was some­thing wrong with the sci­ence or the per­son­nel,’ said a per­son close to the com­pa­ny at the time.’ . . .”
  8. Bolen had com­pa­ny: “ . . . . Bolen wasn’t alone. Chief Infor­ma­tion Offi­cer John Reyn­ders joined in 2013 to make Mod­er­na what he called the world’s ‘first ful­ly dig­i­tal biotech,‘only to step down a year lat­er. Michael Morin, brought in to lead Moderna’s sci­en­tif­ic efforts in can­cer in 2014, last­ed less than 18 months. As did Greg Licholai, hired in 2015 to direct the company’s projects in rare dis­eases. The lat­ter two key lead­er­ship posi­tions remain unfilled. . . .”
  9. The expla­na­tion of CFO Lorence Kim is less than reas­sur­ing from the stand­point of prod­uct safe­ty and reli­a­bil­i­ty: “ . . . . ‘We force every­one to grow with the com­pa­ny at unprece­dent­ed speed,’ Mod­er­na Chief Finan­cial Offi­cer Lorence Kim said. ‘Some peo­ple grow with the com­pa­ny; oth­ers don’t.’ . . .”
  10. Begin­ning in 2013, Mod­er­na part­nered with a series of phar­ma­ceu­ti­cal giants, includ­ing AstraZeneca, which has been select­ed to devel­op a Covid-19 vac­cine: “ . . . . That’s when Mod­er­na — which had just 25 employ­ees — signed a stag­ger­ing $240 mil­lion part­ner­ship with UK phar­ma­ceu­ti­cal giant AstraZeneca. It was the most mon­ey phar­ma had ever spent on drugs that had not yet been test­ed in humans. . . .”
  11. The firm has been lav­ish­ly cap­i­tal­ized: “ . . . . In ear­ly 2015, Mod­er­na dis­closed a $450 mil­lion financ­ing round, the largest ever for a pri­vate biotech com­pa­ny. This month, the com­pa­ny broke its own record, rais­ing anoth­er $474 mil­lion. . . . Though it has yet to reveal data from a sin­gle clin­i­cal tri­al, Mod­er­na is now val­ued at $4.7 bil­lion, accord­ing to Pitch­book. . . .”
  12. Ini­tial­ly, Mod­er­na aimed at devel­op­ing prod­ucts that would be admin­is­tered for a peri­od of years: “ . . . . From the start, Mod­er­na her­ald­ed its abil­i­ty to pro­duce pro­teins with­in cells, which could open up a world of ther­a­peu­tic tar­gets unreach­able by con­ven­tion­al drugs. The most rev­o­lu­tion­ary treat­ments, which could chal­lenge the multi­bil­lion-dol­lar mar­ket for pro­tein ther­a­py, would involve repeat­ed dos­es of mRNA over many years, so a patient’s body con­tin­ued to pro­duce pro­teins to keep dis­ease at bay. . . .”
  13. Instead of pro­duc­ing treat­ments that would be admin­is­tered over a peri­od of years, the com­pa­ny focused on vac­cines: “ . . . . But Moderna’s first human tri­als aren’t so ambi­tious, focus­ing instead on the crowd­ed field of vac­cines, where the com­pa­ny has only been work­ing since 2014. . . . The choice to pri­or­i­tize vac­cines came as a dis­ap­point­ment to many in the com­pa­ny, accord­ing to a for­mer man­ag­er. The plan had been to rad­i­cal­ly dis­rupt the biotech indus­try, the man­ag­er said, so ‘why would you start with a clin­i­cal pro­gram that has very lim­it­ed upside and lots of com­pe­ti­tion?’” . . . .”
  14. The answer to Moderna’s focus on vac­cines may be due to issues of prod­uct safe­ty: “ . . . Deliv­ery — actu­al­ly get­ting RNA into cells — has long bedev­iled the whole field. On their own, RNA mol­e­cules have a hard time reach­ing their tar­gets. They work bet­ter if they’re wrapped up in a deliv­ery mech­a­nism, such as nanopar­ti­cles made of lipids. But those nanopar­ti­cles can lead to dan­ger­ous side effects, espe­cial­ly if a patient has to take repeat­ed dos­es over months or years. . . .”
  15. Vac­cines will only admin­is­ter mRNA at the time of vac­ci­na­tion, rather than over a long peri­od of time: “ . . . . ‘I would say that mRNA is bet­ter suit­ed for dis­eases where treat­ment for short dura­tion is suf­fi­cient­ly cura­tive, so the tox­i­c­i­ties caused by deliv­ery mate­ri­als are less like­ly to occur,’ said Katal­in Karikó, a pio­neer in the field who serves as a vice pres­i­dent at BioN­Tech. . . That makes vac­cines the low­est hang­ing fruit in mRNA, said Franz-Wern­er Haas, CureVac’s chief cor­po­rate offi­cer. ‘From our point of view, it’s obvi­ous why [Mod­er­na] start­ed there,’ he said.’ . . .”
  16. Moderna’s expla­na­tion for its focus on vac­cines is not reassuring—the speed with which it can pro­ceed to human tri­als. The firm’s secre­cy has gen­er­at­ed alarm: “ . . . . Mod­er­na said it pri­or­i­tized vac­cines because they pre­sent­ed the fastest path to human tri­als, not because of set­backs with oth­er projects. ‘The notion that [Mod­er­na] ran into dif­fi­cul­ties isn’t borne in real­i­ty,’ said [chair­man of the board Noubar] Afeyan. But this is where Moderna’s secre­cy comes into play: Until there’s pub­lished data, only the com­pa­ny and its part­ners know what the data show. Every­one out­side is left guess­ing — and, in some cas­es, wor­ry­ing that Mod­er­na won’t live up to its hype. . . .”
  17. Mod­er­na applies soft­ware and a busi­ness mod­el derived from Tes­la, Ama­zon and Uber: “ . . . . Mod­er­na has pio­neered an auto­mat­ed sys­tem mod­eled on the soft­ware Tes­la uses to man­age orders, Ban­cel said: Sci­en­tists sim­ply enter the pro­tein they want a cell to express, and testable mRNA arrives with­in weeks. . . . That has always been part of the plan, for­mer employ­ees said, point­ing to Bancel’s fas­ci­na­tion with the tech indus­try. Uber and Ama­zon were not the first to come up with their respec­tive busi­ness ideas, but they were the ones that built enough scale to ward off com­pe­ti­tion. And Mod­er­na is posi­tion­ing itself to do the same in mRNA. . . .”

“Ego, ambi­tion, and tur­moil: Inside one of biotech’s most secre­tive star­tups” by Dami­an Garde; STAT News; 09/13/2016

At first glance, Mod­er­na Ther­a­peu­tics looks like the most envi­able biotech start­up in the world. It has smashed fundrais­ing records and teamed up with phar­ma­ceu­ti­cal giants as it pur­sues a rad­i­cal plan to rev­o­lu­tion­ize med­i­cine by trans­form­ing human cells into drug fac­to­ries.

But the real­i­ty is more com­pli­cat­ed.

A STAT inves­ti­ga­tion found that the company’s caus­tic work envi­ron­ment has for years dri­ven away top tal­ent and that behind its obses­sion with secre­cy, there are signs Mod­er­na has run into road­blocks with its most ambi­tious projects.

At the cen­ter of it all is Stéphane Ban­cel, a first-time biotech CEO with an unwa­ver­ing belief that Moderna’s sci­ence will work — and that employ­ees who don’t “live the mis­sion” have no place in the com­pa­ny. Con­fi­dent and intense, Ban­cel told STAT that Moderna’s sci­ence is on track and, when it is final­ly made pub­lic, that it will meet the brash goal he him­self has set: The new drugs will change the world.

But inter­views with more than 20 cur­rent and for­mer employ­ees and asso­ciates sug­gest Ban­cel has ham­pered progress at Mod­er­na because of his ego, his need to assert con­trol and his impa­tience with the set­backs that are an inevitable part of sci­enceMod­er­na is worth more than any oth­er pri­vate biotech in the US, and for­mer employ­ees said they felt that Ban­cel prized the company’s ever-increas­ing val­u­a­tion, now approach­ing $5 bil­lion, over its sci­ence.

As he pur­sued a com­plex and risky strat­e­gy for drug devel­op­ment, Ban­cel built a cul­ture of recrim­i­na­tion at Mod­er­na, for­mer employ­ees said. Failed exper­i­ments have been met with rep­ri­mands and even on-the-spot fir­ings. They recalled abu­sive emails, dress­ings down at com­pa­ny meet­ings, exceed­ing­ly long hours, and unex­plained ter­mi­na­tions.

At least a dozen high­ly placed exec­u­tives have quit in the past four years, includ­ing heads of finance, tech­nol­o­gy, man­u­fac­tur­ing, and sci­ence. In just the past 12 months, respect­ed lead­ers of Moderna’s can­cer and rare dis­ease pro­grams both resigned, even though the company’s remark­able fundrais­ing had put ample resources at their dis­pos­al. Each had been at the com­pa­ny less than 18 months, and the posi­tions have yet to be filled.

Low­er-rank­ing employ­ees, mean­while, said they’ve been dis­ap­point­ed and con­fused by Moderna’s piv­ot to less ambi­tious — and less trans­for­ma­tive — treat­ments. Mod­er­na has pushed off projects meant to upend the drug indus­try to focus first on the less daunt­ing (and most like­ly, far less lucra­tive) field of vac­cines — though it is years behind com­peti­tors in that are­na.

The com­pa­ny has pub­lished no data sup­port­ing its vaunt­ed tech­nol­o­gy, and it’s so secre­tive that some job can­di­dates have to sign nondis­clo­sure agree­ments before they come in to inter­view. Out­side ven­ture cap­i­tal­ists said Mod­er­na has so many investors clam­or­ing to get in that it can afford to turn away any who ask too many ques­tions. Some small play­ers have been giv­en only a peek at Moderna’s data before com­mit­ting mil­lions to the com­pa­ny, accord­ing to peo­ple famil­iar with the mat­ter.

“It’s a case of the emperor’s new clothes,” said a for­mer Mod­er­na sci­en­tist. “They’re run­ning an invest­ment firm, and then hope­ful­ly it also devel­ops a drug that’s suc­cess­ful.”

Like many employ­ees and for­mer employ­ees, the sci­en­tist request­ed anonymi­ty because of a nondis­clo­sure agree­ment. Oth­ers would not per­mit their names to be pub­lished out of fear that speak­ing can­did­ly about big play­ers in the indus­try would hurt their job prospects down the road.

Mod­er­na just moved its first two poten­tial treat­ments — both vac­cines — into human tri­als. In keep­ing with the cul­ture of secre­cy, though, exec­u­tives won’t say which dis­eases the vac­cines tar­get, and they have not list­ed the stud­ies on the pub­lic fed­er­al reg­istry, ClinicalTrials.gov. List­ing is option­al for Phase 1 tri­als, which are meant to deter­mine if a drug is safe, but most com­pa­nies vol­un­tar­i­ly dis­close their work.

An ambi­tious CEO dreams big

Ban­cel, 44, had no expe­ri­ence run­ning a drug devel­op­ment oper­a­tion when one of biotech’s most suc­cess­ful ven­ture cap­i­tal­ists tapped him to lead Mod­er­na. He’d spent most of his career in sales and oper­a­tions, not sci­ence.

But he had made no secret of his ambi­tion.

A native of France, Ban­cel earned a master’s in chem­i­cal engi­neer­ing from the Uni­ver­si­ty of Min­neso­ta and an MBA from Har­vard in 2000. As Har­vard Busi­ness School class­mates rushed to cash in on the dot-com boom, Ban­cel laid out a plan to play “chess, not check­ers.”

“I was always think­ing, one day, some­body will have to make a deci­sion about me get­ting a CEO job,” he told an audi­ence at his alma mater in April. “… How do I make sure I’m not the brides­maid? How do I make sure that I’m not always the per­son who’s almost select­ed but doesn’t get the role?”

He went into sales and rose through the oper­a­tional ranks at phar­ma­ceu­ti­cal giant Eli Lil­ly, even­tu­al­ly lead­ing the company’s Bel­gian oper­a­tion. And in 2007, at just 34, he achieved his goal, step­ping in as CEO of the French diag­nos­tics firm bio­Mérieux, which employs rough­ly 6,000 peo­ple.

The com­pa­ny improved its mar­gins under Bancel’s tenure, and he devel­oped a rep­u­ta­tion as a stern man­ag­er who got results, accord­ing to an equi­ties ana­lyst who cov­ered bio­Mérieux at the time.

“He doesn’t suf­fer fools light­ly,” the ana­lyst said, speak­ing on con­di­tion of anonymi­ty to com­ply with com­pa­ny pol­i­cy. “I think if you’re under­per­form­ing, you’ll prob­a­bly find your­self look­ing for anoth­er job.”

Bancel’s rise caught the eye of the biotech invest­ment firm Flag­ship Ven­tures, based here in Cam­bridge. Flag­ship CEO Noubar Afeyan repeat­ed­ly tried to entice him to take over one of the firm’s many star­tups, Ban­cel said. But he reject­ed one prospect after anoth­er because the star­tups seemed too nar­row in scope.

Mod­er­na was dif­fer­ent.

The company’s core idea was seduc­tive­ly sim­ple: cut out the mid­dle­man in biotech.

For decades, com­pa­nies have endeav­ored to craft bet­ter and bet­ter pro­tein ther­a­pies, lead­ing to new treat­ments for can­cer, autoim­mune dis­or­ders, and rare dis­eases. Such ther­a­pies are cost­ly to pro­duce and have many lim­i­ta­tions, but they’ve giv­en rise to a multi­bil­lion-dol­lar indus­try. The anti-inflam­ma­to­ry Humi­ra, the world’s top drug at $14 bil­lion in sales a year, is a shin­ing exam­ple of pro­tein ther­a­py.

Moderna’s tech­nol­o­gy promised to sub­vert the whole field, cre­at­ing ther­a­peu­tic pro­teins inside the body instead of in man­u­fac­tur­ing plants. The key: har­ness­ing mes­sen­ger RNA, or mRNA.

In nature, mRNA mol­e­cules func­tion like recipe books, direct­ing cel­lu­lar machin­ery to make spe­cif­ic pro­teins. Mod­er­na believes it can play that sys­tem to its advan­tage by using syn­thet­ic mRNA to com­pel cells to pro­duce whichev­er pro­teins it choos­es. In effect, the mRNA would turn cells into tiny drug fac­to­ries.

It’s high­ly risky. Big phar­ma com­pa­nies had tried sim­i­lar work and aban­doned it because it’s exceed­ing­ly hard to get RNA into cells with­out trig­ger­ing nasty side effects. But if Mod­er­na can get it to work, the process could be used to treat scores of dis­eases, includ­ing can­cers and rare dis­eases that can be death sen­tences for chil­dren.

Under Ban­cel, Mod­er­na has been loath to pub­lish its work in Sci­ence or Nature, but enthu­si­as­tic to her­ald its poten­tial on CNBC and CNN, tak­ing part in seg­ments on the world’s most dis­rup­tive com­pa­nies and the poten­tial “cure for can­cer.”

Res­ig­na­tions, dis­missals, and churn

From the begin­ning, Ban­cel made clear that Moderna’s sci­ence sim­ply had to work. And that any­one who couldn’t make it work didn’t belong.

The ear­ly Mod­er­na was a chaot­ic, unpre­dictable work­place, accord­ing to for­mer employ­ees. One recalls find­ing him­self out of a job when a quick-turn­around exper­i­ment failed to pan out. Anoth­er helped train a group of new hires only to real­ize they were his replace­ments.

“There was a kind of Jack Welch-ian, ‘We fire the bot­tom 10 per­cent’ from the very begin­ning,” said a for­mer Mod­er­na man­ag­er. “That’s prob­a­bly the biggest HR dif­fer­ence between Mod­er­na and vir­tu­al­ly any oth­er biotech, where they talk so much about devel­op­ing their peo­ple.”

Mod­er­na went through two heads of chem­istry in a sin­gle year, accord­ing to for­mer employ­ees, and its chief sci­en­tif­ic offi­cer and head of man­u­fac­tur­ing left short­ly there­after. Those who fell out of favor with Ban­cel would find them­selves exclud­ed from key meet­ings, pushed aside until they resigned or ulti­mate­ly got dis­missed, employ­ees said.

Most stun­ning to employ­ees was the abrupt depar­ture of Joseph Bolen, who came aboard in 2013 to lead Moderna’s R&D efforts.

Bolen was a big-name hire in biotech cir­cles, an expe­ri­enced chief sci­en­tif­ic offi­cer who had guid­ed Mil­len­ni­um Phar­ma­ceu­ti­cals to FDA approval for a block­buster can­cer drug. He’d been pro­filed in The Sci­en­tist, which dubbed him “the people’s CSO” for his abil­i­ty to keep morale high and research focused. Land­ing him was a coup.

But two years into his tenure at Mod­er­na, he abrupt­ly stepped down last Octo­ber, mak­ing no pub­lic state­ment save for chang­ing his LinkedIn sta­tus to “resigned.”

“No sci­en­tist in his right mind would leave that job unless there was some­thing wrong with the sci­ence or the per­son­nel,” said a per­son close to the com­pa­ny at the time.

Insid­ers said Ban­cel had effec­tive­ly pushed Bolen out, hir­ing par­al­lel exec­u­tives until Bolen was in charge of just “a postage stamp” worth of ter­ri­to­ry, as one for­mer Mod­er­na man­ag­er put it. Bolen declined to com­ment.

For his part, Ban­cel acknowl­edged the changes that lim­it­ed Bolen’s pow­er but insist­ed the part­ing was friend­ly. Ban­cel said he tried to con­vince Bolen to stay, but the sci­en­tist “vot­ed him­self off the island.”

Bolen wasn’t alone. Chief Infor­ma­tion Offi­cer John Reyn­ders joined in 2013 to make Mod­er­na what he called the world’s “first ful­ly dig­i­tal biotech,” only to step down a year lat­er. Michael Morin, brought in to lead Moderna’s sci­en­tif­ic efforts in can­cer in 2014, last­ed less than 18 months. As did Greg Licholai, hired in 2015 to direct the company’s projects in rare dis­eases. The lat­ter two key lead­er­ship posi­tions remain unfilled.

“You won­der,” influ­en­tial biotech blog­ger Derek Lowe wrote last year, “if Mod­er­na real­ly is a rock­et ship get­ting ready to launch and spray a for­ma­tion of new drugs across the sky, then why are these peo­ple leav­ing?”

The com­pa­ny has a sim­ple expla­na­tion: Mod­er­na lives in dog years com­pared with oth­er biotechs.

“We force every­one to grow with the com­pa­ny at unprece­dent­ed speed,” Mod­er­na Chief Finan­cial Offi­cer Lorence Kim said. “Some peo­ple grow with the com­pa­ny; oth­ers don’t.”

A gold rush for Mod­er­na

Hoge, who joined the com­pa­ny in 2012, describes the ear­ly days of Mod­er­na as “when we were liv­ing in the caves.” The com­pa­ny often had only enough cash to keep the lights on for six months at a time, he said. “The strat­e­gy was just to sur­vive.”

Mod­er­na 1.0, and life in the caves, came to a close in 2013, accord­ing to com­pa­ny lore.

That’s when Mod­er­na — which had just 25 employ­ees — signed a stag­ger­ing $240 mil­lion part­ner­ship with UK phar­ma­ceu­ti­cal giant AstraZeneca. It was the most mon­ey phar­ma had ever spent on drugs that had not yet been test­ed in humans.

The agree­ment is com­mem­o­rat­ed in one of Moderna’s offices by a framed clip­ping from the New York Times. Page B7 of the March 21, 2013 edi­tion: “AstraZeneca Makes a Bet On an Untest­ed Tech­nique.”

For AstraZeneca, the unprece­dent­ed deal came at a time of uncer­tain­ty. A series of clin­i­cal fail­ures had led the firm to fire its head of research and lay off 1,600 sci­en­tists. Pas­cal Sori­ot, just six months into his tenure as CEO, was under pres­sure from investors to chart a new course. And Mod­er­na, with its brash ambi­tion to bring 100 drugs to clin­i­cal tri­als with­in a decade, gave Sori­ot a way for­ward.

The rich deal start­ed a gold rush for Mod­er­na. Every­one, it seemed, want­ed in.

Before the end of 2013, Mod­er­na would turn heads again with a $110 mil­lion invest­ment round, fol­lowed by a high-dol­lar part­ner­ship with biotech giant Alex­ion.

In ear­ly 2015, Mod­er­na dis­closed a $450 mil­lion financ­ing round, the largest ever for a pri­vate biotech com­pa­ny. This month, the com­pa­ny broke its own record, rais­ing anoth­er $474 mil­lion.

The run-up was “biotech fer­vor to the extreme,” accord­ing to a ven­ture cap­i­tal­ist not involved with the com­pa­ny, request­ing anonymi­ty to speak can­did­ly. While big­ger investors got to see all the company’s data from ani­mal exper­i­ments, some of Moderna’s small­er investors put in funds based on just a peek, accord­ing to peo­ple famil­iar with the process. Moderna’s fundrais­ing suc­cess had cre­at­ed a seller’s mar­ket: Why deal with the ques­tions of one poten­tial investor when it had 10 more lined up?

Afeyan, Moderna’s chair­man and cofounder, insists the company’s investors have done their home­work. To say they bought in with­out due dili­gence “would be a bit of an insult to these peo­ple,” he said.

Though it has yet to reveal data from a sin­gle clin­i­cal tri­al, Mod­er­na is now val­ued at $4.7 bil­lion, accord­ing to Pitch­book.

That’s twice as much as Spark Ther­a­peu­tics, the com­pa­ny wide­ly expect­ed to mar­ket the Unit­ed States’s first gene ther­a­py, which has shown signs in clin­i­cal tri­als that it can reverse blind­ness caused by a rare genet­ic dis­or­der. Mod­er­na is also worth bil­lions more than Juno Ther­a­peu­tics and Kite Phar­ma, star­tups devel­op­ing nov­el treat­ments for can­cer that have demon­strat­ed promis­ing results in ear­ly human tri­als.

Mod­er­na has long shak­en off rumors that it is soon to mar­ket its shares on Wall Street, with Hoge liken­ing the com­pa­ny to a child star: “You don’t want to go through your ado­les­cence pub­licly,” he told STAT.

But that’s about to change. Moderna’s next planned step is an ini­tial pub­lic offer­ing, accord­ing to a per­son close to the com­pa­ny. Ban­cel declined to say just when Mod­er­na might go pub­lic, but the com­pa­ny has already pre­pared: In its lat­est fil­ings with the Secu­ri­ties and Exchange Com­mis­sion, Mod­er­na changed its busi­ness struc­ture from an LLC to a C cor­po­ra­tion, com­plet­ing a nec­es­sary step before mount­ing an IPO.

A strate­gic shift to less ambi­tious tar­gets

With a pub­lic list­ing come required dis­clo­sures, and many are eager to see what Moderna’s been keep­ing under wraps all these years.

Out­siders and com­peti­tors, look­ing only at Moderna’s pub­lic state­ments, have not­ed a shift in strat­e­gy that might sig­nal undis­closed set­backs.

From the start, Mod­er­na her­ald­ed its abil­i­ty to pro­duce pro­teins with­in cells, which could open up a world of ther­a­peu­tic tar­gets unreach­able by con­ven­tion­al drugs. The most rev­o­lu­tion­ary treat­ments, which could chal­lenge the multi­bil­lion-dol­lar mar­ket for pro­tein ther­a­py, would involve repeat­ed dos­es of mRNA over many years, so a patient’s body con­tin­ued to pro­duce pro­teins to keep dis­ease at bay.

But Moderna’s first human tri­als aren’t so ambi­tious, focus­ing instead on the crowd­ed field of vac­cines, where the com­pa­ny has only been work­ing since 2014.

First are the two vac­cine tri­als for undis­closed infec­tious dis­eases. Com­ing next is a one-time treat­ment for heart fail­ure, devel­oped in part­ner­ship with AstraZeneca, fol­lowed by anoth­er exper­i­men­tal vac­cine, for Zika virus, which sev­er­al oth­er phar­ma com­pa­nies are also work­ing to devel­op. And after that, Mod­er­na is plan­ning a human tri­al of a per­son­al­ized can­cer vac­cine using mRNA, some­thing it just came up with last year.

The choice to pri­or­i­tize vac­cines came as a dis­ap­point­ment to many in the com­pa­ny, accord­ing to a for­mer man­ag­er. The plan had been to rad­i­cal­ly dis­rupt the biotech indus­try, the man­ag­er said, so “why would you start with a clin­i­cal pro­gram that has very lim­it­ed upside and lots of com­pe­ti­tion?”

The answer could be the chal­lenge of ensur­ing drug safe­ty, out­siders said.

Deliv­ery — actu­al­ly get­ting RNA into cells — has long bedev­iled the whole field. On their own, RNA mol­e­cules have a hard time reach­ing their tar­gets. They work bet­ter if they’re wrapped up in a deliv­ery mech­a­nism, such as nanopar­ti­cles made of lipids. But those nanopar­ti­cles can lead to dan­ger­ous side effects, espe­cial­ly if a patient has to take repeat­ed dos­es over months or years.

Novar­tis aban­doned the relat­ed realm of RNA inter­fer­ence over con­cerns about tox­i­c­i­ty, as did Mer­ck and Roche.

Moderna’s most advanced com­peti­tors, Cure­Vac and BioN­Tech, have acknowl­edged the same chal­lenge with mRNA. Each is prin­ci­pal­ly focused on vac­cines for infec­tious dis­ease and can­cer, which the com­pa­nies believe can be attacked with just a few dos­es of mRNA. And each has already test­ed its tech­nol­o­gy on hun­dreds of patients.

“I would say that mRNA is bet­ter suit­ed for dis­eases where treat­ment for short dura­tion is suf­fi­cient­ly cura­tive, so the tox­i­c­i­ties caused by deliv­ery mate­ri­als are less like­ly to occur,” said Katal­in Karikó, a pio­neer in the field who serves as a vice pres­i­dent at BioN­Tech.

That makes vac­cines the low­est hang­ing fruit in mRNA, said Franz-Wern­er Haas, CureVac’s chief cor­po­rate offi­cer. “From our point of view, it’s obvi­ous why [Mod­er­na] start­ed there,” he said.

Mod­er­na said it pri­or­i­tized vac­cines because they pre­sent­ed the fastest path to human tri­als, not because of set­backs with oth­er projects. “The notion that [Mod­er­na] ran into dif­fi­cul­ties isn’t borne in real­i­ty,” said Afeyan.

But this is where Moderna’s secre­cy comes into play: Until there’s pub­lished data, only the com­pa­ny and its part­ners know what the data show. Every­one out­side is left guess­ing — and, in some cas­es, wor­ry­ing that Mod­er­na won’t live up to its hype.

“Frankly, I hope that there’s real sub­stance and I hope they solve those chal­lenges, because it’s not going to be good for the broad­er biotech indus­try in gen­er­al if this thing implodes,” said one investor not involved with Mod­er­na.

And it could still go either way, for­mer employ­ees said. If Moderna’s promis­es come to fruition, it could be a pil­lar of the biotech indus­try. If they don’t, it could find a place among a short list of com­pa­nies that have cast a shad­ow over the entire indus­try and left investors dis­il­lu­sioned.

“Either we’ll be talk­ing about it as the next Genen­tech,” a for­mer Mod­er­na man­ag­er said, “or we’ll think, ‘Well, back then, first there was Tur­ing, then there was Valeant, and then there was Mod­er­na.”

Enough cash to absorb some set­backs

Moderna’s man­age­ment and its investors are keep­ing the faith, point­ing to the company’s pipeline of 11 drug can­di­dates and more than 90 pre­clin­i­cal projects.

And with Moderna’s huge cash reserves — esti­mat­ed at $1.5 bil­lion — it can afford a few set­backs, pro­po­nents said. The com­pa­ny said it’s pour­ing mon­ey into its man­u­fac­tur­ing oper­a­tion, plan­ning to spend $100 mil­lion this year on a new plant. Mod­er­na has pio­neered an auto­mat­ed sys­tem mod­eled on the soft­ware Tes­la uses to man­age orders, Ban­cel said: Sci­en­tists sim­ply enter the pro­tein they want a cell to express, and testable mRNA arrives with­in weeks.

“If we have a bump in the road in the clin­ic, we will not have to wait years to go back to the draw­ing board,” Ban­cel said.

That has always been part of the plan, for­mer employ­ees said, point­ing to Bancel’s fas­ci­na­tion with the tech indus­try. Uber and Ama­zon were not the first to come up with their respec­tive busi­ness ideas, but they were the ones that built enough scale to ward off com­pe­ti­tion. And Mod­er­na is posi­tion­ing itself to do the same in mRNA.

“Now, as we’re going to human [tri­als], it’s pret­ty clear no one else is going to catch us,” said Dr. Ken­neth Chien, a pro­fes­sor at Karolin­s­ka Insti­tutet work­ing with Mod­er­na and AstraZeneca.

Dr. Tal Zaks, Moderna’s chief med­ical offi­cer, promis­es that the com­pa­ny will soon break its silence on the pub­lish­ing front. He said next year Mod­er­na will dis­close the ani­mal data that helped get its two vac­cines into the clin­ic. The com­pa­ny has also com­mit­ted to pub­lish­ing full results from all of its human tri­als, start­ing with the vac­cine stud­ies next year.

Moderna’s ret­i­cence to share data ear­li­er is “not because we decid­ed to be secret,” Zaks said. “This is the nat­ur­al evo­lu­tion of a plat­form. As we go into the clin­ic, we will be very trans­par­ent.”

4. Mon­cef Slaoui’s  opti­mistic state­ment on the Fri­day before the Mon­day announce­ment, presents impor­tant con­text for Moderna’s Mon­day announce­ment. That announce­ment moved mar­kets based on inad­e­quate data. “Oper­a­tion Warp Speed” (head­ed by Slaoui) sug­gests that can­di­date Trump  is very inter­est­ed in those pre­lim­i­nary results as well. 

” . . . . Fol­low­ing Mon­cef Slaoui’s Fri­day appoint­ment as a co-leader of the Warp Speed pro­gram, he’s set to sell about 155,000 shares in Mod­er­na, accord­ing to press reports. They were worth an esti­mat­ed $10 mil­lion Fri­day, but after Monday’s stock run-up on pos­i­tive ear­ly data, they’re now val­ued at about $12.4 mil­lion. . . . Fol­low­ing Slaoui’s selec­tion, Sen. Eliz­a­beth War­ren tweet­ed that it’s a ‘huge con­flict of inter­est’ for him to keep the Mod­er­na stock as he assumes the new role. She said he should ‘divest imme­di­ate­ly.’ In a now-delet­ed tweet, Slaoui respond­ed that there ‘is no con­flict of inter­est, and there nev­er has been,’ Busi­ness Insid­er reports. . . .”

“‘Warp Speed’ head Slaoui, chal­lenged for ‘huge con­flict of inter­est,’ sells off $12.4M in Mod­er­na stock” by Eric Sagonowsky; Fier­cePhar­ma; 05/19/2020

As the Oper­a­tion Warp Speed pro­gram races ahead with COVID-19 vac­cine can­di­dates, one of its new lead­ers kept mil­lions of dol­lars of stock in Mod­er­na, the biotech lead­ing the pack.

But now, after an influ­en­tial sen­a­tor chal­lenged that own­er­ship inter­est, he’s plan­ning to sell.

Fol­low­ing Mon­cef Slaoui’s Fri­day appoint­ment as a co-leader of the Warp Speed pro­gram, he’s set to sell about 155,000 shares in Mod­er­na, accord­ing to press reports. They were worth an esti­mat­ed $10 mil­lion Fri­day, but after Monday’s stock run-up on pos­i­tive ear­ly data, they’re now val­ued at about $12.4 mil­lion.

Slaoui is set to donate to can­cer research the excess pro­ceeds from the sale, or about $2.4 mil­lion, accord­ing to CNBC. Slaoui also resigned as a Mod­er­na board mem­ber with the appoint­ment.

Pres­i­dent Don­ald Trump unveiled the “Warp Speed” project at a Rose Gar­den event on Fri­day. Aside from Slaoui, a Glax­o­SmithK­line vet­er­an, the four-star gen­er­al Gus­tave Per­na will also lead the pro­gram.

