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For The Record  

FTR #1138 Bio-Psy-Op Apocalypse Now, Part 10: Bad Medicine

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FTR #1138 This pro­gram was record­ed in one, 60-minute seg­ment

U.S. Army Med­ical Research Insti­tute of Infec­tious Disease–located at Ft. Det­rick and closed by the CDC for safe­ty vio­la­tions in August, 2019.

Intro­duc­tion: Con­tin­u­ing dis­cus­sion about drug treat­ments for, and vac­cines to pre­vent, Covid-19, this pro­gram sets forth infor­ma­tion about the ongo­ing pro­fes­sion­al mas­sag­ing of Gilead Sci­ences’ anti-viral remde­sivir. Only mod­est­ly suc­cess­ful against SARS Cov‑2 (the virus that caus­es Covid-19), remde­sivir has been pro­pelled to the fore­front of treat­ment reg­i­mens for the pan­dem­ic.

Of par­tic­u­lar inter­est are the cir­cum­stances sur­round­ing the CDC’s clo­sure of the U.S. Army Med­ical Research Insti­tute of Infec­tious Dis­eases. The USAMRIID–located at Ft. Detrick–had host­ed Gilead Sci­ences’ ani­mal tri­als of remde­sivir. Remde­sivir was devel­oped to com­bat Ebo­la, and was a fail­ure in its ini­tial pro­fes­sion­al iter­a­tion.

In March of 2019, rhe­sus macaques were infect­ed with Ebo­la at the USAMRIID as part of a project to allow remde­sivir to be mar­ket­ed as an Ebo­la treat­ment with­out meet­ing the pro­fes­sion­al stan­dards of human test­ing. ” . . . This agree­ment was made pos­si­ble through a 2018 Nat­ur­al His­to­ry Study (NHS) of Ebo­la virus con­duct­ed by USAMRIID in close col­lab­o­ra­tion with Gilead Sci­ences, Inc., the spon­sor of remde­sivir devel­op­ment . . .”

Many of the safe­ty vio­la­tions cit­ed by the CDC in its cri­tique of USAMRIID safe­ty and secu­ri­ty pro­ce­dures con­cerned “non-human pri­mates” infect­ed with one or more “select agents” that were not named. The term “select agent” refers to a pathogen being used in lab­o­ra­to­ry pro­ce­dures. Whether the “select agent” was Ebo­la, and whether the safe­ty laps­es were in con­nec­tion with the remdesivir/rhesus mon­key tri­als was not dis­closed.

” . . . . Sev­er­al of the lab­o­ra­to­ry vio­la­tions the CDC not­ed in 2019 con­cerned ‘non-human pri­mates’ infect­ed with a ‘select agent’, the iden­ti­ty of which is unknown — it was redact­ed in all received doc­u­ments, because dis­clos­ing the iden­ti­ty and loca­tion of the agent would endan­ger pub­lic health or safe­ty, the agency says. In addi­tion to Ebo­la, the lab works with oth­er dead­ly agents like anthrax and small­pox. . . ..”

If, for the sake of argu­ment, SARS-CoV­‑2 research was indeed tak­ing plac­ing there was a very real risk of it escap­ing.

Remde­sivir failed in its human tri­als as a treat­ment for Ebo­la: ” . . . . The antivi­ral drug remde­sivir, made by Gilead, under­per­formed ZMapp. . . .  Remde­sivir and ZMapp have been dropped from the tri­al. . . .”

In FTR #1128, we not­ed that ele­ments asso­ci­at­ed with CIA and apartheid gov­ern­ments and bio­log­i­cal war­fare oper­a­tives had been work­ing with, and/or dis­sem­i­nat­ing Ebo­la. Some of these oper­a­tives had been net­work­ing with Fort Det­rick.

Fol­low­ing that dis­mal per­for­mance against Ebo­la, Gilead Sci­ences recast remde­sivir as a broad spec­trum antivi­ral, a mar­ket­ing approach that has led to the drug being autho­rized to treat Covid-19.

In that pro­fes­sion­al rein­car­na­tion, it demon­strat­ed alto­geth­er mod­est suc­cess in Covid-19 tri­als that were pro­fes­sion­al­ly crit­i­cized and which were bad­ly skewed from a method­olog­i­cal stand­point. 

After a tight­en­ing of pro­fes­sion­al method­olog­i­cal stan­dards at the USAMRIID, it was dis­closed that most of the insti­tu­tion’s oper­a­tives are pri­vate con­trac­tors! From the stand­point of insti­tu­tion­al secu­ri­ty, the broad use of pri­vate con­trac­tors ren­ders USAMRIID sub­ject to pen­e­tra­tion by any num­ber of poten­tial mis­cre­ants. ” . . . . ‘A major­i­ty of our lab­o­ra­to­ry work­ers are contractors–putting teeth in the con­tracts to ensure they’re fol­low­ing the shalls, wills and musts are things we’ve done in the inter­im,’ said [Brigadier Gen­er­al Mike] Tal­ley. . . .”

As not­ed in past pro­grams, Gilead Sci­ences is very well-con­nect­ed pro­fes­sion­al­ly, with for­mer Sec­re­tary of Defense Don­ald Rums­feld (among oth­er polit­i­cal lumi­nar­ies) serv­ing on its board of direc­tors. Rums­feld was chair­man of the board from 1997 until he left in 2001 to become George W. Bush’s Sec­re­tary of Defense. The fir­m’s stock has been heav­i­ly invest­ed in by hedge funds, includ­ing Robert Mer­cer’s Renais­sance Tech­nolo­gies. Gilead Sci­ences’ stock has been a major dri­ver of the stock mar­ket’s per­for­mance.

Sev­er­al years into his tenure at the Pen­ta­gon, Rums­feld made a killing on the sale of Gilead Sci­ences’ stock, which rose expo­nen­tial­ly in val­ue fol­low­ing its devel­op­ment of Tam­i­flu as a treat­ment for H5N1 avian flu. ” . . . . The firm made a loss in 2003, the year before con­cern about bird flu start­ed. Then rev­enues from Tam­i­flu almost quadru­pled, to $44.6m, help­ing put the com­pa­ny well into the black. Sales almost quadru­pled again, to $161.6m last year. Dur­ing this time the share price tre­bled. Mr Rums­feld sold some of his Gilead shares in 2004 reap­ing – accord­ing to the finan­cial dis­clo­sure report he is required to make each year – cap­i­tal gains of more than $5m. The report showed that he still had up to $25m-worth of shares at the end of 2004, and at least one ana­lyst believes his stake has grown well beyond that fig­ure, as the share price has soared. . . .”

The U.S. gov­ern­ment was among the cus­tomers whose pur­chas­es drove up the Gilead earn­ings and stock price: ” . . . . What’s more, the fed­er­al gov­ern­ment is emerg­ing as one of the world’s biggest cus­tomers for Tam­i­flu. In July, the Pen­ta­gon ordered $58 mil­lion worth of the treat­ment for U.S. troops around the world, and Con­gress is con­sid­er­ing a mul­ti-bil­lion dol­lar pur­chase. . . .”

(Recall that the H5N1 virus is one of the gain-of-func­tion exper­i­ments that was sus­pend­ed in 2014 and then green­light­ed by the Trump admin­is­tra­tion in 2017. Those exper­i­ments engi­neered the virus to infect fer­rets, a maneu­ver that made the virus com­mu­ni­ca­ble by upper res­pi­ra­to­ry activ­i­ty. One can but won­der if those G‑O-F exper­i­ments were con­nect­ed to the recast­ing of remde­sivir as a broad spec­trum antivi­ral.)

Dur­ing the post‑9/11 peri­od of explod­ing gov­ern­ment invest­ments in biode­fense pro­grams, Rums­feld was still hold­ing onto mas­sive amounts of Gilead­’s stock, which was rapid­ly increas­ing in val­ue. What kind of rela­tion­ship did Gilead devel­op with the US biode­fense nation­al secu­ri­ty state dur­ing this peri­od? That seems like an  impor­tant ques­tion at this point in time. 

In FTR #1136, we not­ed that the med­ical and sci­en­tif­ic inter­ests in charge of Lyme Dis­ease treat­ment and diag­no­sis were not only finan­cial ben­e­fi­cia­ries of the ther­a­peu­tic sta­tus quo, but were also tasked with dis­cred­it­ing Lyme patients and physi­cians who chal­lenged that sta­tus quo. In light of the evi­dence that Lyme Dis­ease was the out­growth of bio­log­i­cal war­fare research, the pro­fes­sion­al rela­tion­ship between gov­ern­men­tal insti­tu­tions involved with BW research and biotech­nol­o­gy and phar­ma­ceu­ti­cal firms prof­it­ing from the treat­ment of dis­eases those insti­tu­tions devel­op and deploy is worth con­tem­plat­ing! 

Pre­vi­ous broad­casts have doc­u­ment­ed the skewed, pref­er­en­tial treat­ment of remde­sivir by pow­er­ful polit­i­cal and finan­cial play­ers with sig­nif­i­cant invest­ment in the suc­cess of remde­sivir.

The pro­gram con­cludes with three updates of pre­vi­ous lines of inquiry”

  1. Past pro­grams have high­light­ed pos­si­ble vec­tors into Wuhan for the SARS CoV‑2. We note that there was a work­shop held at the Wuhan lab in ear­ly Novem­ber of 2019, fea­tur­ing sci­en­tists and bio-lab pro­fes­sion­als from around the world. This con­fer­ence may have been among the oppor­tu­ni­ties to spread the virus, and/or a co-vec­tor and/or cross-vec­tor. ” . . . . The work­shop is designed for lab­o­ra­to­ry man­agers and direc­tors, research and lab­o­ra­to­ry staffs main­ly from devel­op­ing coun­tries who plan to car­ry out infec­tious dis­ease research in biosafe­ty facil­i­ties. The work­shop will address key aspects of biosafe­ty and pro­vide prac­ti­cal train­ing in high lev­el biosafe­ty lab­o­ra­to­ries (BSL). This work­shop will invite a group of well-known schol­ars and experts from relat­ed fields at home and abroad to pro­vide the the­o­ret­i­cal and prac­ti­cal cours­es. . . .”
  2. As not­ed in past pro­grams the Wuhan Insti­tute of Virol­o­gy was engaged in bat-borne coro­n­avirus research, which includ­ed the genet­ic mod­i­fi­ca­tion of such organ­isms. That research was a joint U.S./Chinese under­tak­ing, with the U.S. fund­ing com­ing from insti­tu­tions which have front­ed for Amer­i­can intel­li­gence and the Pen­ta­gon. That joint U.S./Chinese under­tak­ing was ter­mi­nat­ed by the Trump admin­is­tra­tion in May! In addi­tion: ” . . . . Many of the sci­en­tists at the Wuhan Insti­tute of Virol­o­gy have been trained by the U.S. government’s PREDICT project. . . . USAID’s PREDICT project . . . will end this Sep­tem­ber after 10 years and two six-month exten­sions as USAID launch­es a new project that applies the data PREDICT col­lect­ed. . . .”
  3. Oth­er broad­casts have explored the Wuhan Mil­i­tary World Games–a mil­i­tary sports competition–as a pos­si­ble vec­tor­ing vehi­cle. We update that path of inquiry with dis­cus­sion of the U.S. del­e­ga­tion as a pos­si­ble vec­tor­ing agent for the spread of the dis­ease in the U.S. ” . . . . Con­trary to the Pentagon’s insis­tence, how­ev­er, an inves­ti­ga­tion of COVID-19 cas­es in the mil­i­tary from offi­cial and pub­lic source mate­ri­als shows that a strong cor­re­la­tion exists in COVID-19 cas­es report­ed at U.S. mil­i­tary facil­i­ties that are home bases of mem­bers of the U.S. team that went to Wuhan. Before March 31, when the Pen­ta­gon restrict­ed the release of infor­ma­tion about COVID-19 cas­es at instal­la­tions for secu­ri­ty rea­sons, infec­tions occurred at a min­i­mum of 63 mil­i­tary facil­i­ties where team mem­bers returned after the Wuhan games. Addi­tion­al­ly, the U.S. team used char­tered flights to and from the games via Seat­tle-Taco­ma Inter­na­tion­al Air­port. Wash­ing­ton was one of the ear­li­est states to show a spike in COVID-19. . . .” We also note that the U.S. del­e­ga­tion con­tained: ” . . . . nine pub­lic-affairs offi­cers . . . and two State Depart­ment per­son­nel, accord­ing to DOD doc­u­ments. . . .” “Pub­lic affairs offi­cer” is a com­mon cov­er for CIA per­son­nel.

1. Many of the safe­ty vio­la­tions cit­ed by the CDC in its cri­tique of USAMRIID safe­ty and secu­ri­ty pro­ce­dures con­cerned “non-human pri­mates” infect­ed with one or more “select agents” that were not named. The term “select agent” refers to a pathogen being used in lab­o­ra­to­ry pro­ce­dures. Whether the “select agent” was Ebo­la, and whether the safe­ty laps­es were in con­nec­tion with the remdesivir/rhesus mon­key tri­als was not dis­closed.

” . . . . Sev­er­al of the lab­o­ra­to­ry vio­la­tions the CDC not­ed in 2019 con­cerned ‘non-human pri­mates’ infect­ed with a ‘select agent’, the iden­ti­ty of which is unknown — it was redact­ed in all received doc­u­ments, because dis­clos­ing the iden­ti­ty and loca­tion of the agent would endan­ger pub­lic health or safe­ty, the agency says. In addi­tion to Ebo­la, the lab works with oth­er dead­ly agents like anthrax and small­pox. . . ..”

If, for the sake of argu­ment, SARS-CoV­‑2 research was indeed tak­ing plac­ing there was a very real risk of it escap­ing.

“Army germ lab shut down by CDC in 2019 had sev­er­al ‘seri­ous’ pro­to­col vio­la­tions that year” by Diana DiGan­gi; ABC7 WJLA; 01/22/2020

In 2019, an Army lab­o­ra­to­ry at Fort Det­rick that stud­ies dead­ly infec­tious mate­r­i­al like Ebo­la and small­pox was shut down for a peri­od of time after a CDC inspec­tion, with many projects being tem­porar­i­ly halt­ed.

The lab itself report­ed that the shut­down order was due to ongo­ing infra­struc­ture issues with waste­water decon­t­a­m­i­na­tion, and the CDC declined to pro­vide the rea­son for the shut­down due to nation­al secu­ri­ty con­cerns.

ABC7 has received doc­u­ments from the CDC out­lin­ing vio­la­tions they dis­cov­ered dur­ing a series of inspec­tions that year, some of which were labeled “seri­ous.”

Ear­li­er that year, the US Army Med­ical Research Insti­tute had announced an exper­i­ment at the Fort Det­rick lab­o­ra­to­ry that would involve infect­ing rhe­sus macaque mon­keys with active Ebo­la virus to test a cure they were devel­op­ing.

Sev­er­al of the lab­o­ra­to­ry vio­la­tions the CDC not­ed in 2019 con­cerned “non-human pri­mates” infect­ed with a “select agent”, the iden­ti­ty of which is unknown — it was redact­ed in all received doc­u­ments, because dis­clos­ing the iden­ti­ty and loca­tion of the agent would endan­ger pub­lic health or safe­ty, the agency says. In addi­tion to Ebo­la, the lab works with oth­er dead­ly agents like anthrax and small­pox.

Select agents are defined by the CDC as “bio­log­i­cal agents and tox­ins that have been deter­mined to have the poten­tial to pose a severe threat to pub­lic health and safe­ty, to ani­mal and plant health, or to ani­mal or plant prod­ucts.”