Fol­low­ing Slaoui’s selec­tion, Sen. Eliz­a­beth War­ren tweet­ed that it’s a “huge con­flict of inter­est” for him to keep the Mod­er­na stock as he assumes the new role. She said he should “divest imme­di­ate­ly.”

In a now-delet­ed tweet, Slaoui respond­ed that there “is no con­flict of inter­est, and there nev­er has been,” Busi­ness Insid­er reports.

Slaoui spent near­ly three decades at Glax­o­SmithK­line and retired in 2017. Then, he joined the boards of Mod­er­na and oth­er life sci­ences com­pa­nies.

Oper­a­tion Warp Speed is aim­ing to deliv­er a COVID-19 vac­cine by the end of the year. At Friday’s event, Slaoui said he was “con­fi­dent” in that goal after view­ing ear­ly data from an undis­closed pro­gram. Mod­er­na announced its promis­ing data, from eight patients in a phase 1 study, ear­ly Mon­day morn­ing. . . .

5. Even after agree­ing to sell his Mod­er­na stock, Slaoui’s invest­ments raise alarm­ing ques­tions–note that he is a “ven­ture cap­i­tal­ist” and a long­time for­mer exec­u­tive at Glaxo-Smithk­line:

  1. The cir­cum­stances of his appoint­ment will per­mit him to avoid scruti­ny: ” . . . . In agree­ing to accept the posi­tion, Dr. Slaoui did not come on board as a gov­ern­ment employ­ee. Instead, he is on a con­tract, receiv­ing $1 for his ser­vice. That leaves him exempt from fed­er­al dis­clo­sure rules that would require him to list his out­side posi­tions, stock hold­ings and oth­er poten­tial con­flicts. And the con­tract posi­tion is not sub­ject to the same con­flict-of-inter­est laws and reg­u­la­tions that exec­u­tive branch employ­ees must fol­low. . . .”
  2. He will retain a great deal of Glaxo-Smithk­line stock: ” . . . . He did not say how much his GSK shares were worth. When he left the com­pa­ny in 2017, he held about [500,000 in West­ern Print Edi­tion] 240,000 shares and share equiv­a­lents, accord­ing to the drug company’s annu­al report and an analy­sis by the exec­u­tive com­pen­sa­tion firm Equi­lar. . . .”
  3. Fur­ther analy­sis of Slaoui’s posi­tion deep­ens con­cern about the integri­ty of the process: ” . . . . ‘This is basi­cal­ly absurd,’ said Vir­ginia Can­ter, who is chief ethics coun­sel for Cit­i­zens for Respon­si­bil­i­ty and Ethics in Wash­ing­ton. ‘It allows for no pub­lic scruti­ny of his con­flicts of inter­est.’ Ms. Can­ter also said fed­er­al law barred gov­ern­ment con­trac­tors from super­vis­ing gov­ern­ment employ­ees. . . . Ms. Can­ter, a for­mer ethics lawyer in the Oba­ma and Clin­ton admin­is­tra­tions, the Secu­ri­ties and Exchange Com­mis­sion and oth­er agen­cies, point­ed out that GSK’s vac­cine can­di­date with Sanofi could wind up com­pet­ing with oth­er man­u­fac­tur­ers vying for gov­ern­ment approval and sup­port. ‘If he retains stock in com­pa­nies that are invest­ing in the devel­op­ment of a vac­cine, and he’s involved in over­see­ing this process to select the safest vac­cine to com­bat Covid-19, regard­less of how won­der­ful a per­son he is, we can’t be con­fi­dent of the integri­ty of any process in which he is involved,’ Ms. Can­ter said.In addi­tion, his affil­i­a­tion with Medicxi could com­pli­cate mat­ters: Two of its investors are GSK and a divi­sion of John­son & John­son, which is also devel­op­ing a poten­tial vac­cine. . . .”

“Trump’s Vac­cine Chief Has Vast Ties to Drug Indus­try, Pos­ing Pos­si­ble Con­flicts” by Sheila Kaplan, Matthew Gold­stein and Alexan­dra Steven­son; The New York Times; 5/21/2020.

. . . . The sci­en­tist, Mocef Slaoui, is a ven­ture cap­i­tal­ist and a for­mer long­time exec­u­tive at Glaxo-Smithk­line . . .

. . . . In agree­ing to accept the posi­tion, Dr. Slaoui did not come on board as a gov­ern­ment employ­ee. Instead, he is on a con­tract, receiv­ing $1 for his ser­vice. That leaves him exempt from fed­er­al dis­clo­sure rules that would require him to list his out­side posi­tions, stock hold­ings and oth­er poten­tial con­flicts. And the con­tract posi­tion is not sub­ject to the same con­flict-of-inter­est laws and reg­u­la­tions that exec­u­tive branch employ­ees must fol­low. . . .

. . . . He did not say how much his GSK shares were worth. When he left the com­pa­ny in 2017, he held about [500,000 in West­ern Edi­tion] 240,000 shares and share equiv­a­lents, accord­ing to the drug company’s annu­al report and an analy­sis by the exec­u­tive com­pen­sa­tion firm Equi­lar.

He said he told admin­is­tra­tion offi­cials that he did not want to sell his com­pa­ny stock.

‘I have worked for 29 years for GSK,’ Dr. Slaoui said. ‘I have nev­er sold a sin­gle share of any com­pa­ny in my life. This is my retire­ment. What I said regard­ing the GSK shares, I said I can­not take the job if I have to sell them.’ . . .

. . . . With­out pub­lic dis­clo­sure, some ethics experts called his con­tract an end-run around the rules.

“This is basi­cal­ly absurd,” said Vir­ginia Can­ter, who is chief ethics coun­sel for Cit­i­zens for Respon­si­bil­i­ty and Ethics in Wash­ing­ton. “It allows for no pub­lic scruti­ny of his con­flicts of inter­est.”

Ms. Can­ter also said fed­er­al law barred gov­ern­ment con­trac­tors from super­vis­ing gov­ern­ment employ­ees. . . .

. . . . Ms. Can­ter, a for­mer ethics lawyer in the Oba­ma and Clin­ton admin­is­tra­tions, the Secu­ri­ties and Exchange Com­mis­sion and oth­er agen­cies, point­ed out that GSK’s vac­cine can­di­date with Sanofi could wind up com­pet­ing with oth­er man­u­fac­tur­ers vying for gov­ern­ment approval and sup­port.

“If he retains stock in com­pa­nies that are invest­ing in the devel­op­ment of a vac­cine, and he’s involved in over­see­ing this process to select the safest vac­cine to com­bat Covid-19, regard­less of how won­der­ful a per­son he is, we can’t be con­fi­dent of the integri­ty of any process in which he is involved,” Ms. Can­ter said.

In addi­tion, his affil­i­a­tion with Medicxi could com­pli­cate mat­ters: Two of its investors are GSK and a divi­sion of John­son & John­son, which is also devel­op­ing a poten­tial vac­cine. . . .

6. Mod­er­na stands to make bil­lions of dol­lars if their vac­cine goes to mar­ket:

  1. ” . . . . What investors are bet­ting on, for Mod­er­na and oth­ers devel­op­ing vac­cines against the SARS-CoV­‑2 virus, is that a third of the devel­oped world’s pop­u­la­tion will get vac­ci­nat­ed every year. That could amount to a $10 bil­lion annu­al busi­ness, at an esti­mat­ed price of $30 per vac­ci­na­tion. . . .”
  2. ” . . . . Mor­gan Stan­ley ana­lysts this past week­end sug­gest­ed that pric­ing might start at $5 to $10 a dose dur­ing this first pan­dem­ic cri­sis, then rise to a range of $13 to $30 for pre­ven­tive dos­es in future years. But at BMO Cap­i­tal Mar­kets, ana­lyst George Farmer spec­u­lat­ed that Mod­er­na could start charg­ing $125 per treat­ment in the U.S. mar­ket and raise that price over time to $200. . . . ”

“A Covid-19 Vac­cine Could Be Worth Bil­lions for Mod­er­na and Its Rivals” by Bill Alpert; Barron’s; 05/19/2020

Fresh on the heels of the first data from human tests of its Covid-19 vac­cine, Mod­er­na sold $1.3 bil­lion worth of stock on Mon­day at a price of $76 a share. That’s a four­fold rise from price where the biotech’s stock start­ed the year, and a mar­ket val­ue of $30 bil­lion for a com­pa­ny that has yet to sell its first prod­uct.

What investors are bet­ting on, for Mod­er­na and oth­ers devel­op­ing vac­cines against the SARS-CoV­‑2 virus, is that a third of the devel­oped world’s pop­u­la­tion will get vac­ci­nat­ed every year. That could amount to a $10 bil­lion annu­al busi­ness, at an esti­mat­ed price of $30 per vac­ci­na­tion. At high­er prices, Covid vac­cine rev­enue would be big­ger still.

In Tues­day morn­ing trad­ing, Mod­er­na stock was down 5% from Monday’s close, at $76.

On a Mon­day con­fer­ence call, Mod­er­na CEO Stéphane Ban­cel said the Cam­bridge, Mass., com­pa­ny had not yet decid­ed on a price , in the event that their mRNA-1273 vac­cine proves effec­tive in the Phase 2 and 3 tri­als it will run this year. He said that Mod­er­na was think­ing about what Covid-19 ill­ness costs the health-care sys­tem.

Covid’s cost obvi­ous­ly goes beyond the hos­pi­tal, and it’s already been gigan­tic . In the U.S. alone, near­ly 90,000 have died in a few months’ time. The scale of the coro­n­avirus’ impact explains why there’s such a range of esti­mates on Wall Street for what vac­cine mak­ers will charge. Mor­gan Stan­ley ana­lysts this past week­end sug­gest­ed that pric­ing might start at $5 to $10 a dose dur­ing this first pan­dem­ic cri­sis, then rise to a range of $13 to $30 for pre­ven­tive dos­es in future years.

But at BMO Cap­i­tal Mar­kets, ana­lyst George Farmer spec­u­lat­ed that Mod­er­na could start charg­ing $125 per treat­ment in the U.S. mar­ket and raise that price over time to $200. Most of the world’s health-care sys­tems are gov­ern­ment-run, so Farmer’s mod­el assumes that pric­ing abroad will be a frac­tion of America’s gen­er­ous pric­ing.

Vac­ci­na­tions will like­ly con­sist of a first shot and then a boost­er one month lat­er. After clin­i­cal tri­als answer the first cru­cial ques­tion of whether vac­cine can­di­dates like Moderna’s pre­vent Covid in humans, the next ques­tion will be how long immu­ni­ty lasts. Assum­ing some­what less muta­bil­i­ty than is the case with the flu virus, researchers are guess­ing that peo­ple might need a SARS-CoV­‑2 vac­ci­na­tion every few years. That’s how ana­lysts like BMO’s Farmer arrive at a count of rough­ly a third of the pop­u­la­tion need­ing a vac­ci­na­tion per year.

The U.S. pop­u­la­tion could rise from about 330 mil­lion today to more than 360 mil­lion by the decade’s end, depend­ing on a bunch of social and eco­nom­ic fac­tors, such as future immi­gra­tion lev­els. Dif­fer­ent age groups will get vac­ci­nat­ed at dif­fer­ing rates—hopefully unim­ped­ed by anti­vac­ci­na­tion sen­ti­mentsBMO esti­mates that will work out to about 30% of America’s head count get­ting vac­ci­nat­ed each year, or some 100 mil­lion treat­ments a year by the sec­ond half of this decade. Put a price from $30 to $130 on those num­bers, and you get $3 bil­lion to $13 bil­lion in U.S. sales.

Glob­al sales are hard­er to fore­cast, with prices and vac­ci­na­tion rates like­ly to vary wide­ly through­out the devel­oped and devel­op­ing coun­tries. BMO’s Farmer guessti­mates that sales in the devel­oped world will amount to half or two-thirds the dol­lar lev­els of the U.S. Poor­er nations will only be able to chip in around 5%. Still, he sees Covid vac­cines exceed­ing $30 bil­lion in sales by the end of the decade. That mar­ket size embold­ened him to raise his price tar­get on Mod­er­na stock to $112 from $83, after yesterday’s encour­ag­ing news on the first hand­ful of patients in Moderna’s Phase 1 tri­al.

Even if Moderna’s vac­cine becomes the first one available—perhaps this fall, for front-line workers—it won’t be the only one. Pfiz­er (PFE) and its part­ner BioN­Tech (BNTX) are also in the clin­ic with a vac­cine that uses tech­nol­o­gy sim­i­lar to Moderna’s. And oth­er vac­cine approach­es are being test­ed by the likes of John­son & John­son (JNJ) and the vac­cine mar­ket incum­bents Sanofi (SNY) and Glax­o­SmithK­line (GSK). . . .

7. We close the dis­cus­sion with a reminder of the extent to which fed­er­al fund­ing dri­ves the val­ue of Mod­er­na: ” . . . . ‘Instead of wait­ing for the data and then scal­ing up with man­u­fac­tur­ing process … we can make as many dos­es as we can. We are doing both in par­al­lel,’ he said. The com­pa­ny plans to hire up to 150 peo­ple to sup­port the effort. Ban­cel said the com­pa­ny ‘couldn’t have done this’ with­out the fund­ing com­mit­ment from the Bio­med­ical Advanced Research and Devel­op­ment Author­i­ty, which is part of the Depart­ment of Health and Human Ser­vices. . . .”

“Mod­er­na soars after get­ting $483 mil­lion in fed­er­al fund­ing for coro­n­avirus vac­cine devel­op­ment” by Kevin Stankiewicz; CNBC; 04/17/2020

Moderna’s stock was surg­ing Fri­day after the biotech com­pa­ny announced it has received as much as $483 mil­lion in fed­er­al fund­ing to accel­er­ate devel­op­ment of a coro­n­avirus vac­cine.

Shares of the Cam­bridge, Mass­a­chu­setts-based firm closed 15.4% high­er to $46.85. Dur­ing Friday’s ses­sion, the stock hit an intra­day all-time high of $49.

Mod­er­na CEO Stephane Ban­cel said Fri­day on CNBC’s “Squawk Box” that the fund­ing is par­tic­u­lar­ly crit­i­cal in aid­ing man­u­fac­tur­ing efforts.

“Instead of wait­ing for the data and then scal­ing up with man­u­fac­tur­ing process … we can make as many dos­es as we can. We are doing both in par­al­lel,” he said. The com­pa­ny plans to hire up to 150 peo­ple to sup­port the effort.

Ban­cel said the com­pa­ny “couldn’t have done this” with­out the fund­ing com­mit­ment from the Bio­med­ical Advanced Research and Devel­op­ment Author­i­ty, which is part of the Depart­ment of Health and Human Ser­vices.

Mod­er­na has part­nered with the Nation­al Insti­tutes of Health on devel­op­ment of its Covid-19 vac­cine. Phase 1 human tri­als of the poten­tial vac­cine began in the Seat­tle area in mid-March.

The tri­al was launched in “record speed,” White House health advi­sor Dr. Antho­ny Fau­ci said at the time.

Ban­cel on Fri­day reit­er­at­ed Moderna’s time­line for vac­cine devel­op­ment. He said he hopes to have safe­ty data from the phase 1 tri­al this spring, which could allow it to advance to the next stage in the sec­ond quar­ter of this year.

The phase 1 tri­al is being con­duct­ed with 45 peo­ple, while phase 2 would involve an expan­sion into “hun­dreds of healthy sub­jects,” Ban­cel said.

Devel­op­ment also needs to include a large effec­tive­ness study involv­ing thou­sands of peo­ple, Ban­cel said. Mod­er­na hopes to start that phase in the fall, depend­ing on results from all the pre­ced­ing stages. . . .

 

 

 

Discussion

7 comments for “FTR #1131 Bio-Psy-Op Apocalypse Now, Part 7: Moderna Uber Alles”

  1. There was some good news on the COVID vac­cine hunt revealed on Fri­day. Of course, as we’ll see, it’s the kind of good news that could pos­si­bly be used in a very bad way. So what’s the good news? Well, Mod­er­na just released pre­lim­i­nary data on Fri­day about some safe­ty stud­ies on its COVID-19 vac­cine. The results were pret­ty pos­i­tive but they’re pos­i­tive safe­ty results from stud­ies on mice, so it’s not real­ly clear the find­ings will trans­late to humans. And that’s where this good news could pos­si­bly be used for bad ends. Because as we’ll see, there are grow­ing con­cerns that, as the Novem­ber 2020 US elec­tion grows clos­er the tempt­ing for the Trump admin­is­tra­tion to declare the dis­cov­ery of a vac­cine is only going to grow too. So the temp­ta­tion to basi­cal­ly rush the safe­ty test­ing on a vac­cine will be enor­mous and its a temp­ta­tion that’s going to be felt by Mod­er­na and the rest of the phar­ma­ceu­ti­cal indus­try too.

    And what about the human clin­i­cal tri­als that should be the ulti­mate arbiter of the safe­ty of these vac­cines? Well, those tri­als are under­way too. And as we’ll see in the sec­ond arti­cle below, they’re still con­duct­ing the phase II clin­i­cal tri­als and phase III is going to be get­ting under­way in July. But that’s part of what’s kind of alarm­ing about the sit­u­a­tion: the human clin­i­cal tri­als are already under­way at the same time the ani­mal safe­ty tri­als have yet to be com­plet­ed. That’s how rushed every­thing is with this pan­dem­ic. And the phase II tri­al is going to be fol­low­ing peo­ple for the next year so it’s not real­ly pos­si­ble for the human clin­i­cal tri­als to real­ly run to com­ple­tion before Novem­ber. Side effects can take a while to man­i­fest. So it’s not real­ly pos­si­ble for a human safe­ty tri­als to be com­plete before Novem­ber but it is pos­si­ble for ani­mal safe­ty tri­als to be com­plet­ed. It points to kind of night­mare sit­u­a­tion where polit­i­cal pres­sure results in side-effects that take a while to man­i­fest get­ting missed as deci­sion-mak­ers decide to give undo weight to the ani­mal safe­ty results and just hope for the best.

    So what were the pos­i­tive results from the ani­mal tri­als in mice? Well, mice were giv­en the vac­cine in a range of dos­es, includ­ed dos­es expect­ed to elic­it sub-pro­tec­tive response. Recall how explor­ing the inter­ac­tion of COVID-19 with sub-pro­tec­tive immune respons­es (so low lev­els of anti­bod­ies that can’t pre­vent the dis­ease) is one of the key safe­ty issues to test giv­en the pos­si­bil­i­ty of Anti­body Depen­dent Enhance­ment (ADE), a phe­nom­e­na where low lev­els of inef­fec­tive anti­bod­ies latch onto the virus and exac­er­bate an over­ac­tive immune response that leads to the dead­liest symp­toms likes cytokine-storms. This dan­ger was seen with SARS and attempts to cre­ate a SARS vac­cine so it’s a rea­son­able fear with SARS-CoV­‑2. So find­ing that mice don’t appear to suf­fer from ADE is actu­al­ly great news giv­en on dan­ger­ous ADE could be, espe­cial­ly in the con­text of cre­at­ing a vac­cine. We could lit­er­al­ly cre­ate a vac­cine that pro­tects those who get a strong immune response while endan­ger­ing those with sub-pro­tec­tive respons­es. A kind of eugenic vac­cine. So this should be good news, assum­ing this good news isn’t used in place of mean­ing­ful safe­ty tri­als in humans:

    Reuters

    Mod­er­na COVID-19 vac­cine appears to clear safe­ty hur­dle in mouse study

    Julie Steen­huy­sen
    June 12, 2020 / 12:55 PM / Updat­ed

    CHICAGO (Reuters) — A series of stud­ies in mice of Mod­er­na Inc’s COVID-19 lent some assur­ance that it may not increase the risk of more severe dis­ease, and that one dose may pro­vide pro­tec­tion against the nov­el coro­n­avirus, accord­ing to pre­lim­i­nary data released on Fri­day.

    Pri­or stud­ies on a vac­cine for SARS — a close cousin to the new virus that caus­es COVID-19 — sug­gests vac­cines against this type of virus might have the unin­tend­ed effect of caus­ing more severe dis­ease when the vac­ci­nat­ed per­son is lat­er exposed to the pathogen, espe­cial­ly in indi­vid­u­als who do not pro­duce an ade­quate­ly strong immune response.

    Sci­en­tists have seen this risk as a hur­dle to clear before vac­cines can be safe­ly test­ed in thou­sands of healthy peo­ple.

    While the data released by the U.S. Nation­al Insti­tutes of Aller­gy and Infec­tious Dis­ease (NIAID) and Mod­er­na offered some assur­ance, the stud­ies do not ful­ly answer the ques­tion.

    “This is the barest begin­ning of pre­lim­i­nary infor­ma­tion,” said Dr. Gre­go­ry Poland, an immu­nol­o­gist and vac­cine researcher at the Mayo Clin­ic who has seen the paper, which has yet to under­go peer-review.

    Poland said the paper was incom­plete, dis­or­ga­nized and the num­bers of ani­mals test­ed were small.

    The authors said they have sub­mit­ted the work to a top-tier jour­nal. Moderna’s vac­cine is in mid­stage test­ing in healthy vol­un­teers. Mod­er­na said on Thurs­day it plans to begin final-stage tri­als enrolling 30,000 peo­ple in July.

    In the ani­mal stud­ies, mice received one or two shots of a vari­ety of dos­es of Moderna’s vac­cine, includ­ing dos­es con­sid­ered not strong enough to elic­it a pro­tec­tive immune response. Researchers then exposed the mice to the virus.

    Sub­se­quent analy­ses sug­gest “sub-pro­tec­tive” immune respons­es do not cause what is known as vac­cine-asso­ci­at­ed enhanced res­pi­ra­to­ry dis­ease, a sus­cep­ti­bil­i­ty to more severe dis­ease in the lungs.

    “Sub­pro­tec­tive dos­es did not prime mice for enhanced immunopathol­o­gy fol­low­ing (expo­sure),” Dr. Bar­ney Gra­ham of the Vac­cine Research Cen­ter at NIAID and col­leagues wrote in the man­u­script, post­ed on the bioRx­iv web­site.

    Fur­ther test­ing sug­gest­ed the vac­cine induces anti­body respons­es to block the virus from infect­ing cells.

    The vac­cine also appeared to pro­tect against infec­tion by the coro­n­avirus in the lungs and noses with­out evi­dence of tox­ic effects, the team wrote.

    They not­ed the mice that received just one dose before expo­sure to the virus sev­en weeks lat­er were “com­plete­ly pro­tect­ed against lung viral repli­ca­tion,” sug­gest­ing a sin­gle vac­ci­na­tion pre­vent­ed the virus from repli­cat­ing in the lungs.

    “At first glance, it looks promis­ing in induc­ing neu­tral­iz­ing anti­body pro­tec­tion in mice,” Dr. Peter Hotez, a researcher at Bay­lor Col­lege of Med­i­cine said in an email. He had not reviewed the paper in detail.

    Poland, who was not involved with the research, said the paper leaves out “impor­tant para­me­ters” that could help sci­en­tists judge the work.

    ...

    ————–

    “Mod­er­na COVID-19 vac­cine appears to clear safe­ty hur­dle in mouse study” by Julie Steen­huy­sen; Reuters; 06/12/2020

    “Pri­or stud­ies on a vac­cine for SARS — a close cousin to the new virus that caus­es COVID-19 — sug­gests vac­cines against this type of virus might have the unin­tend­ed effect of caus­ing more severe dis­ease when the vac­ci­nat­ed per­son is lat­er exposed to the pathogen, espe­cial­ly in indi­vid­u­als who do not pro­duce an ade­quate­ly strong immune response.”

    Unin­tend­ed side effects that may future expo­sure worse. Yeah, that’s def­i­nite­ly some­thing we don’t want to do. But at least with mice that does­n’t seem to hap­pen:

    ...
    In the ani­mal stud­ies, mice received one or two shots of a vari­ety of dos­es of Moderna’s vac­cine, includ­ing dos­es con­sid­ered not strong enough to elic­it a pro­tec­tive immune response. Researchers then exposed the mice to the virus.

    Sub­se­quent analy­ses sug­gest “sub-pro­tec­tive” immune respons­es do not cause what is known as vac­cine-asso­ci­at­ed enhanced res­pi­ra­to­ry dis­ease, a sus­cep­ti­bil­i­ty to more severe dis­ease in the lungs.

    “Sub­pro­tec­tive dos­es did not prime mice for enhanced immunopathol­o­gy fol­low­ing (expo­sure),” Dr. Bar­ney Gra­ham of the Vac­cine Research Cen­ter at NIAID and col­leagues wrote in the man­u­script, post­ed on the bioRx­iv web­site.
    ...

    Then again, it’s pos­si­ble the study is incom­plete and dis­or­ga­nized, as one sci­en­tist appeared to see it. It’s a reminder that this good news is actu­al­ly pre­lim­i­nary ten­ta­tive good news:

    ...
    “This is the barest begin­ning of pre­lim­i­nary infor­ma­tion,” said Dr. Gre­go­ry Poland, an immu­nol­o­gist and vac­cine researcher at the Mayo Clin­ic who has seen the paper, which has yet to under­go peer-review.

    Poland said the paper was incom­plete, dis­or­ga­nized and the num­bers of ani­mals test­ed were small.

    ...

    Poland, who was not involved with the research, said the paper leaves out “impor­tant para­me­ters” that could help sci­en­tists judge the work.
    ...

    Ok, now here’s an update on Mod­er­na’s clin­i­cal tri­als on humans. It sounds like the Phase III tri­al is going to be start­ed in July. It’s going to involve 30,000 peo­ple. Alarm­ing­ly, those 30,000 peo­ple will all be receiv­ing the exact same dosage, 100 micro­grams, and that means the phase III tri­al won’t be test­ing sub-opti­mal dosages. It will implic­it­ly be test­ing sub-pro­tec­tive immune respons­es since some of those 30,000 peo­ple will have sub-pro­tec­tive respons­es. But it does­n’t sound like the explo­ration of sub-pro­tec­tive dosages will be thor­ough­ly explored using this large sam­ple size. So we’re already learn­ing that the big Phase III tri­al basi­cal­ly won’t be very inter­est­ed in test­ing ADE in humans.

    What about the Phase II tri­al? Well, that tri­al of 600 healthy peo­ple is ongo­ing. The vol­un­teers will be fol­lowed for a year after their injec­tions to exam­ine the safe­ty of the vac­cine. The Phase II tri­al will also include peo­ple from key pop­u­la­tions like health care work­ers and res­i­dents in long-term care facil­i­ties. So the Phase II tri­al is going to pro­vide cru­cial safe­ty infor­ma­tion on the most vul­ner­a­ble and impor­tant pop­u­la­tions to watch out for with this vac­cine but it won’t be com­plet­ed for a year. All in all, it’s the per­fect storm for hav­ing just enough safe­ty infor­ma­tion to make rushed vague edu­ca­tion guess­es and that’s about it:

    Time

    Mod­er­na Plans To Start Phase 3 Test­ing of its COVID-19 Vac­cine Can­di­date in July

    By Alice Park
    June 11, 2020 10:14 AM EDT

    On June 11, biotech com­pa­ny Mod­er­na announced it had final­ized plans for phase 3 test­ing of its COVID-19 vac­cine can­di­date. The late-stage tri­al will include 30,000 par­tic­i­pants and is expect­ed to begin in July.

    The tri­al will test just one dose lev­el of the vac­cine, 100 micro­grams, giv­en in two shots. In the ear­li­er phase 1 study involv­ing 45 healthy vol­un­teers, the com­pa­ny explored low­er and high­er dos­es, but pre­lim­i­nary results revealed by the com­pa­ny from this tri­al sug­gest­ed that 100 micro­grams pro­vid­ed the desired immune response safe­ly. Accord­ing to the com­pa­ny, the vac­cine pro­duced anti­bod­ies against the COVID-19 virus in those who were vac­ci­nat­ed, and in tests involv­ing a hand­ful of par­tic­i­pants, those anti­bod­ies were able to neu­tral­ize the virus in the lab. The full details of that study aren’t avail­able yet; that will soon be pub­lished by Moderna’s col­lab­o­ra­tors, a team of sci­en­tists at the Nation­al Insti­tute of Aller­gy and Infec­tious Dis­eases.

    The phase 2 study is ongo­ing, and is enrolling 600 healthy peo­ple who will be fol­lowed for a year after their injec­tions. This stage will con­tin­ue to look at the vaccine’s safe­ty as well as col­lect fur­ther data on its effec­tive­ness. This study will include more peo­ple who might be a high risk of expo­sure to COVID-19, such as health care work­ers and res­i­dents in long-term care facil­i­ties.

    In June, Mod­er­na became one of five vac­cine devel­op­ers cho­sen to be part of Pres­i­dent Trump’s Oper­a­tion Warp Speed pro­gram to speed devel­op­ment of a COVID-19 vac­cine. The selec­tion qual­i­fies Mod­er­na to receive fed­er­al gov­ern­ment fund­ing to con­tin­ue devel­op­ment of vac­cine, con­duct tests, as well as scale up man­u­fac­tur­ing to meet the goal of begin­ning to inoc­u­late 300 mil­lion peo­ple begin­ning ear­ly next year. Mod­er­na said it plans to deliv­er 500 mil­lion to 1 bil­lion dos­es a year begin­ning in 2021.

    ————

    “Mod­er­na Plans To Start Phase 3 Test­ing of its COVID-19 Vac­cine Can­di­date in July” by Alice Park; Time; 06/11/2020

    The tri­al will test just one dose lev­el of the vac­cine, 100 micro­grams, giv­en in two shots. In the ear­li­er phase 1 study involv­ing 45 healthy vol­un­teers, the com­pa­ny explored low­er and high­er dos­es, but pre­lim­i­nary results revealed by the com­pa­ny from this tri­al sug­gest­ed that 100 micro­grams pro­vid­ed the desired immune response safe­ly. Accord­ing to the com­pa­ny, the vac­cine pro­duced anti­bod­ies against the COVID-19 virus in those who were vac­ci­nat­ed, and in tests involv­ing a hand­ful of par­tic­i­pants, those anti­bod­ies were able to neu­tral­ize the virus in the lab. The full details of that study aren’t avail­able yet; that will soon be pub­lished by Moderna’s col­lab­o­ra­tors, a team of sci­en­tists at the Nation­al Insti­tute of Aller­gy and Infec­tious Dis­eases.”

    So based on the Phase I tri­al of 45 healthy vol­un­teers, 100 micro­grams was deter­mined to pro­vide the desired immune response safe­ly and that’s the dosage that’s going to be used on 30,000 vol­un­teers for the Phase III tri­al. Let’s hope that Phase I tri­al’s sam­ple size was ade­quate and rep­re­sen­ta­tive of the pop­u­la­tion. Espe­cial­ly the unhealthy part of the pop­u­la­tion that’s going to be most vul­ner­a­ble to side-effects.

    And this Phase III tri­al is going to tak­ing place at the same time Phase II is con­tin­u­ing. It sounds like it’s Phase II where key pop­u­la­tions, like health care work­ers and long-term care facil­i­ty res­i­dents are going to be exam­ined. Specif­i­cal­ly healthy vol­un­teers. So healthy long-term care res­i­dents are being used as the test sam­ple for the safe­ty of this vac­cine. And we’ll find out the results in a year. Hmmm...

    ...
    The phase 2 study is ongo­ing, and is enrolling 600 healthy peo­ple who will be fol­lowed for a year after their injec­tions. This stage will con­tin­ue to look at the vaccine’s safe­ty as well as col­lect fur­ther data on its effec­tive­ness. This study will include more peo­ple who might be a high risk of expo­sure to COVID-19, such as health care work­ers and res­i­dents in long-term care facil­i­ties.
    ...

    Ok, final­ly, here’s a New York Times opin­ion piece by by Drs Ezekiel J. Emanuel and Paul A. Offit where they spec­u­late bout the pos­si­bil­i­ty of some sort of near-future dystopi­an sci-fi night­mare sce­nario play­ing out in the com­ing months. A near-future dystopi­an sci-fi night­mare sce­nario that seems all too plau­si­ble giv­en the dystopi­an polit­i­cal night­mare real­i­ty of present-day Amer­i­ca and its dystopi­an fas­cist pres­i­dent who is des­per­ate for a big COVID ‘win’ ASAP:

    The New York Times

    Could Trump Turn a Vac­cine Into a Cam­paign Stunt?
    In a des­per­ate search for a boost, he could release a coro­n­avirus vac­cine that has not been shown to be safe and effec­tive as an Octo­ber sur­prise.