OBSERVATION 1

Sever­i­ty lev­el: Seri­ous

The CDC report­ed that an indi­vid­ual par­tial­ly entered a room mul­ti­ple times with­out the required res­pi­ra­to­ry pro­tec­tion while oth­er peo­ple in that room were per­form­ing pro­ce­dures with a non-human pri­mate on a necrop­sy table.

“This devi­a­tion from enti­ty pro­ce­dures result­ed in a res­pi­ra­to­ry occu­pa­tion­al expo­sure to select agent aerosols,” the CDC wrote.

OBSERVATION 2

Sever­i­ty lev­el: Seri­ous

The CDC report­ed that the lab did not ensure that employ­ee train­ing was prop­er­ly ver­i­fied when it came to tox­ins and select agents.

“These fail­ures were rec­og­nized through video review of lab­o­ra­to­ri­ans’ work­ing in BSL3 and ABSL3 labs,” their report said. “[These] indi­cate the [lab]’s means used to ver­i­fy per­son­nel under­stood the train­ing had not been effec­tive, lead­ing to increased risk of occu­pa­tion­al expo­sures.”

The CDC went on to spec­i­fy that a lab­o­ra­to­ri­an who was not wear­ing appro­pri­ate res­pi­ra­to­ry pro­tec­tion was seen mul­ti­ple times “par­tial­ly enter­ing” a room where non-human pri­mates that were infect­ed with [redact­ed] were “housed in open caging.” They also observed a lab­o­ra­to­ri­an dis­pos­ing of waste in a bio­haz­ardous waste bin with­out gloves on.

OBSERVATION 3

Sever­i­ty lev­el: Mod­er­ate

In this vio­la­tion obser­va­tion, the CDC went into more detail on the inci­dent of the work­er not wear­ing gloves while dis­pos­ing of bio­haz­ardous waste, writ­ing that “biosafe­ty and con­tain­ment pro­ce­dures must be suf­fi­cient to con­tain the select agent or tox­in.”

The cor­rec­tive action they rec­om­mend­ed was to con­firm that rel­e­vant per­son­nel have been trained to wear gloves to pre­vent expo­sure to haz­ardous mate­ri­als.

OBSERVATION 4

Sever­i­ty lev­el: Seri­ous

In this obser­va­tion, the CDC notes that the Unit­ed States Army Med­ical Research Insti­tute of Infec­tious Dis­eases had “sys­tem­at­i­cal­ly failed to ensure imple­men­ta­tion of biosafe­ty and con­tain­ment pro­ce­dures com­men­su­rate with the risks asso­ci­at­ed with work­ing with select agents and tox­ins.”

The vio­la­tion specif­i­cal­ly observed involved “enti­ty per­son­nel […] prop­ping open” a door while remov­ing “large amounts of bio­haz­ardous waste” from an adja­cent room, “[increas­ing] the risk of con­t­a­m­i­nat­ed air from [the room] escap­ing and being drawn into the [redact­ed]” where the peo­ple work­ing “typ­i­cal­ly do not wear res­pi­ra­to­ry pro­tec­tion.”

OBSERVATION 5

Sever­i­ty lev­el: Mod­er­ate

The CDC report­ed that the lab­o­ra­to­ry failed to safe­guard against unau­tho­rized access to select agents. They wrote that per­son­al pro­tec­tive equip­ment worn while decon­t­a­m­i­nat­ing some­thing con­t­a­m­i­nat­ed by a select agent had been stored in open bio­haz­ard bags, in an area of the facil­i­ty that the CDC has redact­ed for secu­ri­ty rea­sons.

“By stor­ing reg­u­lat­ed waste in this area, the enti­ty did not lim­it access to those with access approval,” they wrote.

OBSERVATION 6

Sever­i­ty lev­el: Mod­er­ate

The CDC reports that some­one at the lab did not main­tain an accu­rate or cur­rent inven­to­ry for a tox­in.

OBSERVATION 7

Sever­i­ty lev­el: Low

The CDC reports that a build­ing at the Fort Det­rick lab­o­ra­to­ry didn’t have a “sealed sur­face to facil­i­tate clean­ing and decon­t­a­m­i­na­tion.” This includ­ed cracks around a con­duit box, cracks in the ceil­ing, and a crack in the seam above a bio­log­i­cal safe­ty cab­i­net.

2a. Of par­tic­u­lar inter­est are the cir­cum­stances sur­round­ing the CDC’s clo­sure of the U.S. Army Med­ical Research Insti­tute of Infec­tious Dis­eases. The USAMRIID–located at Ft. Detrick–had host­ed Gilead Sci­ences’ ani­mal tri­als of remde­sivir. Remde­sivir was devel­oped to com­bat Ebo­la, and was a fail­ure in its ini­tial pro­fes­sion­al iter­a­tion.

In March of 2019, rhe­sus macaques were infect­ed with Ebo­la at the USAMRIID as part of a project to allow remde­sivir to be mar­ket­ed as an Ebo­la treat­ment with­out meet­ing the pro­fes­sion­al stan­dards of human test­ing. ” . . . This agree­ment was made pos­si­ble through a 2018 Nat­ur­al His­to­ry Study (NHS) of Ebo­la virus con­duct­ed by USAMRIID in close col­lab­o­ra­tion with Gilead Sci­ences, Inc., the spon­sor of remde­sivir devel­op­ment . . .”

“USAMRIID Research Pro­vides Reg­u­la­to­ry Frame­work for Devel­op­ing Ebo­la Virus Ther­a­peu­tic under FDA “Ani­mal Rule”” by Caree Van­der Lin­den; 3/28/2019.

The U.S. Army Med­ical Research Insti­tute of Infec­tious Dis­eases (USAMRIID) today announced that, for the first time, the U.S. Food and Drug Admin­is­tra­tion (FDA) has pro­vid­ed for­mal reg­u­la­to­ry agree­ment for use of an ani­mal mod­el to sup­port devel­op­ment of a drug can­di­date, remde­sivir, for treat­ing dead­ly Ebo­la virus (EBOV)infections. This agree­ment was made pos­si­ble through a 2018 Nat­ur­al His­to­ry Study (NHS) of Ebo­la virus con­duct­ed by USAMRIID in close col­lab­o­ra­tion with Gilead Sci­ences, Inc., the spon­sor of remde­sivir devel­op­ment, and The Gene­va Foun­da­tion (Gene­va), and fund­ed by the Joint Project Man­ag­er for Med­ical Coun­ter­mea­sure Sys­tems (JPM-MCS), a com­po­nent of the U.S. Depart­ment of Defense’s Joint Pro­gram Exec­u­tive Office for Chem­i­cal, Bio­log­i­cal, Radi­o­log­i­cal and Nuclear Defense.

Specif­i­cal­ly, FDA agreed that the rhe­sus macaque, infect­ed by intra­mus­cu­lar (IM) injec­tion, is a rel­e­vant and ade­quate­ly char­ac­ter­ized mod­el of Ebo­la virus dis­ease to sup­port fil­ing under the FDA Ani­mal Rule. In addi­tion, the agency agreed that the rhe­sus IM/EBOV dis­ease mod­el is suf­fi­cient as a sin­gle ani­mal mod­el for ther­a­peu­tic prod­uct devel­op­ment. Notably, FDA also agreed that a spe­cif­ic delayed time-to-treat approach is appro­pri­ate for future non­clin­i­cal stud­ies aimed at char­ac­ter­iz­ing the effi­ca­cy of remde­sivir.

Spon­sors must demon­strate effi­ca­cy before a med­ical prod­uct can be approved by the FDA; how­ev­er, for cer­tain prod­ucts, when obtain­ing effi­ca­cy data from human patients is not eth­i­cal or fea­si­ble, the FDA may grant approval under the Ani­mal Rule. Such approval would be based on effi­ca­cy data from well-con­trolled stud­ies in ade­quate­ly char­ac­ter­ized ani­mal model(s), when the results of those stud­ies estab­lish that the drug can­di­date is rea­son­ably like­ly to pro­duce clin­i­cal ben­e­fit in humans. The spon­sor must still demon­strate the product’s safe­ty in humans.

“For years, devel­op­ment of Ebo­la virus med­ical coun­ter­mea­sures has been sub­ject to reg­u­la­to­ry uncer­tain­ties regard­ing which mod­els, if any, would be accept­able to the FDA as a foun­da­tion for eval­u­at­ing effi­ca­cy under the Ani­mal Rule,” said COL Gary Wheel­er, USAMRIID com­man­der. “The study design and data-qual­i­ty pos­ture USAMRIID adopt­ed for the Ebo­la virus NHS sets a prece­dent that has the poten­tial to be use­ful for med­ical coun­ter­mea­sure devel­op­ment efforts tar­get­ing oth­er sim­i­lar human pathogens, such as Mar­burg or Sudan virus­es.

USAMRIID and Gilead Sci­ences, Inc. worked in close part­ner­ship to devel­op the study plan for con­duct­ing the IM/EBOV NHS in rhe­sus mon­keys, ana­lyze the study out­come and sub­mit data to the FDA. A team of over 100 USAMRIID and Gene­va per­son­nel, rep­re­sent­ing the divi­sions of Mol­e­c­u­lar and Trans­la­tion­al Sci­ences, Virol­o­gy, Teleme­try, Pathol­o­gy, Vet­eri­nary Med­i­cine, Advanced Research Stud­ies and Qual­i­ty Assur­ance par­tic­i­pat­ed in the study, which was con­duct­ed in a Biosafe­ty Lev­el 4 (BSL‑4) lab­o­ra­to­ry under max­i­mum con­tain­ment con­di­tions. Impor­tant­ly, this project was the first-ever study to be com­plet­ed in com­pli­ance with Good Lab­o­ra­to­ry Prac­tice (GLP) stan­dards in a BSL‑4 lab­o­ra­to­ry. In Jan­u­ary 2019, FDA audi­tors vis­it­ed USAMRIID to con­duct a data qual­i­ty and integri­ty inspec­tion of USAMRIID’s GLP facil­i­ties and process­es. The results of the audit were report­ed as “No Action Indi­cat­ed,” a clas­si­fi­ca­tion that occurs when no objec­tion­able con­di­tions or prac­tices were found dur­ing the inspec­tion.

“To date, there are no FDA-approved ther­a­peu­tics for treat­ment of Ebo­la virus dis­ease. Both the cur­rent out­break in the Demo­c­ra­t­ic Repub­lic of Con­go and the 2014–2016 West Africa out­break, the largest in his­to­ry, high­light the urgent need for antivi­ral ther­a­py to com­bat this dead­ly dis­ease. We are com­mit­ted to devel­op­ing our inves­ti­ga­tion­al antivi­ral agent, remde­sivir, for the treat­ment of Ebo­la virus infec­tion using the Ani­mal Rule or oth­er appro­pri­ate reg­u­la­to­ry path­way based on feed­back from FDA,” said John McHutchi­son, AO, MD, Chief Sci­en­tif­ic Offi­cer and Head of Research and Devel­op­ment, Gilead Sci­ences, Inc. Remde­sivir is an inves­ti­ga­tion­al agent and is not approved by any reg­u­la­to­ry agency glob­al­ly. Its safe­ty and effi­ca­cy have not been estab­lished.“

This project is a tes­ta­ment to the effi­cien­cy of pub­lic-pri­vate part­ner­ship to accel­er­ate the devel­op­ment of crit­i­cal­ly need­ed med­ical coun­ter­mea­sures,” said COL David Ham­mer, Joint Project Man­ag­er for Med­ical Coun­ter­mea­sure Sys­tems. “We can advance prod­ucts more quick­ly when we work togeth­er to lever­age the skills of mul­ti­ple orga­ni­za­tions.”

The NHS was con­duct­ed as part of the over­all remde­sivir devel­op­ment plan, and prod­uct-inde­pen­dent qual­i­fi­ca­tion of the rhe­sus IM/EBOV mod­el through the FDA Ani­mal Mod­el Qual­i­fi­ca­tion Pro­gram has not been sought or obtained.

2b. In FTR #1128, we not­ed that ele­ments asso­ci­at­ed with CIA and apartheid gov­ern­ments and bio­log­i­cal war­fare oper­a­tives had been work­ing with, and/or dis­sem­i­nat­ing Ebo­la. Some of these oper­a­tives had been net­work­ing with Fort Det­rick.

  1. Ebo­la was appar­ent­ly the focal point of some of Lar­ry Ford’s work: ” . . . . Ford told the Rileys and oth­ers his sub­se­quent work for the mil­i­tary and the CIA includ­ed research on bio­log­i­cal and chem­i­cal weapons, con­sult­ing on Iraqi capa­bil­i­ties dur­ing the Gulf War, and sneak­ing into epi­dem­ic hot zones in Africa to gath­er sam­ples of such killer organ­isms as the Ebo­la and Mar­burg virus­es. . . .”
  2. Dr. Stamps–Zimbabwe’s Health Min­is­ter–had some point­ed obser­va­tions about out­breaks of Ebo­la dur­ing that nation’s war of inde­pen­dence and his belief that they result­ed from Project Coast. Note that Hat­fill was involved with the Rhode­sian Selous Scouts: “ . . . . ‘I have my sus­pi­cions about Ebo­la too. [Dr. Stamps is quoted–the Health Min­is­ter of Zim­bab­we] It devel­oped along the line of the Zam­bezi Riv­er, and I sus­pect that this may have been an exper­i­ment to see if a new virus could be estab­lished to infect peo­ple. We looked on the sero­log­i­cal evi­dence on strange cas­es, includ­ing a fif­teen-year-old child which occurred in 1980. Noth­ing real­ly made epi­demi­o­log­i­cal sense. Do I have evi­dence? Only cir­cum­stan­tial. In fact, the Rhode­sian secu­ri­ty forces were more expert than the Nazis at cov­er­ing up evi­dence.’ . . .”
  3. Cor­rob­o­rat­ing some of Dr. Stamps’ sus­pi­cions con­cern­ing Ebo­la, “Gert” (a pseu­do­nym for a vet­er­an of Project Coast) dis­cussed the use of that virus and the relat­ed Mar­burg virus in Project Coast. “Gert” also implies that US sci­en­tists from Ft. Det­rick (Dr. Ford? Steven Hat­fill) were involved with a Zairi­an out­break. “ . . . . ‘Look, I know what one of the very, very, very secret spe­cial­ized units had. We had to test it. And that was viral cap­sules that were specif­i­cal­ly relat­ed to Con­go fever and the hem­or­rhag­ic fevers.’ Ebo­la? ‘Yes.’ So Gert is begin­ning to cor­rob­o­rate Dr. Stamp’s sus­pi­cions in Harare that Ebo­la and Mar­burg, although indige­nous, were also arti­fi­cial­ly seed­ed into South­ern Africa. Bas­son, says Gert, was involved in all this. (when the last ter­ri­ble Ebo­la out­break occurred in Kik­wit, Zaire, as late as 1995, Gert claims that Bas­son was there, unof­fi­cial­ly. Twen­ty years ear­li­er, when the vil­lage of Yam­buku in north­ern Zaire wit­nessed one of the first major Ebo­la out­breaks, two South African sci­en­tists were there, alleged­ly work­ing hand in glove with US mil­i­tary per­son­nel from Fort Det­rick.) . . . . ”

3. Fol­low­ing a tight­en­ing of pro­fes­sion­al method­olog­i­cal stan­dards at the USAMRIID, it was dis­closed that most of the insti­tu­tion’s oper­a­tives are pri­vate con­trac­tors! From the stand­point of insti­tu­tion­al secu­ri­ty, the broad use of pri­vate con­trac­tors ren­ders USAMRIID sub­ject to pen­e­tra­tion by any num­ber of poten­tial mis­cre­ants.

” . . . . ‘A major­i­ty of our lab­o­ra­to­ry work­ers are contractors–putting teeth in the con­tracts to ensure they’re fol­low­ing the shalls, wills and musts are things we’ve done in the inter­im,’ said [Brigadier Gen­er­al Mike] Tal­ley. . . .”

“Army lead­er­ship share details on changes made to reopen Fort Det­rick labs” by Jas­mine Pelaez; WDVM; 10/09/2019

Octo­ber marks three months since the clo­sure of U.S. Army med­ical research lab­o­ra­to­ries at Fort Det­rick. . . .

Army lead­er­ship from Fort Det­rick report­ed to mem­bers of the Con­tain­ment Lab­o­ra­to­ry Com­mu­ni­ty Advi­so­ry Com­mit­tee Tues­day to address the sus­pen­sion of biosafe­ty lev­el 3 and 4 labs at the Unit­ed States Army Med­ical Research Insti­tute of Infec­tious Dis­eases (USAMRIID).

“We’ve had to make adjust­ments. We can’t keep doing things the way we’ve always done it,” explained Com­mand­ing Gen­er­al for Med­ical Research and Devel­op­ment Com­mand at Fort Det­rick, Brigadier Gen­er­al Mike Tal­ley

The labs were closed down on July 18 after a cease and desist order by the Cen­ter for Dis­ease Con­trol and Pre­ven­tion (CDC) after find­ing mechan­i­cal issues and human error in treat­ing lab­o­ra­to­ry waste­water.

Tal­ley out­lined that CDC per­son­nel have been embed­ded in the labs. Progress includes review­ing about 31 stan­dard oper­at­ing pro­ce­dures, and adding more non-com­mis­sioned offi­cer involve­ment.

“A major­i­ty of our lab­o­ra­to­ry work­ers are contractors–putting teeth in the con­tracts to ensure they’re fol­low­ing the shalls, wills and musts are things we’ve done in the inter­im,” said Tal­ley.

Train­ing is a main focus mov­ing forward–Talley explains that per­son­nel work­ing with­in the high­er-lev­el labs will go through cer­ti­fi­ca­tion.

“Only those per­son­nel that have been cer­ti­fied through the train­ing are going to be allowed to go back into the lab­o­ra­to­ries, and there is a sol­id sus­tain­ment plan to keep their skills up– we haven’t done this before,” Tal­ley explained.

May­or Michael O’Connor says the plans do sound promis­ing to ensure com­mu­ni­ty safe­ty, but com­mu­ni­ca­tion is key.

“The ongo­ing com­mu­ni­ca­tion is what’s real­ly crit­i­cal. When there’s any kind of inci­dent at the Fort that the com­mu­ni­ty could learn about, it’s impor­tant for us in lead­er­ship to hear about that before we read about it in the news­pa­per,” O’Connor said.

Army lead­er­ship aims to con­struct a new steam ster­il­iza­tion plant at Fort Det­rick. This will be put out for bid world­wide.

4. Remde­sivir failed in its human tri­als as a treat­ment for Ebo­la: ” . . . . The antivi­ral drug remde­sivir, made by Gilead, under­per­formed ZMapp. . . .  Remde­sivir and ZMapp have been dropped from the tri­al. . . .”

Fol­low­ing that dis­mal per­for­mance against Ebo­la, Gilead Sci­ences recast remde­sivir as a broad spec­trum antivi­ral, a mar­ket­ing approach that has led to the drug being autho­rized to treat Covid-19. In that pro­fes­sion­al rein­car­na­tion, it demon­strat­ed alto­geth­er mod­est suc­cess in Covid-19 tri­als that were pro­fes­sion­al­ly crit­i­cized and which were bad­ly skewed from a method­olog­i­cal stand­point. 

“For the first time, clin­i­cal tri­al results show Ebo­la drugs improve sur­vival rates” by Helen Bran­swell; STAT News; 08/12/2019

A his­toric clin­i­cal tri­al has shown that two ther­a­pies made from Ebo­la anti­bod­ies appear to be improv­ing sur­vival rates among peo­ple who receive them, health offi­cials announced Mon­day. The announce­ment marks the first time a clin­i­cal tri­al has suc­cess­ful­ly shown that an Ebo­la ther­a­py improves sur­vival in peo­ple who have been infect­ed.

Two oth­er ther­a­pies used in the clin­i­cal tri­al per­formed less well and will be dis­con­tin­ued.

The ther­a­pies that have improved sur­vival rates are REGN-EB3, a cock­tail of three mon­o­clon­al Ebo­la anti­bod­ies made by Regen­eron Phar­ma­ceu­ti­cals, and mAb114, a sin­gle mon­o­clon­al anti­body devel­oped by the Nation­al Insti­tute of Aller­gy and Infec­tious Dis­eases, part of the Nation­al Insti­tutes of Health. The clin­i­cal tri­al will con­tin­ue com­par­ing these two drugs in Ebo­la treat­ment cen­ters in the Demo­c­ra­t­ic Repub­lic of the Con­go.

“It means that we do have now what looks like treat­ments for a dis­ease which not too long ago we real­ly had no ther­a­peu­tic approach at all,” said Dr. Antho­ny Fau­ci, direc­tor of NIAID.

“We feel that with agents such as these … that we may be able to improve the sur­vival of peo­ple with Ebo­la and … might even make peo­ple more enthu­si­as­tic about com­ing for care,” he said. “Because when you have some­thing to offer an indi­vid­ual, it makes it much more like­ly that you might get to them ear­ly. And the ear­li­er the bet­ter, as in any dis­ease.”

A num­ber of clin­i­cal tri­als were start­ed near the end of the 2014–2016 West African Ebo­la out­break, but they either revealed that pro­posed ther­a­pies did not work or failed to reach a result before the out­break end­ed.

One of the drugs test­ed in West Africa, ZMapp, had shown a sig­nal that it was improv­ing sur­vival, but the out­break end­ed before the tri­al could con­clude. In the cur­rent clin­i­cal tri­al, called the PALM study — the acronym stands for Pamo­ja Tulinde Maisha, which is Swahili for Togeth­er Save Lives — three ther­a­peu­tics were test­ed against ZMapp.

The orig­i­nal plan for the tri­al involved enrolling 725 patients. But the trial’s data and safe­ty mon­i­tor­ing board, which has con­duct­ed spo­radic reviews of the data, ana­lyzed find­ings based on 499 patients late last week.

That analy­sis showed REGN-EB3 was per­form­ing bet­ter than ZMapp at sta­tis­ti­cal­ly sig­nif­i­cant rates, doing well enough that it crossed a pre-estab­lished thresh­old that requires alter­ing the pro­to­col of the study. Close behind was mAb114, which will be devel­oped by Ridge­back Bio­ther­a­peu­ticsThe antivi­ral drug remde­sivir, made by Gilead, under­per­formed ZMapp.

The board decid­ed the tri­al should be revamped to test REGN-EB3 and mAB114 against each oth­er. Remde­sivir and ZMapp have been dropped from the tri­al.

The clin­i­cal tri­al was con­duct­ed at Ebo­la treat­ment cen­ters in Beni, Kat­wa, Butem­bo, and Mang­i­na, all hotspots at var­i­ous points in the out­break. Patients who are cared for in treat­ment cen­ters that are not involved in the tri­al have been receiv­ing the drugs under com­pas­sion­ate use pro­to­cols. Going for­ward, only the two drugs will be used in those cir­cum­stances as well.

Dr. Sumathi Siva­palasingam, Regeneron’s med­ical lead on the REGN-EB3 project, said the com­pa­ny was in a state of shock. They had expect­ed the drug to work, she said, but were still sur­prised at how well it per­formed vis-à-vis the oth­er ther­a­pies.

There were only lim­it­ed and pre­lim­i­nary data avail­able at this point. But they showed mor­tal­i­ty rates of 49% in peo­ple treat­ed with ZMapp, 53% in those who received remde­sivir, 34% in peo­ple treat­ed with mAb114, and 29% for peo­ple who received the Regen­eron cock­tail. The fatal­i­ty rate for the out­break as a whole is 67%.

Leah Lip­sich, Regeneron’s vice pres­i­dent for strate­gic pro­gram direc­tion, said the com­pa­ny believes it has ade­quate sup­plies of REGN-EB3, with cur­rent stock “in the high hun­dreds” of dos­es, with anoth­er round of pro­duc­tion about to start.

The NIH has about 300 dos­es of mAb114 at the moment, Fau­ci said, with addi­tion prod­uct com­ing avail­able in ear­ly Sep­tem­ber.

To date more than 1,400 peo­ple have received one of the exper­i­men­tal ther­a­pies.

The results put into ques­tion the future of ZMapp, the first mon­o­clon­al anti­body prepa­ra­tion to be used to fight Ebo­la.

A state­ment from Gilead said the com­pa­ny remains com­mit­ted to study­ing remde­sivir as a pos­si­ble treat­ment for Ebo­la and oth­er emerg­ing viral dis­eases. “A full analy­sis of the PALM tri­al data will help to inform future study [and] use of remde­sivir. Poten­tial learn­ings may include insight into the impact of viral strain and sever­i­ty of dis­ease pro­gres­sion on treat­ment strate­gies and the poten­tial for both sin­gle agent and com­bi­na­tion treat­ment approach­es,” it said.

The new results are based on a tri­al that was start­ed last Novem­ber. At the time, it was thought that it might take mul­ti­ple Ebo­la out­breaks before researchers had enough data. It was designed to be a rolling tri­al that could incor­po­rate data from future out­breaks in oth­er coun­tries, if need­ed.

But the ongo­ing out­break in the Demo­c­ra­t­ic Repub­lic of the Con­go, now in its sec­ond year, has been so large there were enough patients enrolled to come up with answers.

The out­break, occur­ring in the north­east­ern provinces of North Kivu and Ituri, is the sec­ond largest on record. To date, 2,831 peo­ple have been infect­ed with the virus, and near­ly 1,900 have died.

Dr. Jean-Jacques Muyem­be, direc­tor of DRC’s Nation­al Insti­tute of Bio­med­ical Research, and the first sci­en­tist to pro­pose using blood from Ebo­la sur­vivors to help peo­ple suf­fer­ing from the dis­ease, said for years he could not have imag­ined the devel­op­ment announced Mon­day, pre­dict­ing thou­sands of lives will be saved in future Ebo­la out­breaks.

— An ear­li­er ver­sion of this sto­ry report­ed the anti­bod­ies from both of the suc­cess­ful treat­ments were derived from Ebo­la sur­vivors. In fact the Regen­eron anti­bod­ies were gen­er­at­ed in mice.

5. As not­ed in past pro­grams, Gilead Sci­ences is very well-con­nect­ed pro­fes­sion­al­ly, with for­mer Sec­re­tary of Defense Don­ald Rums­feld (among oth­er polit­i­cal lumi­nar­ies) serv­ing on its board of direc­tors. Rums­feld was chair­man of the board from 1997 until he left in 2001 to become George W. Bush’s Sec­re­tary of Defense. The fir­m’s stock has been heav­i­ly invest­ed in by hedge funds, includ­ing Robert Mer­cer’s Renais­sance Tech­nolo­gies. Gilead Sci­ences’ stock has been a major dri­ver of the stock mar­ket’s per­for­mance.

Dur­ing the post‑9/11 peri­od of explod­ing gov­ern­ment invest­ments in biode­fense pro­grams, Don­ald Rums­feld was still hold­ing onto mas­sive amounts of Gilead stock, which was increas­ing in val­ue dra­mat­i­cal­ly. What kind of rela­tion­ship did Gilead devel­op with the US biode­fense nation­al secu­ri­ty state dur­ing this peri­od? That seems like a pret­ty impor­tant ques­tion at this point in time. 

The U.S. gov­ern­ment was among the cus­tomers whose pur­chas­es drove up the Gilead earn­ings and stock price: ” . . . . What’s more, the fed­er­al gov­ern­ment is emerg­ing as one of the world’s biggest cus­tomers for Tam­i­flu. In July, the Pen­ta­gon ordered $58 mil­lion worth of the treat­ment for U.S. troops around the world, and Con­gress is con­sid­er­ing a mul­ti-bil­lion dol­lar pur­chase. . . .”

“Rumsfeld’s grow­ing stake in Tam­i­flu” by Nel­son D. Schwartz; CNN; 10/31/2005

The prospect of a bird flu out­break may be pan­ick­ing peo­ple around the globe, but it’s prov­ing to be very good news for Defense Sec­re­tary Don­ald Rums­feld and oth­er polit­i­cal­ly con­nect­ed investors in Gilead Sci­ences, the Cal­i­for­nia biotech com­pa­ny that owns the rights to Tam­i­flu, the influen­za rem­e­dy that’s now the most-sought after drug in the world.

The forms don’t reveal the exact num­ber of shares Rums­feld owns, but in the past six months fears of a pan­dem­ic and the ensu­ing scram­ble for Tam­i­flu have sent Gilead’s stock from $35 to $47. That’s made the Pen­ta­gon chief, already one of the wealth­i­est mem­bers of the Bush cab­i­net, at least $1 mil­lion rich­er.

Rums­feld isn’t the only polit­i­cal heavy­weight ben­e­fit­ing from demand for Tam­i­flu, which is man­u­fac­tured and mar­ket­ed by Swiss phar­ma giant Roche. (Gilead receives a roy­al­ty from Roche equal­ing about 10% of sales.) For­mer Sec­re­tary of State George Shultz, who is on Gilead’s board, has sold more than $7 mil­lion worth of Gilead since the begin­ning of 2005.

Anoth­er board mem­ber is the wife of for­mer Cal­i­for­nia Gov. Pete Wil­son.

“I don’t know of any biotech com­pa­ny that’s so polit­i­cal­ly well-con­nect­ed,” says ana­lyst Andrew McDon­ald of Think Equi­ty Part­ners in San Fran­cis­co.

What’s more, the fed­er­al gov­ern­ment is emerg­ing as one of the world’s biggest cus­tomers for Tam­i­flu. In July, the Pen­ta­gon ordered $58 mil­lion worth of the treat­ment for U.S. troops around the world, and Con­gress is con­sid­er­ing a mul­ti-bil­lion dol­lar pur­chase. Roche expects 2005 sales for Tam­i­flu to be about $1 bil­lion, com­pared with $258 mil­lion in 2004.

Rums­feld recused him­self from any deci­sions involv­ing Gilead when he left Gilead and became Sec­re­tary of Defense in ear­ly 2001. And late last month, notes a senior Pen­ta­gon offi­cial, Rums­feld went even fur­ther and had the Pentagon’s gen­er­al coun­sel issue addi­tion­al instruc­tions out­lin­ing what he could and could not be involved in if there were an avian flu pan­dem­ic and the Pen­ta­gon had to respond.

As the flu issue heat­ed up ear­ly this year, accord­ing to the Pen­ta­gon offi­cial, Rums­feld con­sid­ered unload­ing his entire Gilead stake and sought the advice of the Depart­ment of Jus­tice, the SEC and the fed­er­al Office of Gov­ern­ment Ethics.