    By Ezekiel J. Emanuel and Paul A. Offit
    Dr. Emanuel and Dr. Offit are pro­fes­sors at the Uni­ver­si­ty of Penn­syl­va­nia.
    June 8, 2020

    Oct. 23, 2020, 9 a.m., with 10 days before the elec­tion, Fox New releas­es a poll show­ing Pres­i­dent Trump trail­ing Joe Biden by eight per­cent­age points.

    Oct. 23, 2020, 3 p.m., at a hasti­ly con­vened news con­fer­ence, Pres­i­dent Trump announces that the Food and Drug Admin­is­tra­tion has just issued an Emer­gency Use Autho­riza­tion for a coro­n­avirus vac­cine. Mr. Trump declares vic­to­ry over Covid-19, demands that all busi­ness­es reopen imme­di­ate­ly and pre­dicts a rapid eco­nom­ic recov­ery.

    Giv­en how this pres­i­dent has behaved, this incred­i­bly dan­ger­ous sce­nario is not far-fetched. In a des­per­ate search for a polit­i­cal boost, he could release a coro­n­avirus vac­cine before it had been thor­ough­ly test­ed and shown to be safe and effec­tive.

    There are 123 can­di­date Covid-19 vac­cines in devel­op­ment, and 10 are in human tri­als. Many have not even been test­ed, or only per­func­to­ri­ly test­ed, in ani­mals. In July, the Nation­al Insti­tutes of Health is plan­ning to begin ran­dom­ized phase III tri­als to test whether some of the 10 vac­cines pre­vent infec­tion with coro­n­avirus. Some phar­ma­ceu­ti­cal com­pa­nies are plan­ning to start their own tri­als at about the same time. Astra Zeneca has already men­tioned it plans to begin deliv­ery of its vac­cine in Octo­ber.

    Pfiz­er is plan­ning to give its vac­cine to approx­i­mate­ly 8,000 patients. The N.I.H. is plan­ning to enroll 30,000 par­tic­i­pants — 20,000 get­ting a can­di­date vac­cine and 10,000 research con­trols.

    By com­par­i­son, the Phase III effec­tive­ness tri­al for one rotavirus vac­cine, RotaTeq, to pre­vent diar­rhea involved about 70,000 infants from 2001 to 2004 and anoth­er rotavirus vac­cine tri­al, Rotar­ix, involved 63,000 infants, from 2003 to 2006.

    Researchers are expect­ing that it will be like­ly to take at least anoth­er eight to 12 months to deter­mine whether these coro­n­avirus vac­cines are effec­tive. Sci­en­tists have to wait until a suf­fi­cient num­ber of patients are exposed to coro­n­avirus to see if the vac­cine real­ly reduces the infec­tion rate, as well as how many peo­ple devel­op uncom­mon side effects. For com­par­i­son, the effec­tive­ness tri­al for the rotavirus vac­cines took about four years and the human papil­lo­mavirus vac­cine stud­ies to pre­vent cer­vi­cal can­cer took sev­en years.

    So could Mr. Trump real­ly pull an “Octo­ber Sur­prise” with a vac­cine less than five months from today?

    One high­ly unlike­ly pos­si­bil­i­ty is that recruit­ment of vol­un­teers in a coro­n­avirus “hot spot” would be so rapid that it would allow for an ade­quate assess­ment of the vaccine’s safe­ty and effec­tive­ness very quick­ly.

    There is anoth­er sce­nario that is far more omi­nous: Three months after the N.I.H. tri­als begin in July — so, mid Octo­ber — stud­ies reveal many patients are devel­op­ing high lev­els of anti­bod­ies to the coro­n­avirus with­out severe side effects. As the White House did with its relent­less pro­mo­tion of hydrox­y­chloro­quine as a cure, it would bad­ger the F.D.A. to per­mit use of the vac­cine. More pres­sure would come from drug com­pa­nies, some of whom may spend up to $1 bil­lion on research and are intense­ly com­pet­ing for pres­tige and glo­ry. They are plan­ning to begin man­u­fac­tur­ing their vac­cine can­di­dates at-risk — that is, before com­plet­ed stud­ies show­ing their vac­cine is actu­al­ly effec­tive.

    Cog­nizant of the fate of Rick Bright — the head of the Bio­med­ical Advanced Research and Devel­op­ment Author­i­ty, who was sum­mar­i­ly demot­ed when he resist­ed the president’s wish­es to ramp up pur­chase of hydrox­y­chloro­quine — the F.D.A. could issue an Emer­gency Use Autho­riza­tion for one or more vac­cines. These autho­riza­tions only require that the F.D.A. finds it “rea­son­able to believe” that a vac­cine “may be effec­tive” in pre­vent­ing a life-threat­en­ing dis­ease for it to be put on the mar­ket, with­out being for­mal­ly licensed.

    An emer­gency autho­riza­tion would allow Mr. Trump to hold his news con­fer­ence and declare vic­to­ry. But like Pres­i­dent George W. Bush’s “Mis­sion Accom­plished” procla­ma­tion, it has the poten­tial to be a trav­es­ty. Mil­lions of vac­cines could be dis­trib­uted with­out proof that the vac­cine can pre­vent dis­ease or trans­mis­sion.

    No vac­cine since the 1950s has been approved and licensed with­out com­plet­ing large, prospec­tive, place­bo-con­trolled stud­ies of safe­ty and effec­tive­ness.

    Even if a vac­cine gen­er­ates anti­bod­ies, it does not prove that the vac­cine is effec­tive at pre­vent­ing infec­tion; it only makes it more like­ly that the vac­cine would be effec­tive. Indeed, about half of the vac­cines for oth­er dis­eases that work and are on the mar­ket actu­al­ly lack clear immuno­log­i­cal cor­re­lates for pro­tec­tion, mean­ing they are effec­tive but patients’ anti­bod­ies, immune cells or oth­er mark­ers do not iden­ti­fy whether a patient is pro­tect­ed. Even with the ini­tial tri­als, we are like­ly to have scant data on whether old­er peo­ple will mount an immune reac­tion and be pro­tect­ed.

    Giv­ing peo­ple a false sense of being pro­tect­ed will most like­ly lead to seri­ous out­breaks of the dis­ease as peo­ple reduce their com­pli­ance with phys­i­cal dis­tanc­ing and oth­er pub­lic health mea­sures.

    If only 20,000 par­tic­i­pants receive the vac­cine, seri­ous but rare side effects might be missed. If such harms even­tu­al­ly arise, it could fur­ther erode a frag­ile vac­cine con­fi­dence and threat­en the abil­i­ty to get enough peo­ple vac­ci­nat­ed to estab­lish herd immu­ni­ty. That would be a dis­as­ter.

    We were once in a sit­u­a­tion very sim­i­lar to the cur­rent one. Like Covid-19 today, polio in the 1950s was a hor­rif­ic dis­ease feared by every par­ent. Each sum­mer 1,500 chil­dren died and as many as 30,000 became par­a­lyzed for the rest of their lives. Jonas Salk pro­duced his vac­cine and test­ed it on 700 chil­dren in the Pitts­burgh area. It was safe and pro­duced anti­bod­ies. But proof that it was effec­tive at pre­vent­ing polio was demand­ed. A ran­dom­ized, con­trolled tri­al was required before the vac­cine would be licensed and dis­trib­uted. More than 400,000 chil­dren got the vac­cine and 200,000 got place­bo. Only after this effec­tive­ness tri­al was com­plet­ed was the Salk vac­cine licensed and all chil­dren final­ly pro­tect­ed from the dread­ed dis­ease.

    The F.D.A. must require more than the pro­duc­tion of anti­bod­ies to approve a vac­cine, even for an emer­gency autho­riza­tion, much less licens­ing. Only when the inde­pen­dent data safe­ty and mon­i­tor­ing board com­posed of physi­cians, researchers and bio­sta­tis­ti­cians reviews the accu­mu­lat­ed tri­al data to assess the safe­ty and effec­tive­ness of the vac­cines, should the F.D.A. be allowed to decide on approval.

    ...

    ———–

    “Could Trump Turn a Vac­cine Into a Cam­paign Stunt?” by Ezekiel J. Emanuel and Paul A. Offit; The New York Times; 06/08/2020

    “Giv­en how this pres­i­dent has behaved, this incred­i­bly dan­ger­ous sce­nario is not far-fetched. In a des­per­ate search for a polit­i­cal boost, he could release a coro­n­avirus vac­cine before it had been thor­ough­ly test­ed and shown to be safe and effec­tive.

    That’s the gener­ic sce­nario that seems all too plau­si­ble: In a des­per­ate search for a polit­i­cal boost, Trump basi­cal­ly pres­sures the FDA into approv­ing a vac­cine before the elec­tion. A sce­nario the vac­cine man­u­fac­tur­ers show no incli­na­tion to resist. As they note, Mod­er­na isn’t the only com­pa­ny talk­ing about deliv­er­ing a vac­cine before fall. Astra Zeneca has been mak­ing those kinds of bold pledges too:

    ...
    There are 123 can­di­date Covid-19 vac­cines in devel­op­ment, and 10 are in human tri­als. Many have not even been test­ed, or only per­func­to­ri­ly test­ed, in ani­mals. In July, the Nation­al Insti­tutes of Health is plan­ning to begin ran­dom­ized phase III tri­als to test whether some of the 10 vac­cines pre­vent infec­tion with coro­n­avirus. Some phar­ma­ceu­ti­cal com­pa­nies are plan­ning to start their own tri­als at about the same time. Astra Zeneca has already men­tioned it plans to begin deliv­ery of its vac­cine in Octo­ber.

    ...

    One high­ly unlike­ly pos­si­bil­i­ty is that recruit­ment of vol­un­teers in a coro­n­avirus “hot spot” would be so rapid that it would allow for an ade­quate assess­ment of the vaccine’s safe­ty and effec­tive­ness very quick­ly.

    There is anoth­er sce­nario that is far more omi­nous: Three months after the N.I.H. tri­als begin in July — so, mid Octo­ber — stud­ies reveal many patients are devel­op­ing high lev­els of anti­bod­ies to the coro­n­avirus with­out severe side effects. As the White House did with its relent­less pro­mo­tion of hydrox­y­chloro­quine as a cure, it would bad­ger the F.D.A. to per­mit use of the vac­cine. More pres­sure would come from drug com­pa­nies, some of whom may spend up to $1 bil­lion on research and are intense­ly com­pet­ing for pres­tige and glo­ry. They are plan­ning to begin man­u­fac­tur­ing their vac­cine can­di­dates at-risk — that is, before com­plet­ed stud­ies show­ing their vac­cine is actu­al­ly effec­tive.

    Cog­nizant of the fate of Rick Bright — the head of the Bio­med­ical Advanced Research and Devel­op­ment Author­i­ty, who was sum­mar­i­ly demot­ed when he resist­ed the president’s wish­es to ramp up pur­chase of hydrox­y­chloro­quine — the F.D.A. could issue an Emer­gency Use Autho­riza­tion for one or more vac­cines. These autho­riza­tions only require that the F.D.A. finds it “rea­son­able to believe” that a vac­cine “may be effec­tive” in pre­vent­ing a life-threat­en­ing dis­ease for it to be put on the mar­ket, with­out being for­mal­ly licensed.

    An emer­gency autho­riza­tion would allow Mr. Trump to hold his news con­fer­ence and declare vic­to­ry. But like Pres­i­dent George W. Bush’s “Mis­sion Accom­plished” procla­ma­tion, it has the poten­tial to be a trav­es­ty. Mil­lions of vac­cines could be dis­trib­uted with­out proof that the vac­cine can pre­vent dis­ease or trans­mis­sion.

    ...

    And note their warn­ings about the sam­ple sizes need­ed to detect rare side-effects and the impor­tance of find­ing those rare effects: Even if they’re rare and there­fore don’t impact a huge por­tion of the pop­u­lace, if we miss those rare effect and a bunch of peo­ple are harmed by these vac­cines that’s only going to erode already frag­ile pub­lic con­fi­dence in vac­cines in gen­er­al and fuel the anti-vaxxer crowd:

    ...
    Even if a vac­cine gen­er­ates anti­bod­ies, it does not prove that the vac­cine is effec­tive at pre­vent­ing infec­tion; it only makes it more like­ly that the vac­cine would be effec­tive. Indeed, about half of the vac­cines for oth­er dis­eases that work and are on the mar­ket actu­al­ly lack clear immuno­log­i­cal cor­re­lates for pro­tec­tion, mean­ing they are effec­tive but patients’ anti­bod­ies, immune cells or oth­er mark­ers do not iden­ti­fy whether a patient is pro­tect­ed. Even with the ini­tial tri­als, we are like­ly to have scant data on whether old­er peo­ple will mount an immune reac­tion and be pro­tect­ed.

    Giv­ing peo­ple a false sense of being pro­tect­ed will most like­ly lead to seri­ous out­breaks of the dis­ease as peo­ple reduce their com­pli­ance with phys­i­cal dis­tanc­ing and oth­er pub­lic health mea­sures.

    If only 20,000 par­tic­i­pants receive the vac­cine, seri­ous but rare side effects might be missed. If such harms even­tu­al­ly arise, it could fur­ther erode a frag­ile vac­cine con­fi­dence and threat­en the abil­i­ty to get enough peo­ple vac­ci­nat­ed to estab­lish herd immu­ni­ty. That would be a dis­as­ter.

    ...

    The F.D.A. must require more than the pro­duc­tion of anti­bod­ies to approve a vac­cine, even for an emer­gency autho­riza­tion, much less licens­ing. Only when the inde­pen­dent data safe­ty and mon­i­tor­ing board com­posed of physi­cians, researchers and bio­sta­tis­ti­cians reviews the accu­mu­lat­ed tri­al data to assess the safe­ty and effec­tive­ness of the vac­cines, should the F.D.A. be allowed to decide on approval.
    ...

    And that’s all why this ini­tial pre­lim­i­nary good news from Mod­er­na’s ani­mal stud­ies on the COVID vac­cine is poten­tial­ly bad news: when one of the biggest dan­gers is the pre­emp­tive abuse of pre­lim­i­nary good news by Trump good news becomes poten­tial­ly cat­a­stroph­ic news.

    So over­all, the good news is that Mod­er­na’s COVID vac­cine does­n’t appear to trig­ger ADE in lab rats with sub-pro­tec­tive immune respons­es. The bad news is that if this good news is used by Trump to push a pre­ma­ture release of the vac­cine before the human clin­i­cal tri­als are com­plet­ed it’s going to effec­tive­ly turn every­one who gets the vac­cine into a lab rat. It’s going to be a real­ly, real­ly, real­ly large human clin­i­cal safe­ty tri­al and every­one will be enrolled.

    Posted by Pterrafractyl | June 13, 2020, 1:21 pm
  2. Mod­er­na is launch­ing its Phase III coro­n­avirus vac­cine tri­al today with 30,000 peo­ple. This is the tri­al that’s going to deter­mine if the vac­cine actu­al­ly works in a mean­ing­ful way. If it works it will prob­a­bly be approved for wide­spread use so the stakes are quite high. Espe­cial­ly since, as we’ve seen, this Phase III tri­al is tak­ing place at the same time the Phase II safe­ty tri­als are still ongo­ing along with ani­mal safe­ty exper­i­ments.

    It’s that con­text that brings us to a STAT News arti­cle from last week that rec­om­mend­ed to mem­bers of the House Ener­gy and Com­merce Over­sight and Inves­ti­ga­tions Sub­com­mit­tee six burn­ing ques­tions they should ask for coro­n­avirus vac­cine man­u­fac­tur­ers dur­ing the com­mit­tee hear­ing that took place last Tues­day.

    Exec­u­tives from a num­ber of dif­fer­ent com­pa­nies rac­ing to devel­op a SARS-CoV­‑2 vac­cine appeared before the com­mit­tee to take ques­tions about their plans to both devel­op a safe vac­cine and mas­sive­ly scale up pro­duc­tion to make it avail­able to the pub­lic and there was one par­tic­u­lar rec­om­mend­ed ques­tion for the vac­cine man­u­fac­tur­ers that real­ly stood out in part because it’s so rarely asked amidst this unprece­dent­ed vac­cine race: so in 2005 the US passed a law that shields vac­cine and drug devel­op­ers from lia­bil­i­ty if a drug or vac­cine devel­oped in response to a health emer­gency caus­es injuries to the peo­ple who receive it. If that lia­bil­i­ty pro­tec­tion was not in place would these com­pa­nies be pur­su­ing this vac­cine? And per­haps more impor­tant­ly, since this is glob­al pan­dem­ic that needs to be addressed at a glob­al lev­el to tru­ly be fixed, will US vac­cine man­u­fac­tur­ers make the vac­cines they devel­op avail­able in coun­tries that don’t offer them the same lia­bil­i­ty shield?

    They’re the kinds of ques­tions that indi­rect­ly ask a ques­tion vac­cine and drug devel­op­ers undoubt­ed­ly have asked them­selves many times but would pre­fer not to answer in pub­lic: just how much are they rely­ing on this lia­bil­i­ty shield when mak­ing cost/benefit analy­ses involv­ing patient safe­ty. Keep in mind that Health and Human Ser­vices sec­re­tary Alex Azar announced back in March that the pan­dem­ic qual­i­fied as the kind of pub­lic health emer­gency that waived lia­bil­i­ty for vac­cine and drug devel­op­ers so this 2005 rule is cur­rent­ly in effect.

    And sure, the com­pa­nies would obvi­ous­ly pre­fer it if there are no neg­a­tive side-effects from their prod­ucts. But how much do they real­ly care if there are side-effects thanks to that lia­bil­i­ty shield? We’re talk­ing about prof­it-max­i­miz­ing enti­ties, after all.

    Plus, as we’ve already seen with Mod­er­na’s hunt for an COVID mRNA vac­cine, it’s not just a hunt for a vac­cine that can stop the virus. It’s also a hunt to estab­lish the safe­ty of mRNA tech­nol­o­gy in humans for the first time ever. An entire indus­try of new med­i­cine that rely on this mRNA ther­a­peu­tic approach but it’s nev­er actu­al­ly been estab­lished that this is safe and, as we’ve seen, the phar­ma­ceu­ti­cal indus­try has been try­ing and fail­ing to devel­op the tech­nol­o­gy with­out side-effects for years now. They just can’t avoid the side-effects thus far. So that makes this pan­dem­ic an incred­i­ble oppor­tu­ni­ty specif­i­cal­ly for mRNA vac­cine man­u­fac­tur­ers to get that untest­ed tech­nol­o­gy wide­ly rolled out to the pub­lic while avoid­ing lia­bil­i­ty if there are unfore­seen (or fore­seen and ignored) neg­a­tive side-effects. And that per­verse­ly could encour­age the mRNA vac­cine man­u­fac­tur­ers to take even greater risks with the pub­lic’s safe­ty because this is the kind of oppor­tu­ni­ty that could estab­lish mRNA tech­nol­o­gy as a safe and effec­tive plat­form that could be used for all sorts of oth­er prod­ucts but this pre­cious lia­bil­i­ty shield fades away as soon as a viable com­peti­tor vac­cine gets devel­oped.

    Unfor­tu­nate­ly, it does­n’t sound like these ques­tions were actu­al­ly asked dur­ing the hear­ing so these ques­tions remain urgent open burn­ing ques­tions:

    STAT News

    6 burn­ing ques­tions Con­gress could push Covid-19 vac­cine mak­ers to answer today

    By Dami­an Garde and Helen Bran­swell

    July 20, 2020

    Some drug com­pa­nies say we’ll have a coro­n­avirus vac­cine by the win­ter. Oth­ers say that’s an irre­spon­si­ble pre­dic­tion. Some promise to for­go prof­its on a vac­cine, but oth­ers believe they’re enti­tled to their mon­e­tary due.

    Now, law­mak­ers can force the indus­try to get its sto­ry straight. On Tues­day, exec­u­tives from five drug com­pa­nies lead­ing the vac­cine race are due at a con­gres­sion­al hear­ing to talk about their progress in devel­op­ing a prod­uct the entire world des­per­ate­ly needs. Rep­re­sen­ta­tives from AstraZeneca, John­son & John­son, Mer­ck, Mod­er­na, and Pfiz­er will appear in front of the House Ener­gy and Com­merce Over­sight and Inves­ti­ga­tions Sub­com­mit­tee.

    Peo­ple weary of the con­straints Covid-19 is plac­ing on lives are pin­ning a lot of hopes on the promis­es those com­pa­nies have made, par­tic­u­lar­ly when it comes to when a vac­cine might be ready. But there are still loom­ing ques­tions, from who will get a suc­cess­ful vac­cine first to how much it might cost.

    Here are six burn­ing ques­tions the pan­el could pose.
    0
    Can you tru­ly make Covid-19 vac­cines for wide­spread deploy­ment in the U.S. by Jan­u­ary 2021?

    Most of the man­u­fac­tur­ers in the hunt for Covid-19 vac­cines are mak­ing very bold promis­es about how quick­ly vac­cines will be ready to be deployed and how rapid­ly they’ll be able to pro­duce their vac­cines to the kind of scale need­ed to com­bat the pan­dem­ic. Many are promis­ing tens, even hun­dreds of mil­lions of dos­es by ear­ly 2021, and some even pre­dict they can scale to the bil­lion-dose range with­in the next cal­en­dar year.

    But in a recent inter­view with Har­vard pro­fes­sor Tsedal Nee­ley, Mer­ck CEO Ken Fra­zier warned that these pre­dict­ed time­lines are doing “a grave dis­ser­vice to the pub­lic.”

    For one thing, he said, vac­cine devel­op­ment takes time. The fastest vac­cine ever devel­oped before now was the mumps vac­cine, which took four years.

    Cut­ting cor­ners is a risky busi­ness, Fra­zier sug­gest­ed: “If you’re going to use a vac­cine in bil­lions of peo­ple, you bet­ter know what that vac­cine does.”

    Implied in the state­ment is the risk that any prob­lems that might arise from use of the vac­cines would throw fuel on the fire of the anti-vac­cine move­ment, which is already sow­ing doubts about the safe­ty of these fast-tracked Covid-19 vac­cines.

    Fra­zier also warned that giv­ing peo­ple the sense a vac­cine may be com­ing soon allows politi­cians to down­play oth­er tools that can sup­press spread of the dis­ease, such as “[wear­ing] the damn masks.”

    Will you com­mit to a price for your vac­cine?

    The most press­ing ques­tion fac­ing the drug indus­try is how soon it can come up with an effec­tive vac­cine. But right behind that is just how much it’ll cost. And the indus­try could answer now by com­mit­ting to a price before a vac­cine is approved.

    The U.S. gov­ern­ment has some lever­age for such a demand. With the excep­tion of Pfiz­er, each of the com­pa­nies at the table has received sub­stan­tial fed­er­al fund­ing to sup­port its vac­cine devel­op­ment. Through the government’s Oper­a­tion Warp Speed project, tax­pay­ers are on the line for more than $3 bil­lion in research sup­port, and the Nation­al Insti­tutes of Health is pick­ing up the tab for at least three mas­sive vac­cine stud­ies.

    So, what does the Amer­i­can pub­lic get in exchange? Some man­u­fac­tur­ers have promised to sell their vac­cines on a not-for-prof­it basis, at least for the extent of the pan­dem­ic. Oth­ers have not. Either way, it’s look­ing increas­ing­ly like­ly that the nov­el coro­n­avirus will not sim­ply van­ish once the cur­rent cri­sis sub­sides, mean­ing there will demand for vac­cines for years to come. If that’s the case, will com­pa­nies come to charge what­ev­er the mar­ket will bear? Or are they will­ing to make pric­ing com­mit­ments now?

    How are you going to release the data?

    Since the start of the cri­sis, news about vac­cine tri­als has made glob­al head­lines, moved mar­kets, and seeped into pol­i­tics. But the process of dis­sem­i­nat­ing that data has been incon­sis­tent. In May, Mod­er­na put out a press release with vague pos­i­tive lan­guage about its ear­ly-stage tri­al, frus­trat­ing experts who want­ed more. Pfiz­er chose to upload its data to a preprint serv­er, where sci­en­tif­ic papers are post­ed with­out peer review, while AstraZeneca is hold­ing out for pub­li­ca­tion in the Lancet.

    A work­ing vac­cine is key to restor­ing any­thing resem­bling nor­mal­cy, and the pub­lic is des­per­ate for infor­ma­tion on the process. But with­out stan­dard­iz­ing the cur­rent sys­tem, the pub­lic is left to parse press releas­es, rumors, and, worst of all, Twit­ter. Can the com­pa­nies devel­op­ing vac­cines estab­lish a sys­tem where­by the world gets clear, time­ly updates on their progress?

    Who’s going to get the vac­cine?

    The sec­ond a coro­n­avirus vac­cine proves to be safe and effec­tive, the entire world is going to be call­ing its man­u­fac­tur­er. The U.S. has already moved to secure mil­lions of future dos­es, and the Euro­pean Union is report­ed­ly nego­ti­at­ing to do the same, but what’s the plan for the world at large?

    Scal­ing up man­u­fac­tur­ing is a time-con­sum­ing process, mean­ing drug mak­ers will be deal­ing with a con­strained sup­ply in the months fol­low­ing a vaccine’s approval. Beyond the wealthy nations that are already lock­ing in bids, how can coun­tries in the devel­op­ing world ensure they get access?

    That may seem like a ques­tion beyond the scope of a House hear­ing, but the U.S. has a pub­lic health inter­est in vac­cines being wide­ly avail­able. With an econ­o­my deeply reliant on glob­al trade — and trav­el — the U.S. will be at risk of anoth­er Covid-19 out­break as long as the virus per­sists any­where in the world.

    How do lia­bil­i­ty pro­tec­tions fac­tor into your accel­er­at­ed time­line?

    Some man­u­fac­tur­ers are sug­gest­ing that there may be enough data to war­rant emer­gency use autho­riza­tions as soon as Octo­ber. If that hap­pens, vac­cines des­tined for use in poten­tial­ly bil­lions of peo­ple will be deployed after mere months of human test­ing.

    In the U.S., man­u­fac­tur­ers are shield­ed from lia­bil­i­ty if a vac­cine or drug devel­oped in response to a health emer­gency caus­es injuries to peo­ple who receive it. That pro­tec­tion comes from the Pub­lic Readi­ness and Emer­gency Pre­pared­ness Act of 2005.

    If that pro­tec­tion were not in place, would vac­cine man­u­fac­tur­ers be will­ing to roll out vac­cines on such a slight evi­dence base? Will they make them avail­able to coun­tries that don’t offer sim­i­lar pro­tec­tion against lia­bil­i­ty?

    Are you hav­ing prob­lems scal­ing up pro­duc­tion of your can­di­date vac­cines?

    The major man­u­fac­tur­ers are all mak­ing vac­cine “at-risk,” mean­ing they are already work­ing to pro­duce at com­mer­cial scale, even before they deter­mine whether their vac­cine can­di­date actu­al­ly works. The goal is to have large amounts avail­able for use as soon as the Food and Drug Admin­is­tra­tion green-lights a vac­cine. If some can­di­dates fail to clear the FDA’s bar, that prod­uct will be destroyed.

    ...

    ————-

    “6 burn­ing ques­tions Con­gress could push Covid-19 vac­cine mak­ers to answer today” by Dami­an Garde and Helen Bran­swell; STAT News; 07/20/2020

    Some man­u­fac­tur­ers are sug­gest­ing that there may be enough data to war­rant emer­gency use autho­riza­tions as soon as Octo­ber. If that hap­pens, vac­cines des­tined for use in poten­tial­ly bil­lions of peo­ple will be deployed after mere months of human test­ing.”

    Emer­gency use autho­riza­tions for these vac­cines could come as soon as Octo­ber accord­ing to some of the vac­cine man­u­fac­tur­ers. Keep in mind that emer­gency use autho­riza­tions imply the safe­ty stud­ies won’t have been com­plet­ed by that point. So the indus­try is clear­ly very keen on get­ting these vac­cines into peo­ple ASAP. But it’s the large-scale use of the vac­cine that could come lat­er where many of the rar­er side-effects would be expect­ed to man­i­fest and it’s at that point that the lia­bil­i­ty shield from the Pub­lic Readi­ness and Emer­gency Pre­pared­ness Act of 2005 becomes invalu­able for these com­pa­nies. So would these com­pa­nies still be pur­su­ing these vac­cines with­out the lia­bil­i­ty pro­tec­tion? And what about coun­tries with­out sim­i­lar lia­bil­i­ty pro­tec­tions? Are they going to be blocked from receiv­ing the vac­cine unless they extend the pro­tec­tions? These are the kinds of ques­tions that are going to become more and more impor­tant the clos­er we get to reach­ing a point where a vac­cine has been approved for large-scale use:

    ...
    In the U.S., man­u­fac­tur­ers are shield­ed from lia­bil­i­ty if a vac­cine or drug devel­oped in response to a health emer­gency caus­es injuries to peo­ple who receive it. That pro­tec­tion comes from the Pub­lic Readi­ness and Emer­gency Pre­pared­ness Act of 2005.

    If that pro­tec­tion were not in place, would vac­cine man­u­fac­tur­ers be will­ing to roll out vac­cines on such a slight evi­dence base? Will they make them avail­able to coun­tries that don’t offer sim­i­lar pro­tec­tion against lia­bil­i­ty?
    ...

    But these are also the of course the kinds of ques­tions that we would­n’t real­ly expect these com­pa­nies to hon­est­ly answer any­way. That’s why, while it’s kind of sad that these ques­tions did­n’t actu­al­ly get asked of the phar­ma­ceu­ti­cal exec­u­tives dur­ing the con­gres­sion­al hear­ing last week, it’s not like they were going to give mean­ing­ful answers any­way. They’re real­ly ques­tions con­gress and the pub­lic should be ask­ing itself. Espe­cial­ly before we all start inject­ing these vac­cines.

    It’s also worth keep­ing in mind anoth­er night­mar­ish sce­nario we could be lurch­ing towards: polls show around a third of Amer­i­cans won’t take the vac­cine even when it’s devel­oped, which to some extent reflects the deep anti-vac­cine skep­ti­cism that per­vades the US soci­ety, espe­cial­ly among right-wing vot­ers who have been bing­ing on Alex Jones-style far right con­spir­a­cy the­o­ries for the last decade (or, increas­ing­ly, just bing­ing on main­stream con­ser­v­a­tive media that has now main­streamed Alex Jones). Now imag­ine a sit­u­a­tion where a vac­cine does get rushed to the pub­lic and there are real­ly are wide­spread side-effects. That expe­ri­ence is going to cre­ate the kind of anti-vaxxer sen­ti­ment and gen­er­al dis­trust of sci­ence in this soci­ety that could last gen­er­a­tions, espe­cial­ly if the man­u­fac­tur­ers man­age make a wild prof­it and escape lia­bil­i­ties at the same time. In oth­er words, if Oper­a­tion Warp Speed moves too fast and peo­ple get hurt while investors remain untouched it could end up warp­ing the US pub­lic’s abil­i­ty to trust pub­lic health experts — by trans­lat­ing legit­i­mate con­cerns about the for-prof­it nature of the US’s econ­o­my into gener­ic con­cerns about the safe­ty of vac­cines — with all sorts of con­se­quences dur­ing future pan­demics.

    So that’s all some­thing that’s going to be increas­ing­ly impor­tant to keep in mind as we get clos­er and clos­er to rolling out a vac­cine: It’s gen­er­al­ly assumed that phar­ma­ceu­ti­cal com­pa­nies won’t know­ing­ly release a prod­uct they don’t know is safe due to con­cerns about pos­si­ble legal lia­bil­i­ties but those lia­bil­i­ties don’t exist in this case. Big gam­bles can be tak­en with mas­sive upsides and min­i­mal down­sides. At least min­i­mal down­sides for the investors.