Those agen­cies didn’t offer an opin­ion so Rums­feld con­sult­ed a pri­vate secu­ri­ties lawyer, who advised him that it was safer to hold on to the stock and be quite pub­lic about his recusal rather than sell and run the risk of being accused of trad­ing on insid­er infor­ma­tion, some­thing Rums­feld doesn’t believe he pos­sess­es. So he’s keep­ing his shares for the time being.

6a. Sev­er­al years into his tenure at the Pen­ta­gon, Rums­feld made a killing on the sale of Gilead Sci­ences’ stock, which rose expo­nen­tial­ly in val­ue fol­low­ing its devel­op­ment of Tam­i­flu as a treat­ment for H5N1 avian flu.” . . . . The firm made a loss in 2003, the year before con­cern about bird flu start­ed. Then rev­enues from Tam­i­flu almost quadru­pled, to $44.6m, help­ing put the com­pa­ny well into the black. Sales almost quadru­pled again, to $161.6m last year. Dur­ing this time the share price tre­bled. Mr Rums­feld sold some of his Gilead shares in 2004 reap­ing – accord­ing to the finan­cial dis­clo­sure report he is required to make each year – cap­i­tal gains of more than $5m. The report showed that he still had up to $25m-worth of shares at the end of 2004, and at least one ana­lyst believes his stake has grown well beyond that fig­ure, as the share price has soared. . . .”

“Don­ald Rums­feld makes $5m killing on bird flu drug” by Geof­frey Lean and Jonathan Owen; The Inde­pe­nent; 03/12/2006

Don­ald Rums­feld has made a killing out of bird flu. The US Defence Sec­re­tary has made more than $5m (£2.9m) in cap­i­tal gains from sell­ing shares in the biotech­nol­o­gy firm that dis­cov­ered and devel­oped Tam­i­flu, the drug being bought in mas­sive amounts by Gov­ern­ments to treat a pos­si­ble human pan­dem­ic of the dis­ease.

More than 60 coun­tries have so far ordered large stocks of the antivi­ral med­ica­tion – the only oral med­i­cine believed to be effec­tive against the dead­ly H5N1 strain of the dis­ease – to try to pro­tect their peo­ple. The Unit­ed Nations esti­mates that a pan­dem­ic could kill 150 mil­lion peo­ple world­wide.

Britain is about halfway through receiv­ing an order of 14.6 mil­lion cours­es of the drug, which the Gov­ern­ment hopes will avert some of the 700,000 deaths that might be expect­ed. Tam­i­flu does not cure the dis­ease, but if tak­en soon after symp­toms appear it can reduce its sever­i­ty.

The drug was devel­oped by a Cal­i­forn­ian biotech com­pa­ny, Gilead Sci­ences. It is now made and sold by the giant chem­i­cal com­pa­ny Roche, which pays it a roy­al­ty on every tablet sold, cur­rent­ly about a fifth of its price.

Mr Rums­feld was on the board of Gilead from 1988 to 2001, and was its chair­man from 1997. He then left to join the Bush admin­is­tra­tion, but retained a huge share­hold­ing .

The firm made a loss in 2003, the year before con­cern about bird flu start­ed. Then rev­enues from Tam­i­flu almost quadru­pled, to $44.6m, help­ing put the com­pa­ny well into the black. Sales almost quadru­pled again, to $161.6m last year. Dur­ing this time the share price tre­bled.

Mr Rums­feld sold some of his Gilead shares in 2004 reap­ing – accord­ing to the finan­cial dis­clo­sure report he is required to make each year – cap­i­tal gains of more than $5m. The report showed that he still had up to $25m-worth of shares at the end of 2004, and at least one ana­lyst believes his stake has grown well beyond that fig­ure, as the share price has soared. Fur­ther details are not like­ly to become known, how­ev­er, until Mr Rums­feld makes his next dis­clo­sure in May.

The 2005 report showed that, in all, he owned shares worth up to $95.9m, from which he got an income of up to $13m, owned land worth up to $17m, and made $1m from rent­ing it out. . . .

6b. Don­ald Rums­feld was a sig­na­to­ry to the 1998 let­ter to Pres­i­dent Clin­ton by the Project for a New Amer­i­can Cen­tu­ry. That let­ter advo­cat­ed a hard­er line against Iraq.

DARPA and the Pen­ta­gon have into the appli­ca­tion of genet­ic engi­neer­ing in order to cre­ate eth­no-spe­cif­ic bio­log­i­cal war­fare weapons, as dis­cussed by the Project for a New Amer­i­can Cen­tu­ry.

“Bats, Gene Edit­ing and Bioweapons: Rec­cent DARPA Exper­i­ments Raise Con­cerns Amid Coro­n­avirus Out­break” by Whit­ney Webb; The Last Amer­i­can Vagabond; 1/30/2020.

” . . . . In what is arguably the think tank’s most con­tro­ver­sial doc­u­ment, titled ‘Rebuild­ing America’s Defens­es,’ there are a few pas­sages that open­ly dis­cuss the util­i­ty of bioweapons, includ­ing the fol­low­ing sen­tences: ‘…com­bat like­ly will take place in new dimen­sions: in space, ‘cyber-space,’ and per­haps the world of microbes…advanced forms of bio­log­i­cal war­fare that can ‘tar­get’ spe­cif­ic geno­types may trans­form bio­log­i­cal war­fare from the realm of ter­ror to a polit­i­cal­ly use­ful tool.’ . . .”

7. In ear­ly Novem­ber of last year, there was an inter­na­tion­al work­shop about man­ag­ing and oper­at­ing Biosafe­ty labs, held at the Wuhan Insti­tute of Virol­o­gy. At this work­shop there were invi­tees who includ­ed per­son­nel who might have served as vec­tor­ing agents. Bear in mind, again, that bio­log­i­cal war­fare requires a very small num­ber of oper­a­tional per­son­nel to do some very effec­tive and destruc­tive work. ” . . . . The work­shop is designed for lab­o­ra­to­ry man­agers and direc­tors, research and lab­o­ra­to­ry staffs main­ly from devel­op­ing coun­tries who plan to car­ry out infec­tious dis­ease research in biosafe­ty facil­i­ties. The work­shop will address key aspects of biosafe­ty and pro­vide prac­ti­cal train­ing in high lev­el biosafe­ty lab­o­ra­to­ries (BSL). This work­shop will invite a group of well-known schol­ars and experts from relat­ed fields at home and abroad to pro­vide the the­o­ret­i­cal and prac­ti­cal cours­es. . . .”

“Inter­na­tion­al Work­shop on Biosafe­ty Lab Man­age­ment and Tech­niques: Novem­ber 3–9, 2019 Wuhan, Chi­na”; Wuhan Insti­tute of Virol­o­gy, Chi­nese Acad­e­my of Sci­ences; 05/09/2020 Inter­net Archive cap­ture

With the devel­op­ment of glob­al­iza­tion, indus­tri­al­iza­tion and mod­ern­iza­tion, and the changes in the envi­ron­ment and cli­mate, dif­fer­ent infec­tious dis­eases and var­i­ous pub­lic health emer­gen­cies are pos­ing seri­ous threats to human health. In addi­tion, as the glob­al pace of build­ing lab­o­ra­to­ries has been accel­er­at­ed sig­nif­i­cant­ly, lab­o­ra­to­ry safe­ty issues have become increas­ing­ly promi­nent. Thus, the glob­al com­mu­ni­ty is fac­ing new chal­lenges in pub­lic health. Two ses­sions of the Inter­na­tion­al Work­shop on Biosafe­ty Lab­o­ra­to­ry Man­age­ment and Tech­niques were suc­cess­ful­ly held in 2017 and 2018. The series of work­shops, as the first offer sub­mit­ted by Chi­na to the Bio­log­i­cal Weapons Con­ven­tion (BWC) Assis­tance and Coop­er­a­tion Data­base, con­sti­tutes China’s major con­tri­bu­tion to the imple­men­ta­tion of BWC.

In 2019, the work­shop will be host­ed by the Min­istry of For­eign Affairs of the People’s Repub­lic of Chi­na and the Chi­nese Acad­e­my of Sci­ences (CAS), and orga­nized by Wuhan Insti­tute of Virol­o­gy (WIV), CAS, and will be held from Novem­ber 03–09, 2019 in Wuhan, Chi­na.

The work­shop is designed for lab­o­ra­to­ry man­agers and direc­tors, research and lab­o­ra­to­ry staffs main­ly from devel­op­ing coun­tries who plan to car­ry out infec­tious dis­ease research in biosafe­ty facil­i­ties. The work­shop will address key aspects of biosafe­ty and pro­vide prac­ti­cal train­ing in high lev­el biosafe­ty lab­o­ra­to­ries (BSL). This work­shop will invite a group of well-known schol­ars and experts from relat­ed fields at home and abroad to pro­vide the the­o­ret­i­cal and prac­ti­cal cours­es. The par­tic­i­pants will be sup­posed to dis­cuss bioethics and biosafe­ty poli­cies, under­stand key com­po­nents (risk recog­ni­tion, risk assess­ment and risk mit­i­ga­tion) of a biorisk man­age­ment sys­tem, acquire hands-on expe­ri­ence of safe oper­a­tions in biosafe­ty lab­o­ra­to­ries and know basic design prin­ci­ples of biosafe­ty lab­o­ra­to­ries.

8a. In past posts and pro­grams, we have not­ed that the Wuhan Insti­tute of Virology–the focal point of right-wing pro­pa­gan­da and disinformation–was engaged in projects involv­ing bat-borne coro­n­avirus­es of the same type as SARS CoV‑2. That research was a joint U.S. and Chi­nese project, with fund­ing com­ing from USAID (a U.S. intel­li­gence cut-out) and the NIH (which has net­worked with, and front­ed for, both CIA and Pen­ta­gon.) In May, the Trump admin­is­tra­tion ter­mi­nat­ed the fund­ing for the project.

“Trump admin pulls NIH grant for coro­n­avirus research over ties to Wuhan lab at heart of con­spir­a­cy the­o­ries” by Conor Finnegan; ABC News; 05/01/2020

The Trump admin­is­tra­tion has pulled fund­ing for a group of sci­en­tists study­ing coro­n­avirus­es in bats and the risk of their spillover into humans — the very kind of infec­tion that start­ed the COVID-19 pan­dem­ic — accord­ing to Eco­Health Alliance, the New York-based non­prof­it orga­ni­za­tion con­duct­ing the research.

The can­cel­la­tion of the grant after more than a decade of work in this field seems to be tied to Eco­Health Alliance’s part­ner­ship with the Wuhan Insti­tute of Virol­o­gy, the bio­med­ical lab at the heart of con­spir­a­cy the­o­ries that the Chi­nese gov­ern­ment cre­at­ed or unleashed the virus or the unproven the­sis that the out­break start­ed with an acci­dent because of faulty safe­ty stan­dards in the lab.

Either way, the group expressed regret at the deci­sion by the Nation­al Insti­tutes of Health to ter­mi­nate fund­ing, say­ing its work has helped in “design­ing vac­cines and drugs to pro­tect us from COVID-19 and oth­er coro­n­avirus threats” and point­ing out the Wuhan Institute’s par­tic­i­pa­tion had been approved by the NIH for years, includ­ing just last year under Pres­i­dent Don­ald Trump.

The pres­i­dent has tak­en a hard­er line on Chi­na in recent days, say­ing Thurs­day he has seen evi­dence that the Wuhan Insti­tute is respon­si­ble for the out­break, although he wasn’t clear whether he believes it was some­how man­u­fac­tured in the lab or the result of an acci­dent. Most experts have told ABC News the first human infec­tion — what’s known a “zoonot­ic spillover” — is much more like­ly to have hap­pened in the wild, where that kind of trans­mis­sion occurs increas­ing­ly often.

“It’s a ter­ri­ble thing that hap­pened,” Trump told reporters at the White House Thurs­day evening. “Whether they made a mis­take or whether it start­ed off as a mis­take and then they made anoth­er one, or did some­body do some­thing on pur­pose?

The U.S. intel­li­gence com­mu­ni­ty agrees with the sci­en­tif­ic con­sen­sus that the virus is “not man-made or genet­i­cal­ly mod­i­fied,” the Office of the Direc­tor of Nation­al Intel­li­gence said in a rare state­ment Thurs­day, but it announced its intel agen­cies are inves­ti­gat­ing whether the out­break could be “the result of an acci­dent at a lab­o­ra­to­ry in Wuhan.”

Eco­Health Alliance has worked with that lab for over a decade, accord­ing to a source famil­iar with the grant, as has the U.S. Agency for Inter­na­tion­al Development’s PREDICT project, which for over 10 years has also stud­ied virus­es in ani­mals and pre­pared local part­ners around the world to detect that kind of “spillover.”

But in a let­ter last Fri­day, the Nation­al Insti­tutes of Health informed the Eco­Health Alliance it was ter­mi­nat­ing the grant and deny­ing it access to the remain­ing $369,819 in its account for Fis­cal Year 2020.

“At this time, NIH does not believe that the cur­rent project out­comes align with the pro­gram goals and agency pri­or­i­ties,” Michael Lauer, NIH’s deputy direc­tor for out­side research, wrote, accord­ing to a copy obtained by Politi­co, which first report­ed the news.

Lauer’s let­ter made no direct ref­er­ence to the pres­i­dent, accord­ing to the source famil­iar with the grant, but just one week pri­or, Trump said he would ter­mi­nate it “very quick­ly” and blamed the Oba­ma admin­is­tra­tion for it, even though his admin­is­tra­tion also approved the fund­ing.

Last Friday’s ter­mi­na­tion let­ter came after NIH asked Eco­Health Alliance not to send any more fund­ing to the Wuhan Insti­tute of Virol­o­gy ear­li­er this month, accord­ing to the source. The group had halt­ed fund­ing, but large­ly because the pan­dem­ic had put a halt to near­ly all its research oper­a­tions.

Eco­Health Alliance has received NIH fund­ing for this work since 2008, amount­ing to $5.96 mil­lion over 12 years, accord­ing to NIHdata. That work has helped “devel­op pre­dic­tive mod­els of glob­al ‘hot spots’ for the future emer­gence of bat virus­es” and used its “large repos­i­to­ry of bat bio­log­i­cal sam­ples to con­duct tar­get­ed sur­veil­lance in these ‘hot spots’ for known and undis­cov­ered bat pathogens,” accord­ing to the group.

That work is now at risk, accord­ing to the source, who said U.S. access to those sam­ples and at least some of that data held by the Wuhan Insti­tute would be cut off.

Since Fis­cal Year 2014, that work has been award­ed to Eco­Health Alliance’s “Under­stand­ing the Risk of Bat Coro­n­avirus Emer­gence” project in par­tic­u­lar, which is explic­it­ly focused on Chi­na and done in part­ner­ship with the Wuhan Insti­tute and oth­ers.

“This project aims to under­stand what fac­tors increase the risk of the next CoV [coro­n­avirus] emerg­ing in peo­ple by study­ing CoV diver­si­ty in a crit­i­cal zoonot­ic reser­voir (bats), at sites of high risk for emer­gence (wildlife mar­kets) in an emerg­ing dis­ease hotspot (Chi­na),” the group’s NIH-approved research abstract said.

Sci­en­tists have deter­mined that the nov­el coro­n­avirus that caus­es COVID-19 orig­i­nat­ed in a bat, although there’s been no con­clu­sion yet about how it jumped from bats to humans. Many of the ear­li­est cas­es were con­nect­ed to a wet mar­ket in Wuhan, where live and fresh­ly killed ani­mals are sold, but some sci­en­tists have cast doubt on it being the orig­i­nal source. The Wuhan munic­i­pal gov­ern­ment closed the mar­ket on Jan. 1 and cleaned it, poten­tial­ly mak­ing the inves­ti­ga­tion more dif­fi­cult.

But while U.S. intel­li­gence agen­cies look for clues of a poten­tial lab acci­dent, epi­demi­o­log­i­cal experts say it’s high­ly unlike­ly the first trans­mis­sion hap­pened that way. Virus sam­ples in labs are almost nev­er still infec­tious, after being frozen in nitro­gen dur­ing the col­lec­tion process and then inac­ti­vat­ed in the lab to pre­serve their genet­ic sequence.

“It’s an unlike­ly prob­a­bil­i­ty because the lab­o­ra­to­ry is a con­trolled set­ting and peo­ple wear per­son­al pro­tec­tive equip­ment. I’ve seen hearsay that they maybe didn’t have enough or they weren’t skilled enough, but there are bar­ri­ers, huge bar­ri­ers between peo­ple and virus­es in the lab­o­ra­to­ry set­ting,” said Dr. Chris­tine John­son, prin­ci­pal inves­ti­ga­tor with USAID’s PREDICT project, which will end this Sep­tem­ber after 10 years and two six-month exten­sions as USAID launch­es a new project that applies the data PREDICT col­lect­ed.

The prob­a­bil­i­ty of infec­tion “is so much high­er in the real world, where there are more peo­ple and more bats. It’s vast­ly more like­ly than the poten­tial for a human-bat inter­ac­tion in the lab,” added John­son, a pro­fes­sor of epi­demi­ol­o­gy and ecosys­tem health at UC Davis School of Vet­eri­nary Med­i­cine and direc­tor of its Epi­Cen­ter for Dis­ease Dynam­ic.

In the face of that, Sec­re­tary of State Mike Pom­peo has now start­ed to call into the ques­tion of China’s bio­med­ical labs, demand­ing that they pro­vide inter­na­tion­al inspec­tors access to them, although it’s unclear if the admin­is­tra­tion has for­mal­ly request­ed that of the Chi­nese gov­ern­ment. Many of the sci­en­tists at the Wuhan Insti­tute of Virol­o­gy have been trained by the U.S. government’s PREDICT project.

Some experts believe there was like­ly an inter­me­di­ary ani­mal infect­ed by a bat that then infect­ed a human, such as a pan­golin, a scaly-skinned mam­mal that resem­bles an armadil­lo and is sold for meat and tra­di­tion­al med­i­cine, or a civet, a slinky cat-like mam­mal eat­en as a del­i­ca­cy and believed to be the inter­me­di­ary respon­si­ble for the 2003 SARS out­break.

But it could also be from direct expo­sure to a bat. A 2017 report by Eco­Health Alliance’s project, whose authors include Wuhan Insti­tute sci­en­tists, was pub­lished in the research jour­nal Viro­log­i­ca Sini­ca and warned that “some bat SARSr-CoVs [severe acute res­pi­ra­to­ry syn­drome-relat­ed coro­n­avirus­es] are able to direct­ly infect humans with­out inter­me­di­ate host.”

8b. In past pro­grams and posts, we have not­ed that DARPA was research­ing these virus­es: ” . . . . the Pentagon’s Defense Advanced Research Project Agency (DARPA), began spend­ing mil­lions on such research in 2018 and some of those Pen­ta­gon-fund­ed stud­ies were con­duct­ed at known U.S. mil­i­tary bioweapons labs bor­der­ing Chi­na and result­ed in the dis­cov­ery of dozens of new coro­n­avirus strains as recent­ly as last April. Fur­ther­more, the ties of the Pentagon’s main biode­fense lab to a virol­o­gy insti­tute in Wuhan, Chi­na — where the cur­rent out­break is believed to have begun — have been unre­port­ed in Eng­lish lan­guage media thus far. . . . For instance, DARPA spent $10 mil­lion on one project in 2018 ‘to unrav­el the com­plex caus­es of bat-borne virus­es that have recent­ly made the jump to humans, caus­ing con­cern among glob­al health offi­cials.” Anoth­er research project backed by both DARPA and NIH saw researchers at Col­orado State Uni­ver­si­ty exam­ine the coro­n­avirus that caus­es Mid­dle East Res­pi­ra­to­ry Syn­drome (MERS) in bats and camels ‘to under­stand the role of these hosts in trans­mit­ting dis­ease to humans.’  . . . For instance, one study con­duct­ed in South­ern Chi­na in 2018 result­ed in the dis­cov­ery of 89 new ‘nov­el bat coro­n­avirus’ strains that use the same recep­tor as the coro­n­avirus known as Mid­dle East Res­pi­ra­to­ry Syn­drome (MERS). That study was joint­ly fund­ed by the Chi­nese government’s Min­istry of Sci­ence and Tech­nol­o­gy, USAID — an orga­ni­za­tion long alleged to be a front for U.S. intel­li­gence, and the U.S. Nation­al Insti­tute of Health — which has col­lab­o­rat­ed with both the CIA and the Pen­ta­gon on infec­tious dis­ease and bioweapons research. . . . .”

9. Oth­er broad­casts have explored the Wuhan Mil­i­tary World Games–a mil­i­tary sports competition–as a pos­si­ble vec­tor­ing vehi­cle. We update that path of inquiry with dis­cus­sion of the U.S. del­e­ga­tion as a pos­si­ble vec­tor­ing agent for the spread of the dis­ease in the U.S. ” . . . . Con­trary to the Pentagon’s insis­tence, how­ev­er, an inves­ti­ga­tion of COVID-19 cas­es in the mil­i­tary from offi­cial and pub­lic source mate­ri­als shows that a strong cor­re­la­tion exists in COVID-19 cas­es report­ed at U.S. mil­i­tary facil­i­ties that are home bases of mem­bers of the U.S. team that went to Wuhan. Before March 31, when the Pen­ta­gon restrict­ed the release of infor­ma­tion about COVID-19 cas­es at instal­la­tions for secu­ri­ty rea­sons, infec­tions occurred at a min­i­mum of 63 mil­i­tary facil­i­ties where team mem­bers returned after the Wuhan games. Addi­tion­al­ly, the U.S. team used char­tered flights to and from the games via Seat­tle-Taco­ma Inter­na­tion­al Air­port. Wash­ing­ton was one of the ear­li­est states to show a spike in COVID-19. . . .”

We also note that the U.S. del­e­ga­tion con­tained: ” . . . . nine pub­lic-affairs offi­cers . . . and two State Depart­ment per­son­nel, accord­ing to DOD doc­u­ments. . . .” “Pub­lic affairs offi­cer” is a com­mon cov­er for CIA per­son­nel. 

In FTR #1122, we made the fol­low­ing com­ment in con­nec­tion with the Mil­i­tary World Games: ” . . . . A Chi­nese For­eign Min­istry offi­cial cit­ed the Mil­i­tary World Games in Wuhan as a pos­si­ble vec­tor­ing point. (We believe this is pos­si­ble, although we sus­pect the Shin­cheon­ji cult and a USAMRIID asso­ci­a­tion with a Wuhan viro­log­i­cal insti­tute as oth­er pos­si­ble vec­tors.) IF, for the sake of argu­ment, fas­cist ele­ments (CIA, Under­ground Reich or what­ev­er) chose the US mil­i­tary ath­letes as a vec­tor, it would have been alto­geth­er pos­si­ble to do so with­out attract­ing atten­tion. Mil­i­tary ath­letes are in superb con­di­tion and, if infect­ed with one of the milder strains of Covid-19, their robust immune sys­tems might well leave them asymp­to­matic, yet still con­ta­gious, or mild­ly ill at worst. They could then com­mu­ni­cate the virus to oth­er mil­i­tary ath­letes, who would then serve as a vec­tor for oth­er coun­tries. . . .”

“Did the Mil­i­tary World Games Spread COVID-19?” by Tom Squitieri; The Amer­i­can Prospect; 06/30/2020

Less than a month before data shows the first Chi­nese cit­i­zen became ill with coro­n­avirus, near­ly 300 mem­bers of the U.S. mil­i­tary, Depart­ment of Defense, and sup­port per­son­nel attend­ed the 2019 Mil­i­tary World Games in Wuhan, Chi­na. When the games end­ed, they returned to at least 219 home bases in 25 states, with­out ever being screened for pos­si­ble COVID-19 infec­tion.

Accord­ing to the Pen­ta­gon, there was no rea­son to do so then, or sub­se­quent­ly. A spokesper­son issued a terse email response to the ques­tion, say­ing there was no screen­ing because the event—held from Octo­ber 18 to 27, 2019—“was pri­or to the report­ed out­break.”

The spokesper­son cit­ed Decem­ber 31, 2019, as the crit­i­cal out­break day and that no test­ing was deemed nec­es­sary for any pos­si­ble expo­sure pri­or to Feb­ru­ary 1, 2020.

Since that email, Pen­ta­gon offi­cials have repeat­ed­ly declined to speak on or off the record regard­ing the sub­ject.

Con­trary to the Pentagon’s insis­tence, how­ev­er, an inves­ti­ga­tion of COVID-19 cas­es in the mil­i­tary from offi­cial and pub­lic source mate­ri­als shows that a strong cor­re­la­tion exists in COVID-19 cas­es report­ed at U.S. mil­i­tary facil­i­ties that are home bases of mem­bers of the U.S. team that went to Wuhan.

Before March 31, when the Pen­ta­gon restrict­ed the release of infor­ma­tion about COVID-19 cas­es at instal­la­tions for secu­ri­ty rea­sons, infec­tions occurred at a min­i­mum of 63 mil­i­tary facil­i­ties where team mem­bers returned after the Wuhan games.

Addi­tion­al­ly, the U.S. team used char­tered flights to and from the games via Seat­tle-Taco­ma Inter­na­tion­al Air­port. Wash­ing­ton was one of the ear­li­est states to show a spike in COVID-19.

“I do think that it is a con­cern that these peo­ple were not test­ed, espe­cial­ly going into an area that might be a cen­ter, a huge prob­a­bil­i­ty,” Dr. Rav­ina Kullar, an infec­tious dis­eases expert and epi­demi­ol­o­gist based out of San­ta Mon­i­ca, Cal­i­for­nia, said in an inter­view.

“It may have hap­pened before Decem­ber, that is the unknown fac­tor,” Kullar said. “We still don’t know who is patient zero. The Chi­nese gov­ern­ment is not being trans­par­ent enough.”

Kullar is with Expert Stew­ard­ship, Inc., a com­pa­ny that pro­motes infec­tion pre­ven­tion in long-term care facil­i­ties. She is also a mem­ber of the Infec­tious Dis­eases Soci­ety of Amer­i­ca, a med­ical asso­ci­a­tion rep­re­sent­ing physi­cians, sci­en­tists, and oth­er health care pro­fes­sion­als who spe­cial­ize in infec­tious dis­eases.

She stressed that the Chi­nese have not coop­er­at­ed with the inter­na­tion­al com­mu­ni­ty in shar­ing crit­i­cal infor­ma­tion, which is one more rea­son the Pen­ta­gon should have test­ed the ath­letes.

“I feel strong­ly about going with a high preva­lence to get test­ed,” she said.

New data con­tin­ues to emerge that COVID-19 had already infect­ed peo­ple in Wuhan in mid- or ear­ly Novem­ber of 2019, weeks after the games’ con­clu­sion. Recent research released from Har­vard and Boston Uni­ver­si­ty sug­gests COVID-19 might have been present in Chi­na as ear­ly as last August, well before the ill­ness was first pub­licly iden­ti­fied in Wuhan on Decem­ber 31.

Ath­letes who par­tic­i­pat­ed from oth­er nations—both U.S. allies like France and Italy and adver­saries like Iran—have report­ed suf­fer­ing from COVID-19 symp­toms. Some Iran­ian ath­letes died from COVID-19, includ­ing some who were in Wuhan, accord­ing to news reports not ver­i­fied by Tehran.

The Pentagon’s reluc­tance to test ath­letes return­ing from Wuhan was not unique. No oth­er nation’s mil­i­tary appears to have test­ed their par­tic­i­pants in the 2019 World Mil­i­tary Games specif­i­cal­ly for COVID-19. French doc­tors exam­ined their ath­letes upon their return from the games as part of over­all exams.

When asked why the ath­letes and sup­port staff who had been in Chi­na were not screened as a pre­cau­tion once the COVID-19 threat was known in Jan­u­ary, Defense Sec­re­tary Mark Esper said at the end of an April 14 press con­fer­ence: “I am not aware of what you are talk­ing about.”

The ques­tion and response were not includ­ed in the Pentagon’s offi­cial writ­ten tran­script of the brief­ing, as is the nor­mal pro­ce­dure. The offi­cial video of the brief­ing goes silent when the ques­tion is asked and Esper can be seen—but not heard—reacting to the ques­tion.

The full audio and video exchange remains on the C‑SPAN video of the event.

As of June 5, there were 10,462 COVID-19 cas­es in the Depart­ment of Defense in the mil­i­tary, civil­ian, depen­dent, and con­trac­tor cat­e­gories. As of June 12, 2020, there have been 36 deaths linked to COVID-19 among those groups.

The del­e­ga­tion to Wuhan includ­ed 188 ath­letes, 24 coach­es, 18 team cap­tains, 15 med­ical providers, 10 ref­er­ees, nine pub­lic-affairs offi­cers, sev­en “senior lead­ers,” nine CISM (Inter­na­tion­al Mil­i­tary Sports Coun­cil), and two State Depart­ment per­son­nel, accord­ing to DOD doc­u­ments.

Spokesper­sons for the var­i­ous ser­vice branch­es, all of which were rep­re­sent­ed in Wuhan, either declined to com­ment on the sub­ject or said that no COVID-19 screen­ing was required for any­one with pos­si­ble expo­sure pri­or to Feb­ru­ary. . . .

 

 

Discussion

7 comments for “FTR #1138 Bio-Psy-Op Apocalypse Now, Part 10: Bad Medicine”

  1. Here’s a pair of arti­cles about recent COVID research that high­light the ongo­ing chal­lenges in under­stand­ing both how the human immune sys­tem deals with the SARS-CoV­‑2 virus, ques­tions of how wide­spread the out­break actu­al­ly is, and how those two ques­tions inter­re­late:

    First, there was anoth­er study that found a sub­stan­tial num­ber of peo­ple who were infect­ed by the virus but only had mild or no symp­toms did­n’t have anti­bod­ies after recov­er­ing. But many of them did have T‑cells that were tar­get­ing the virus. It’s the kind of find­ing that’s both good news in the sense that it means peo­ple with­out anti­bod­ies might still have some degree of remain­ing immu­ni­ty but also bad news in the sense that it’s much hard­er to mea­sure the pres­ence of these T‑cells, which might be hid­ing in lymph nodes or oth­er hard-to-mea­sure tis­sues, com­pared to anti­bod­ies that are going to be cir­cu­lat­ing in the blood­stream and can there­fore be more eas­i­ly mea­sured.

    Recall the pre­vi­ous small study out of Chi­na that found that a lack of anti­bod­ies in around a third of the recov­ered patients they exam­ine, with younger and health­i­er patients being more like­ly to lack the anti­bod­ies. This raised the ques­tion of whether or not the anti­body lev­els dis­si­pate quick­ly but also led the researchers to spec­u­late that T‑cells might be fight­ing off the virus instead of anti­bod­ies for these indi­vid­u­als. So it sounds like their spec­u­la­tion panned out and T‑cells were play­ing a role in these anti­body-free patients suf­fer­ing mild or no symp­toms, although it remains unclear if the peo­ple who are lack­ing anti­bod­ies in the study nev­er devel­oped them at all or the anti­bod­ies devel­oped and fad­ed before they were mea­sured in these stud­ied.