    Posted by Pterrafractyl | July 27, 2020, 3:34 pm
  3. Now that Pres­i­dent Trump has made sab­o­tag­ing the US Postal Sys­tem — as a jus­ti­fi­ca­tion for not deploy­ing uni­ver­sal mail-in vot­ing in response to the coro­n­avirus pan­dem­ic — a key plank in his 2020 reelec­tion plat­form, it’s worth not­ing how this scan­dal could poten­tial­ly become inter­twined with anoth­er major elec­tion-relat­ed sto­ry: the race to devel­op a coro­n­avirus vac­cine as soon as pos­si­ble.

    How could the sab­o­tage of the US Postal Sys­tem relate to the vac­cine hunt? Well, imag­ine that a vac­cine gets declared to be safe and effec­tive by the US gov­ern­ment before elec­tion day. Let’s say a few weeks before the elec­tion. And let’s say there are around 100 mil­lion dos­es avail­able, which would­n’t be enough for every Amer­i­can but could still poten­tial­ly cov­er a large num­ber of the most vul­ner­a­ble peo­ple. How would a vac­cine announce­ment impact the ongo­ing GOP demands that mail-in vot­ing be restrict­ed as much as pos­si­ble? It’s the kind of ques­tion Democ­rats should prob­a­bly be ask­ing them­selves right because we can be sure the Trump team has been ask­ing them­selves sim­i­lar ques­tions and it’s the Trump team, with its con­trol over the Oper­a­tion Warp Speed project, that will have the pow­er to make such a vac­cine readi­ness dec­la­ra­tion. And that, of course, makes all of the con­cerns and crit­i­cisms over how Oper­a­tion Warp Speed is being man­aged all the more con­cern­ing.

    So with those grow­ing con­cerns about the verac­i­ty of the Oper­a­tion Warp Speed vac­cine devel­op­ment process in mind, here’s anoth­er reminder that those con­cerns over Oper­a­tion Warp Speed haven’t gone away. Crit­ics are still point­ing out that the group con­tin­ues to lack trans­paren­cy, includ­ing trans­paren­cy over the results from the var­i­ous vac­cine clin­i­cal tri­als under­way.

    There’s also new con­cerns over the pro­posed pric­ing of the poten­tial vac­cines and whether or not the project is being turned into a Gold­en Goose for con­nect­ed insid­ers. For exam­ple, we’re learn­ing that AstraZeneca has already pledged to deliv­ery 300 mil­lion dos­es to the US at a cost of around $4/dose. Mod­er­na, on the oth­er hand, has already received $1 bil­lion in gov­ern­ment fund­ing and secured a con­tract with the US gov­ern­ment to deliv­er 100 mil­lion dos­es for anoth­er $1.5 bil­lion, bring­ing it to a cost of around $25/dose paid by US tax-pay­ers, putting Mod­er­na’s vac­cine at the high end of the cost/dose for the vac­cines that Oper­a­tion Warp Speed is work­ing on. Why the price dif­fer­ence, espe­cial­ly giv­en that Mod­er­na has already received over $1 bil­lion from the US gov­ern­ment to help devel­op its vac­cine? Well, the head of Oper­a­tion Warp Speed, Mon­cef Slaoui, did­n’t address the spe­cif­ic con­cerns about Mod­er­na but instead made gen­er­al assur­ances that the pub­lic is get­ting a good deal no mat­ter what as long as it gets a work­ing vac­cine. The fact that Slaoui was for­mer­ly the chair­man of Moderna’s prod­uct devel­op­ment com­mit­tee does­n’t exact­ly help with those pric­ing con­cerns.

    But there’s one aspect of Mod­er­na’s vac­cine that makes its vac­cine par­tic­u­lar­ly impor­tant to keep an eye on in the con­text of this sit­u­a­tion where a pre-elec­tion vac­cine announce­ment could be used as an excuse to thwart mail-in vot­ing: recall that part of what makes Mod­er­na’s vac­cine con­tro­ver­sial is that it relies on mRNA deliv­ery tech­nol­o­gy that has­n’t been approved for safe using in humans before. But there’s one mas­sive advan­tage to mRNA vac­cines over more tra­di­tion­al vac­cine in that they are rel­a­tive­ly cheap and easy to pro­duce so rapid large-scale pro­duc­tion of the mRNA vac­cine is tech­no­log­i­cal­ly con­ceiv­able. It’s the kind of sit­u­a­tion that’s going to poten­tial­ly make the Trump team even more keen on get­ting approval for Mod­er­na’s vac­cine as soon as pos­si­ble. Because the soon­er the Mod­er­na vac­cine is declared safe and ready to use, the soon­er the Trump team can declare that actu­al­ly mail-in vot­ing isn’t need­ed any­more than any­one con­cerned about vot­ing in the pan­dem­ic can just go and get the vac­cine:

    Bloomberg
    Opin­ion

    Covid-19 Vac­cine Push Lacks a Key Ingre­di­ent: Trust

    Oper­a­tion Warp Speed is pur­su­ing a wor­thy goal, but it still oper­ates in the shad­ows.

    By Tim­o­thy L. O’Brien and Max Nisen
    August 17, 2020, 6:00 AM CDT

    In the war against the coro­n­avirus, only one weapon has the poten­tial to ease the con­flict quick­ly: a vac­cine. With about 164,000 Amer­i­cans dead from Covid-19, the econ­o­my bat­tered and com­mu­ni­ties forced into recur­ring lock­downs, the fed­er­al gov­ern­ment has made a $10 bil­lion wager that pub­lic funds and exper­tise wed­ded to pri­vate research and pro­duc­tion can jump-start a vaccine’s arrival — pos­si­bly by ear­ly next year.

    Oper­a­tion Warp Speed, launched in April, is admin­is­tered by the Depart­ment of Health and Human Ser­vices, the Bio­med­ical Advance Research and Devel­op­ment Author­i­ty, and the Depart­ment of Defense, along with sev­er­al oth­er fed­er­al agen­cies. A hand­ful of phar­ma­ceu­ti­cal com­pa­nies, includ­ing AstraZeneca Plc, Glax­o­SmithK­line Plc, John­son & John­son, Mod­er­na Inc., Novavax Inc., Pfiz­er Inc. and Sanofi SA, have received the lion’s share of the fed­er­al fund­ing.

    The com­pa­nies are spend­ing those bil­lions on vac­cine devel­op­ment and clin­i­cal tri­als, as well as the cost of man­u­fac­tur­ing and deliv­er­ing a suc­cess­ful can­di­date to the gov­ern­ment. Com­pa­nies aren’t required to repay the mon­ey, and the gov­ern­ment is get­ting no equi­ty stake or prof­it par­tic­i­pa­tion in return for the tax­pay­er dol­lars. But the com­pa­nies have com­mit­ted to deliv­er­ing hun­dreds of mil­lions of dos­es of their vac­cines direct­ly to the gov­ern­ment, which promis­es free inoc­u­la­tions for Amer­i­cans.

    There’s like­ly to be plen­ty of wreck­age along the way. Many com­pa­nies may not be able to engi­neer a vac­cine, much less deliv­er one, and bil­lions of dol­lars will go down the drain. It’s a cal­cu­lat­ed risk worth tak­ing, as long as it speeds an effec­tive vac­cine to mar­ket. Drug com­pa­nies nor­mal­ly devel­op drugs slow­ly in order to min­i­mize pricey fail­ures. A cush­ion of fed­er­al fund­ing allows Big Phar­ma to begin man­u­fac­tur­ing pos­si­bly mon­ey-los­ing drugs even while tri­als are under­way, com­press­ing years of work into months.

    Warp Speed’s upside — sav­ing lives — is well worth any mon­ey that may get lost. But the pro­gram also has been shroud­ed in secre­cy. The gov­ern­ment has good rea­sons to keep some parts of the pro­gram under wraps, par­tic­u­lar­ly nego­ti­a­tions that could affect the stock prices of com­pa­nies mak­ing bids. But the process for decid­ing which com­pa­nies were tapped to par­tic­i­pate in the pub­lic health equiv­a­lent of the Man­hat­tan Project has been entire­ly too opaque. And that lack of trans­paren­cy is also like­ly to make the pub­lic — the folks who will have to line up for inoc­u­la­tions — skep­ti­cal that the gov­ern­ment has ensured that we wind up with an effec­tive, safe vac­cine.

    Two of the men over­see­ing Warp Speed, Mon­cef Slaoui and Gary Dis­brow, say they aren’t cut­ting any cor­ners around test­ing or safe­ty pro­to­cols before a vac­cine is released into the wild, but time is of the essence.

    “If we were to wait to scale up man­u­fac­tur­ing until we had results of Phase 3 clin­i­cal tri­als, we would be look­ing at a six- to eight-month delay before we even start­ed man­u­fac­tur­ing,” says Dis­brow, who has worked for Bar­da since 2007 and is now the agency’s act­ing direc­tor. “The finan­cial bur­den for lives lost and the finan­cial bur­den to our over­all econ­o­my for not allow­ing our peo­ple to go back to a some­what nor­mal rou­tine is much greater than the finan­cial bur­den that we’re assum­ing in devel­op­ing these vac­cines.”

    Slaoui is a well-regard­ed, Moroc­can-born research sci­en­tist who spent three decades at Glax­o­SmithK­line, most recent­ly as head of the drug giant’s vac­cines depart­ment, before he retired in 2017. He also served on sev­er­al cor­po­rate boards of direc­tors, includ­ing Moderna’s, before Pres­i­dent Don­ald Trump’s admin­is­tra­tion appoint­ed him as Warp Speed’s chief advis­er in May.

    “As I took the role com­ing from indus­try, I had a few hes­i­ta­tions, con­cerns that I may get myself into some kind of a mov­ing sand and bureau­cra­cy,” he says. “And it’s just in the reverse. It’s incred­i­ble. I think the lev­el of focus and align­ment and empow­er­ment and lack of inter­fer­ence — it’s just per­fect. And I think as an exec­u­tive team we’re run­ning at a thou­sand miles an hour.”

    Slaoui also has lit­tle patience for crit­ics of Warp Speed’s struc­ture or goals: “Many, many experts are say­ing, ‘Why, this has nev­er been done,’ and ‘Why, it’s impos­si­ble to do.’ I would like to ask them: Please, can you take 10% of your time and help us try to make it work? … Of course its very dif­fi­cult. Of course it could fail.”

    That doesn’t address one of the most per­ti­nent crit­i­cisms: that Warp Speed’s con­tracts and spend­ing aren’t trans­par­ent. The House Select Com­mit­tee on the Coro­n­avirus Cri­sis has just called for Warp Speed offi­cials to pro­vide more infor­ma­tion on its oper­a­tions.

    In a recent Sen­ate hear­ing, leg­is­la­tors grilled Dis­brow, along with Robert Red­field, direc­tor of the Cen­ters for Dis­ease Con­trol and Pre­ven­tion, and Fran­cis Collins, direc­tor of the Nation­al Insti­tutes of Health, about how the oper­a­tion is being run.

    “The admin­is­tra­tion still has not pro­vid­ed any expla­na­tion of how it is select­ing vac­cine can­di­dates, what the risks are of nar­row­ing down that short­list or addressed con­cerns about poten­tial con­flicts in con­tracts that pre­date this cri­sis,” Sen­a­tor Pat­ty Mur­ray, a Demo­c­rat from Wash­ing­ton state, observed dur­ing the hear­ing.

    The Warp Speed lead­ers declined to offer specifics to sen­a­tors on which com­pa­nies were can­di­dates or how the selec­tion process works. Dis­brow not­ed that Bar­da has been mak­ing Warp Speed invest­ments pub­lic as soon as the agency believes it’s appro­pri­ate to do so. (The full list can be found here.) Collins said his agency con­vened a pan­el of experts who reviewed 50 Covid-19 vac­cine can­di­dates before the list was win­nowed down.

    All three men told the sen­a­tors that they hadn’t come under pres­sure from the White House or any­one else in gov­ern­ment to select par­tic­u­lar Warp Speed par­tic­i­pants or to expe­dite the deliv­ery of a vac­cine to improve Pres­i­dent Trump’s re-elec­tion prospects.

    But polit­i­cal con­tro­ver­sy has haunt­ed every dis­cus­sion of Warp Speed and its time­line for deliv­er­ing a vac­cine. And for good rea­son. Trump has fre­quent­ly high­light­ed the pos­si­bil­i­ty that a vac­cine will arrive much soon­er than experts and Warp Speed’s own lead­ers pre­dict, and he has forced agen­cies such as the CDC and the Food and Drug Admin­is­tra­tion — both part of the Warp Speed effort — to bend to his will or fol­low his lead on med­ical­ly dubi­ous ini­tia­tives.

    Slaoui says a vac­cine could be avail­able by the end of the year for some at-risk indi­vid­u­als, but that would require emer­gency approval from the FDA. Stephen Hahn, the FDA com­mis­sion­er, has said his agency will main­tain high stan­dards in its approval process, but Trump has also made his pref­er­ences clear. That could put pres­sure on Hahn, an inex­pe­ri­enced com­mis­sion­er who already flip-flopped on grant­i­ng emer­gency autho­riza­tion for the use of hydrox­y­chloro­quine, a con­tro­ver­sial and inef­fec­tive drug favored by the pres­i­dent.

    Mem­bers of the med­ical com­mu­ni­ty have also raised red flags about Warp Speed’s opaque selec­tion process. They con­tend that some com­pa­nies appeared to have been select­ed because they could man­u­fac­ture a vac­cine quick­ly, not because they demon­strat­ed the most promis­ing sci­en­tif­ic approach­es. “It’s typ­i­cal Oper­a­tion Warp Speed, where every­thing is sort of cryp­tic and it’s unclear what they’re actu­al­ly say­ing,” Peter Hotez, a vac­cine researcher at Bay­lor Col­lege of Med­i­cine, told Sci­ence Mag­a­zine in June. “What have these vac­cines been cho­sen to do?”

    Slaoui and Dis­brow say trans­paren­cy is a pri­or­i­ty but that they’re nego­ti­at­ing with pub­licly trad­ed com­pa­nies and have to be cir­cum­spect about dis­clo­sure to avoid mov­ing their stock prices. They say they will soon dis­close exten­sive data from tri­als the com­pa­nies have con­duct­ed.

    “We intend to pub­lish it in a way that does not inter­fere with the qual­i­ty and out­come of the clin­i­cal tri­als,” Slaoui says. “That would be the only lim­i­ta­tion I can think of: Would this under­mine the qual­i­ty of the work?”

    “We have to be trans­par­ent,” he adds. “We have to be account­able, of course, of course. Don’t assume that some­thing Machi­avel­lian is hap­pen­ing. … Some­thing beau­ti­ful is hap­pen­ing, which is we’re get­ting our act togeth­er to help human­i­ty.”

    Because the Trump admin­is­tra­tion hired Slaoui as a con­sul­tant rather than as an employ­ee, he isn’t required to dis­close his finan­cial hold­ings or adhere to fed­er­al ethics guide­lines. Crit­ics say this could allow him to ben­e­fit finan­cial­ly from Warp Speed.

    Slaoui dis­closed that he sold his Mod­er­na shares, worth at least $10 mil­lion, when he joined Warp Speed — and for­feit­ed options that were worth about $4.2 mil­lion. He still holds about $10 mil­lion of Glax­o­SmithK­line shares; he says he relies on div­i­dend pay­ments to fund his retire­ment. He has promised to make a char­i­ta­ble dona­tion based on any appre­ci­a­tion in the price of those shares dur­ing his time with Warp Speed.

    HHS says it has reviewed Slaoui’s finances and busi­ness rela­tion­ships and doesn’t believe there are finan­cial con­flicts that would pre­vent him from doing his job prop­er­ly. Dis­brow point­ed out that Slaoui has no pow­er to award Warp Speed con­tracts and that indi­vid­ual con­tracts are man­aged by oth­er gov­ern­ment employ­ees. While Slaoui says he under­stands and respects the need for the scruti­ny his finances have received, he also feels his hon­esty has been unfair­ly put into play. “The ques­tion is asked in a way that assumes that I’m a thief,” he says. “Doing this to enrich my for­mer col­leagues or myself. I dis­agree with that state­ment.”

    Dis­brow says that pub­lic ser­vice, not enrich­ment, is what drew him and his col­leagues to Warp Speed. “I’ve worked in the gov­ern­ment now for 14 years. This is an unprece­dent­ed col­lab­o­ra­tion,” he says. “We’re doing this for the Amer­i­can peo­ple and for the world. I mean, I know that may sound like a cliche, but we all have friends and fam­i­ly mem­bers who poten­tial­ly could be impact­ed by this, so our No. 1 goal is to devel­op a safe and effec­tive vac­cine.”

    Warp Speed award­ed con­tracts after com­pa­nies applied through an open solic­i­ta­tion process run by Bar­da and the Depart­ment of Defense (Gus­tave Per­na, a four-star U.S. Army gen­er­al, is Warp Speed’s chief oper­at­ing offi­cer). Dis­brow says that experts across the fed­er­al gov­ern­ment, includ­ing con­tract­ing offi­cers, reviewed all of the pro­pos­als and finan­cial awards.

    John Shiv­er, the head of vac­cine research and devel­op­ment at Sanofi, a Warp Speed par­tic­i­pant, describes the process as involved. “There is a for­mal appli­ca­tion process and a fair­ly detailed plan in the appli­ca­tion on the tech­ni­cal aspects,” he says. “How it’s made, how it’s char­ac­ter­ized, data that evolves, data pre­clin­i­cal­ly and in devel­op­ment, ani­mal immuno­genic­i­ty, are all pro­vid­ed in great detail as well as data on man­u­fac­tur­ing and the dos­es we can pro­vide.”

    Slaoui says speed was a pri­or­i­ty in what he describes as a well-defined selec­tion strat­e­gy, but it wasn’t the only one. Warp Speed want­ed to fund a broad array of vac­cine research and man­u­fac­tur­ing in order to avoid focus­ing on a sin­gle approach, ensure abun­dant sup­ply and hedge against pos­si­ble fail­ures. “Our first pri­or­i­ty was, and con­tin­ues to be, we must be able to have vac­cines that are safe and effec­tive, and we must have enough dos­es of vac­cines as quick­ly as pos­si­ble,” he says.

    The gov­ern­ment is fund­ing two cut­ting-edge shots from Mod­er­na and Pfiz­er that use mes­sen­ger RNA or mRNA, mol­e­cules that car­ry genet­ic instruc­tions, to turn cells into tiny vac­cine fac­to­ries that gen­er­ate antivi­ral pro­tec­tion. These shots are eas­i­er to make than oth­er options and have raced into clin­i­cal tri­als, but reg­u­la­tors haven’t pre­vi­ous­ly approved such a vac­cine.

    Warp Speed is also fund­ing more proven approach­es. Sanofi’s effort relies on chunks of fac­to­ry-grown virus pro­tein made with the same process used for one of its suc­cess­ful flu vac­cines. This vac­cine is to be paired with a boost­er made by Glax­o­SmithK­line that could make it more effec­tive and eas­i­er to pro­duce in large vol­umes. Novavax is using a sim­i­lar method.

    In the mid­dle of the range between brand-new and tried-and-true approach­es are can­di­dates from AstraZeneca and John­son & John­son. Both drug­mak­ers are using a harm­less virus to deliv­er mate­r­i­al that helps the immune sys­tem rec­og­nize the nov­el coro­n­avirus. There is no broad­ly used vac­cine of this type on the mar­ket, but the approach has more human test­ing behind it than mRNA does. John­son & John­son hopes that its vac­cine will work with just one shot, in con­trast to the two-dose reg­i­men required by oth­er final­ists.

    Hav­ing already secured 800 mil­lion poten­tial dos­es of six shots, Warp Speed plans to fund at least two more unspec­i­fied vac­cines that would pro­tect against the virus in yet anoth­er way.

    Each Warp Speed par­tic­i­pant has a bespoke deal with the gov­ern­ment based on how well-devel­oped its vac­cine is, how much fund­ing it needs to com­plete tri­als, and the scope of its man­u­fac­tur­ing demands.

    Pric­ing is also a piv­otal issue. Warp Speed com­pa­nies are, for the most part, huge­ly prof­itable enter­pris­es that charge Amer­i­cans the high­est drug prices in the world. With the gov­ern­ment absorb­ing much of the finan­cial risk these com­pa­nies usu­al­ly point to as jus­ti­fi­ca­tion for lofty prices, the expec­ta­tion is that any vac­cine that emerges from Warp Speed should come with a rock-bot­tom price. Although the vac­cines will be free to the pub­lic, the ulti­mate cost to tax­pay­ers is still impor­tant.

    AstraZeneca, which has pledged to for­go prof­its from any vac­cines it sells dur­ing the pan­dem­ic, plans to deliv­er 300 mil­lion dos­es to the gov­ern­ment in exchange for $1.2 bil­lion in total fund­ing — about $4 a dose.

    Mod­er­na has received near­ly $1 bil­lion and is slat­ed to get as much as $1.525 bil­lion more if it can deliv­er 100 mil­lion dos­es — about $25 per dose.

    Dis­brow argues that Warp Speed isn’t pay­ing only for shots. The ini­tial $1 bil­lion for Mod­er­na, for exam­ple, was a one-time pay­ment to fund clin­i­cal tri­als and fac­to­ries. Amer­i­cans will ben­e­fit if this helps speed a vac­cine to mar­ket, and the spend­ing could pay off over time if Mod­er­na pro­duces addi­tion­al dos­es. (The com­pa­ny will get less fed­er­al mon­ey if it doesn’t get an approval by Jan. 31.) Even so, Moderna’s pro­posed pric­ing has been espe­cial­ly con­tro­ver­sial, and not only because it’s rel­a­tive­ly high. Tax­pay­ers have been help­ing finance Moderna’s vac­cine research since long before Warp Speed came along. The NIH, as Axios and Pub­lic Cit­i­zen have report­ed, has been such a sig­nif­i­cant backer of Mod­er­na that it may own a stake in the intel­lec­tu­al prop­er­ty under­gird­ing the company’s coro­n­avirus vac­cine.

    In that con­text, it’s rea­son­able to expect Mod­er­na to set a low­er price.

    Rep­re­sen­ta­tive Lloyd Doggett, a Texas Demo­c­rat who is a fre­quent crit­ic of high drug prices and heads a pow­er­ful House sub­com­mit­tee that deals with health-care fund­ing, is not a fan of Warp Speed’s Mod­er­na deal. “For Mod­er­na, the first bil­lion was just not enough,” he wrote in a pub­lic state­ment about the con­tract. “After Amer­i­can tax­pay­ers gave it over $1 bil­lion to devel­op, test and man­u­fac­ture a vac­cine, Mod­er­na offers us the priv­i­lege of pur­chas­ing that same vac­cine we already paid for with anoth­er $1.525 bil­lion and an option to pay even more for addi­tion­al dos­es.”

    While not address­ing Moderna’s deal specif­i­cal­ly, Slaoui argues that the gov­ern­ment is get­ting a sol­id return on its Warp Speed invest­ments because vac­cine recip­i­ents will ulti­mate­ly get a low-cost treat­ment.

    Warp Speed’s con­tracts are clear­ly prefer­able to pos­si­ble alter­na­tives, he says: research delays and dose costs clos­er to the $100-plus prices of some vac­cines. With­out Warp Speed’s deals, the U.S. might have had to com­pete with oth­er coun­tries for a lim­it­ed sup­ply of vac­cines — boost­ing prices even fur­ther and delay­ing inoc­u­la­tions.

    Also unre­solved, and poten­tial­ly trou­bling, is the way in which vac­cines will be priced after Warp Speed com­pa­nies deliv­er their first batch of treat­ments. If Covid-19 flares up sea­son­al­ly and ini­tial vac­cine pro­tec­tions fade, boost­er shots may become expen­sive. Pfiz­er and Mod­er­na have both indi­cat­ed that they might charge high­er prices for their vac­cines post-pan­dem­ic.

    Slaoui con­cedes that future prices for a vac­cine are like­ly to go up.

    Warp Speed isn’t per­fect. A bid­ding process or pub­lic auc­tion for con­tracts might have saved tax­pay­ers’ mon­ey. Join­ing forces with oth­er coun­tries could have allowed for more sub­stan­tial invest­ments in new vac­cines and helped ensure more equal dis­tri­b­u­tion of vac­cines world­wide.

    Nev­er­the­less, cre­at­ing a coro­n­avirus vac­cine is cru­cial. Years of under­in­vest­ment in pub­lic health and cor­po­rate pref­er­ences for pricey drugs over oth­er med­ical neces­si­ties have left vac­cine research in a state of neglect. Now, with a pan­dem­ic rav­aging the coun­try, the only option is to gam­ble on tech­nol­o­gy.

    In years ahead, it will be “unsus­tain­able” for coun­tries to rely on stop­gap pro­grams like Warp Speed, Slaoui says. In a world where pan­demics hap­pen again and again, he says, gov­ern­ments will need “ded­i­cat­ed orga­ni­za­tions” that spe­cial­ize in devel­op­ing vac­cines.

    To be sure, those orga­ni­za­tions already exist — the NIH, for exam­ple, and foun­da­tions such as the Coali­tion for Epi­dem­ic Pre­pared­ness. Unfor­tu­nate­ly, these insti­tu­tions aren’t fund­ed or empow­ered at the lev­el required to meet a Covid-sized cri­sis.

    ...

    ————-

    “Covid-19 Vac­cine Push Lacks a Key Ingre­di­ent: Trust” by Tim­o­thy L. O’Brien and Max Nisen; Bloomberg; 08/17/2020

    “Warp Speed’s upside — sav­ing lives — is well worth any mon­ey that may get lost. But the pro­gram also has been shroud­ed in secre­cy. The gov­ern­ment has good rea­sons to keep some parts of the pro­gram under wraps, par­tic­u­lar­ly nego­ti­a­tions that could affect the stock prices of com­pa­nies mak­ing bids. But the process for decid­ing which com­pa­nies were tapped to par­tic­i­pate in the pub­lic health equiv­a­lent of the Man­hat­tan Project has been entire­ly too opaque. And that lack of trans­paren­cy is also like­ly to make the pub­lic — the folks who will have to line up for inoc­u­la­tions — skep­ti­cal that the gov­ern­ment has ensured that we wind up with an effec­tive, safe vac­cine.

    As we can see, the ear­ly crit­i­cisms over Oper­a­tion Warp Speed’s lack of trans­paren­cy haven’t been resolved. It’s still opaque. Even to mem­bers of Con­gress appar­ent­ly:

    ...
    Slaoui also has lit­tle patience for crit­ics of Warp Speed’s struc­ture or goals: “Many, many experts are say­ing, ‘Why, this has nev­er been done,’ and ‘Why, it’s impos­si­ble to do.’ I would like to ask them: Please, can you take 10% of your time and help us try to make it work? … Of course its very dif­fi­cult. Of course it could fail.”

    That doesn’t address one of the most per­ti­nent crit­i­cisms: that Warp Speed’s con­tracts and spend­ing aren’t trans­par­ent. The House Select Com­mit­tee on the Coro­n­avirus Cri­sis has just called for Warp Speed offi­cials to pro­vide more infor­ma­tion on its oper­a­tions.

    In a recent Sen­ate hear­ing, leg­is­la­tors grilled Dis­brow, along with Robert Red­field, direc­tor of the Cen­ters for Dis­ease Con­trol and Pre­ven­tion, and Fran­cis Collins, direc­tor of the Nation­al Insti­tutes of Health, about how the oper­a­tion is being run.

    “The admin­is­tra­tion still has not pro­vid­ed any expla­na­tion of how it is select­ing vac­cine can­di­dates, what the risks are of nar­row­ing down that short­list or addressed con­cerns about poten­tial con­flicts in con­tracts that pre­date this cri­sis,” Sen­a­tor Pat­ty Mur­ray, a Demo­c­rat from Wash­ing­ton state, observed dur­ing the hear­ing.

    The Warp Speed lead­ers declined to offer specifics to sen­a­tors on which com­pa­nies were can­di­dates or how the selec­tion process works. Dis­brow not­ed that Bar­da has been mak­ing Warp Speed invest­ments pub­lic as soon as the agency believes it’s appro­pri­ate to do so. (The full list can be found here.) Collins said his agency con­vened a pan­el of experts who reviewed 50 Covid-19 vac­cine can­di­dates before the list was win­nowed down.
    ...

    Then there are con­cerns that the com­pa­nies select­ed to par­tic­i­pate in Oper­a­tion Warp Speed were select­ed not because they had the most sci­en­tif­i­cal­ly promis­ing approach but instead because they appeared to be able to man­u­fac­ture a vac­cine quick­ly. And when it comes to quick vac­cine man­u­fac­tur­ing it’s the mRNA-based vac­cines like Mod­er­na’s that lead the pack. The prob­lem is mRNA vac­cines haven’t actu­al­ly been approved before:

    ...
    Slaoui says a vac­cine could be avail­able by the end of the year for some at-risk indi­vid­u­als, but that would require emer­gency approval from the FDA. Stephen Hahn, the FDA com­mis­sion­er, has said his agency will main­tain high stan­dards in its approval process, but Trump has also made his pref­er­ences clear. That could put pres­sure on Hahn, an inex­pe­ri­enced com­mis­sion­er who already flip-flopped on grant­i­ng emer­gency autho­riza­tion for the use of hydrox­y­chloro­quine, a con­tro­ver­sial and inef­fec­tive drug favored by the pres­i­dent.

    Mem­bers of the med­ical com­mu­ni­ty have also raised red flags about Warp Speed’s opaque selec­tion process. They con­tend that some com­pa­nies appeared to have been select­ed because they could man­u­fac­ture a vac­cine quick­ly, not because they demon­strat­ed the most promis­ing sci­en­tif­ic approach­es. “It’s typ­i­cal Oper­a­tion Warp Speed, where every­thing is sort of cryp­tic and it’s unclear what they’re actu­al­ly say­ing,” Peter Hotez, a vac­cine researcher at Bay­lor Col­lege of Med­i­cine, told Sci­ence Mag­a­zine in June. “What have these vac­cines been cho­sen to do?”

    ...

    The gov­ern­ment is fund­ing two cut­ting-edge shots from Mod­er­na and Pfiz­er that use mes­sen­ger RNA or mRNA, mol­e­cules that car­ry genet­ic instruc­tions, to turn cells into tiny vac­cine fac­to­ries that gen­er­ate antivi­ral pro­tec­tion. These shots are eas­i­er to make than oth­er options and have raced into clin­i­cal tri­als, but reg­u­la­tors haven’t pre­vi­ous­ly approved such a vac­cine.
    ...

    And then there’s the fact that Mod­er­na appears to be get­ting kind of a sweet­heart deal in terms of the pric­ing of vac­cine com­pared to the oth­er vac­cine devel­op­ers. With a gov­ern­ment con­tract of $1.5 bil­lion for 100 mil­lion dos­es ($15/dose) on top of the $1 bil­lion the gov­ern­ment already gave to Mod­er­na, that’s com­ing out to around $25/dose for those 100 mil­lion dos­es. And yet AstraZeneca — which is rely­ing on a less risky tech­nol­o­gy for its vac­cine — signed a deal that comes out to around $4/dose. Why the extra high price for a vac­cine with unproven safe­ty and mas­sive gov­ern­ment invest­ments? Well, Slaoui — the for­mer chair­man of Moderna’s prod­uct devel­op­ment com­mit­tee — gives us a gen­er­al assur­ance that the deal could be worse com­pared to oth­er hypo­thet­i­cal deals and if the US had­n’t cre­at­ed Oper­a­tion Warp Speed it could have been forced to buy anoth­er coun­try’s vac­cine at a much high­er price with lim­it­ed sup­ply. That was his answer to ques­tions about why the US gov­ern­ment is pay­ing such a high price for a vac­cine it paid to devel­oped: that if the US did­n’t do this it might end up pay­ing an even high­er price buy­ing the vac­cine from some­one else:

    ...
    Pric­ing is also a piv­otal issue. Warp Speed com­pa­nies are, for the most part, huge­ly prof­itable enter­pris­es that charge Amer­i­cans the high­est drug prices in the world. With the gov­ern­ment absorb­ing much of the finan­cial risk these com­pa­nies usu­al­ly point to as jus­ti­fi­ca­tion for lofty prices, the expec­ta­tion is that any vac­cine that emerges from Warp Speed should come with a rock-bot­tom price. Although the vac­cines will be free to the pub­lic, the ulti­mate cost to tax­pay­ers is still impor­tant.

    AstraZeneca, which has pledged to for­go prof­its from any vac­cines it sells dur­ing the pan­dem­ic, plans to deliv­er 300 mil­lion dos­es to the gov­ern­ment in exchange for $1.2 bil­lion in total fund­ing — about $4 a dose.

    Mod­er­na has received near­ly $1 bil­lion and is slat­ed to get as much as $1.525 bil­lion more if it can deliv­er 100 mil­lion dos­es — about $25 per dose.

    Dis­brow argues that Warp Speed isn’t pay­ing only for shots. The ini­tial $1 bil­lion for Mod­er­na, for exam­ple, was a one-time pay­ment to fund clin­i­cal tri­als and fac­to­ries. Amer­i­cans will ben­e­fit if this helps speed a vac­cine to mar­ket, and the spend­ing could pay off over time if Mod­er­na pro­duces addi­tion­al dos­es. (The com­pa­ny will get less fed­er­al mon­ey if it doesn’t get an approval by Jan. 31.) Even so, Moderna’s pro­posed pric­ing has been espe­cial­ly con­tro­ver­sial, and not only because it’s rel­a­tive­ly high. Tax­pay­ers have been help­ing finance Moderna’s vac­cine research since long before Warp Speed came along. The NIH, as Axios and Pub­lic Cit­i­zen have report­ed, has been such a sig­nif­i­cant backer of Mod­er­na that it may own a stake in the intel­lec­tu­al prop­er­ty under­gird­ing the company’s coro­n­avirus vac­cine.

    In that con­text, it’s rea­son­able to expect Mod­er­na to set a low­er price.

    ...

    While not address­ing Moderna’s deal specif­i­cal­ly, Slaoui argues that the gov­ern­ment is get­ting a sol­id return on its Warp Speed invest­ments because vac­cine recip­i­ents will ulti­mate­ly get a low-cost treat­ment.

    Warp Speed’s con­tracts are clear­ly prefer­able to pos­si­ble alter­na­tives, he says: research delays and dose costs clos­er to the $100-plus prices of some vac­cines. With­out Warp Speed’s deals, the U.S. might have had to com­pete with oth­er coun­tries for a lim­it­ed sup­ply of vac­cines — boost­ing prices even fur­ther and delay­ing inoc­u­la­tions.
    ...

    And that’s how Mon­cef Slaoui answered ques­tions posed to him about Oper­a­tion Warp Speed: with non-answer deflec­tions.

    So as we get clos­er and clos­er to the elec­tion in the midst of this Post Sys­tem sab­o­tage sce­nario it’s going to be extra grim­ly inter­est­ing to watch how the var­i­ous clin­i­cal tri­als involv­ing Oper­a­tion Warp Speed vac­cines plays out, espe­cial­ly giv­en the appar­ent lack of trans­paren­cy even for health experts. If the Trump admin­is­tra­tion is going to use a vac­cine announce­ment as an excuse to min­i­mize mail-in vot­ing that announce­ment is prob­a­bly going to have to hap­pen at least by ear­ly Octo­ber.

    Now here’s anoth­er sto­ry that reveals a new area of con­cern over the vac­cine clin­i­cal tri­als. In par­tic­u­lar Mod­er­na’s big Phase III clin­i­cal tri­al that’s cur­rent­ly under­way: despite the fact that over half othe patients hos­pi­tal­ized for the coro­n­avirus in the US have been black and lati­no these groups only account for 15 per­cent of the clin­i­cal tri­al par­tic­i­pants. Keep in mind that the black and lati­no pop­u­la­tion play a dis­pro­por­tion­ate role in the kinds of “essen­tial” ser­vice jobs — like food ser­vices — that can’t be done remote­ly and instead puts them reg­u­lar con­tact with the pub­lic and makes them the most like­ly to be exposed. That is pre­cise­ly the demo­graph­ic you want to use for your vac­cine tri­al while wide­spread social-dis­tanc­ing is being deployed pre­cise­ly because these front-line work­ers will almost cer­tain­ly be exposed to the virus and are the most like­ly to get sick. As the fol­low­ing arti­cle notes, by sys­tem­at­i­cal­ly exclud­ing from the clin­i­cal tri­als the very pop­u­la­tion that is most like­ly to get sick it’s pos­si­ble the vac­cine’s roll out will have to be delayed. Would the Trump admin­is­tra­tion allow for a delay in the vac­cine roll­out due to a lack of minori­ties in the clin­i­cal tri­al? Keep in mind that by dis­pro­por­tion­ate­ly include whites in the clin­i­cal tri­al the vac­cine is get­ting extra-safe test­ing in the white pop­u­la­tion. Might the admin­is­tra­tion instead approve the vac­cine for whites only? Will we have a sce­nario where white peo­ple are told they can safe­ly get the vac­cine before the elec­tion while non-whites should abstain?:

    CNN

    First Covid-19 vac­cine tri­al mov­ing at a good clip, but offi­cials still “very con­cerned”

    By Eliz­a­beth Cohen, CNN Senior Med­ical Cor­re­spon­dent
    Updat­ed 4:50 PM ET, Tue August 18, 2020

    (CNN)The first coro­n­avirus vac­cine tri­al in the US is mov­ing along at a good clip, but needs more minori­ties to enroll if it is to suc­ceed, offi­cials tell CNN.

    While Black peo­ple and Lati­nos account for more than 50% of Covid-19 cas­es nation­wide, so far they make up only about 15% of par­tic­i­pants in the nation’s first large-scale clin­i­cal tri­al to test out a coro­n­avirus vac­cine, accord­ing to data obtained by CNN from a gov­ern­ment offi­cial.

    That could poten­tial­ly delay a vac­cine from get­ting to the mar­ket­place.

    Mod­er­na, the first com­pa­ny in the US to con­duct a Phase 3 clin­i­cal tri­al, is aim­ing to enroll 30,000 vol­un­teers. In the first three weeks, it already recruit­ed 8,374, accord­ing to an email obtained by CNN from the com­pa­ny to its researchers.

    While that’s an impres­sive num­ber, offi­cials at Oper­a­tion Warp Speed, the gov­ern­men­t’s ini­tia­tive to deliv­er 300 mil­lion dos­es of a coro­n­avirus vac­cine by Jan­u­ary, are “very con­cerned” about the low per­cent­age of minori­ties in the tri­al, accord­ing to Dr. Nel­son Michael, direc­tor of the Cen­ter for Infec­tious Dis­eases Research at Wal­ter Reed Army Insti­tute of Research, who has been assigned to work with Oper­a­tion Warp Speed.

    Chop­py Waters

    Michael reviewed Mod­er­na’s enroll­ment data and shared the minor­i­ty per­cent­ages with CNN.

    “There’s a lot of dis­cus­sion now about how Mod­er­na can change the direc­tion of their ship so they can opti­mize the enroll­ment of key pop­u­la­tions,” Michael said.

    Mod­er­na is on track to fin­ish enrolling its 30,000 par­tic­i­pants by mid to late Sep­tem­ber. But if they can’t increase the num­ber of minori­ties, the pan­el of experts over­see­ing the tri­al could tell Mod­er­na they need to take the time to recruit more par­tic­i­pants from minor­i­ty groups.

    “The Data Safe­ty Mon­i­tor­ing Board could slow the tri­al down,” Michael said.

    ...

    Mod­er­na has con­tract­ed with 89 sites around the US to con­duct its Phase 3 clin­i­cal tri­al. Researchers at two of those sites tell CNN that the com­pa­ny has asked them to lim­it the num­ber of par­tic­i­pants they enroll to no more than 20 per day.

    Part of the rea­son is so that care can be tak­en to recruit more minori­ties, they said.

    “We need to take the time to eval­u­ate the peo­ple who want to be in study to make sure they meet inclu­sion cri­te­ria,” said Dr. Richard Novak, who’s run­ning the site at the Uni­ver­si­ty of Illi­nois at Chica­go.

    Dr. Carl Ficht­en­baum, the prin­ci­pal inves­ti­ga­tor at the Uni­ver­si­ty of Cincin­nati, echoed the sen­ti­ment. “We want the right peo­ple in this tri­al, and that can take time,” he said.

    Recruit­ing the right peo­ple

    There are two major rea­sons why vac­cine tri­als need to include more minori­ties.

    Fed­er­al law and Nation­al Insti­tutes of Health pol­i­cy man­date inclu­sion of minori­ties into clin­i­cal tri­als because vac­cines and drugs might have a dif­fer­ent effect on them than they do on White peo­ple. Ide­al­ly, vac­cine tri­al par­tic­i­pants should reflect the pop­u­la­tion that’s affect­ed by the dis­ease to deter­mine the vac­cine’s effi­ca­cy and safe­ty in those groups.

    Blacks and Lati­nos make up more than half of all coro­n­avirus cas­es, accord­ing to a study by the US Cen­ters for Dis­ease Con­trol and Pre­ven­tion.

    Black peo­ple rep­re­sent 22% of coro­n­avirus cas­es, but only 4.5% of Mod­er­na’s study par­tic­i­pants. Lati­nos rep­re­sent 33% of cas­es, but only 10% of Mod­er­na’s par­tic­i­pants.

    The oth­er rea­son it’s impor­tant to include sub­stan­tial num­bers of minori­ties is that in order for the study to suc­ceed, a sig­nif­i­cant num­ber of vol­un­teers need to be at high-risk for becom­ing infect­ed and sick with Covid-19 in the first place.

    If those who vol­un­teer for a coro­n­avirus vac­cine tri­al get their shots and then stay at home, at the end of the study they may very well test neg­a­tive for the virus, not nec­es­sar­i­ly because the vac­cine worked, but because they nev­er encoun­tered the virus in the first place.

    So in any vac­cine study, includ­ing this one, researchers seek out study sub­jects who are most like­ly to come in con­tact with the virus in their dai­ly lives.

    That includes health care work­ers, for exam­ple, and also minori­ties, who are more like­ly to have essen­tial jobs that require in-per­son work, and more like­ly to live in multi­gen­er­a­tional, mul­ti­fam­i­ly house­holds, among oth­er fac­tors.

    Eas­i­er said than done

    Minori­ties have often refrained from join­ing med­ical stud­ies for sev­er­al rea­sons. For exam­ple, med­ical insti­tu­tions his­tor­i­cal­ly have per­formed dan­ger­ous exper­i­ments on minori­ties with­out the study sub­jects’ knowl­edge or con­sent, and even now deep racial injus­tices and dis­par­i­ties still exist in health­care.

    That’s led gov­ern­ment agen­cies to reach out to minor­i­ty groups to encour­age par­tic­i­pa­tion in this and oth­er coro­n­avirus tri­als.

    “There is a tremen­dous amount of pres­sure on this now. I’ve nev­er seen com­mu­ni­ty engage­ment get this lev­el of play. Not even close. Ever,” Michael said.

    In an ear­li­er state­ment for a pre­vi­ous sto­ry, a Mod­er­na spokesman said the com­pa­ny’s 89 tri­al sites are “active­ly work­ing with their local com­mu­ni­ties to reach a diverse pop­u­la­tion of vol­un­teers.”

    The spokesman, Ray Jor­dan, added that “we hope to achieve a shared goal that the par­tic­i­pants in the [Covid-19 vac­cine] study are rep­re­sen­ta­tive of the com­mu­ni­ties at high­est risk for COVID-19 and of our diverse soci­ety.”

    He said recent­ly Mod­er­na has recent­ly tak­en “sig­nif­i­cant action” to recruit minori­ties to their study.

    “They are very active­ly seek­ing solu­tions so they don’t wind up with a cohort that is too young, too low risk, and frankly too White,” Michael said. “I think this issue is get­ting the atten­tion it needs and got­ten it very quick­ly,” Michael said.

    But so far the effort has­n’t been very suc­cess­ful.

    A Mod­er­na inves­ti­ga­tor recent­ly reached out to Renee Mahaf­fey Har­ris, pres­i­dent of The Cen­ter for Clos­ing the Health Gap in Cincin­nati, ask­ing for help in recruit­ing minori­ties into the tri­al. She still has not met with the researcher, nor has she put infor­ma­tion about the tri­als on Covid19communityresources.com, a web­site run by her group, the Nation­al Asso­ci­a­tion for the Advance­ment of Col­ored Peo­ple, and oth­er orga­ni­za­tions.

    “When we Black peo­ple hear ‘clin­i­cal tri­als,’ we think ‘We’re not going to be researched on’ — and that’s across eco­nom­ic sta­tus and across edu­ca­tion­al sta­tus, not just one sec­tor,” Har­ris said.

    ————-

    “First Covid-19 vac­cine tri­al mov­ing at a good clip, but offi­cials still “very con­cerned”” by Eliz­a­beth Cohen; CNN; 08/18/2020

    “Black peo­ple rep­re­sent 22% of coro­n­avirus cas­es, but only 4.5% of Mod­er­na’s study par­tic­i­pants. Lati­nos rep­re­sent 33% of cas­es, but only 10% of Mod­er­na’s par­tic­i­pants.”

    As we can see, Mod­er­na’s phase III clin­i­cal tri­als, which are sup­posed to be large scale enough to assess the safe­ty and effi­ca­cy of the vac­cine for final approval, aren’t large scale enough when it comes to blacks and Lati­nos. And that could, in the­o­ry, result in gov­ern­ment agen­cies like the CDC telling Mod­er­na they need to con­tin­ue their tri­als. At least assum­ing the Trump admin­is­tra­tion allows such a delay to hap­pen:

    ...
    That could poten­tial­ly delay a vac­cine from get­ting to the mar­ket­place.

    Mod­er­na, the first com­pa­ny in the US to con­duct a Phase 3 clin­i­cal tri­al, is aim­ing to enroll 30,000 vol­un­teers. In the first three weeks, it already recruit­ed 8,374, accord­ing to an email obtained by CNN from the com­pa­ny to its researchers.

    While that’s an impres­sive num­ber, offi­cials at Oper­a­tion Warp Speed, the gov­ern­men­t’s ini­tia­tive to deliv­er 300 mil­lion dos­es of a coro­n­avirus vac­cine by Jan­u­ary, are “very con­cerned” about the low per­cent­age of minori­ties in the tri­al, accord­ing to Dr. Nel­son Michael, direc­tor of the Cen­ter for Infec­tious Dis­eases Research at Wal­ter Reed Army Insti­tute of Research, who has been assigned to work with Oper­a­tion Warp Speed.

    ...

    Mod­er­na is on track to fin­ish enrolling its 30,000 par­tic­i­pants by mid to late Sep­tem­ber. But if they can’t increase the num­ber of minori­ties, the pan­el of experts over­see­ing the tri­al could tell Mod­er­na they need to take the time to recruit more par­tic­i­pants from minor­i­ty groups.

    “The Data Safe­ty Mon­i­tor­ing Board could slow the tri­al down,” Michael said.
    ...

    And then there’s the fact that by under­sam­pling minor­i­ty groups the clin­i­cal tri­als are effec­tive­ly under­sam­pling the part of the US pop­u­lace that’s most like­ly to actu­al­ly be exposed to the virus. So this is poten­tial­ly screw­ing up the abil­i­ty to mean­ing­ful­ly inter­pret the results of the clin­i­cal tri­als for all groups:

    ...
    The oth­er rea­son it’s impor­tant to include sub­stan­tial num­bers of minori­ties is that in order for the study to suc­ceed, a sig­nif­i­cant num­ber of vol­un­teers need to be at high-risk for becom­ing infect­ed and sick with Covid-19 in the first place.

    If those who vol­un­teer for a coro­n­avirus vac­cine tri­al get their shots and then stay at home, at the end of the study they may very well test neg­a­tive for the virus, not nec­es­sar­i­ly because the vac­cine worked, but because they nev­er encoun­tered the virus in the first place.

    So in any vac­cine study, includ­ing this one, researchers seek out study sub­jects who are most like­ly to come in con­tact with the virus in their dai­ly lives.

    That includes health care work­ers, for exam­ple, and also minori­ties, who are more like­ly to have essen­tial jobs that require in-per­son work, and more like­ly to live in multi­gen­er­a­tional, mul­ti­fam­i­ly house­holds, among oth­er fac­tors.
    ...

    Is Mod­er­na going to ade­quate find enough minor­i­ty par­tic­i­pants for its tri­al? Hope­ful­ly, but if not that’s going to poten­tial­ly cre­ate a very awk­ward sit­u­a­tion if the phase III results indi­cate the vac­cine is safe and effec­tive for use. It’s one of the many ques­tions swirling around Oper­a­tion Warp Speed as we get clos­er and clos­er to the elec­tion. Ques­tions that now include whether or not the Trump admin­is­tra­tion is going to try to use a vac­cine announce­ment as a rea­son to con­tin­ue block­ing mail-in vot­ing. And ques­tions of whether or not hav­ing a ‘approved-for-whites-only’ vac­cine is exact­ly what the Trump admin­is­tra­tion prefers. At a min­i­mum such a vac­cine would be very on-brand for Trump’s reelec­tion cam­paign.

    Posted by Pterrafractyl | August 19, 2020, 2:33 pm
  4. Here’s an arti­cle about the ongo­ing clin­i­cal tri­als of Mod­er­na’s COVID-19 vac­cine and con­cerns over the inher­ent weak­ness­es in how those clin­i­cal tri­als were struc­tured. First, recall the con­cerns over the sig­nif­i­cant lack of non-white par­tic­i­pants in Mod­er­na’s large-scale phase III clin­i­cal tri­al that recent­ly got under­way. Next, recall the intrigu­ing find­ing that the T‑cells gen­er­at­ed by expo­sure to com­mon cold coro­n­avirus­es have demon­strat­ed an abil­i­ty to fight off SARS-CoV­‑2 which is an excit­ing find­ing but also present a poten­tial com­pli­ca­tion when assess­ing the effec­tive­ness of vac­cines because pre­ex­ist­ing T‑cells may be a con­found­ing fac­tor in deter­min­ing whether or not the vac­cine trig­gers the pro­duc­tion of T‑cells. Also recall the stud­ies that found obe­si­ty appears to com­pli­cate the effec­tive­ness of vac­cines, a prob­lem that could be par­tic­u­lar­ly acute in the US but also in the elder­ly in gen­er­al. Next, recall how the Phase III clin­i­cal tri­als are get­ting under­way at the same time the Phase II tri­als — which are intend­ed to assess longer-term safe­ty con­cerns — aren’t going to be com­plet­ed until next year. Final­ly, recall how when Mod­er­na ini­tial­ly released ear­ly results from its Phase I tri­als — a release that hap­pened to trig­ger a Mod­er­na stock surge — tout­ing how it dis­cov­ered the vac­cine trig­gered the pro­duc­tion of neu­tral­iz­ing anti­bod­ies, it was data based on only 8 indi­vid­u­als in a tri­al of 45 peo­ple and all we were told about the demo­graph­ics of those 8 peo­ple was that they were aged 18–55, leav­ing open the ques­tion of how effec­tive the vac­cine is in the elder­ly adults.

    Well, Mod­er­na just released more results from its Phase I clin­i­cal tri­al and this time it’s results for their elder­ly test set. Mod­er­na char­ac­ter­izes the results as “promis­ing”. Each per­son got two 100 micro­gram vac­cine dos­es 28 days apart and all devel­oped neu­tral­iz­ing anti­bod­ies and T‑cells. There were also no major side effects report­ed. Some report­ed fatigue, chills, headaches and pain at the injec­tion site, but the major­i­ty of symp­toms resolved with­in two days. Over­all, that sounds like good news.

    But of course there’s a catch: these results are based on 20 peo­ple in total. 10 indi­vid­u­als aged 56–70 were in one group and anoth­er 10 indi­vid­u­als aged 71 and old­er were in the sec­ond group. That’s it. From a sta­tis­ti­cal stand­point it’s not exact­ly a large sam­ple that should lend con­fi­dence to the results, espe­cial­ly since the elder­ly is tar­get pop­u­la­tion for this vac­cine. Giv­en the wild range of health com­pli­ca­tions the elder­ly expe­ri­ence it’s vir­tu­al­ly impos­si­ble they could have explored all of the var­i­ous sub­groups (i.e. peo­ple suf­fer­ing from obe­si­ty, dia­betes, heart com­pli­ca­tions, etc). And giv­en the dif­fi­cul­ties Mod­er­na has had in get­ting non-white par­tic­i­pants for their Phase III tri­als we can also be pret­ty con­fi­dent that this tiny the cohort prob­a­bly was­n’t very demo­graph­i­cal­ly diverse, although no infor­ma­tion on the race or the par­tic­i­pants was released.

    Now, in fair­ness to Mod­er­na, they prob­a­bly should­n’t be test­ing their vac­cine on large num­bers of elder­ly in a Phase I tri­al since one of the main pur­pos­es of the Phase I tri­al is estab­lish­ing safe para­me­ters for con­duct­ing the larg­er Phase II and Phase III tri­als. So we can’t real­ly blame Mod­er­na for hav­ing a tiny sam­ple size. The prob­lems from the tiny sam­ple size are instead relat­ed to the extreme­ly rushed nature of this whole vac­cine devel­op­ment process and the temp­ta­tion to read too much into these sta­tis­ti­cal­ly ques­tion­able results. For exam­ple, is the elder­ly cohort used for this tiny tri­al that found min­i­mal side-effects going to be mean­ing­ful­ly rep­re­sen­ta­tive of the safe­ty of this vac­cine for the much larg­er Phase III tri­als? Were the 10 peo­ple over the age of 70 rel­a­tive­ly healthy indi­vid­u­als for their age? If so, are the much larg­er num­ber par­tic­i­pants over age 70 in the Phase III tri­al also just going to be rel­a­tive­ly healthy too? Will patients with typ­i­cal elder­ly comor­bidi­ties like obe­si­ty, heart dis­ease or dia­betes also going to be includ­ed in the Phase III tri­al? If so, we prob­a­bly should­n’t be sur­prised if there are a num­ber of sur­prise side-effects for that group. And if not, then the Phase III tri­al won’t real­ly be reflect­ing a true safe­ty assess­ment for lit­er­al­ly the tar­get demo­graph­ic for the vac­cine. These are exam­ples of the high­ly pre­car­i­ous nature of a rushed vaccine...especially when it involves mRNA tech­nol­o­gy that’s nev­er been approved for use before.

    So, over­all, the news out of Mod­er­na’s tri­al could be worse. They could have found that none of the par­tic­i­pants gen­er­at­ed anti­bod­ies and instead just got nasty side-effects but that’s now what they found. But thanks to the extreme­ly tiny size of this cohort it’s still an open ques­tion as to whether or not these rel­a­tive­ly pos­i­tive results actu­al­ly apply to the group of peo­ple who need the vac­cine the most:

    CNBC

    Mod­er­na says its coro­n­avirus vac­cine shows promis­ing results in small tri­al of elder­ly patients

    * The vac­cine was test­ed on 10 adults between the ages of 56 and 70 and 10 elder­ly adults aged 71 and old­er, Mod­er­na said.
    * Each par­tic­i­pant received two 100 micro­gram dos­es of the vac­cine 28 days apart.
    * The vac­cine pro­duced neu­tral­iz­ing anti­bod­ies, which researchers believe are nec­es­sary to build immu­ni­ty to the virus, and T‑cells, Mod­er­na said.

    Berke­ley Lovelace Jr.
    Pub­lished Wed, Aug 26 2020 10:40 AM EDT
    Updat­ed Wed, Aug 26 2020 2:12 PM EDT

    Moderna’s poten­tial coro­n­avirus vac­cine gen­er­at­ed a promis­ing immune response in elder­ly patients in an ear­ly stage clin­i­cal tri­al, the biotech firm announced Wednes­day.

    The com­pa­ny test­ed its vac­cine on 10 adults between the ages of 56 and 70 and 10 elder­ly adults aged 71 and old­er, Mod­er­na said. Each par­tic­i­pant received two 100 micro­gram dos­es of the vac­cine 28 days apart.

    The vol­un­teers pro­duced neu­tral­iz­ing anti­bod­ies, which researchers believe are nec­es­sary to build immu­ni­ty to the virus, and T‑cells, Mod­er­na said in its results, which have not yet been pub­lished in a peer-reviewed jour­nal. Addi­tion­al­ly, the anti­bod­ies that were pro­duced were high­er than those seen in peo­ple who have recov­ered from Covid-19.

    The vac­cine also appeared to be well tol­er­at­ed, with no seri­ous adverse events report­ed, the com­pa­ny said. Some patients report­ed fatigue, chills, headaches and pain at the injec­tion site, though the major­i­ty of symp­toms resolved with­in two days, the com­pa­ny said.

    Shares of Mod­er­na were up near­ly 6% in intra­day trad­ing Wednes­day. The com­pa­ny will hold a con­fer­ence call at 4:30 p.m. ET to dis­cuss the results.

    ...

    U.S. health offi­cials say there is no return­ing to “nor­mal” until there is a vac­cine.

    Moderna’s exper­i­men­tal vac­cine con­tains genet­ic mate­r­i­al called mes­sen­ger RNA, or mRNA, which sci­en­tists hope pro­vokes the immune sys­tem to fight the virus. In May, the com­pa­ny released pre­lim­i­nary data that showed the vac­cine pro­duced anti­bod­ies in 45 healthy adults.

    Sci­en­tists had pre­vi­ous­ly cau­tioned that the phase one study was small, and the results may dif­fer for oth­er pop­u­la­tions, includ­ing the elder­ly who gen­er­al­ly mount a weak­er immune response. The new data Wednes­day will like­ly boost hopes that there could be a safe and effec­tive vac­cine to pre­vent Covid-19 by the end of the year or ear­ly 2021.

    Last month, the com­pa­ny start­ed a phase three tri­al test­ing how safe and effec­tive it is on 30,000 peo­ple with results expect­ed as ear­ly as Octo­ber. The com­pa­ny said it antic­i­pates com­plet­ing enroll­ment for its phase three tri­al in Sep­tem­ber.

    Mod­er­na is charg­ing between $32 and $37 per dose for its coro­n­avirus vac­cine for some cus­tomers, under cheap­er “pan­dem­ic pric­ing,” it said ear­li­er this month. At the time, the com­pa­ny said it was in dis­cus­sion for larg­er vol­ume agree­ments that will have a low­er price.

    Ear­li­er this month, Pres­i­dent Don­ald Trump announced the U.S. gov­ern­ment would pur­chase 100 mil­lion dos­es of Moderna’s vac­cine in a deal worth $1.53 bil­lion. The U.S. has already invest­ed $955 mil­lion in Moderna’s vac­cine devel­op­ment, bring­ing its total invest­ment up to near­ly $2.5 bil­lion.

    While there is hope sci­en­tists will find a safe and effec­tive vac­cine, there is nev­er a guar­an­tee, sci­en­tists say. They warn that ques­tions remain about how the human body responds once it’s been infect­ed with the virus.

    One ques­tion among sci­en­tists is whether anti­bod­ies pro­duced in response to Covid-19 offer pro­tec­tion against get­ting infect­ed again.

    Sci­en­tists expect that anti­bod­ies pro­vide some degree of pro­tec­tion against get­ting Covid-19, but they can’t say that defin­i­tive­ly yet since the coro­n­avirus was first dis­cov­ered less than eight months ago. Hong Kong researchers on Mon­day report­ed what appears to be the first con­firmed case of Covid-19 rein­fec­tion, a man who was first infect­ed by the virus in late March and then, 4½ months lat­er, seem­ing­ly con­tract­ed the virus again.

    ————–

    “Mod­er­na says its coro­n­avirus vac­cine shows promis­ing results in small tri­al of elder­ly patients” by Berke­ley Lovelace Jr.; CNBC; 08/26/2020

    Sci­en­tists had pre­vi­ous­ly cau­tioned that the phase one study was small, and the results may dif­fer for oth­er pop­u­la­tions, includ­ing the elder­ly who gen­er­al­ly mount a weak­er immune response. The new data Wednes­day will like­ly boost hopes that there could be a safe and effec­tive vac­cine to pre­vent Covid-19 by the end of the year or ear­ly 2021.”

    Yes, sci­en­tists had pre­vi­ous­ly warned that the ear­li­er Phase I results was too small and may not be rep­re­sen­ta­tive of how the vac­cine will react in oth­er groups like the elder­ly. So now that Mod­er­na has released rel­a­tive­ly pos­i­tive results from an extreme­ly tiny cohort of the elder­ly hopes are up that a vac­cine could be avail­able by the end of the year despite the fact that a 10 per­son cohort of peo­ple over the age of 70 could­n’t pos­si­ble be rep­re­sen­ta­tive of the full range of peo­ple in that demo­graph­ic, both from a race/ethnicity stand­point but also from a health com­pli­ca­tion stand­point. After all, when it comes to health com­pli­ca­tions you aren’t going to find a more diverse group than the elder­ly.

    But, again, the results could be worse. They could have found no anti­body or T‑cell pro­duc­tion and lots of side-effects on this tiny cohort but that’s not what they found. The vol­un­teers gen­er­at­ed neu­tral­iz­ing anti­bod­ies and T‑cells. As the arti­cle notes, we just recent­ly had the first con­firmed case of some­one catch­ing COVID-19 again after recov­ery months ear­li­er so the gen­er­a­tion of those T‑cell is a cru­cial find­ing since T‑cells are what pro­vide the longer-term immu­ni­ty after the anti­bod­ies fade:

    ...
    The vol­un­teers pro­duced neu­tral­iz­ing anti­bod­ies, which researchers believe are nec­es­sary to build immu­ni­ty to the virus, and T‑cells, Mod­er­na said in its results, which have not yet been pub­lished in a peer-reviewed jour­nal. Addi­tion­al­ly, the anti­bod­ies that were pro­duced were high­er than those seen in peo­ple who have recov­ered from Covid-19.

    The vac­cine also appeared to be well tol­er­at­ed, with no seri­ous adverse events report­ed, the com­pa­ny said. Some patients report­ed fatigue, chills, headaches and pain at the injec­tion site, though the major­i­ty of symp­toms resolved with­in two days, the com­pa­ny said.

    ..

    One ques­tion among sci­en­tists is whether anti­bod­ies pro­duced in response to Covid-19 offer pro­tec­tion against get­ting infect­ed again.

    Sci­en­tists expect that anti­bod­ies pro­vide some degree of pro­tec­tion against get­ting Covid-19, but they can’t say that defin­i­tive­ly yet since the coro­n­avirus was first dis­cov­ered less than eight months ago. Hong Kong researchers on Mon­day report­ed what appears to be the first con­firmed case of Covid-19 rein­fec­tion, a man who was first infect­ed by the virus in late March and then, 4½ months lat­er, seem­ing­ly con­tract­ed the virus again.
    ...

    But that T‑cell find­ing rais­es the ques­tion: Are we sure these are T‑cells gen­er­at­ed by the vac­cine or might these be pre­ex­ist­ing T‑cells that were already present from past expo­sure to com­mon-cold coro­nar­avirus­es? At this point we don’t know because those details of the study aren’t yet pub­licly avail­able.

    And that’s all why these reports of pos­si­ble good news from the vac­cine tri­als are pos­si­ble going to be bad news in the long run. These bits of good news would be great if these vac­cines were being devel­oped under a nor­mal vac­cine devel­op­ment sched­ule that takes years. But that’s not our cir­cum­stance. Instead, we’re going to be forced to essen­tial­ly make edu­cat­ed guess­es about the safe­ty and effi­ca­cy of these vac­cines based on incom­plete or inad­e­quate clin­i­cal tri­als.

    There’s the old say­ing about prod­uct devel­op­ment: Good/Cheap/Fast. Pick two. But it’s going to be impor­tant to keep in mind that when it comes to rushed vac­cine devel­op­ment, the “Good/Fast” option isn’t real­ly available...unless it’s part of a “Good/Fast/Lucky” com­bo.

    Posted by Pterrafractyl | August 28, 2020, 1:39 pm
  5. Oh look at that: it turns out Mod­er­na did­n’t dis­close its bil­lions of dol­lars in sub­si­dies pro­vid­ed by the US gov­ern­ment for devel­op­ing a COVID-19 vac­cine when the com­pa­ny applied for its vac­cine patents. No men­tion at all. That was the find­ing of an NGO, Knowl­edge Ecol­o­gy Inter­na­tion­al, that exam­ined over a dozen of Mod­er­na’s patent appli­ca­tions relat­ed to the vac­cine. The group is argu­ing that these fed­er­al sub­si­dies should be dis­closed not only due to basic trans­paren­cy con­cerns but also because Mod­er­na has yet to pledge to make a vac­cine wide­ly avail­able for cheap.