    It also opti­misti­cal­ly sug­gests that the lev­els of expo­sure of the virus are actu­al­ly much high­er than cur­rent anti­body-based sur­veys sug­gest. Recall the study from back in April con­duct­ed in New York City that con­clud­ed that 20 per­cent of the city’s pop­u­la­tion might have already been exposed to the virus because around 20 per­cent of the peo­ple in a sam­ple of 1300 New York­ers had anti­bod­ies. If around a third of exposed peo­ple don’t have anti­bod­ies but do have T‑cells that sug­gest around 27% of New York­ers may have already had some degree of immu­ni­ty to the virus back in April. In gen­er­al the find­ing on anti­bod­ies and T‑cells sug­gests that assess­ing the lev­el of col­lec­tive immu­ni­ty in a pop­u­la­tion is going to be more chal­leng­ing than we hoped.

    It’s also worth recall­ing the study that found that SARS-CoV­‑2 might actu­al­ly infect and kill T‑cells, via a dif­fer­ent mode of entry into the cell that does­n’t involve the ACE2 recep­tor. The virus thank­ful­ly could­n’t repli­cate in the T‑cell (which could have made it more like HIV) but it can still kill the cells. It rais­es all sorts of the ques­tion of how re-expo­sure to the virus might affect those pro­tec­tive T‑cell lev­els.

    Addi­tion­al­ly, there was anoth­er recent study that found that T cells devel­oped from expo­sure to oth­er coro­n­avirus­es, like coro­n­avirus­es that cause the com­mon cold, might help fight the SARS-CoV­‑2 virus. A study out of the La Jol­la Insti­tute found that T cells from blood sam­ples col­lect­ed by 2015 and 2018 were react­ing to the SARS-CoV­‑2 virus. So sim­ply hav­ing had a lot of pre­vi­ous immuno­log­i­cal expo­sure could give one an addi­tion­al edge against this virus. On the oth­er hand, if you already avoid expo­sure to virus­es due to a weak immune sys­tem you’re might be extra vul­ner­a­ble to SARS-CoV­‑2. It’s anoth­er exam­ple of this being a eugenic virus.

    The sec­ond arti­cle we’re going to look at also cov­ers stud­ies that point to sig­nif­i­cant com­pli­ca­tions in how to treat the virus. In part because it sounds like SARS-CoV­‑2 impacts the immune sys­tem in ways no oth­er stud­ied virus does and this might explain the mech­a­nisms through which the virus trig­gers the cas­cade of immune over-response that ends up killing patients: Most virus­es try to accom­plish two key tasks in order to suc­cess­ful­ly repro­duce with­out the immune sys­tem squash­ing the infec­tion. First, typ­i­cal virus­es try to sup­press the cells genes that trig­ger the cel­l’s “call to arms” sig­nal­ing mech­a­nisms that pro­duce inter­fer­ons. Inter­fer­ons cause sur­round­ing cells to turn on a num­ber of genes that com­pli­cate the virus’s abil­i­ty to repli­cate itself, slow­ing down the infec­tion. The sec­ond set of genes typ­i­cal virus­es tar­get are the genes that pro­duce chemokines which are like the “call for rein­force­ments” sig­nal­ing mol­e­cules that recruit B‑cells and T‑cells from far away to the site of the infec­tion.

    So the first “call to arms” genes buy time while the sec­ond “call for rein­force­ments” genes recruit the spe­cial­ized immune cells that can come in an fin­ish off the infec­tion. Tar­get­ing those two areas is how virus­es nor­mal­ly. But what researchers out of Mount Sinai dis­cov­ered back in May is that SARS-CoV­‑2 ONLY blocks the “call to arms” genes, mean­ing that the virus is allowed to repli­cate uncon­trol­lably while the spe­cial­ized immune cells like B and T‑cells are still get­ting recruit­ed to the site of infec­tion. It’s this dynam­ic that appears to lead to the kind of over­whelm­ing immune response that ends up killing patients and SARS-CoV­‑2 is the only known virus to induce this.

    An addi­tion, anoth­er study out of Japan found pub­lished back in May iden­ti­fied the SARS-CoV­‑2 pro­tein (known as a tran­scrip­tion fac­tor) that blocks the cel­l’s inter­fer­on sig­nalling and found that the SARS-CoV­‑2 tran­scrip­tion fac­tor is stronger than the orig­i­nal 2003 SARS vari­ant of the pro­tein as well as influen­za­’s ver­sion. So SARS-CoV­‑2 appears to be excep­tion­al at block­ing the “call to arms” sig­nal­ing at the same time it’s the only known virus that does­n’t even try to block the “call for rein­force­ments” sig­nal­ing.

    All in all, it’s more dis­turb­ing SARS-CoV­‑2 news, but there was one bit of good news from the dis­cov­ery of this anom­alous “call to arms” vs “call for rein­force­ments” behav­ior of the virus: pro­vid­ing patients with inter­fer­ons can poten­tial­ly pre­emp­tive­ly pre­vent a full blown infec­tion. That’s what Uni­ver­si­ty of Texas Med­ical Branch researchers dis­cov­ered when they exposed human cells in cell cul­tures to inter­fer­on and then tried to infect them with the virus. Inter­fer­on expo­sure real­ly did seem to sup­press the virus’s abil­i­ty to repli­cate. So that opens a third avenue for treat­ing the pan­dem­ic: pre­ven­ta­tive drugs. But, of course, drugs have side-effects includ­ing inter­fer­on so this is far from an ide­al solu­tion. But at least it’s anoth­er tool in the tool­box.

    Ok, first, here’s a recent arti­cle about how a large por­tion of patients who had mild or no symp­toms and recov­ered appear to only pos­sess T‑cell fol­low­ing recov­er­ing and how it rais­es the ques­tion of whether or not these patients are fight­ing off the virus with T‑cells alone of if they devel­oped anti­bod­ies but they already fad­ed away, leav­ing just the T‑cells behind for longer-term immu­ni­ty:

    Reuters

    Sci­en­tists focus on how immune sys­tem T cells fight coro­n­avirus in absence of anti­bod­ies

    Deena Beasley
    July 10, 2020 / 6:09 AM

    (Reuters) — As sci­en­tists ques­tion whether the pres­ence, or absence, of anti­bod­ies to the nov­el coro­n­avirus can reli­ably deter­mine immu­ni­ty, some are look­ing to a dif­fer­ent com­po­nent of the immune sys­tem, known as T cells, for their role in pro­tect­ing peo­ple in the pan­dem­ic.

    Recent stud­ies show that some recov­ered patients who test­ed neg­a­tive for coro­n­avirus anti­bod­ies did devel­op T cells in response to their COVID-19 infec­tion. While the stud­ies are small and have yet to be reviewed by out­side experts, some sci­en­tists now say that peo­ple who expe­ri­ence a mild ill­ness, or no symp­toms at all, from the new coro­n­avirus, may be elim­i­nat­ing the infec­tion through this T cell response.

    The find­ings add to the evi­dence that an effec­tive COVID-19 vac­cine will need to prompt T cells to work in addi­tion to pro­duc­ing anti­bod­ies, and may have impli­ca­tions for sev­er­al treat­ments in devel­op­ment. They may also shed light on how immu­ni­ty to new expo­sure to infec­tion could work.

    There is mount­ing evi­dence that peo­ple exposed to the virus have a tran­sient (short-lived) anti­body response, or have a T cell response in spite of a minor or absent anti­body response Dr Alessan­dro Sette, pro­fes­sor and mem­ber of the La Jol­la Institute’s Infec­tious Dis­ease and Vac­cine Cen­ter in Cal­i­for­nia, told Reuters.

    When a virus gets past the body’s ini­tial defens­es — which include infec­tion-fight­ing white blood cells — a more spe­cif­ic “adap­tive” response kicks in, trig­ger­ing pro­duc­tion of cells that tar­get the invad­er. These include anti­bod­ies that can rec­og­nize a virus and lock onto it, pre­vent­ing its entry into a person’s cells, as well as T cells that can kill both invaders and the cells they have infect­ed.

    Six months into a glob­al COVID-19 pan­dem­ic that has infect­ed more than 12 mil­lion peo­ple, ques­tions remain about whether the anti­body response to this virus is robust and lasts over time. That could mean T cells have a more impor­tant role in offer­ing pro­tec­tion against the ill­ness.

    ...

    A recent small French study here not yet reviewed by experts, found that six out of eight fam­i­ly mem­bers in close con­tact with rel­a­tives who had COVID-19 devel­oped a T cell response, but did not test pos­i­tive for anti­bod­ies.

    A Swedish study here of 200 peo­ple found a strong T cell response in most indi­vid­u­als who had mild ill­ness or no symp­toms fol­low­ing coro­n­avirus infec­tion, regard­less of whether they showed an anti­body response. The find­ing sug­gests that coro­n­avirus infec­tion rates may be high­er than what has been stud­ied using anti­body tests alone, the researchers said.

    MEMORIES OF CORONAVIRUS

    The focus on T cell respons­es could also shed light on the prospect for longer-term immu­ni­ty.

    There is some evi­dence that T cells devel­oped after expo­sure to oth­er coro­n­avirus­es that cause the com­mon cold could help fight off the new virus, known as SARS-CoV­‑2.

    A study led by the La Jol­la Insti­tute detect­ed T cells that react­ed to SARS-CoV­‑2 in about half of stored blood sam­ples col­lect­ed between 2015 and 2018, sug­gest­ing that the immune sys­tem cells devel­oped after pre­vi­ous infec­tion with cir­cu­lat­ing com­mon cold coro­n­avirus­es, and that they might help pro­tect against the new virus.

    “It is a poten­tial­ly encour­ag­ing piece of evi­dence,” Wher­ry said.

    Vac­cine can­di­dates against COVID-19 cur­rent­ly in the works aim to gen­er­ate anti­body and T cell respons­es, and the recent find­ings high­light the impor­tance of gaug­ing the T cell response seen in human clin­i­cal tri­als.

    “We believe that the opti­mal vac­cine design would be one that induces both an anti­body and T cell response,” Sette said.

    After an infec­tion or vac­ci­na­tion, the immune sys­tem retains a num­ber of “mem­o­ry” cells that are already primed to quick­ly attack the same virus in case of a future infec­tion.

    Many coun­tries are using blood tests that look for anti­bod­ies to esti­mate how many peo­ple have been infect­ed with the new virus even if they nev­er showed symp­toms. But sci­en­tists still do not know how anti­body lev­els cor­re­late to expo­sure to the virus or how long they may last. There are also ques­tions about exact­ly which com­bi­na­tion of immune-sys­tem cells will result in sig­nif­i­cant pro­tec­tion.

    Mea­sur­ing the lev­el of mem­o­ry T cells is much more com­pli­cat­ed, espe­cial­ly if the cells are in lymph nodes or oth­er hard-to-access areas of the body. In addi­tion, T‑cell respons­es are high­ly vari­able.

    “It is a lot eas­i­er to col­lect anti­body data,” said Dr Daniela Weiskopf, an assis­tant pro­fes­sor at the La Jol­la Insti­tute.

    ———–

    “Sci­en­tists focus on how immune sys­tem T cells fight coro­n­avirus in absence of anti­bod­ies” by Deena Beasley; Reuters; 07/10/2020

    Recent stud­ies show that some recov­ered patients who test­ed neg­a­tive for coro­n­avirus anti­bod­ies did devel­op T cells in response to their COVID-19 infec­tion. While the stud­ies are small and have yet to be reviewed by out­side experts, some sci­en­tists now say that peo­ple who expe­ri­ence a mild ill­ness, or no symp­toms at all, from the new coro­n­avirus, may be elim­i­nat­ing the infec­tion through this T cell response.

    The evi­dence keeps com­ing in: this virus is fought off dif­fer­ent­ly by dif­fer­ent peo­ple, and if you’re young and healthy you’re less like­ly to even need anti­bod­ies at all. Your T‑cells can do the job on their own. And if those T‑cells are stick­ing around after the infec­tion that rep­re­sents a form of immu­ni­ty that we aren’t going to detect in anti­body sur­veys. It also sug­gests there’s a lot more peo­ple with immu­ni­ty already than anti­body sur­veys sug­gest:

    ...
    There is mount­ing evi­dence that peo­ple exposed to the virus have a tran­sient (short-lived) anti­body response, or have a T cell response in spite of a minor or absent anti­body response Dr Alessan­dro Sette, pro­fes­sor and mem­ber of the La Jol­la Institute’s Infec­tious Dis­ease and Vac­cine Cen­ter in Cal­i­for­nia, told Reuters.

    ...

    A Swedish study here of 200 peo­ple found a strong T cell response in most indi­vid­u­als who had mild ill­ness or no symp­toms fol­low­ing coro­n­avirus infec­tion, regard­less of whether they showed an anti­body response. The find­ing sug­gests that coro­n­avirus infec­tion rates may be high­er than what has been stud­ied using anti­body tests alone, the researchers said.

    ...

    Mea­sur­ing the lev­el of mem­o­ry T cells is much more com­pli­cat­ed, espe­cial­ly if the cells are in lymph nodes or oth­er hard-to-access areas of the body. In addi­tion, T‑cell respons­es are high­ly vari­able.

    “It is a lot eas­i­er to col­lect anti­body data,” said Dr Daniela Weiskopf, an assis­tant pro­fes­sor at the La Jol­la Insti­tute.
    ...

    And then there’s the intrigu­ing find­ing that T cells from pre­vi­ous expo­sure to dif­fer­ent coro­n­avirus­es can help fight off SARS-CoV­‑2. So if you’ve been healthy enough to allow your­self to get exposed to lots of virus­es before this pan­dem­ic you’re more like­ly to sur­vive it:

    ...
    MEMORIES OF CORONAVIRUS

    The focus on T cell respons­es could also shed light on the prospect for longer-term immu­ni­ty.

    There is some evi­dence that T cells devel­oped after expo­sure to oth­er coro­n­avirus­es that cause the com­mon cold could help fight off the new virus, known as SARS-CoV­‑2.

    A study led by the La Jol­la Insti­tute detect­ed T cells that react­ed to SARS-CoV­‑2 in about half of stored blood sam­ples col­lect­ed between 2015 and 2018, sug­gest­ing that the immune sys­tem cells devel­oped after pre­vi­ous infec­tion with cir­cu­lat­ing com­mon cold coro­n­avirus­es, and that they might help pro­tect against the new virus.
    ...

    You have to won­der if a SARS-CoV-2-like cold virus designed to induce a mild cold but gen­er­ate T‑cells that attack SARS-CoV­‑2 is some­thing that can be devel­oped.

    It’s also worth recall­ing the phe­nom­e­na of anti­body-depen­dent enhance­ment (ADE) — the phe­nom­e­na of the infec­tion being more seri­ous if you’re pre­vi­ous­ly been exposed to the virus and have low but inad­e­quate remain­ing anti­body lev­els, trig­ger­ing an over­ag­gres­sive immune response — that was observed with the orig­i­nal SARS virus and might be present with SARS-CoV­‑2. And while we don’t know yet if ADE is going to be an issue with SARS-CoV­‑2, if your body can fight off the virus with­out hav­ing to gen­er­ate anti­bod­ies that would pre­sum­ably help avoid future ADE events.