    The group cites one par­tic­u­lar patent for a coro­n­avirus vac­cine that Mod­er­na filed in Feb­ru­ary of this year call the “Beta­coro­n­avirus mRNA vac­cine”. The vac­cine appears to be based on the work Mod­er­na had pre­vi­ous­ly done on a Mid­dle East res­pi­ra­to­ry syn­drome (MERS) vac­cine. As the fol­low­ing STAT News arti­cle notes, this patent cites two Mod­er­na researchers as the inven­tors and while both of them men­tion in pub­lished aca­d­e­m­ic papers that they were work­ing under DARPA awards there’s no men­tion of this in the patent appli­ca­tion.

    Inter­est­ing­ly, the patent describes it as a vac­cine for the entire fam­i­ly of known Beta­coro­n­avirus­es like SARS-CoV (the orig­i­nal SARS), MERS, and the ‘com­mon cold’ coro­n­avirus­es. But there’s no men­tion in the patent of the SARS-CoV­‑2 virus that was already caus­ing a pan­dem­ic at the time of the fil­ing. So that’s pret­ty inter­est­ing: in Feb­ru­ary of this year Mod­er­na filed for a patent for a gener­ic Beta­coro­n­avirus vac­cine and in the patent they sug­gest it could be used against all known Beta­coro­n­avirus­es known infect humans, with no men­tions of SARS-CoV­‑2. Here’s the sum­ma­ry descrip­tion from the patent appli­ca­tion:

    ...
    SUMMARY

    Pro­vid­ed here­in are ribonu­cle­ic acid (RNA) vac­cines that build on the knowl­edge that RNA (e.g., mes­sen­ger RNA (mRNA)) can safe­ly direct the body’s cel­lu­lar machin­ery to pro­duce near­ly any pro­tein of inter­est, from native pro­teins to anti­bod­ies and oth­er entire­ly nov­el pro­tein con­structs that can have ther­a­peu­tic activ­i­ty inside and out­side of cells. The RNA (e.g., mRNA) vac­cines of the present dis­clo­sure may be used to induce a bal­anced immune response against hMPV, PIV, RSV, MeV, and/or Beta­CoV (e.g., MERS-CoV, SARS-CoV, HCoV-OC43, HCoV-229E, HCoV-NL63, HCoV-NL, HCoV-NH and/or HCoV-HKU1), or any com­bi­na­tion of two or more of the fore­go­ing virus­es, com­pris­ing both cel­lu­lar and humoral immu­ni­ty, with­out risk­ing the pos­si­bil­i­ty of inser­tion­al muta­ge­n­e­sis, for exam­ple. hMPV, PIV, RSV, MeV, Beta­CoV (e.g., MERS-CoV, SARS-CoV, HCoV-OC43, HCoV-229E, HCoV-NL63, HCoV-NL, HCoV-NH and HCoV-HKU1) and com­bi­na­tions there­of are referred to here­in as “res­pi­ra­to­ry virus­es.” Thus, the term “res­pi­ra­to­ry virus RNA vac­cines” encom­pass­es hMPV RNA vac­cines, PIV RNA vac­cines, RSV RNA vac­cines, MeV RNA vac­cines, Beta­CoV RNA vac­cines, and any com­bi­na­tion of two or more of hMPV RNA vac­cines, PIV RNA vac­cines, RSV RNA vac­cines, MeV RNA vac­cines, and Beta­CoV RNA vac­cines.

    The RNA (e.g., mRNA) vac­cines may be uti­lized in var­i­ous set­tings depend­ing on the preva­lence of the infec­tion or the degree or lev­el of unmet med­ical need. The RNA (e.g. mRNA) vac­cines may be uti­lized to treat and/or pre­vent a hMPV, PIV, RSV, MeV, a Beta­CoV (e.g., MERS-CoV, SARS-CoV, HCoV-OC43, HCoV-229E, HCoV-NL63, HCoV-NL, HCoV-NH, HCoV-HKU1), or any com­bi­na­tion of two or more of the fore­go­ing virus­es, of var­i­ous geno­types, strains, and iso­lates. The RNA (e.g., mRNA) vac­cines have supe­ri­or prop­er­ties in that they pro­duce much larg­er anti­body titers and pro­duce respons­es ear­li­er than com­mer­cial­ly avail­able anti-viral ther­a­peu­tic treat­ments. While not wish­ing to be bound by the­o­ry, it is believed that the RNA (e.g., mRNA) vac­cines, as mRNA polynu­cleotides, are bet­ter designed to pro­duce the appro­pri­ate pro­tein con­for­ma­tion upon trans­la­tion as the RNA (e.g., mRNA) vac­cines co-opt nat­ur­al cel­lu­lar machin­ery. Unlike tra­di­tion­al vac­cines, which are man­u­fac­tured ex vivo and may trig­ger unwant­ed cel­lu­lar respons­es, RNA (e.g., mRNA) vac­cines are pre­sent­ed to the cel­lu­lar sys­tem in a more native fash­ion.
    ...

    A text search of that patent fil­ing reveals no instance of with “SARS-CoV­‑2”, “COVID-19”, or “2019-nCoV” (the orig­i­nal name for the virus) and you will find no hits. So it sounds like this Beta­coro­n­avirus vac­cine was pro­posed to work against a wide vari­ety of Beta­coro­n­avirus­es, and yet there was no men­tion of the Beta­coro­n­avirus that was already threat­en­ing the world by Feb­ru­ary of this year which rais­es the obvi­ous ques­tion of what’s dif­fer­ence is between this vac­cine and the vac­cine Mod­er­na is devel­op­ing for SARS-CoV­‑2. Is there a dif­fer­ence? The SARS-CoV­‑2 vac­cine is pre­sum­ably based specif­i­cal­ly on the SARS-CoV­‑2 sequence so it seems like­ly the vac­cine is is bet­ter tai­lored to this par­tic­u­lar virus. Still, as we’ll also see, one of the rea­sons Mod­er­na was allowed to fast track its SARS-CoV­‑2 vac­cine for clin­i­cal tri­als is because of the clin­i­cal tri­als it had already con­duct­ed on its MERS vaccine...clinical tri­als done in part­ner­ship with the Nation­al Insti­tute of Aller­gy and Infec­tious Dis­eases (NIAID). It’s anoth­er exam­ple of the exten­sive gov­ern­ment fund­ing involved with the devel­op­ment of Mod­er­na’s SARS-CoV­‑2 vac­cine. Exten­sive gov­ern­ment fund­ing Mod­er­na just could­n’t both­er to men­tion in its patent fil­ing:

    STAT News

    Mod­er­na failed to dis­close fed­er­al fund­ing for vac­cine patent appli­ca­tions, advo­cates say

    By Ed Sil­ver­man
    August 28, 2020

    An advo­ca­cy group has asked the Depart­ment of Defense to inves­ti­gate what it called “an appar­ent fail­ure” by Mod­er­na (MRNA) to dis­close mil­lions of dol­lars in awards received from the Defense Advanced Research Projects Agency in patent appli­ca­tions the com­pa­ny filed for vac­cines.

    In a let­ter to the agency, Knowl­edge Ecol­o­gy Inter­na­tion­al explained that a review of dozens of patent appli­ca­tions found the com­pa­ny received approx­i­mate­ly $20 mil­lion from the fed­er­al gov­ern­ment in grants sev­er­al years ago and the funds “like­ly” led to the cre­ation of its vac­cine tech­nol­o­gy. This was used to devel­op vac­cines to com­bat dif­fer­ent virus­es, such as Zika and, lat­er, the virus that caus­es Covid-19.

    In argu­ing for an inves­ti­ga­tion, the advo­ca­cy group main­tained Mod­er­na is oblig­at­ed under fed­er­al law to dis­close the grants that led to near­ly a dozen spe­cif­ic patent appli­ca­tions and explained the finan­cial sup­port means the U.S. gov­ern­ment would have cer­tain rights over the patents. In oth­er words, U.S. tax­pay­ers would have an own­er­ship stake in vac­cines devel­oped by the com­pa­ny.

    “This clar­i­fies the public’s right in the inven­tions,” said Jamie Love, who heads Knowl­edge Ecol­o­gy Inter­na­tion­al, a non­prof­it that tracks patents and access to med­i­cines issues. “The dis­clo­sure (also) changes the nar­ra­tive about who has financed the inven­tive activ­i­ty, often the most risky part of devel­op­ment.”
    Relat­ed:

    One par­tic­u­lar patent assigned to Mod­er­na con­cerns meth­ods and com­po­si­tions that can be used specif­i­cal­ly against coro­n­avirus­es, includ­ing COVID-19. The patent names a Mod­er­na sci­en­tist and a for­mer Mod­er­na sci­en­tist as inven­tors, both of which acknowl­edged per­form­ing work under the DARPA awards in two aca­d­e­m­ic papers, accord­ing to the report by the advo­ca­cy group.

    The group exam­ined the 126 patents assigned to Mod­er­na or Mod­er­naTx as well as 154 patent appli­ca­tions. “Despite the evi­dence that mul­ti­ple inven­tions were con­ceived in the course of research sup­port­ed by the DARPA awards, not a sin­gle one of the patents or appli­ca­tions assigned to Mod­er­na dis­close U.S. fed­er­al gov­ern­ment fund­ing,” the report stat­ed.

    ...

    The mis­sive to the Depart­ment of Defense fol­lows a recent analy­sis by Pub­lic Cit­i­zen, anoth­er advo­ca­cy group, indi­cat­ing the Nation­al Insti­tutes of Health may own mRNA-1273, the Mod­er­na vac­cine can­di­date for Covid-19. The advo­ca­cy group not­ed the fed­er­al gov­ern­ment filed mul­ti­ple patents cov­er­ing the vac­cine and two patent appli­ca­tions, in par­tic­u­lar, list fed­er­al sci­en­tists as co-inven­tors.

    The analy­ses are part of a larg­er cam­paign among advo­ca­cy groups and oth­ers in the U.S. and else­where to ensure that Covid-19 med­ical prod­ucts are avail­able to poor pop­u­la­tions around the world. The con­cern reflects the unprece­dent­ed glob­al demand for ther­a­pies and vac­cines, and a race among wealthy nations to snap up sup­plies from vac­cine mak­ers.

    In the U.S., the effort has focused on the extent to which the fed­er­al gov­ern­ment has pro­vid­ed tax­pay­er dol­lars to dif­fer­ent com­pa­nies to help fund their dis­cov­er­ies. In some cas­es, advo­cates argue that fed­er­al fund­ing mat­ters because it clar­i­fies the rights that the U.S. gov­ern­ment has to ensure a ther­a­py or vac­cine is avail­able to Amer­i­cans on rea­son­able terms.

    One exam­ple has been remde­sivir, the Gilead Sci­ences (GILD) treat­ment being giv­en to hos­pi­tal­ized Covid-19 patients. The role played by the U.S. gov­ern­ment in devel­op­ing remde­sivir to com­bat coro­n­avirus­es involved con­tri­bu­tions from gov­ern­ment per­son­nel at such agen­cies as the U.S. Army Med­ical Research Insti­tute of Infec­tious Dis­eases.

    As for the Mod­er­na vac­cine, ear­li­er this month, the com­pa­ny was award­ed a $1.525 bil­lion con­tract by the Depart­ment of Defense and the Depart­ment of Health and Human Ser­vices to man­u­fac­ture and deliv­er 100 mil­lion dos­es of its Covid-19 vac­cine. The agree­ment also includes an option to pur­chase anoth­er 400 mil­lion dos­es, although the terms were not dis­closed.

    In announc­ing the agree­ment, the gov­ern­ment said it would ensure Amer­i­cans receive the Covid-19 vac­cine at no cost, although they may be charged by health care providers for admin­is­ter­ing a shot.

    In this instance, how­ev­er, Love said the “let­ter is not about price or prof­its. It’s about (Mod­er­na) not own­ing up to DARPA fund­ing inven­tions. If the U.S. wants to pay for all of the devel­op­ment of Moderna’s vac­cine, as Mod­er­na now acknowl­edges, and throw in a few more bil­lion now, and an option to spend bil­lions more, it’s not unrea­son­able to have some trans­paren­cy over who paid for their inven­tions.”

    This is not the first time Mod­er­na has been accused of insuf­fi­cient dis­clo­sure. Ear­li­er this month, Knowl­edge Ecol­o­gy Inter­na­tion­al and Pub­lic Cit­i­zen main­tained the com­pa­ny failed to dis­close devel­op­ment costs in a $955 mil­lion con­tract award­ed by BARDA for its Covid-19 vac­cine. In all, the fed­er­al gov­ern­ment has award­ed the com­pa­ny approx­i­mate­ly $2.5 bil­lion to devel­op the vac­cine.

    ———-

    “Mod­er­na failed to dis­close fed­er­al fund­ing for vac­cine patent appli­ca­tions, advo­cates say” by Ed Sil­ver­man; STAT News; 08/28/2020

    “In argu­ing for an inves­ti­ga­tion, the advo­ca­cy group main­tained Mod­er­na is oblig­at­ed under fed­er­al law to dis­close the grants that led to near­ly a dozen spe­cif­ic patent appli­ca­tions and explained the finan­cial sup­port means the U.S. gov­ern­ment would have cer­tain rights over the patents. In oth­er words, U.S. tax­pay­ers would have an own­er­ship stake in vac­cines devel­oped by the com­pa­ny.

    Did Mod­ern vio­late fed­er­al law? That’s that these NGOs are argu­ing, along with the argu­ment that the US gov­ern­ment should own a stake in these vac­cines. And when you put those two argu­ments togeth­er you can under­stand why Mod­er­na would have been so inter­est­ed in not men­tion­ing this exten­sive gov­ern­ment sup­port. And it’s par­tic­u­lar­ly notable in the patent from Feb­ru­ary of this year for a gener­ic Beta­coro­n­avirus that lists two DARPA-fund­ed Mod­er­na researchers as the inven­tors:

    ...
    One par­tic­u­lar patent assigned to Mod­er­na con­cerns meth­ods and com­po­si­tions that can be used specif­i­cal­ly against coro­n­avirus­es, includ­ing COVID-19. The patent names a Mod­er­na sci­en­tist and a for­mer Mod­er­na sci­en­tist as inven­tors, both of which acknowl­edged per­form­ing work under the DARPA awards in two aca­d­e­m­ic papers, accord­ing to the report by the advo­ca­cy group.

    The group exam­ined the 126 patents assigned to Mod­er­na or Mod­er­naTx as well as 154 patent appli­ca­tions. “Despite the evi­dence that mul­ti­ple inven­tions were con­ceived in the course of research sup­port­ed by the DARPA awards, not a sin­gle one of the patents or appli­ca­tions assigned to Mod­er­na dis­close U.S. fed­er­al gov­ern­ment fund­ing,” the report stat­ed.

    ...

    The mis­sive to the Depart­ment of Defense fol­lows a recent analy­sis by Pub­lic Cit­i­zen, anoth­er advo­ca­cy group, indi­cat­ing the Nation­al Insti­tutes of Health may own mRNA-1273, the Mod­er­na vac­cine can­di­date for Covid-19. The advo­ca­cy group not­ed the fed­er­al gov­ern­ment filed mul­ti­ple patents cov­er­ing the vac­cine and two patent appli­ca­tions, in par­tic­u­lar, list fed­er­al sci­en­tists as co-inven­tors.
    ...

    But while Mod­er­na may not have been open about its exten­sive gov­ern­ment sup­port in its patent fil­ings, the com­pa­ny has been pret­ty open about it with the press. And for good rea­son: the fast-track­ing of Mod­er­na’s COVID-19 vac­cine devel­op­ment has been jus­ti­fied in large part based on that exten­sive past gov­ern­ment sup­port, in par­tic­u­lar the close work Mod­er­na and US gov­ern­ment agen­cies have con­duct­ed togeth­er over the years devel­op­ing this vac­cine tech­nol­o­gy for MERS:

    Genet­ic Engi­neer­ing & Biotech­nol­o­gy News

    Moderna’s SARS-CoV­‑2 Vaccine’s Fast Track to Clin­i­cal Tri­als

    As Mod­er­na’s vac­cine devel­op­ment moves at unprece­dent­ed speed, the com­pa­ny’s CEO explains how they have moved so quick­ly and why he is hope­ful that their pace will con­tin­ue.

    By Julian­na LeMieux, PhD -
    March 26, 2020

    The holy grail of the cur­rent pandemic—a vac­cine for COVID-19—will not be avail­able next month. It may not even be ready by next year. Regard­less, the strides being made are hap­pen­ing at unprece­dent­ed speed. One of the com­pa­nies at the front of the pack is Mod­er­na Ther­a­peu­tics.

    Syn­bio­be­ta, the net­work of the syn­thet­ic biol­o­gy world, has host­ed “town halls” for the past few weeks. This week, their guest host was Stéphane Ban­cel, Moderna’s CEO. Hail­ing orig­i­nal­ly from France, Ban­cel spoke about Moderna’s efforts to make a vac­cine for SARS-CoV­‑2, how Mod­er­na has moved as rapid­ly as they have, and why he is hope­ful that they will con­tin­ue on this pro­gres­sion.

    ...

    MERS-CoV set the stage

    Mod­er­na has been work­ing on mul­ti­ple viral “first in class” vac­cines for years, includ­ing cytomegalovirus, Zika virus, res­pi­ra­to­ry syn­cy­tial virus, Epstein Barr virus, Flu H7N9, to name a few. In order to use their plat­form to pro­duce vac­cines, the intro­duced mRNA encodes a viral anti­gen that is rec­og­nized by the immune sys­tem and elic­its a pro­tec­tive response in the body.

    One of the rea­sons the SARS-CoV­‑2 vac­cine devel­op­ment has been so fast (for details, see the time­line of events at the bot­tom of the sto­ry) is the work Mod­er­na has done over the past two years in an exist­ing col­lab­o­ra­tion with the Vac­cine Research Cen­ter (VRC) of NIAID to devel­op a vac­cine against MERS-CoV.

    The rab­bit infec­tion data, Mod­er­na chart to the left, mea­sures the amount of neu­tral­iz­ing anti­bod­ies pro­duced by the rab­bits is response to the vac­cine. The first dose of Moderna’s vac­cine pro­duced neu­tral­iz­ing anti­bod­ies in the blood, with pro­duc­tion great­ly increased upon the sec­ond dose—or booster—on day 21.

    A chal­lenge of the rab­bits with MERS-CoV virus at day 46, result­ed in a huge reduc­tion of MERS viral load in the nose, throat, and bron­choalve­o­lar lavage (data shown to the right.)

    When the com­pa­ny received the SARS-CoV­‑2 genom­ic sequences from Chi­na on Jan­u­ary 11, the stage was already set.

    The mRNA vac­cine against SARS-CoV­‑2 (mRNA-1273) was quick­ly designed, test­ed for steril­i­ty, and shipped to the NIAID for clin­i­cal study. The IND was filed on Feb­ru­ary 21 and, on March 2, FDA gave the green light to start clin­i­cal study. The first per­son was dosed last Mon­day and the com­pa­ny is cur­rent­ly fil­ing an IND to start Phase II.

    When asked to pull out his crys­tal ball, and pre­dict a time­line, Ban­cel not­ed that the most opti­mistic sce­nario, “which would require 20 dif­fer­ent things to work,” is that they may progress through Phase II and III this year and have a vac­cine in 2021. Although that may sound like a long way off, he added that it “would be a world record,” not­ing that vac­cines nor­mal­ly take 10 years to make.

    But, he added, it is a very unique sit­u­a­tion to be work­ing on a vac­cine in the mid­dle of a pan­dem­ic. Every­one, he not­ed, “needs to be aware that the NIH, CDC, FDA, and oth­ers are col­lab­o­rat­ing like noth­ing I have ever seen before.” He said the amount of email that occurs in the mid­dle of the night is a tes­ta­ment to that.

    The biggest rea­son for Moderna’s progress on this vac­cine is because a lot of the work had been done before—given the time and ener­gy they invest­ed into the MERS vac­cine. He explained that, with­out that, they nev­er would have been able to move as fast.

    He hopes that they can con­tin­ue to do this work up front, for the next 10 or 20 virus­es that could cause epi­demics. Ban­cel stressed that time is need­ed in order to do things cor­rect­ly. “You need to get ahead of things,” he explained, because, “chas­ing a pan­dem­ic is not some­thing that can be done well.”

    Time­line of Moderna’s Path to the SARS-CoV­‑2 Vac­cine

    Jan­u­ary 11 The Chi­nese author­i­ties shared the genet­ic sequence of SARS-CoV­‑2.

    Jan­u­ary 13 The U.S. Nation­al Insti­tutes of Health (NIH) and Moderna’s infec­tious dis­ease research team final­ized the sequence for mRNA-1273, the company’s vac­cine against the nov­el coro­n­avirus.

    Feb­ru­ary 7 The first clin­i­cal batch was com­plet­ed, a total of 25 days from sequence selec­tion to vac­cine man­u­fac­ture. The batch then pro­ceed­ed to ana­lyt­i­cal test­ing for release
    .

    Feb­ru­ary 24 The clin­i­cal batch was shipped from Mod­er­na to the NIH for use in their Phase I clin­i­cal study.

    March 4 The FDA com­plet­ed its review of the Inves­ti­ga­tion­al New Drug (IND) appli­ca­tion filed by the NIH for mRNA-1273 and allowed to the study to pro­ceed to begin clin­i­cal tri­als.

    March 16 The NIH announced that the first par­tic­i­pant in its Phase I study for mRNA-1273 was dosed, a total of 63 days from sequence selec­tion to first human dos­ing. The open-label tri­al is expect­ed to enroll 45 healthy adult vol­un­teers ages 18 to 55 years over approx­i­mate­ly six weeks.

    March 23 Mod­er­na filed a Cur­rent Report on Form 8‑K which includ­ed, among oth­er things, infor­ma­tion regard­ing the poten­tial tim­ing of the avail­abil­i­ty of a vac­cine against COVID-19. The com­pa­ny report­ed that the Phase I study is pro­ceed­ing in accor­dance with the pro­to­col under the direc­tion of NIAID. Mod­er­na fur­ther report­ed that while a com­mer­cial­ly-avail­able vac­cine is not like­ly to be avail­able for at least 12–18 months, it is pos­si­ble that under emer­gency use, a vac­cine could be avail­able to some peo­ple, pos­si­bly includ­ing health­care pro­fes­sion­als, in the fall of 2020. Any emer­gency use would be sub­ject to autho­riza­tion by the appro­pri­ate reg­u­la­to­ry agen­cies, based on the emer­gence of clin­i­cal data for mRNA-1273 that would sup­port use of the vac­cine pri­or to licen­sure. In addi­tion, Mod­er­na con­firmed that it is scal­ing up man­u­fac­tur­ing capac­i­ty toward the pro­duc­tion of mil­lions of dos­es per month, in the poten­tial form of indi­vid­ual or mul­ti-dose vials. As has pre­vi­ous­ly been dis­closed, the abil­i­ty of the com­pa­ny to make mil­lions of dos­es per month is con­tin­gent on invest­ments in the scale up and fur­ther build­out of the company’s exist­ing man­u­fac­tur­ing infra­struc­ture.

    ———–

    “Moderna’s SARS-CoV­‑2 Vaccine’s Fast Track to Clin­i­cal Tri­als” by Julian­na LeMieux; Genet­ic Engi­neer­ing & Biotech­nol­o­gy News; 03/26/2020

    “One of the rea­sons the SARS-CoV­‑2 vac­cine devel­op­ment has been so fast (for details, see the time­line of events at the bot­tom of the sto­ry) is the work Mod­er­na has done over the past two years in an exist­ing col­lab­o­ra­tion with the Vac­cine Research Cen­ter (VRC) of NIAID to devel­op a vac­cine against MERS-CoV.”

    Yes, with­out all of the pre­vi­ous work on on devel­op­ing a MERS vac­cine the com­pa­ny would­n’t have been capa­ble of doing this fast-tracked devel­op­ment pipeline. Pre­vi­ous work done in col­lab­o­ra­tion with the Vac­cine Research Cen­ter (VRC) of NIAID:

    ...
    When the com­pa­ny received the SARS-CoV­‑2 genom­ic sequences from Chi­na on Jan­u­ary 11, the stage was already set.

    The mRNA vac­cine against SARS-CoV­‑2 (mRNA-1273) was quick­ly designed, test­ed for steril­i­ty, and shipped to the NIAID for clin­i­cal study. The IND was filed on Feb­ru­ary 21 and, on March 2, FDA gave the green light to start clin­i­cal study. The first per­son was dosed last Mon­day and the com­pa­ny is cur­rent­ly fil­ing an IND to start Phase II.

    ...

    The biggest rea­son for Moderna’s progress on this vac­cine is because a lot of the work had been done before—given the time and ener­gy they invest­ed into the MERS vac­cine. He explained that, with­out that, they nev­er would have been able to move as fast.
    ...

    And that col­lab­o­ra­tion rais­es anoth­er ques­tion: so was it Mod­er­na staff or their gov­ern­ment col­lab­o­ra­tors at the NIAID who first devel­oped this new COVID-19 vac­cine ear­li­er this year after the viral sequence was first release? Well, based on the fol­low­ing Nature arti­cle from last month describ­ing the ear­ly race for a vac­cine, it sounds like the exist­ing col­lab­o­ra­tion between the NIAID’s Vac­cine Research Cen­ter and Mod­er­na that was on a dif­fer­ent vac­cine sim­ply shift­ed gears and start­ed work­ing on the COVID-19 vac­cine which means it’s been a US government/Moderna col­lab­o­ra­tion from the very begin­ning:

    Nature

    Coro­n­avirus vac­cines get a biotech boost
    Advances in tech­nol­o­gy are accel­er­at­ing the search for drugs to arm the immune sys­tem against SARS-CoV­‑2.

    Amber Dance
    21 July 2020

    In Jan­u­ary, Bar­ney Gra­ham had a new vac­cine ready for test­ing. Its tar­get was the Nipah virus, which had caused res­pi­ra­to­ry ill­ness and brain infec­tions in past out­breaks in south­east Asia. Gra­ham, a vac­ci­nol­o­gist and deputy direc­tor at the US Nation­al Insti­tute of Aller­gy and Infec­tious Dis­eases (NIAID) Vac­cine Research Cen­ter in Bethes­da, Mary­land, was work­ing with Mod­er­na Ther­a­peu­tics in Cam­bridge, Mass­a­chu­setts, to build a type of vac­cine nev­er before approved for use. Unlike most vac­cines, which are based on intact pathogens or their struc­tur­al com­po­nents, Moderna’s are built from a pathogen’s RNA. The team hoped that a vac­ci­nat­ed person’s cells would use the RNA to make pro­tein, prim­ing their immune sys­tem to gen­er­ate a pro­tec­tive response.

    Gra­ham and his col­leagues were just about to start man­u­fac­tur­ing the Nipah vac­cine for human tri­als when they got wind of a dis­ease caused by a new coro­n­avirus, now known as SARS-CoV­‑2, wreak­ing hav­oc in Wuhan, Chi­na. They quick­ly changed their plans, but not the design on which their vac­cine was based. Armed with the draft genome for SARS-CoV­‑2, which was shared online on 11 Jan­u­ary, Mod­er­na swapped in the coro­n­avirus RNA and start­ed ship­ping a poten­tial vac­cine to the NIAID for clin­i­cal tests. The process took just six weeks — the fastest turn­around from project start to vac­cine can­di­date in med­ical his­to­ry.

    Graham’s team is one of more than 150 vac­cine devel­op­ers rac­ing against time to devel­op vac­cines that reduce the sever­i­ty of COVID-19, or block infec­tion by SARS-CoV­‑2. Thanks to a wave of new vac­cine tech­nolo­gies, these sci­en­tists stand a bet­ter chance of suc­cess than against any pre­vi­ous new virus. “The real chal­lenge is speed,” says Drew Weiss­man, an immu­nol­o­gist at the Uni­ver­si­ty of Penn­syl­va­nia in Philadel­phia. How­ev­er, he adds, it should not come at the expense of safe­ty or effi­ca­cy — whether it pro­tects humans from get­ting the dis­ease.

    Today, approach­es such as RNA vac­cines are help­ing researchers to cre­ate and test vac­cine can­di­dates at break­neck speed. Antho­ny Fau­ci, direc­tor of the NIAID, told a con­gres­sion­al com­mit­tee on 23 June that he is “cau­tious­ly opti­mistic” that there will be a work­ing vac­cine by ear­ly 2021. Vac­ci­nol­o­gists who spoke to Nature echo that sen­ti­ment — although they say that the first vac­cines might not be the best pos­si­ble designs, and improved ver­sions are like­ly to come lat­er. Many of the vac­cines already in devel­op­ment have poten­tial to become those sec­ond-gen­er­a­tion vac­cines. Sev­er­al groups are apply­ing struc­ture- and com­put­er-based analy­ses of the inter­ac­tions between the immune sys­tem and viral anti­gens, the parts of virus­es that pro­voke an immune response. These tech­niques have already been tried against numer­ous pathogens, and are now being applied to SARS-CoV­‑2.

    ...

    ———–

    “Coro­n­avirus vac­cines get a biotech boost” by Amber Dance; Nature; 07/21/2020

    Gra­ham and his col­leagues were just about to start man­u­fac­tur­ing the Nipah vac­cine for human tri­als when they got wind of a dis­ease caused by a new coro­n­avirus, now known as SARS-CoV­‑2, wreak­ing hav­oc in Wuhan, Chi­na. They quick­ly changed their plans, but not the design on which their vac­cine was based. Armed with the draft genome for SARS-CoV­‑2, which was shared online on 11 Jan­u­ary, Mod­er­na swapped in the coro­n­avirus RNA and start­ed ship­ping a poten­tial vac­cine to the NIAID for clin­i­cal tests. The process took just six weeks — the fastest turn­around from project start to vac­cine can­di­date in med­ical his­to­ry.”

    As we can see, it’s been a pub­lic-pri­vate part­ner­ship from the very begin­ning. A pub­lic-pri­vate part­ner­ship with exclu­sive­ly pri­vate prof­its. At least that’s the stunt Mod­er­na tried to pull with these patent appli­ca­tions. A stunt that just might suc­ceed. We’ll see. DARPA has report­ed­ly just opened an inves­ti­ga­tion of the patent fil­ings today. Hope­ful­ly a fast-tracked inves­ti­ga­tion.

    Posted by Pterrafractyl | August 29, 2020, 3:53 pm
  6. Here’s a set of dis­turbing­ly opti­mistic updates on the sta­tus of Oper­a­tion Warp Speed and the US race for a COVID vac­cine:

    First, the Cen­ters for Dis­ease Con­trol (CDC) sent a let­ter to all 50 states and 5 major cities to be pre­pared for the pos­si­bil­i­ty of a vac­cine dis­tri­b­u­tion as ear­ly as late Octo­ber or ear­ly Novem­ber. The tim­ing is obvi­ous­ly fuel­ing the grow­ing con­cerns of a rushed and politi­cized vac­cine approval process, in part because they were sent on the same day of Pres­i­dent Trump’s Thurs­day night Repub­li­can Nation­al Con­ven­tion accep­tance speech where he sug­gest­ed that a vac­cine might be avail­able by the end of the year.

    But as we’ll see in the sec­ond an third arti­cle excerpt below, those con­cerns are also height­ened due to the recent com­ments from both the head of FDA, Stephen Hahn, and Nation­al Insti­tute of Aller­gy and Infec­tious Dis­eases (NIAID) chief Dr. Antho­ny Fau­ci. Hahn just sug­gest­ed that emer­gency autho­riza­tion could be issue before the Phase III clin­i­cal tri­als, but just for cer­tain groups, mak­ing it appear to be a kind of des­per­a­tion-based rea­son for ear­ly vac­cine approval. Fau­ci, on the oth­er hand, described a far more opti­mistic sce­nario: that the inde­pen­dent advi­so­ry boards — which include mem­bers who are not part of the gov­ern­ment and in the­o­ry would­n’t be sub­ject to the same pres­sures from the Trump admin­is­tra­tion as gov­ern­ment employ­ees — has to pow­er to rec­om­mend the end­ing of clin­i­cal tri­als ear­ly and grant approval for the vac­cine if the clin­i­cal tri­als show over­whelm­ing effi­ca­cy. At that point, the vac­cine devel­op­er would have to go to the FDA to request emer­gency autho­riza­tion. So if the FDA does indeed issue emer­gency autho­riza­tion before Novem­ber it’s going to be cru­cial to find out of the inde­pen­dent advi­so­ry board rec­om­mend­ed this or if it was a deci­sion made uni­lat­er­al­ly by the FDA.

    But there’s anoth­er ear­ly vac­cine release sce­nario that was just described by the last FDA chief, Scott Got­tlieb, in an inter­view: one of the lim­it­ing fac­tors in assess­ing the effi­ca­cy of a vac­cine is the preva­lence of the dis­ease with vac­cines for more preva­lent and eas­i­ly trans­mis­si­ble dis­eases being eas­i­er and faster to assess. So as Got­tlieb point­ed out, if the num­ber of cas­es explodes so much in com­ing months that there’s a very large num­ber of cas­es and the vac­cine proves to be high­ly effec­tive dur­ing this out­break that could cre­ate the kind of epi­demi­o­log­i­cal sit­u­a­tion where we could fea­si­ble approve the vac­cine before Novem­ber.

    So Trump can get his vac­cine ‘Octo­ber Sur­prise’ as long as the vac­cine is shown to be high­ly effec­tive in the midst of an explo­sion of new cas­es and all indi­ca­tions are that the fed­er­al gov­ern­ment is try­ing to make that sce­nario hap­pen. It’s a sit­u­a­tion where there’s simul­ta­ne­ous­ly incen­tives to exag­ger­ate the safe­ty of the vac­cines while encour­ag­ing the spread of the virus. That’s why the CDC’s hyper-opti­mistic let­ter to the states is so omi­nous:

    The New York Times

    C.D.C. Tells States How to Pre­pare for Covid-19 Vac­cine by Ear­ly Novem­ber

    As Pres­i­dent Trump push­es the pos­si­bil­i­ty of a vac­cine this year, the C.D.C. has out­lined tech­ni­cal sce­nar­ios to state pub­lic health offi­cials for an uniden­ti­fied “Vac­cine A” and “Vac­cine B.”

    By Sheila Kaplan, Kather­ine J. Wu and Katie Thomas

    Sept. 2, 2020
    Updat­ed 3:37 p.m. ET

    The Cen­ters for Dis­ease Con­trol and Pre­ven­tion has noti­fied pub­lic health offi­cials in all 50 states and five large cities to pre­pare to dis­trib­ute a coro­n­avirus vac­cine to health care work­ers and oth­er high-risk groups as soon as late Octo­ber or ear­ly Novem­ber.

    The new C.D.C. guid­ance is the lat­est sign of an accel­er­at­ing race for a vac­cine to great­ly ease a pan­dem­ic that has killed more than 184,000 Amer­i­cans. The doc­u­ments were sent out on the same day that Pres­i­dent Trump told the nation in his speech to the Repub­li­can Nation­al Con­ven­tion that a vac­cine might arrive before the end of the year.

    Over the past week, both Dr. Antho­ny S. Fau­ci, the country’s top infec­tious dis­ease expert, and Dr. Stephen Hahn, who heads the Food and Drug Admin­is­tra­tion, have said in inter­views with news orga­ni­za­tions that a vac­cine may be avail­able for cer­tain groups before clin­i­cal tri­als have been com­plet­ed, if the data is over­whelm­ing­ly pos­i­tive.

    Pub­lic health experts agree that agen­cies at all lev­els of gov­ern­ment should urgent­ly pre­pare for what will even­tu­al­ly be a vast, com­plex effort to vac­ci­nate hun­dreds of mil­lions of Amer­i­cans. But the pos­si­bil­i­ty of a roll­out in late Octo­ber or ear­ly Novem­ber has also height­ened con­cerns that the Trump admin­is­tra­tion is seek­ing to rush the dis­tri­b­u­tion of a vac­cine — or sim­ply to hype that one is pos­si­ble — before Elec­tion Day on Nov. 3.

    The C.D.C. plans lay out tech­ni­cal spec­i­fi­ca­tions for two can­di­dates described as “Vac­cine A” and “Vac­cine B,” includ­ing require­ments for ship­ping, mix­ing, stor­age and admin­is­tra­tion. The details seem to match the prod­ucts devel­oped by Pfiz­er and Mod­er­na, which are the fur­thest along in late-stage clin­i­cal tri­als. On Aug. 20, Pfiz­er said it was “on track” for seek­ing gov­ern­ment review “as ear­ly as Octo­ber 2020.”

    “This time­line of the ini­tial deploy­ment at the end of Octo­ber is deeply wor­ri­some for the politi­ciza­tion of pub­lic health and the poten­tial safe­ty ram­i­fi­ca­tions,” said Sask­ia Popes­cu, an infec­tion pre­ven­tion epi­demi­ol­o­gist based in Ari­zona. “It’s hard not to see this as a push for a pre-elec­tion vac­cine.”

    Three doc­u­ments were sent to pub­lic health offi­cials in all states and ter­ri­to­ries as well as New York, Chica­go, Philadel­phia, Hous­ton and San Anto­nio on Aug. 27. They out­lined detailed sce­nar­ios for dis­trib­ut­ing two uniden­ti­fied vac­cine can­di­dates, each requir­ing two dos­es a few weeks apart, at hos­pi­tals, mobile clin­ics and oth­er facil­i­ties offer­ing easy access to the first tar­get­ed recip­i­ents.

    The guid­ance not­ed that health care pro­fes­sion­als, includ­ing long-term care employ­ees, would be among the first to receive the prod­uct, along with oth­er essen­tial work­ers and nation­al secu­ri­ty employ­ees. Peo­ple 65 or old­er, as well as Native Amer­i­cans and those who are from “racial and eth­nic minor­i­ty pop­u­la­tions” or incar­cer­at­ed — all com­mu­ni­ties known to be at greater risk of con­tract­ing the virus and expe­ri­enc­ing severe dis­ease — were also pri­or­i­tized in the doc­u­ments.

    That’s a pos­i­tive devel­op­ment, “so it doesn’t just all wind up in high-income, afflu­ent sub­urbs,” said Dr. Cedric Dark, an emer­gency med­i­cine physi­cian at Bay­lor Col­lege of Med­i­cine in Texas.

    The C.D.C. not­ed in its guid­ance that “lim­it­ed Covid ‑19 vac­cine dos­es may be avail­able by ear­ly Novem­ber 2020.” The doc­u­ments were dis­patched the same day that Dr. Robert Red­field, direc­tor of the C.D.C., sent a let­ter to gov­er­nors ask­ing them to ready vac­cine dis­tri­b­u­tion sites by Nov. 1, as McClatchy report­ed.

    The agency also said its plans were as yet hypo­thet­i­cal, not­ing, “The Covid-19 vac­cine land­scape is evolv­ing and uncer­tain, and these sce­nar­ios may evolve as more infor­ma­tion is avail­able.” A C.D.C. spokes­woman con­firmed that the doc­u­ments were sent but declined to com­ment fur­ther.

    Many of the details list­ed for the two vac­cines — includ­ing required stor­age tem­per­a­ture, the num­ber of days need­ed between dos­es, and the type of med­ical cen­ter that can accom­mo­date the product’s stor­age — match what Pfiz­er and Mod­er­na have said about their prod­ucts, which are based on so-called mRNA tech­nol­o­gy. Nei­ther com­pa­ny respond­ed to requests for com­ment.

    The sce­nar­ios, which assume that the two vac­cines could demon­strate suf­fi­cient safe­ty and effec­tive­ness for an emer­gency autho­riza­tion from the F.D.A. by the end of Octo­ber, note that Vac­cine A, which seems to match Pfizer’s, would have about two mil­lion dos­es ready with­in this time frame, and that Vac­cine B, whose descrip­tion match­es Moderna’s, would have about one mil­lion dos­es ready, with tens of mil­lions of dos­es of each vac­cine ready by the end of the year. Although it’s pos­si­ble that some promis­ing pre­lim­i­nary data may emerge by the end of Octo­ber, experts are skep­ti­cal.

    “The time­line that’s report­ed seems a bit ambi­tious to me,” Dr. Dark said. “October’s like 30 days away.”

    Tri­als that test a vaccine’s effec­tive­ness can take years to yield reli­able results. It’s pos­si­ble to draw con­clu­sions soon­er “if there is an over­whelm­ing effect” in which vac­ci­nat­ed peo­ple appear to be far bet­ter pro­tect­ed from dis­ease, said Pad­mi­ni Pil­lai, a vac­cine researcher and immu­nol­o­gist at M.I.T. But data gath­ered ear­ly in a tri­al might not hold true months down the line. And researchers need time to test large num­bers of peo­ple from a vari­ety of back­grounds to deter­mine how well the vac­cine works in dif­fer­ent pop­u­la­tions — includ­ing the vul­ner­a­ble com­mu­ni­ties iden­ti­fied in the guide­lines.

    Should any of these snags occur, Dr. Pil­lai said, “all of this togeth­er could dimin­ish pub­lic trust in the vac­cine.”

    James S. Blu­men­stock, senior vice pres­i­dent of pan­dem­ic response and recov­ery at the Asso­ci­a­tion of State and Ter­ri­to­r­i­al Health Offi­cials, con­firmed that the three C.D.C. doc­u­ments were sent to all state and ter­ri­to­r­i­al health depart­ments last week. “It is now the time to enhance orga­ni­za­tion­al struc­ture and involve all part­ners in this plan­ning process going for­ward,” he said.

    Lisa Stromme, a spokes­woman for the Wash­ing­ton State Depart­ment of Health, said that her state’s health offi­cials were still at “a very ear­ly stage in a plan­ning process,” but were already work­ing toward devel­op­ing infra­struc­ture “that would accom­mo­date” the assump­tions laid out by the C.D.C.

    The C.D.C. doc­u­ments said that pub­lic health admin­is­tra­tors should review lessons learned from the 2009 H1N1 pan­dem­ic vac­ci­na­tion cam­paign, which did not have enough dos­es at the begin­ning to meet demand.

    “It’s good to have a plan out for hos­pi­tals and health care sys­tems to pre­pare” for a poten­tial roll­out, said Dr. Tai­son Bell, a pul­monary and crit­i­cal care physi­cian at the Uni­ver­si­ty of Vir­ginia. But Dr. Bell added that he is con­cerned that the time­line out­lined in the doc­u­ments “is incred­i­bly ambi­tious and makes me wor­ry that the admin­is­tra­tion will pri­or­i­tize this arbi­trary dead­line rather than main­tain­ing dili­gence with fol­low­ing the sci­ence.”

    The tech­ni­cal com­par­i­son of Vac­cine A and Vac­cine B has some echoes of what was dis­cussed at an Aug. 26 meet­ing of the C.D.C.’s Advi­so­ry Com­mit­tee on Immu­niza­tion Prac­tices. At the meet­ing, Dr. Kath­leen Dool­ing, a C.D.C. med­ical offi­cer, laid out three sce­nar­ios: Vac­cine A, or the Pfiz­er vac­cine, is approved, Vac­cine B, the Mod­er­na vac­cine, is approved, or both. The require­ment that Pfizer’s vac­cine be stored at minus 70 degrees Cel­sius would mean that it couldn’t be admin­is­tered at most small sites, she not­ed. The C.D.C. doc­u­ments note that orders of Vac­cine A would go “to large admin­is­tra­tion sites only.” The Mod­er­na vac­cine requires stor­age at minus 20 degrees Cel­sius.

    The C.D.C. doc­u­ments said the vac­cine would be free to patients, but that providers might not be reim­bursed for admin­is­tra­tive costs if the vac­cine was giv­en an emer­gency autho­riza­tion, rather than a stan­dard approval.

    Experts wor­ry that the process is unlike­ly to go off with­out a hitch, giv­en the last-minute scram­ble and the mixed mes­sag­ing so far. “I think dis­tri­b­u­tion is going to be very tricky for the vac­cine, par­tic­u­lar­ly if there is a cold stor­age require­ment,” Dr. Bell said.

    ...

    ———–

    “C.D.C. Tells States How to Pre­pare for Covid-19 Vac­cine by Ear­ly Novem­ber” by Sheila Kaplan, Kather­ine J. Wu and Katie Thomas; The New York Times; 09/02/2020

    “Pub­lic health experts agree that agen­cies at all lev­els of gov­ern­ment should urgent­ly pre­pare for what will even­tu­al­ly be a vast, com­plex effort to vac­ci­nate hun­dreds of mil­lions of Amer­i­cans. But the pos­si­bil­i­ty of a roll­out in late Octo­ber or ear­ly Novem­ber has also height­ened con­cerns that the Trump admin­is­tra­tion is seek­ing to rush the dis­tri­b­u­tion of a vac­cine — or sim­ply to hype that one is pos­si­ble — before Elec­tion Day on Nov. 3.

    Any­one want an over­hyped, rushed vac­cine? Any­one? That’s the iron­ic chal­lenge fac­ing the Trump admin­is­tra­tion: if it rolls out the thing every­one wants too soon no one is going to want it.

    And note that the “Vac­cine A” and “Vac­cine B” sce­nar­ios described in the CDC memo appear to match Pfiz­er’s and Mod­er­na’s vac­cines. And Pfiz­er has been indi­cat­ing that it might be ready to seek gov­ern­ment review for its vac­cine as ear­ly as Octo­ber. So the vac­cine man­u­fac­tur­ers appear to be hap­py to play along with any Octo­ber Sur­pris­es:

    ...
    The C.D.C. plans lay out tech­ni­cal spec­i­fi­ca­tions for two can­di­dates described as “Vac­cine A” and “Vac­cine B,” includ­ing require­ments for ship­ping, mix­ing, stor­age and admin­is­tra­tion. The details seem to match the prod­ucts devel­oped by Pfiz­er and Mod­er­na, which are the fur­thest along in late-stage clin­i­cal tri­als. On Aug. 20, Pfiz­er said it was “on track” for seek­ing gov­ern­ment review “as ear­ly as Octo­ber 2020.”

    “This time­line of the ini­tial deploy­ment at the end of Octo­ber is deeply wor­ri­some for the politi­ciza­tion of pub­lic health and the poten­tial safe­ty ram­i­fi­ca­tions,” said Sask­ia Popes­cu, an infec­tion pre­ven­tion epi­demi­ol­o­gist based in Ari­zona. “It’s hard not to see this as a push for a pre-elec­tion vac­cine.”
    ...

    Adding to poten­tial con­cerns is that the CDC doc­u­ments indi­cat­ed that cer­tain groups would be pri­or­i­tized for ear­ly access to the vac­cine. And some of those groups, like the elder­ly and minori­ties, are also the groups that many are con­cerned have been under­rep­re­sent­ed in the ongo­ing clin­i­cal tri­als:

    ...
    Over the past week, both Dr. Antho­ny S. Fau­ci, the country’s top infec­tious dis­ease expert, and Dr. Stephen Hahn, who heads the Food and Drug Admin­is­tra­tion, have said in inter­views with news orga­ni­za­tions that a vac­cine may be avail­able for cer­tain groups before clin­i­cal tri­als have been com­plet­ed, if the data is over­whelm­ing­ly pos­i­tive.

    ...

    The guid­ance not­ed that health care pro­fes­sion­als, includ­ing long-term care employ­ees, would be among the first to receive the prod­uct, along with oth­er essen­tial work­ers and nation­al secu­ri­ty employ­ees. Peo­ple 65 or old­er, as well as Native Amer­i­cans and those who are from “racial and eth­nic minor­i­ty pop­u­la­tions” or incar­cer­at­ed — all com­mu­ni­ties known to be at greater risk of con­tract­ing the virus and expe­ri­enc­ing severe dis­ease — were also pri­or­i­tized in the doc­u­ments.

    ...

    Tri­als that test a vaccine’s effec­tive­ness can take years to yield reli­able results. It’s pos­si­ble to draw con­clu­sions soon­er “if there is an over­whelm­ing effect” in which vac­ci­nat­ed peo­ple appear to be far bet­ter pro­tect­ed from dis­ease, said Pad­mi­ni Pil­lai, a vac­cine researcher and immu­nol­o­gist at M.I.T. But data gath­ered ear­ly in a tri­al might not hold true months down the line. And researchers need time to test large num­bers of peo­ple from a vari­ety of back­grounds to deter­mine how well the vac­cine works in dif­fer­ent pop­u­la­tions — includ­ing the vul­ner­a­ble com­mu­ni­ties iden­ti­fied in the guide­lines.
    ...

    Next, here’s an inter­view of the head of the FDA, Stephen Hahn, about his will­ing­ness to fast-track a vac­cine. The way Hahn puts it, the cri­te­ria for his deci­sion to fast track is sim­ply as long as the ben­e­fits out­weigh the risks:

    The Finan­cial Times

    FDA head says he is will­ing to fast-track Covid-19 vac­cine
    Stephen Hahn insists he will not rush process just to help Don­ald Trump’s elec­tion chances

    Kiran Stacey in Wash­ing­ton
    08/30/2020 6:00am

    The head of the US Food and Drug Admin­is­tra­tion has said he is will­ing to bypass the nor­mal approval process to autho­rise a Covid-19 vac­cine as soon as pos­si­ble — but has insist­ed he will not do so to please Pres­i­dent Don­ald Trump.

    In an inter­view with the Finan­cial Times, Stephen Hahn said his agency was pre­pared to autho­rise a vac­cine before Phase Three clin­i­cal tri­als were com­plete, as long as offi­cials believed the ben­e­fits out­weighed the risks. But he defend­ed his embat­tled organ­i­sa­tion against accu­sa­tions that it was rush­ing the process to boost Mr Trump’s re-elec­tion prospects.

    “It is up to the spon­sor [vac­cine devel­op­er] to apply for autho­ri­sa­tion or approval, and we make an adju­di­ca­tion of their appli­ca­tion,” Dr Hahn said. “If they do that before the end of Phase Three, we may find that appro­pri­ate. We may find that inap­pro­pri­ate, we will make a deter­mi­na­tion.”

    Dr Hahn’s deci­sion whether to give the go-ahead for a Covid-19 vac­cine is like­ly to be one of the most impor­tant and sen­si­tive in US pub­lic health his­to­ry.

    Chi­na and Rus­sia have both approved vac­cines with­out wait­ing for the end of Phase Three tri­als, which are the largest and most rig­or­ous of all the tests that a poten­tial new drug. But they have been crit­i­cised by pub­lic health offi­cials — includ­ing ones in the US — who have warned that doing so could be unsafe.

    Dr Hahn insist­ed there was a safe way to make a vac­cine avail­able before the end of Phase Three tri­als — poten­tial­ly by issu­ing an emer­gency autho­ri­sa­tion for use by cer­tain groups rather than a blan­ket approval.

    “Our emer­gency use autho­ri­sa­tion is not the same as a full approval,” he said. “The legal, med­ical and sci­en­tif­ic stan­dard for that is that the ben­e­fit out­weighs the risk in a pub­lic health emer­gency.”

    But he insist­ed he would not rush a vac­cine to please the pres­i­dent, amid reports that Mr Trump wants a vac­cine to be avail­able before November’s elec­tion to help improve his chance of vic­to­ry.

    “We have a con­ver­gence of the Covid-19 pan­dem­ic with the polit­i­cal sea­son, and we’re just going to have to get through that and stick to our core prin­ci­ples,” he said. “This is going to be a sci­ence, med­i­cine, data deci­sion. This is not going to be a polit­i­cal deci­sion.”

    ...

    Last Sat­ur­day, Mr Trump accused “deep state” ele­ments at the FDA of mov­ing too slow­ly in approv­ing new treat­ments for coro­n­avirus in an effort to harm him polit­i­cal­ly. A day lat­er, Dr Hahn and Mr Trump joint­ly announced emer­gency autho­ri­sa­tion for con­va­les­cent plas­ma, which uses the plas­ma of recov­ered Covid-19 patients as a treat­ment. But Dr Hahn was imme­di­ate­ly crit­i­cised for over­stat­ing its ben­e­fits.

    The FDA chief told the FT he regret­ted his com­ment that plas­ma treat­ment would have saved the lives of 35 out of 100 patients. Data sug­gest that fig­ure is clos­er to 5 out of 100.

    “I cer­tain­ly regret con­tribut­ing to any mis­per­cep­tion,” he said. “I could have done a much bet­ter job last Sun­day explain­ing rel­a­tive risks.”

    ————

    “FDA head says he is will­ing to fast-track Covid-19 vac­cine” by Kiran Stacey; The Finan­cial Times; 08/30/2020

    “In an inter­view with the Finan­cial Times, Stephen Hahn said his agency was pre­pared to autho­rise a vac­cine before Phase Three clin­i­cal tri­als were com­plete, as long as offi­cials believed the ben­e­fits out­weighed the risks. But he defend­ed his embat­tled organ­i­sa­tion against accu­sa­tions that it was rush­ing the process to boost Mr Trump’s re-elec­tion prospects.”

    Will the ben­e­fits of fast-tracked vac­cine approval out­weigh the risks? That’s going to be up to the FDA to decide and based on Dr. Hah­n’s com­ments it sounds like he’s going to be quite open to the idea. It’s unclear to what extent Trump’s recent accu­sa­tions of a “Deep State” plot at the FDA to slow down approvals is impact­ing Hah­n’s deci­sion-mak­ing, but the fact that Hahn and Trump joint­ly over­hyped the val­ue of con­va­les­cent plas­ma one day lat­er does­n’t exact­ly lend con­fi­dence to Hah­n’s abil­i­ty to with­stand Trump’s pres­sure:

    ...
    Dr Hahn insist­ed there was a safe way to make a vac­cine avail­able before the end of Phase Three tri­als — poten­tial­ly by issu­ing an emer­gency autho­ri­sa­tion for use by cer­tain groups rather than a blan­ket approval.

    “Our emer­gency use autho­ri­sa­tion is not the same as a full approval,” he said. “The legal, med­ical and sci­en­tif­ic stan­dard for that is that the ben­e­fit out­weighs the risk in a pub­lic health emer­gency.

    ...

    Last Sat­ur­day, Mr Trump accused “deep state” ele­ments at the FDA of mov­ing too slow­ly in approv­ing new treat­ments for coro­n­avirus in an effort to harm him polit­i­cal­ly. A day lat­er, Dr Hahn and Mr Trump joint­ly announced emer­gency autho­ri­sa­tion for con­va­les­cent plas­ma, which uses the plas­ma of recov­ered Covid-19 patients as a treat­ment. But Dr Hahn was imme­di­ate­ly crit­i­cised for over­stat­ing its ben­e­fits.

    The FDA chief told the FT he regret­ted his com­ment that plas­ma treat­ment would have saved the lives of 35 out of 100 patients. Data sug­gest that fig­ure is clos­er to 5 out of 100.

    “I cer­tain­ly regret con­tribut­ing to any mis­per­cep­tion,” he said. “I could have done a much bet­ter job last Sun­day explain­ing rel­a­tive risks.”
    ...

    Now here’s an inter­view Antho­ny Fau­ci just gave about what is prob­a­bly the most opti­mistic sce­nario pos­si­ble for end­ing the Phase III clin­i­cal tri­als ear­ly: if the ear­ly results are so pos­i­tive there’s a per­ceived moral oblig­a­tion to end the tri­al and make it avail­able as soon as pos­si­ble. If that hap­pens, the inde­pen­dent advi­so­ry boards com­prised of sci­en­tif­ic experts — who hope­ful­ly aren’t sub­ject to gov­ern­ment pres­sures — can rec­om­mend end­ing the tri­al ear­ly, at which point it’s up to the vac­cine devel­op­er to go to the FDA and request emer­gency autho­riza­tion access.

    Still, as crit­ics point out, even if ear­ly results are over­whelm­ing­ly pos­i­tive that does­n’t mean there aren’t dan­ger­ous side effects that can take longer to be detect­ed. In addi­tion, by end­ing the tri­al ear­ly that’s going to reduce the oppor­tu­ni­ty for recruit­ing more peo­ple from the groups that are cur­rent­ly under-rep­re­sent­ed in the tri­als like blacks and His­pan­ics. So it’s pos­si­ble end­ing the tri­als ear­ly due to very pos­i­tive ear­ly results could end up hid­ing very neg­a­tive lat­er results and end up obscur­ing com­pli­ca­tions that only show up in minor­i­ty pop­u­la­tions:

    Kaiser Health News

    Fau­ci Says COVID Vac­cine Tri­als Could End Ear­ly If Results Are Over­whelm­ing

    By Liz Szabo
    Sep­tem­ber 1, 2020

    A COVID-19 vac­cine could be avail­able ear­li­er than expect­ed if ongo­ing clin­i­cal tri­als pro­duce over­whelm­ing­ly pos­i­tive results, said Dr. Antho­ny Fau­ci, the nation’s top infec­tious dis­ease offi­cial, in an inter­view Tues­day with KHN.

    Although two ongo­ing clin­i­cal tri­als of 30,000 vol­un­teers are expect­ed to con­clude by the end of the year, Fau­ci said an inde­pen­dent board has the author­i­ty to end the tri­als weeks ear­ly if inter­im results are over­whelm­ing­ly pos­i­tive or neg­a­tive.

    The Data and Safe­ty Mon­i­tor­ing Board could say, “‘The data is so good right now that you can say it’s safe and effec­tive,’” Fau­ci said. In that case, researchers would have “a moral oblig­a­tion” to end the tri­al ear­ly and make the active vac­cine avail­able to every­one in the study, includ­ing those who had been giv­en place­bos — and accel­er­ate the process to give the vac­cine to mil­lions.

    Fauci’s com­ments come at a time of grow­ing con­cern about whether polit­i­cal pres­sure from the Trump admin­is­tra­tion could influ­ence fed­er­al reg­u­la­tors and sci­en­tists over­see­ing the nation’s response to the nov­el coro­n­avirus pan­dem­ic, and erode shaky pub­lic con­fi­dence in vac­cines. Promi­nent vac­cine experts have said they fear Trump is push­ing for an ear­ly vac­cine approval to help win reelec­tion.

    Fau­ci, direc­tor of the Nation­al Insti­tute of Aller­gy and Infec­tious Dis­eases, said he trusts the inde­pen­dent mem­bers of the DSMB — who are not gov­ern­ment employ­ees — to hold vac­cines to high stan­dards with­out being polit­i­cal­ly influ­enced. Mem­bers of the board are typ­i­cal­ly experts in vac­cine sci­ence and bio­sta­tis­tics who teach at major med­ical schools.

    “If you are mak­ing a deci­sion about the vac­cine, you’d bet­ter be sure you have very good evi­dence that it is both safe and effec­tive,” Fau­ci said. “I’m not con­cerned about polit­i­cal pres­sure.”

    The safe­ty board peri­od­i­cal­ly looks at data from a clin­i­cal tri­al to deter­mine if it’s eth­i­cal to con­tin­ue enrolling vol­un­teers, who are ran­dom­ly assigned to receive either an exper­i­men­tal vac­cine or a place­bo shot. Nei­ther the vol­un­teers nor the health work­ers who vac­ci­nate them know which shot they’re receiv­ing.

    Man­u­fac­tur­ers are now test­ing three COVID vac­cines in large-scale U.S. tri­als. The first two stud­ies — one led by Mod­er­na and the Nation­al Insti­tutes of Health and the oth­er led by Pfiz­er and BioN­Tech — began in late July. Each study was designed to enroll 30,000 par­tic­i­pants. Com­pa­ny offi­cials have said both tri­als have enrolled about half that total. AstraZeneca, which has been run­ning large-scale clin­i­cal tri­als in Great Britain, Brazil and South Africa, launched anoth­er large-scale vac­cine study this week in the U.S., involv­ing 30,000 vol­un­teers. Addi­tion­al vac­cine tri­als are expect­ed to begin this month.

    In tri­als of this size, researchers will know if a vac­cine is effec­tive after as few as 150 to 175 infec­tions, said Dr. Robert Red­field, direc­tor of the Cen­ters for Dis­ease Con­trol and Pre­ven­tion, in a call with reporters Fri­day.

    “It may be sur­pris­ing, but the num­ber of events that need to occur is rel­a­tive­ly small,” Red­field said.

    Right now, only the safe­ty board has access to the tri­al data, said Paul Man­go, deputy chief of staff for pol­i­cy at the Depart­ment of Health and Human Ser­vices. As for when tri­al results will be avail­able, “we can­not deter­mine if it will be the mid­dle of Octo­ber or Decem­ber.”

    Safe­ty boards set “stop­ping rules” at the begin­ning of a study, mak­ing their cri­te­ria for end­ing a tri­al very clear, said Dr. Eric Topol, exec­u­tive vice pres­i­dent for research at Scripps Research in San Diego and an expert on the use of data in med­ical research.

    Although the safe­ty board can rec­om­mend stop­ping a tri­al, the ulti­mate deci­sion to halt a study is made by the sci­en­tists run­ning the tri­al, Topol said.

    A vac­cine man­u­fac­tur­er could then apply to the Food and Drug Admin­is­tra­tion for an emer­gency use autho­riza­tion, which can be grant­ed quick­ly, or con­tin­ue through the reg­u­lar drug approval process, which requires more time and evi­dence.

    ...

    Fau­ci said peo­ple can trust the process, because all the data that out­side mon­i­tors used to make their deci­sions would be made pub­lic.

    “All of that has to be trans­par­ent,” Fau­ci said. “The only time you get con­cerned is if there is any pres­sure to ter­mi­nate the tri­al before you have enough data on safe­ty and effi­ca­cy.”

    Topol and oth­er sci­en­tists have sharply crit­i­cized the FDA in recent weeks, accus­ing Com­mis­sion­er Stephen Hahn of bow­ing to polit­i­cal pres­sure from the Trump admin­is­tra­tion, which has pushed the agency to approve COVID treat­ments faster.

    Stop­ping tri­als ear­ly pos­es a num­ber of risks, such as mak­ing a vac­cine look more effec­tive than it real­ly is, Topol said.

    “If you stop some­thing ear­ly, you can get an exag­ger­at­ed ben­e­fit that isn’t real,” because less pos­i­tive evi­dence only emerges lat­er, Topol said.

    Stop­ping the stud­ies ear­ly also could pre­vent researchers from recruit­ing more minor­i­ty vol­un­teers. So far, only about 1 in 5 tri­al par­tic­i­pants are Black or His­pan­ic. Giv­en that Blacks and His­pan­ics have been hit hard­er than oth­er groups by the pan­dem­ic, Topol said, it’s impor­tant that they make up a larg­er part of vac­cine tri­als.

    End­ing vac­cine tri­als ear­ly also car­ries safe­ty risks, said Dr. Paul Offit, a vac­cine devel­op­er who serves on an NIH advi­so­ry pan­el on COVID vac­cines and treat­ments.

    A small­er, short­er tri­al could fail to detect impor­tant vac­cine side effects, which could become appar­ent only after mil­lions of peo­ple have been immu­nized, said Offit, direc­tor of the Vac­cine Edu­ca­tion Cen­ter at Children’s Hos­pi­tal of Philadel­phia.

    Researchers will con­tin­ue to fol­low vac­ci­nat­ed vol­un­teers for a full year to look for long-term side effects, Red­field said.

    And Fau­ci acknowl­edged that cut­ting a tri­al short could under­mine pub­lic con­fi­dence in COVID vac­cines. One Amer­i­can in three is unwill­ing to get a COVID vac­cine, accord­ing to a recent Gallup Poll.

    ————

    “Fau­ci Says COVID Vac­cine Tri­als Could End Ear­ly If Results Are Over­whelm­ing” by Liz Szabo; Kaiser Health News; 09/01/2020

    The Data and Safe­ty Mon­i­tor­ing Board could say, “‘The data is so good right now that you can say it’s safe and effec­tive,’” Fau­ci said. In that case, researchers would have “a moral oblig­a­tion” to end the tri­al ear­ly and make the active vac­cine avail­able to every­one in the study, includ­ing those who had been giv­en place­bos — and accel­er­ate the process to give the vac­cine to mil­lions.”