    Ok, now here’s the arti­cle from back in May about a pair of stud­ies exam­in­ing how the virus actu­al­ly car­ries out its infec­tion. One study out of Mount Sinai found that the virus does try to block the “call-to-arms” ini­tial immune response that warns sur­round­ing cells to pre­pare to thwart the virus’s repli­ca­tion but it does­n’t block the “call-for-rein­force­ments” sig­nal­ing that brings in spe­cial­ized B and T‑cells to actu­al­ly clear up the infec­tion, a com­bi­na­tion nev­er before observed in a virus that might also explain why it induces a lethal immune response in some patients. And then there’s a study out of Japan that found that SARS-CoV­‑2 blocks that “call-to-arms” sig­nal­ing even more effec­tive­ly than SARS or influen­za. So SARS-CoV­‑2 appears to unique­ly excep­tion­al at induc­ing a lethal immune response:

    STAT News

    ‘It’s some­thing I have nev­er seen’: How the Covid-19 virus hijacks cells

    By Sharon Beg­ley
    May 21, 2020

    A deep dive into how the new coro­n­avirus infects cells has found that it orches­trates a hos­tile takeover of their genes unlike any oth­er known virus­es do, pro­duc­ing what one lead­ing sci­en­tist calls “unique” and “aber­rant” changes.

    Recent stud­ies show that in seiz­ing con­trol of genes in the human cells it invades, the virus changes how seg­ments of DNA are read, doing so in a way that might explain why the elder­ly are more like­ly to die of Covid-19 and why antivi­ral drugs might not only save sick patients’ lives but also pre­vent severe dis­ease if tak­en before infec­tion.

    “It’s some­thing I have nev­er seen in my 20 years of” study­ing virus­es, said virol­o­gist Ben­jamin tenO­ev­er of the Icahn School of Med­i­cine at Mount Sinai, refer­ring to how SARS-CoV­‑2, the virus that caus­es Covid-19, hijacks cells’ genomes.

    The “some­thing” he and his col­leagues saw is how SARS-CoV­‑2 blocks one virus-fight­ing set of genes but allows anoth­er set to launch, a pat­tern nev­er seen with oth­er virus­es. Influen­za and the orig­i­nal SARS virus (in the ear­ly 2000s), for instance, inter­fere with both arms of the body’s immune response — what tenO­ev­er dubs “call to arms” genes and “call for rein­force­ment” genes.

    The first group of genes pro­duces inter­fer­ons. These pro­teins, which infect­ed cells release, are bio­log­i­cal sem­a­phores, sig­nal­ing to neigh­bor­ing cells to acti­vate some 500 of their own genes that will slow down the virus’ abil­i­ty to make mil­lions of copies of itself if it invades them. This lasts sev­en to 10 days, tenO­ev­er said, con­trol­ling virus repli­ca­tion and there­by buy­ing time for the sec­ond group of genes to act.

    This sec­ond set of genes pro­duce their own secret­ed pro­teins, called chemokines, that emit a bio­chem­i­cal “come here!” alarm. When far-flung anti­body-mak­ing B cells and virus-killing T cells sense the alarm, they race to its source. If all goes well, the first set of genes holds the virus at bay long enough for the lethal pro­fes­sion­al killers to arrive and start erad­i­cat­ing virus­es.

    “Most oth­er virus­es inter­fere with some aspect of both the call to arms and the call for rein­force­ments,” tenO­ev­er said. “If they didn’t, no one would ever get a viral ill­ness”: The one-two punch would pum­mel any incip­i­ent infec­tion into sub­mis­sion.

    SARS-CoV­‑2, how­ev­er, unique­ly blocks one cel­lu­lar defense but acti­vates the oth­er, he and his col­leagues report­ed in a study pub­lished last week in Cell. They stud­ied healthy human lung cells grow­ing in lab dish­es, fer­rets (which the virus infects eas­i­ly), and lung cells from Covid-19 patients. In all three, they found that with­in three days of infec­tion, the virus induces cells’ call-for-rein­force­ment genes to pro­duce cytokines. But it blocks their call-to-arms genes — the inter­fer­ons that damp­en the virus’ repli­ca­tion.

    The result is essen­tial­ly no brakes on the virus’s repli­ca­tion, but a storm of inflam­ma­to­ry mol­e­cules in the lungs, which is what tenO­ev­er calls an “unique” and “aber­rant” con­se­quence of how SARS-CoV­‑2 manip­u­lates the genome of its tar­get.

    In anoth­er new study, sci­en­tists in Japan last week iden­ti­fied how SARS-CoV­‑2 accom­plish­es that genet­ic manip­u­la­tion. Its ORF3b gene pro­duces a pro­tein called a tran­scrip­tion fac­tor that has “strong anti-inter­fer­on activ­i­ty,” Kei Sato of the Uni­ver­si­ty of Tokyo and col­leagues found — stronger than the orig­i­nal SARS virus or influen­za virus­es. The pro­tein basi­cal­ly blocks the cell from rec­og­niz­ing that a virus is present, in a way that pre­vents inter­fer­on genes from being expressed.

    In fact, the Icahn School team found no inter­fer­ons in the lung cells of Covid-19 patients. With­out inter­fer­ons, tenO­ev­er said, “there is noth­ing to stop the virus from repli­cat­ing and fes­ter­ing in the lungs for­ev­er.”

    That caus­es lung cells to emit even more “call-for-rein­force­ment” genes, sum­mon­ing more and more immune cells. Now the lungs have macrophages and neu­trophils and oth­er immune cells “every­where,” tenO­ev­er said, caus­ing such run­away inflam­ma­tion “that you start hav­ing inflam­ma­tion that induces more inflam­ma­tion.”

    At the same time, unchecked viral repli­ca­tion kills lung cells involved in oxy­gen exchange. “And sud­den­ly you’re in the hos­pi­tal in severe res­pi­ra­to­ry dis­tress,” he said.

    In elder­ly peo­ple, as well as those with dia­betes, heart dis­ease, and oth­er under­ly­ing con­di­tions, the call-to-arms part of the immune sys­tem is weak­er than in younger, health­i­er peo­ple, even before the coro­n­avirus arrives. That reduces even fur­ther the cells’ abil­i­ty to knock down virus repli­ca­tion with inter­fer­ons, and imbal­ances the immune sys­tem toward the dan­ger­ous inflam­ma­to­ry response.

    The dis­cov­ery that SARS-CoV­‑2 strong­ly sup­press­es infect­ed cells’ pro­duc­tion of inter­fer­ons has raised an intrigu­ing pos­si­bil­i­ty: that tak­ing inter­fer­ons might pre­vent severe Covid-19 or even pre­vent it in the first place, said Vineet Men­ach­ery of the Uni­ver­si­ty of Texas Med­ical Branch.

    In a study of human cells grow­ing in lab dish­es, described in a preprint (not peer-reviewed or pub­lished in a jour­nal yet), he and his col­leagues also found that SARS-CoV­‑2 “pre­vents the vast amount” of inter­fer­on genes from turn­ing on. But when cells grow­ing in lab dish­es received the inter­fer­on IFN‑1 before expo­sure to the coro­n­avirus, “the virus has a dif­fi­cult time repli­cat­ing.”

    After a few days, the amount of virus in infect­ed but inter­fer­on-treat­ed cells was 1,000- to 10,000-fold low­er than in infect­ed cells not pre-treat­ed with inter­fer­on. (The orig­i­nal SARS virus, in con­trast, is insen­si­tive to inter­fer­on.)

    End­ing the pan­dem­ic and pre­vent­ing its return is assumed to require an effec­tive vac­cine to pre­vent infec­tion and antivi­ral drugs such as remde­sivir to treat the very sick, but the genet­ic stud­ies sug­gest a third strat­e­gy: pre­ven­tive drugs.

    It’s pos­si­ble that treat­ment with so-called type‑1 inter­fer­on “could stop the virus before it could get estab­lished,” Men­ach­ery said.

    Giv­ing drugs to healthy peo­ple is always a dicey propo­si­tion, since all drugs have side effects — some­thing con­sid­ered less accept­able than when a drug is used to treat an ill­ness. “Inter­fer­on treat­ment is rife with com­pli­ca­tions,” Men­ach­ery warned. The var­i­ous inter­fer­ons, which are pre­scribed for hepati­tis, can­cers, and many oth­er dis­eases, can cause flu-like symp­toms.

    But the risk-ben­e­fit equa­tion might shift, both for indi­vid­u­als and for soci­ety, if inter­fer­ons or antivi­rals or oth­er med­ica­tions are shown to reduce the risk of devel­op­ing seri­ous Covid-19 or even make any infec­tion near­ly asymp­to­matic.

    ...

    ————–

    “‘It’s some­thing I have nev­er seen’: How the Covid-19 virus hijacks cells” by Sharon Beg­ley; STAT News; 05/21/2020

    “The “some­thing” he and his col­leagues saw is how SARS-CoV­‑2 blocks one virus-fight­ing set of genes but allows anoth­er set to launch, a pat­tern nev­er seen with oth­er virus­es. Influen­za and the orig­i­nal SARS virus (in the ear­ly 2000s), for instance, inter­fere with both arms of the body’s immune response — what tenO­ev­er dubs “call to arms” genes and “call for rein­force­ment” genes.”

    A pat­tern nev­er seen with oth­er virus­es. It’s unfor­tu­nate­ly becom­ing a meta-pat­tern with this virus: find­ing things nev­er seen before:

    ...
    The first group of genes pro­duces inter­fer­ons. These pro­teins, which infect­ed cells release, are bio­log­i­cal sem­a­phores, sig­nal­ing to neigh­bor­ing cells to acti­vate some 500 of their own genes that will slow down the virus’ abil­i­ty to make mil­lions of copies of itself if it invades them. This lasts sev­en to 10 days, tenO­ev­er said, con­trol­ling virus repli­ca­tion and there­by buy­ing time for the sec­ond group of genes to act.

    This sec­ond set of genes pro­duce their own secret­ed pro­teins, called chemokines, that emit a bio­chem­i­cal “come here!” alarm. When far-flung anti­body-mak­ing B cells and virus-killing T cells sense the alarm, they race to its source. If all goes well, the first set of genes holds the virus at bay long enough for the lethal pro­fes­sion­al killers to arrive and start erad­i­cat­ing virus­es.

    ...

    SARS-CoV­‑2, how­ev­er, unique­ly blocks one cel­lu­lar defense but acti­vates the oth­er, he and his col­leagues report­ed in a study pub­lished last week in Cell. They stud­ied healthy human lung cells grow­ing in lab dish­es, fer­rets (which the virus infects eas­i­ly), and lung cells from Covid-19 patients. In all three, they found that with­in three days of infec­tion, the virus induces cells’ call-for-rein­force­ment genes to pro­duce cytokines. But it blocks their call-to-arms genes — the inter­fer­ons that damp­en the virus’ repli­ca­tion.

    The result is essen­tial­ly no brakes on the virus’s repli­ca­tion, but a storm of inflam­ma­to­ry mol­e­cules in the lungs, which is what tenO­ev­er calls an “unique” and “aber­rant” con­se­quence of how SARS-CoV­‑2 manip­u­lates the genome of its tar­get.
    ...

    And the virus isn’t just unique in how it only blocks the “call-to-arms” expres­sion of inter­fer­on that would tell sur­round­ing cells to pre­pare to stop the virus from repli­cat­ing. It blocks inter­fer­on excep­tion­al­ly well. So well that the Mount Sinai team found NO inter­fer­on at all in the infect­ed lung cells they stud­ied. At the same time, the unin­hib­it­ed viral repli­ca­tion ends up killing cells involved in oxy­gen exchange and trig­ger­ing an even stronger “call-for-rein­force­ments” response, thus set­ting up a per­fect storm of over-inflam­ma­tion:

    ...
    In anoth­er new study, sci­en­tists in Japan last week iden­ti­fied how SARS-CoV­‑2 accom­plish­es that genet­ic manip­u­la­tion. Its ORF3b gene pro­duces a pro­tein called a tran­scrip­tion fac­tor that has “strong anti-inter­fer­on activ­i­ty,” Kei Sato of the Uni­ver­si­ty of Tokyo and col­leagues found — stronger than the orig­i­nal SARS virus or influen­za virus­es. The pro­tein basi­cal­ly blocks the cell from rec­og­niz­ing that a virus is present, in a way that pre­vents inter­fer­on genes from being expressed.

    In fact, the Icahn School team found no inter­fer­ons in the lung cells of Covid-19 patients. With­out inter­fer­ons, tenO­ev­er said, “there is noth­ing to stop the virus from repli­cat­ing and fes­ter­ing in the lungs for­ev­er.”

    That caus­es lung cells to emit even more “call-for-rein­force­ment” genes, sum­mon­ing more and more immune cells. Now the lungs have macrophages and neu­trophils and oth­er immune cells “every­where,” tenO­ev­er said, caus­ing such run­away inflam­ma­tion “that you start hav­ing inflam­ma­tion that induces more inflam­ma­tion.”

    At the same time, unchecked viral repli­ca­tion kills lung cells involved in oxy­gen exchange. “And sud­den­ly you’re in the hos­pi­tal in severe res­pi­ra­to­ry dis­tress,” he said.

    ...

    So that’s all rather omi­nous, except it might lead to a pre­ven­ta­tive drug treat­ment by treat­ing pre­emp­tive­ly treat­ing peo­ple with inter­fer­on. It’s not an ide­al solu­tion giv­en the side-effects of inter­fer­on but we may not be able to rely on a vac­cine if a large por­tion of the pop­u­lace does­n’t devel­op anti­bod­ies so the more tools the bet­ter. All in all, the more we learn about this virus the more we’re learn­ing how unusu­al it is. It’s an awful pat­tern that hope­ful­ly remains unique to this virus.

    Posted by Pterrafractyl | July 17, 2020, 3:11 pm
  2. Here’s a pair of arti­cles that high­light some­thing that could be done right now that would help con­trol the cur­rent coro­n­avirus pan­dem­ic while simul­ta­ne­ous­ly help­ing to pre­pare for future pan­demics and ret­ro­spec­tive exam­ine where and when the cur­rent out­break start­ed. It’s some­thing that could be par­tic­u­lar­ly use­ful for the US right now where mas­sive delays in coro­n­avirus test­ing has made test­ing effec­tive­ly use­less as an imme­di­ate con­trol strat­e­gy:

    First, here’s a STAT News piece that calls for the US to do some­thing many coun­tries are already doing to take advan­tage of the fact that SARS-CoV­‑2 can be detect­ed in the feces of infect­ed peo­ple to detect emerg­ing new COVID out­breaks in par­tic­u­lar towns are regions: test sewage for the virus. It’s that sim­ple. Just rou­tine­ly sam­ple and test sewage across the US. It’s a rel­a­tive­ly cheap solu­tion that does­n’t rely on indi­vid­u­als going in to get test­ed which is cru­cial giv­en the grow­ing evi­dence of the role asymp­to­matic spread­ing is play­ing. In addi­tion, this approach can poten­tial­ly be car­ried out in a high­ly local­ized man­ner, like just test­ing the sewage of a retire­ment home so it can be used to cre­ate ear­ly warn­ing sys­tems for the most vul­ner­a­ble com­mu­ni­ties.

    Also note that there remain major open ques­tions like how wide­spread the infec­tions real­ly com­pared to the offi­cial case num­bers. The CDC recent­ly reit­er­at­ing that the num­ber of infect­ed peo­ple is prob­a­bly 2 to 24 times high­er than the offi­cial num­bers in the US. Waste­water sam­pling, how­ev­er, can be used for quan­ti­ta­tive esti­mates too so it could invalu­able for esti­mat­ing the true scope of the num­ber of cas­es.