    If the best case sce­nario plays out and ear­ly results are amaz­ing there’s noth­ing stop­ping the inde­pen­dent Data and Safe­ty Mon­i­tor­ing Board from rec­om­mend­ing an ear­ly end to the tri­al, although at that point it will still be up to the FDA to grant emer­gency autho­riza­tion approval. This is why it’s going to be so impor­tant to deter­mine whether or not the inde­pen­dent boards rec­om­mend­ed any FDA emer­gency autho­riza­tions:

    ...
    Although the safe­ty board can rec­om­mend stop­ping a tri­al, the ulti­mate deci­sion to halt a study is made by the sci­en­tists run­ning the tri­al, Topol said.

    A vac­cine man­u­fac­tur­er could then apply to the Food and Drug Admin­is­tra­tion for an emer­gency use autho­riza­tion, which can be grant­ed quick­ly, or con­tin­ue through the reg­u­lar drug approval process, which requires more time and evi­dence.
    ...

    But even if the inde­pen­dent board does rec­om­mend end­ing the clin­i­cal tri­als ear­ly and autho­riz­ing emer­gency approval there’s still no way to tru­ly assess the long-term risks of a vac­cine. In addi­tion, end­ing the tri­al ear­ly is only going to exac­er­bate exist­ing short-com­ings in the tri­als like not hav­ing enough minor­i­ty vol­un­teers:

    ...
    Stop­ping tri­als ear­ly pos­es a num­ber of risks, such as mak­ing a vac­cine look more effec­tive than it real­ly is, Topol said.

    “If you stop some­thing ear­ly, you can get an exag­ger­at­ed ben­e­fit that isn’t real,” because less pos­i­tive evi­dence only emerges lat­er, Topol said.

    Stop­ping the stud­ies ear­ly also could pre­vent researchers from recruit­ing more minor­i­ty vol­un­teers. So far, only about 1 in 5 tri­al par­tic­i­pants are Black or His­pan­ic. Giv­en that Blacks and His­pan­ics have been hit hard­er than oth­er groups by the pan­dem­ic, Topol said, it’s impor­tant that they make up a larg­er part of vac­cine tri­als.

    End­ing vac­cine tri­als ear­ly also car­ries safe­ty risks, said Dr. Paul Offit, a vac­cine devel­op­er who serves on an NIH advi­so­ry pan­el on COVID vac­cines and treat­ments.

    A small­er, short­er tri­al could fail to detect impor­tant vac­cine side effects, which could become appar­ent only after mil­lions of peo­ple have been immu­nized, said Offit, direc­tor of the Vac­cine Edu­ca­tion Cen­ter at Children’s Hos­pi­tal of Philadel­phia.

    Researchers will con­tin­ue to fol­low vac­ci­nat­ed vol­un­teers for a full year to look for long-term side effects, Red­field said.
    ...

    And final­ly, here’s an inter­view by Trump’s pre­vi­ous FDA chief, Scott Got­tlieb, where he express­es skep­ti­cism that a vac­cine could be ready before the Novem­ber elec­tions. It’s notable that Got­tlieb sits on the board of Pfiz­er. But there is one sce­nario he saw as fea­si­ble for a pre-elec­tion vac­cine release: if the clin­i­cal tri­als demon­strate that the vac­cine is high­ly effec­tive in the mid­dle of a new “dense” wave of cas­es. In oth­er words, Trump’s hope for a pre-elec­tion vac­cine relies on an ongoin pre-elec­tion surge in cas­es because if you’re going to assess a vac­cine in a short peri­od of time the only way to do it is with a high­ly preva­lent dis­ease:

    CNBC

    Coro­n­avirus vac­cine before elec­tion unlike­ly — Dr. Got­tlieb on FDA chief’s pos­si­ble fast track

    * Late-stage U.S. coro­n­avirus vac­cine tri­als are unlike­ly to have gath­ered enough evi­dence to receive emer­gency approval ahead the elec­tion, Dr. Scott Got­tlieb told CNBC on Mon­day.
    * “I think it’s more like­ly you’re going to get a top-line result some point in Novem­ber and maybe be able to make a deci­sion about an emer­gency use autho­riza­tion after that,” he added.
    * The for­mer FDA com­mis­sion­er said the more effec­tive the vac­cine is, and the more seri­ous the U.S. coro­n­avirus out­break is, the soon­er the tri­als could pro­duce data.

    Kevin Stankiewicz
    Pub­lished Mon, Aug 31 2020 11:40 AM EDT
    Updat­ed Mon, Aug 31 2020 2:52 PM EDT

    Dr. Scott Got­tlieb told CNBC on Mon­day that the late-stage coro­n­avirus vac­cine tri­als under­way in the U.S. are unlike­ly to have gath­ered enough evi­dence to receive emer­gency approval ahead of the Novem­ber pres­i­den­tial elec­tion.

    “I think it’s very unlike­ly. I think it’s more like­ly you’re going to get a top-line result some point in Novem­ber and maybe be able to make a deci­sion about an emer­gency use autho­riza­tion after that,” the for­mer Food and Drug Admin­is­tra­tion com­mis­sion­er said on “Squawk Box.”

    Got­tlieb — who sits on the board of Pfiz­er, which is devel­op­ing a vac­cine to pre­vent Covid-19 — said the more effec­tive the vac­cine is, the soon­er the tri­al is like­ly to gen­er­ate data on effec­tive­ness.

    “If the vac­cines are very effec­tive at pre­vent­ing Covid dis­ease, prob­a­bly 70% to 80% effec­tive based on how the tri­als are pow­ered, you could get a read­out at some point in Octo­ber, a sort of top-line read­out,” he said. “But it’s more like­ly that you’re going to get a read­out from those tri­als in Novem­ber.”

    Got­tlieb said the only cir­cum­stance in which a vac­cine tri­al could offer suf­fi­cient effec­tive­ness data in Octo­ber would be if the U.S. coro­n­avirus out­break is “very dense,” mean­ing there is high trans­mis­sion rates through­out the gen­er­al pop­u­la­tion, and the vac­cines prove to be “very effec­tive” in those in tri­als.

    “But that prob­a­bly wouldn’t leave enough time to issue an emer­gency use autho­riza­tion by Novem­ber, regard­less,” said Got­tlieb, who led the FDA in the Trump admin­is­tra­tion from May 2017 to April 2019.

    Gottlieb’s com­ments Mon­day came after the cur­rent FDA chief, Dr. Stephen Hahn, indi­cat­ed the pub­lic health agency could issue emer­gency autho­riza­tion for a vac­cine before phase three clin­i­cal tri­als are com­plet­ed if the ben­e­fits out­weigh the risks.

    “It is up to the [vac­cine devel­op­er] to apply for autho­riza­tion or approval, and we make an adju­di­ca­tion of their appli­ca­tion,” Hahn said in an inter­view with the Finan­cial Times. “If they do that before the end of phase three, we may find that appro­pri­ate. We may find that inap­pro­pri­ate, we will make a deter­mi­na­tion.”

    Got­tlieb, who pre­ced­ed Hahn at the FDA, said he was not exact­ly sure what Hahn’s com­ments meant.

    “It’s pos­si­ble what Dr. Hahn was refer­ring to was issu­ing an emer­gency use autho­riza­tion before the tri­als are ful­ly com­plete, inso­far as these are two-year tri­als. There’s going to be a two-year peri­od of safe­ty fol­low up on these clin­i­cal tri­als,” Got­tlieb said.

    “It’s like­ly to be the case that there’s going to be an emer­gency use autho­riza­tion if these vac­cines are oth­er­wise safe and effec­tive for some select, high-risk pop­u­la­tions like per­haps front-line health-care work­ers or peo­ple who have infir­mi­ties, elder­ly patients in nurs­ing homes who are at high­er risk of a bad out­come,” Got­tlieb added. “That might be what he meant by say­ing they might issue an emer­gency use autho­riza­tion before the tri­als are quote-unquote com­plete.”

    Pres­i­dent Don­ald Trump has embarked on an effort to accel­er­ate vac­cine devel­op­ment in the U.S. called Oper­a­tion Warp Speed, which aims to pro­vide at least 300 mil­lion dos­es of a coro­n­avirus vac­cine by Jan­u­ary 2021.

    Last week, at the Repub­li­can Nation­al Con­ven­tion, Trump said the U.S. “will pro­duce a vac­cine before the end of the year, or maybe even soon­er,” set­ting off con­cerns again that the approval process could be influ­enced by polit­i­cal con­sid­er­a­tions instead of health and sci­ence.

    Ear­li­er this month, Trump was asked in a radio inter­view whether a vac­cine could be ready before Nov. 3, the date of the pres­i­den­tial elec­tion. “I think in some cas­es, it’s pos­si­ble before but right around that time,” he said in response.

    Devel­op­ing a safe and effec­tive vac­cine to pre­vent a dis­ease is a process that usu­al­ly takes years. But sci­en­tists in the U.S. and around the globe are work­ing with inten­si­fied urgency to come up with a vac­cine to slow the trans­mis­sion of the coro­n­avirus, which has infect­ed more than 25 mil­lion peo­ple world­wide and killed near­ly 847,000 since it was first dis­cov­ered in Wuhan, Chi­na, late last year. The pan­dem­ic also has had dev­as­tat­ing eco­nom­ic con­se­quences.

    Mul­ti­ple com­pa­nies, includ­ing Pfiz­er and Mod­er­na, are in late-stage human tri­als, with thou­sands of peo­ple receiv­ing vac­cines as part of the sci­en­tif­ic stud­ies. John­son & John­son plans to begin its phase three tri­al, poten­tial­ly enrolling up 60,000 peo­ple, in Sep­tem­ber.

    ...

    ————

    “Coro­n­avirus vac­cine before elec­tion unlike­ly — Dr. Got­tlieb on FDA chief’s pos­si­ble fast track” by Kevin Stankiewicz; CNBC; 08/31/2020

    ““I think it’s very unlike­ly. I think it’s more like­ly you’re going to get a top-line result some point in Novem­ber and maybe be able to make a deci­sion about an emer­gency use autho­riza­tion after that,” the for­mer Food and Drug Admin­is­tra­tion com­mis­sion­er said on “Squawk Box.”

    A pre-elec­tion vac­cine announce­ment is very unlike­ly accord­ing to Got­tlieb. But there’s one excep­tion: the more effec­tive the vac­cine is the ear­li­er that effec­tive­ness will man­i­fest itself in the clin­i­cal tri­als. So if the the vac­cine is high­ly effec­tive it’s pos­si­ble that will because sta­tis­ti­cal­ly appar­ent by October...if the pan­dem­ic also end up becom­ing “very dense” with a high trans­mis­sion rate. Keep in mind that low­er the trans­mis­sion rate has been at the core of the efforts to pre­vent the spread of the virus:

    ...
    Got­tlieb — who sits on the board of Pfiz­er, which is devel­op­ing a vac­cine to pre­vent Covid-19 — said the more effec­tive the vac­cine is, the soon­er the tri­al is like­ly to gen­er­ate data on effec­tive­ness.

    “If the vac­cines are very effec­tive at pre­vent­ing Covid dis­ease, prob­a­bly 70% to 80% effec­tive based on how the tri­als are pow­ered, you could get a read­out at some point in Octo­ber, a sort of top-line read­out,” he said. “But it’s more like­ly that you’re going to get a read­out from those tri­als in Novem­ber.”

    Got­tlieb said the only cir­cum­stance in which a vac­cine tri­al could offer suf­fi­cient effec­tive­ness data in Octo­ber would be if the U.S. coro­n­avirus out­break is “very dense,” mean­ing there is high trans­mis­sion rates through­out the gen­er­al pop­u­la­tion, and the vac­cines prove to be “very effec­tive” in those in tri­als.

    “But that prob­a­bly wouldn’t leave enough time to issue an emer­gency use autho­riza­tion by Novem­ber, regard­less,” said Got­tlieb, who led the FDA in the Trump admin­is­tra­tion from May 2017 to April 2019.
    ...

    And notice Got­tlieb’s inter­pre­ta­tion of Stephan Hah­n’s com­ments about issu­ing pre-elec­tion emer­gency autho­riza­tions: Got­tlieb was­n’t sure what Hahn was refer­ring to but sug­gest­ed that maybe cer­tain groups, like front-line health­care work­ers or the elder­ly and nurs­ing home res­i­dents, might be grant­ed emer­gency autho­riza­tion. Don’t for­get that it’s the elder­ly who are at most risk of any vac­cine side-effects that aren’t detect­ed in trun­cat­ed clin­i­cal tri­als end­ed ear­ly:

    ...
    Got­tlieb, who pre­ced­ed Hahn at the FDA, said he was not exact­ly sure what Hahn’s com­ments meant.

    “It’s pos­si­ble what Dr. Hahn was refer­ring to was issu­ing an emer­gency use autho­riza­tion before the tri­als are ful­ly com­plete, inso­far as these are two-year tri­als. There’s going to be a two-year peri­od of safe­ty fol­low up on these clin­i­cal tri­als,” Got­tlieb said.

    It’s like­ly to be the case that there’s going to be an emer­gency use autho­riza­tion if these vac­cines are oth­er­wise safe and effec­tive for some select, high-risk pop­u­la­tions like per­haps front-line health-care work­ers or peo­ple who have infir­mi­ties, elder­ly patients in nurs­ing homes who are at high­er risk of a bad out­come,” Got­tlieb added. “That might be what he meant by say­ing they might issue an emer­gency use autho­riza­tion before the tri­als are quote-unquote com­plete.”
    ...

    A rushed vac­cine autho­rized for just the elder­ly and nurs­ing home patients. Is that going to be Trump’s Octo­ber Sur­prise? If would be eas­i­er to dis­miss the pos­si­bil­i­ty if we had­n’t heard
    all of these top offi­cial talk­ing about the pos­si­bil­i­ty of just that sce­nario this week. It would also be eas­i­er to dis­miss if the Trump admin­is­tra­tion had­n’t just start­ing push­ing a new “herd immu­ni­ty” strat­e­gy this week. Yep, rac­ing for “herd immu­ni­ty” is back on the agen­da of the White House thanks to, Scott Atlas, a new coro­n­avirus advis­er brought into the White House last month. And that “herd immu­ni­ty” pol­i­cy is pre­cise­ly what could bring about the high trans­mis­sion rates Got­tlieb said would be required for ear­ly emer­gency autho­riza­tion. So the good new relat­ed to all of this is that the vac­cine is set to be very thor­ough­ly test­ed thanks to the large num­ber of cas­es in the US. That’s it. The rest is omi­nous news at best.

    Posted by Pterrafractyl | September 2, 2020, 3:32 pm
  7. Here’s a trou­bling update on the AstraZeneca/OSI coro­n­avirus vac­cine safe­ty tri­als that under­scores how fun­da­men­tal­ly dif­fi­cult it can be to safe­ly devel­op a vac­cine: One of the vol­un­teers expe­ri­enced the kind of seri­ous safe­ty issue that, if seen again, could end the vac­cine’s tri­al. The patient is sus­pect­ed of expe­ri­enc­ing some­thing called trans­verse myelitis, which is an autoim­mune response trig­gered by an anti­body that caus­es the immune sys­tem to attack the body’s own tis­sue and can cause pain, mus­cle weak­ness, and paral­y­sis and attack the spinal cord or brain. In this case the patient had an inflamed spinal cord. And while tra­verse myelitis may not be caused by the vac­cine, the fear is that the vac­cine induced a phe­nom­e­non called “mol­e­c­u­lar mim­ic­ry” where a piece of the vac­cine is sim­i­lar enough to tis­sue in the brain or spinal cord that it trig­gers the immune sys­tem to attack that tis­sue.

    AstraZeneca is being crit­i­cized for the rel­a­tive lack of infor­ma­tion about the patient. It sounds like a vol­un­teer in an ear­li­er phase of the AstraZeneca tri­al also expe­ri­enced a sim­i­lar side effect, but it turns out she had mul­ti­ple scle­ro­sis that was unre­lat­ed to the vac­ci­na­tion which could have explained the phe­nom­e­na. In the new case, AstraZeneca is refus­ing to release more infor­ma­tion on the patient, cit­ing patient pri­va­cy, although the com­pa­ny isn’t say­ing how dis­clos­ing more infor­ma­tion would vio­late the their pri­va­cy. So the com­pa­ny itself is being dis­turbing­ly none forth­right about this issue.

    Keep in mind that the AstraZeneca vac­cine isn’t based on the same exper­i­men­tal mRNA tech­nol­o­gy that Mod­er­na’s and Pfiz­er’s vac­cine use. Instead, it relies on a mod­i­fied com­mon cold virus. But that does­n’t mean there could­n’t be impli­ca­tions for these oth­er vac­cines. As the fol­low­ing arti­cle notes, one approach US vac­cine researchers could take in light of this find­ing is to inves­ti­gate the vol­un­teers in the US-based tri­als for signs of inflam­ma­tion in the spinal cord or brain, but it’s an inves­ti­ga­tion that could take one to two months. It’s an exam­ple of the many per­ils of a rushed vac­cine. Per­ils that include pos­si­ble autoim­mune respons­es that attack the brain and spinal cord:

    Kaiser Health News

    NIH ‘Very Con­cerned’ About Seri­ous Side Effect in Coro­n­avirus Vac­cine Tri­al

    By Arthur Allen and Liz Szabo
    Sep­tem­ber 14, 2020

    The Food and Drug Admin­is­tra­tion is weigh­ing whether to fol­low British reg­u­la­tors in resum­ing a coro­n­avirus vac­cine tri­al that was halt­ed when a par­tic­i­pant suf­fered spinal cord dam­age, even as the Nation­al Insti­tutes of Health has launched an inves­ti­ga­tion of the case.

    “The high­est lev­els of NIH are very con­cerned,” said Dr. Avin­dra Nath, intra­mur­al clin­i­cal direc­tor and a leader of viral research at the Nation­al Insti­tute for Neu­ro­log­i­cal Dis­or­ders and Stroke, an NIH divi­sion. “Everyone’s hopes are on a vac­cine, and if you have a major com­pli­ca­tion the whole thing could get derailed.”

    A great deal of uncer­tain­ty remains about what hap­pened to the unnamed patient, to the frus­tra­tion of those avid­ly fol­low­ing the progress of vac­cine test­ing. AstraZeneca, which is run­ning the glob­al tri­al of the vac­cine it pro­duced with Oxford Uni­ver­si­ty, said the tri­al vol­un­teer recov­ered from a severe inflam­ma­tion of the spinal cord and is no longer hos­pi­tal­ized.

    AstraZeneca has not con­firmed that the patient was afflict­ed with trans­verse myelitis, but Nath and anoth­er neu­rol­o­gist said they under­stood this to be the case. Trans­verse myelitis pro­duces a set of symp­toms involv­ing inflam­ma­tion along the spinal cord that can cause pain, mus­cle weak­ness and paral­y­sis. Britain’s reg­u­la­to­ry body, the Med­i­cines and Health­care Prod­ucts Reg­u­la­to­ry Agency, reviewed the case and has allowed the tri­al to resume in the Unit­ed King­dom.

    AstraZeneca “need[s] to be more forth­com­ing with a poten­tial com­pli­ca­tion of a vac­cine which will even­tu­al­ly be giv­en to mil­lions of peo­ple,” said Nath. “We would like to see how we can help, but the lack of infor­ma­tion makes it dif­fi­cult to do so.”

    Any deci­sion about whether to con­tin­ue the tri­al is com­plex because it’s dif­fi­cult to assess the cause of a rare injury that occurs dur­ing a vac­cine tri­al — and because sci­en­tists and author­i­ties have to weigh the risk of uncom­mon side effects against a vac­cine that might curb the pan­dem­ic.

    ...

    The NIH has yet to get tis­sue or blood sam­ples from the British patient, and its inves­ti­ga­tion is “in the plan­ning stages,” Nath said. U.S. sci­en­tists could look at sam­ples from oth­er vac­ci­nat­ed patients to see whether any of the anti­bod­ies they gen­er­at­ed in response to the coro­n­avirus also attack brain or spinal cord tis­sue.

    Such stud­ies might take a month or two, he said. The FDA declined to com­ment on how long it would take before it decides whether to move for­ward.

    Dr. Jesse Good­man, a George­town Uni­ver­si­ty pro­fes­sor and physi­cian who was chief sci­en­tist and lead vac­cine reg­u­la­tor at the FDA dur­ing the Oba­ma admin­is­tra­tion, said the agency will review the data and pos­si­bly con­sult with British reg­u­la­tors before allow­ing resump­tion of the U.S. study, which had just begun when the injury was report­ed. Two oth­er coro­n­avirus vac­cines are also in late-stage tri­als in the U.S.

    If it deter­mines the injury in the British tri­al was caused by the vac­cine, the FDA could pause the tri­al. If it allows it to resume, reg­u­la­tors and sci­en­tists sure­ly will be on the watch for sim­i­lar symp­toms in oth­er tri­al par­tic­i­pants.

    A vol­un­teer in an ear­li­er phase of the AstraZeneca tri­al expe­ri­enced a sim­i­lar side effect, but inves­ti­ga­tors dis­cov­ered she had mul­ti­ple scle­ro­sis that was unre­lat­ed to the vac­ci­na­tion, accord­ing to Dr. Elliot Frohman, direc­tor of the Mul­ti­ple Scle­ro­sis & Neu­roim­munol­o­gy Cen­ter at the Uni­ver­si­ty of Texas.

    Neu­rol­o­gists who study ill­ness­es like trans­verse myelitis say they are rare — occur­ring at a rate of per­haps 1 in 250,000 peo­ple — and strike most often as a result of the body’s immune response to a virus. Less fre­quent­ly, such episodes have also been linked to vac­cines.

    The pre­cise cause of the dis­ease is key to the deci­sion by author­i­ties whether to resume the tri­al. Some­times an under­ly­ing med­ical con­di­tion is “unmasked” by a person’s immune response to the vac­cine, lead­ing to ill­ness, as hap­pened with the MS patient. In that case, the tri­al might be con­tin­ued with­out fear, because the ill­ness was not spe­cif­ic to the vac­cine.

    More wor­ri­some is a phe­nom­e­non called “mol­e­c­u­lar mim­ic­ry.” In such cas­es, some small piece of the vac­cine may be sim­i­lar to tis­sue in the brain or spinal cord, result­ing in an immune attack on that tis­sue in response to a vac­cine com­po­nent. Should that be the case, anoth­er occur­rence of trans­verse myelitis would be like­ly if the tri­al resumed, said Dr. William Schaffn­er, an infec­tious dis­ease spe­cial­ist at the Van­der­bilt Uni­ver­si­ty School of Med­i­cine. A sec­ond case would shut down the tri­al, he said.

    In 1976, a mas­sive swine flu vac­ci­na­tion pro­gram was halt­ed when doc­tors began diag­nos­ing a sim­i­lar dis­or­der, Guil­lain-Bar­ré syn­drome, in peo­ple who received the vac­cine. At the time no one knew how com­mon GBS was, so it was dif­fi­cult to tell whether the episodes were relat­ed to the vac­cine.

    Even­tu­al­ly, sci­en­tists found that the vac­cine increased the risk of the dis­or­der by an addi­tion­al one case among every 100,000 vac­ci­nat­ed patients. Typ­i­cal sea­son­al flu vac­ci­na­tion rais­es the risk of GBS in about one addi­tion­al case in every 1 mil­lion peo­ple.

    “It’s very, very hard” to deter­mine if one rare event was caused by a vac­cine, Schaffn­er said. “How do you attribute an increased risk for some­thing that occurs in one in a mil­lion peo­ple?”

    Before allow­ing U.S. tri­als to restart, the FDA will want to see why the com­pa­ny and an inde­pen­dent data and safe­ty mon­i­tor­ing board (DSMB) in the U.K. felt it was safe to con­tin­ue, Good­man said. The AstraZeneca tri­al in the Unit­ed States has a sep­a­rate safe­ty board.

    FDA offi­cials will need to review full details of the case and may request more infor­ma­tion about the affect­ed study vol­un­teer before decid­ing whether to allow the U.S. tri­al to con­tin­ue, Good­man said. They may also require AstraZeneca to update the safe­ty infor­ma­tion it pro­vides to study par­tic­i­pants.

    It’s pos­si­ble that the volunteer’s health prob­lem was a coin­ci­dence unre­lat­ed to the vac­cine, said Dr. Amesh Adal­ja, a senior schol­ar at the Johns Hop­kins Cen­ter for Health Secu­ri­ty. Stud­ies aren’t usu­al­ly stopped over a sin­gle health prob­lem, even if it’s seri­ous.

    Yet many health lead­ers have expressed frus­tra­tion that AstraZeneca hasn’t released more infor­ma­tion about the health prob­lem that led it to halt its U.K. tri­al.

    “There is just so lit­tle infor­ma­tion about this that it’s impos­si­ble to under­stand what the diag­no­sis was or why the DSMB and spon­sor were reas­sured” that it was safe to con­tin­ue, Good­man said.

    AstraZeneca has said it’s unable to pro­vide more infor­ma­tion about the health prob­lem, say­ing this would vio­late patient pri­va­cy, although it didn’t say how.

    But there’s an excep­tion­al need for trans­paren­cy in a polit­i­cal cli­mate rife with vac­cine hes­i­tan­cy and mis­trust of the Trump administration’s han­dling of the COVID-19 response, lead­ing sci­en­tists say.

    “While I respect the crit­i­cal need for patient con­fi­den­tial­i­ty, I think it would be real­ly help­ful to know what their assess­ment of these issues was,” Good­man said. “What was the diag­no­sis? If there wasn’t a clear diag­no­sis, what is it that led them to feel the tri­al could be restart­ed? There is so much inter­est and poten­tial con­cern about a COVID-19 vac­cine that the more infor­ma­tion that can be pro­vid­ed, the more reas­sur­ing that would be.”

    The FDA will need to bal­ance any pos­si­ble risks from an exper­i­men­tal vac­cine with the dan­ger posed by COVID-19, which has killed near­ly 200,000 Amer­i­cans.

    “There are also poten­tial con­se­quences if you stop a study,” Good­man said.

    If the AstraZeneca vac­cine fails, the U.S. gov­ern­ment is sup­port­ing six oth­er COVID vac­cines in the hope at least one will suc­ceed. The poten­tial prob­lems with the AstraZeneca vac­cine show this to be a wise invest­ment, Adal­ja said.

    “This is part of the idea of not hav­ing just one vac­cine can­di­date going for­ward,” he said. “It gives you a lit­tle more insur­ance.”

    Schaffn­er said researchers need to remem­ber that vac­cine research is unpre­dictable.

    “The inves­ti­ga­tors have inad­vis­ed­ly been hyp­ing their own vac­cine,” Schaffn­er said. “The Oxford inves­ti­ga­tors were out there this sum­mer say­ing, ‘We’re going to get there first.’ But this is exact­ly the sort of rea­son … Dr. [Antho­ny] Fau­ci and the rest of us have been say­ing, ‘You nev­er know what will hap­pen once you get into large-scale human tri­als.’”

    ————

    “NIH ‘Very Con­cerned’ About Seri­ous Side Effect in Coro­n­avirus Vac­cine Tri­al” by Arthur Allen and Liz Szabo; Kaiser Health News; 09/14/2020

    “The NIH has yet to get tis­sue or blood sam­ples from the British patient, and its inves­ti­ga­tion is “in the plan­ning stages,” Nath said. U.S. sci­en­tists could look at sam­ples from oth­er vac­ci­nat­ed patients to see whether any of the anti­bod­ies they gen­er­at­ed in response to the coro­n­avirus also attack brain or spinal cord tis­sue.”

    An autoim­mune response that attacks the brain and spinal cord. Yeah, that’s def­i­nite­ly one of the night­mare side-effects we’d like to avoid. So night­mar­ish that if anoth­er per­son ends up with trans­verse myelitis they’ll prob­a­bly shut the tri­al down. And yet despite the poten­tial sever­i­ty of this find­ing AstraZeneca is remain­ing tight-lipped on any details:

    ...
    A vol­un­teer in an ear­li­er phase of the AstraZeneca tri­al expe­ri­enced a sim­i­lar side effect, but inves­ti­ga­tors dis­cov­ered she had mul­ti­ple scle­ro­sis that was unre­lat­ed to the vac­ci­na­tion, accord­ing to Dr. Elliot Frohman, direc­tor of the Mul­ti­ple Scle­ro­sis & Neu­roim­munol­o­gy Cen­ter at the Uni­ver­si­ty of Texas.

    Neu­rol­o­gists who study ill­ness­es like trans­verse myelitis say they are rare — occur­ring at a rate of per­haps 1 in 250,000 peo­ple — and strike most often as a result of the body’s immune response to a virus. Less fre­quent­ly, such episodes have also been linked to vac­cines.

    The pre­cise cause of the dis­ease is key to the deci­sion by author­i­ties whether to resume the tri­al. Some­times an under­ly­ing med­ical con­di­tion is “unmasked” by a person’s immune response to the vac­cine, lead­ing to ill­ness, as hap­pened with the MS patient. In that case, the tri­al might be con­tin­ued with­out fear, because the ill­ness was not spe­cif­ic to the vac­cine.

    More wor­ri­some is a phe­nom­e­non called “mol­e­c­u­lar mim­ic­ry.” In such cas­es, some small piece of the vac­cine may be sim­i­lar to tis­sue in the brain or spinal cord, result­ing in an immune attack on that tis­sue in response to a vac­cine com­po­nent. Should that be the case, anoth­er occur­rence of trans­verse myelitis would be like­ly if the tri­al resumed, said Dr. William Schaffn­er, an infec­tious dis­ease spe­cial­ist at the Van­der­bilt Uni­ver­si­ty School of Med­i­cine. A sec­ond case would shut down the tri­al, he said.

    ...

    It’s pos­si­ble that the volunteer’s health prob­lem was a coin­ci­dence unre­lat­ed to the vac­cine, said Dr. Amesh Adal­ja, a senior schol­ar at the Johns Hop­kins Cen­ter for Health Secu­ri­ty. Stud­ies aren’t usu­al­ly stopped over a sin­gle health prob­lem, even if it’s seri­ous.

    Yet many health lead­ers have expressed frus­tra­tion that AstraZeneca hasn’t released more infor­ma­tion about the health prob­lem that led it to halt its U.K. tri­al.

    “There is just so lit­tle infor­ma­tion about this that it’s impos­si­ble to under­stand what the diag­no­sis was or why the DSMB and spon­sor were reas­sured” that it was safe to con­tin­ue, Good­man said.

    AstraZeneca has said it’s unable to pro­vide more infor­ma­tion about the health prob­lem, say­ing this would vio­late patient pri­va­cy, although it didn’t say how.
    ...

    Will we even­tu­al­ly get those patient details? We’ll see. But as the arti­cle notes, it’s still pos­si­ble the vac­cine will be released even know­ing a small num­ber of peo­ple might expe­ri­ence this side-effect pos­si­bly. There’s a bal­ance of risks when you’re rac­ing for a vac­cine in the mid­dle of a pan­dem­ic, after all:

    ...
    The FDA will need to bal­ance any pos­si­ble risks from an exper­i­men­tal vac­cine with the dan­ger posed by COVID-19, which has killed near­ly 200,000 Amer­i­cans.

    “There are also poten­tial con­se­quences if you stop a study,” Good­man said.
    ...

    And that will­ing­ness of the FDA to weigh the rel­a­tive risks of not releas­ing a vac­cine and poten­tial­ly approve a vac­cine despite these known risks is part of what this is sig­nif­i­cant update on the vac­cine race. Because while a weigh­ing of risks is cer­tain­ly very appro­pri­ate and nec­es­sary, it’s hard to avoid the con­clu­sion that if the FDA is forced to weigh those risks in, say, mid-Octo­ber, those risks might include the risk of Pres­i­dent Trump not get­ting re-elect­ed with­out a vac­cine announce­ment. It’s a time­ly reminder that if the FDA does indeed end up approv­ing a vac­cine “Octo­ber Sur­prise”, that vac­cine might con­tain a few sur­pris­es of its own. Sur­pris­es for the peo­ple receiv­ing the vac­cine, in this case. The FDA and AstraZeneca pre­sum­ably would­n’t be super sur­prised.

    Posted by Pterrafractyl | September 16, 2020, 4:06 pm

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