    And once this kind of test­ing infra­struc­ture is set up it can be applied for future pan­demics too, at least for virus­es that show up in fecal mat­ter. Or, if sam­ples are pre­served, to ret­ro­spec­tive­ly look back after a pan­dem­ic has start­ed to try to find where and when the virus first start­ed appear­ing. And that’s part of what’s going to be inter­est­ing to watch as viral waste­water sur­vey­ing becomes more com­mon­place: giv­en the accu­mu­la­tion of evi­dence that this pan­dem­ic did­n’t start in Wuhan in Decem­ber and may have been cir­cu­lat­ing on mil­i­tary bases around the world for long before that, any sort of mean­ing­ful ret­ro­spec­tive analy­sis could be extreme­ly polit­i­cal­ly unwel­come for a num­ber of nations but espe­cial­ly the US gov­ern­ment that has made direct­ing anger at Chi­na one of the core ele­ments of its pan­dem­ic response. And as we’ll see in the sec­ond arti­cle below, researchers in Barcelona have already con­duct­ed this kind of ret­ro­spec­tive analy­sis using frozen waste­water sam­ples and detect­ed the SARS-CoV­‑2 virus in a sin­gle sam­ple back in March of 2019. If those results could be repro­duced else­where it would fun­da­men­tal­ly alter the pre­vail­ing “Chi­na did it!” nar­ra­tive that gov­ern­ments around the world are rely­ing on to deflect cul­pa­bil­i­ty. So it’s going to be inter­est­ing to see if there’s any real attempt to set up a nation­al waste­water viral sur­veil­lance net­work and even more inter­est­ing to see if any sort of ret­ro­spec­tive analy­sis will be allowed to hap­pen if such a net­work is indeed set up:

    STAT News

    It’s time to begin a nation­al waste­water test­ing pro­gram for Covid-19

    By Anna Mehro­tra, David A. Larsen, and Ashish K. Jha
    July 9, 2020

    As the Covid-19 pan­dem­ic march­es across Amer­i­ca, caus­ing record-break­ing num­bers of cas­es, almost every solu­tion for con­trol­ling the dis­ease includes more test­ing, espe­cial­ly as cities and states try to reopen. But with states hit­ting their lim­its on test­ing, we need new tools for under­stand­ing Covid-19 trans­mis­sion. A nation­al waste­water sur­veil­lance pro­gram offers a cost-effec­tive approach to track Covid-19 across the major­i­ty of the U.S. pop­u­la­tion and pro­vide ear­ly warn­ings of resur­gence.

    Sim­ply test­ing indi­vid­u­als with symp­toms won’t be enough to track how many peo­ple are infect­ed. Giv­en the high degree of asymp­to­matic spread — even in the absence of super­spread­ing events — we need a nation­al strat­e­gy that relies heav­i­ly on sur­veil­lance. Experts increas­ing­ly argue that we should be test­ing nurs­ing home res­i­dents every week. Some uni­ver­si­ties are plan­ning to test every stu­dent mul­ti­ple times per week. And the fed­er­al gov­ern­ment is talk­ing about pooled test­ing as a strat­e­gy for test­ing large groups of indi­vid­u­als at once. The hope is that such test­ing, when cou­pled with robust con­tact trac­ing, can iden­ti­fy infec­tions before they spread.

    Since the start of the pan­dem­ic in Feb­ru­ary, approx­i­mate­ly 30 mil­lion indi­vid­ual Covid-19 tests have been per­formed in the U.S. Nobel lau­re­ate Paul Romer and oth­ers argue that we need the capac­i­ty to per­form this num­ber of tests every day — about 80 times our cur­rent capac­i­ty. Even if we could afford the $3 bil­lion dai­ly expense, it would be logis­ti­cal­ly near­ly impos­si­ble to achieve, at least with­out sub­stan­tial fed­er­al engage­ment and lead­er­ship, which does not appear to be immi­nent.

    Test­ing indi­vid­u­als is the only way to find out who is infect­ed, iso­late them, and trace their con­tacts. But we should not rely on indi­vid­ual test­ing to under­stand trans­mis­sion trends in com­mu­ni­ties. An alter­na­tive approach that com­ple­ments the cur­rent need for test­ing more indi­vid­u­als is test­ing entire com­mu­ni­ties by track­ing the coro­n­avirus in waste­water. This is logis­ti­cal­ly eas­i­er, would serve as an ear­ly warn­ing sig­nal of the pres­ence of SARS-CoV­‑2 in a com­mu­ni­ty, and result in near­ly con­tin­u­ous track­ing of Covid-19 in three-quar­ters of the U.S. pop­u­la­tion at a cost of $40 mil­lion to $80 mil­lion per week.

    Peo­ple infect­ed with SARS-CoV­‑2 shed the virus in their stool even before they show symp­toms of Covid-19. Ana­lyz­ing sewage for the virus, using meth­ods like the ones used for test­ing indi­vid­u­als, can pre­dict the com­mu­ni­ty lev­el of infec­tion one week to two weeks in advance of clin­i­cal diag­noses, and show increas­ing and decreas­ing lev­els of coro­n­avirus infec­tion and trans­mis­sion. Test­ing the waste­water of a nurs­ing home, prison, or dor­mi­to­ry could poten­tial­ly give an ear­ly sig­nal that one or more res­i­dents are infect­ed and there­fore prompt test­ing of each res­i­dent.

    Nation­al waste­water sur­veil­lance would require at least week­ly test­ing at waste­water treat­ment plants and in sew­ers. Although some states, such as Col­orado, Ohio, and New York, have tak­en steps toward imple­ment­ing waste­water sur­veil­lance efforts, the U.S. lacks a nation­al Covid-19 pro­gram for it.

    Oth­er coun­tries have nation­al pro­grams in place. Aus­tralia is work­ing with state and ter­ri­to­ry author­i­ties and 16 of the largest util­i­ties in the coun­try to imple­ment week­ly waste­water mon­i­tor­ing as part of the Col­lab­o­ra­tion on Sewage Sur­veil­lance of SARS-COV‑2 project. In Fin­land, the Finnish Insti­tute for Health and Wel­fare is over­see­ing sam­pling at 28 waste­water treat­ment plants in a mon­i­tor­ing pro­gram that cov­ers 60% of the Finnish pop­u­la­tion. The Nether­lands has imple­ment­ed week­ly test­ing at 29 plants that cov­er about 25% of the Dutch pop­u­la­tion. Pak­istan has insti­tut­ed a pro­gram that lever­ages the exist­ing polio envi­ron­men­tal sur­veil­lance net­work to mon­i­tor SARS-CoV­‑2 at 78 waste­water treat­ment plants across the coun­try.

    Although we can learn from the nation­al waste­water sur­veil­lance expe­ri­ence of oth­er coun­tries, any pro­gram designed for the U.S. will nec­es­sar­i­ly be larg­er and more com­plex. At last count in 2012, there were 14,748 waste­water treat­ment plants pro­vid­ing sewage col­lec­tion and treat­ment to 80% of peo­ple liv­ing in the U.S. The oth­er 20% are served by sep­tic sys­tems. While reg­u­lar sam­pling for all waste­water treat­ment plants is cer­tain­ly fea­si­ble, even focus­ing on just the 542 largest ones — those with treat­ment capac­i­ties exceed­ing 10 mil­lion gal­lons of sewage per day — would cov­er half the U.S. pop­u­la­tion.

    To be effec­tive, waste­water sur­veil­lance needs to use a sen­si­tive and spe­cif­ic test­ing method that gives reli­able and repeat­able results that are avail­able with­in a day. The results need to be quan­ti­ta­tive, such as genome copies per liter of waste­water, which can then be trans­lat­ed into an esti­mate of peo­ple infect­ed. Such ana­lyt­i­cal capa­bil­i­ties already exist in com­mer­cial envi­ron­men­tal test­ing lab­o­ra­to­ries. And efforts are under­way to adapt elec­tro­chem­i­cal biosen­sors pre­vi­ous­ly devel­oped for virus detec­tion, includ­ing microflu­idic paper-based devices, for near real-time SARS-CoV­‑2 quan­tifi­ca­tion in waste­water.

    There are still impor­tant ques­tions to be answered about nation­al waste­water sur­veil­lance for SARS-CoV­‑2: How should sam­ples be col­lect­ed? (We rec­om­mend com­bin­ing sam­ples tak­en from one loca­tion over the course of a day, although a sam­ple from one point in time could also suf­fice.) How often should test­ing be done? (We rec­om­mend two to three times per week.) Where should test­ing be done? (We rec­om­mend test­ing at waste­water treat­ment plants and in select loca­tions in the sew­er sys­tem feed­ing the plants). Col­lect­ing sam­ples in the sew­er sys­tem could be accom­plished by deploy­ing autosam­plers at man­holes, ide­al­ly select­ing those down­stream of nurs­ing homes and oth­er vul­ner­a­ble facil­i­ties.

    We will also need a nation­al sur­veil­lance data­base that allows seam­less input of ana­lyt­i­cal results, visu­al­iza­tion of trends, and ulti­mate­ly pre­dic­tions of where the next out­break will be.

    The U.S. needs to get start­ed with waste­water sur­veil­lance now. The sci­ence clear­ly sup­ports this strat­e­gy. Doing so will pro­vide a cost-effec­tive method of under­stand­ing the pan­dem­ic and an ear­ly warn­ing sys­tem for increased and decreased trans­mis­sion as the pan­dem­ic wax­es and wanes.

    ...

    Anna Mehro­tra is a senior waste­water engi­neer with CDM Smith Inc., in Boston. David A. Larsen is an envi­ron­men­tal epi­demi­ol­o­gist and asso­ciate pro­fes­sor of pub­lic health at Syra­cuse Uni­ver­si­ty in New York. Ashish Jha is the direc­tor of the Har­vard Glob­al Health Insti­tute and pro­fes­sor of glob­al health at the Har­vard T.H. Chan School of Pub­lic Health.

    ————

    “It’s time to begin a nation­al waste­water test­ing pro­gram for Covid-19” by Anna Mehro­tra, David A. Larsen, and Ashish K. Jha; STAT News; 07/09/2020

    “Since the start of the pan­dem­ic in Feb­ru­ary, approx­i­mate­ly 30 mil­lion indi­vid­ual Covid-19 tests have been per­formed in the U.S. Nobel lau­re­ate Paul Romer and oth­ers argue that we need the capac­i­ty to per­form this num­ber of tests every day — about 80 times our cur­rent capac­i­ty. Even if we could afford the $3 bil­lion dai­ly expense, it would be logis­ti­cal­ly near­ly impos­si­ble to achieve, at least with­out sub­stan­tial fed­er­al engage­ment and lead­er­ship, which does not appear to be immi­nent.”

    There’s sim­ply no way the US is going to have the nec­es­sar­i­ly indi­vid­ual-lev­el test­ing capac­i­ty required in time to deal with a grow­ing pan­dem­ic. That’s the pic­ture that’s emerged over the sum­mer: the explo­sion in cas­es has­n’t been met with an explo­sion of test­ing capac­i­ty and there’s no sign this is going to change any time soon. It’s the kind of sit­u­a­tion that points towards an even greater test­ing capac­i­ty deficit in future months. And that’s why solu­tions that can track the spread of the virus that don’t rely on indi­vid­ual tests are going to be increas­ing­ly tempt­ing going for­ward too. Espe­cial­ly since these solu­tions are much cheap­er than indi­vid­ual-lev­el test­ing too and this kind of test­ing can be extreme­ly local­ized down to just indi­vid­ual nurs­ing homes or pris­ons:

    ...
    Test­ing indi­vid­u­als is the only way to find out who is infect­ed, iso­late them, and trace their con­tacts. But we should not rely on indi­vid­ual test­ing to under­stand trans­mis­sion trends in com­mu­ni­ties. An alter­na­tive approach that com­ple­ments the cur­rent need for test­ing more indi­vid­u­als is test­ing entire com­mu­ni­ties by track­ing the coro­n­avirus in waste­water. This is logis­ti­cal­ly eas­i­er, would serve as an ear­ly warn­ing sig­nal of the pres­ence of SARS-CoV­‑2 in a com­mu­ni­ty, and result in near­ly con­tin­u­ous track­ing of Covid-19 in three-quar­ters of the U.S. pop­u­la­tion at a cost of $40 mil­lion to $80 mil­lion per week.

    Peo­ple infect­ed with SARS-CoV­‑2 shed the virus in their stool even before they show symp­toms of Covid-19. Ana­lyz­ing sewage for the virus, using meth­ods like the ones used for test­ing indi­vid­u­als, can pre­dict the com­mu­ni­ty lev­el of infec­tion one week to two weeks in advance of clin­i­cal diag­noses, and show increas­ing and decreas­ing lev­els of coro­n­avirus infec­tion and trans­mis­sion. Test­ing the waste­water of a nurs­ing home, prison, or dor­mi­to­ry could poten­tial­ly give an ear­ly sig­nal that one or more res­i­dents are infect­ed and there­fore prompt test­ing of each res­i­dent.
    ...

    A nation­al waste­water test­ing net­work that rou­tine­ly checks waste­water and feeds the infor­ma­tion back to the net­work. The sh*ternet. Is such a sys­tem fea­si­ble? Of course it is because nations like Pak­istan have already been doing it for virus­es like polio and states like New York, Col­orado and Ohio have already tak­en steps to set up their own sys­tems:

    ...
    Nation­al waste­water sur­veil­lance would require at least week­ly test­ing at waste­water treat­ment plants and in sew­ers. Although some states, such as Col­orado, Ohio, and New York, have tak­en steps toward imple­ment­ing waste­water sur­veil­lance efforts, the U.S. lacks a nation­al Covid-19 pro­gram for it.

    Oth­er coun­tries have nation­al pro­grams in place. Aus­tralia is work­ing with state and ter­ri­to­ry author­i­ties and 16 of the largest util­i­ties in the coun­try to imple­ment week­ly waste­water mon­i­tor­ing as part of the Col­lab­o­ra­tion on Sewage Sur­veil­lance of SARS-COV‑2 project. In Fin­land, the Finnish Insti­tute for Health and Wel­fare is over­see­ing sam­pling at 28 waste­water treat­ment plants in a mon­i­tor­ing pro­gram that cov­ers 60% of the Finnish pop­u­la­tion. The Nether­lands has imple­ment­ed week­ly test­ing at 29 plants that cov­er about 25% of the Dutch pop­u­la­tion. Pak­istan has insti­tut­ed a pro­gram that lever­ages the exist­ing polio envi­ron­men­tal sur­veil­lance net­work to mon­i­tor SARS-CoV­‑2 at 78 waste­water treat­ment plants across the coun­try.
    ...

    So we’ll hope­ful­ly be get­ting a much bet­ter sense of how fea­si­ble these kinds of sys­tems are and what types of chal­lenges they’ll face as states like New York and Ohio begin exper­i­ment­ing with set­ting up these kinds of sys­tems. But as the fol­low­ing arti­cle makes clear, one thing they should be sure to include is frozen sam­ples for future analy­sis so researchers can ask ques­tions months or years from now that they know to ask or need to ask. For exam­ple, if there’s a new nov­el coro­n­avirus out­break in 2022, it would be real­ly use­ful to have frozen sewage sam­ples sit­ting there from 2021 to ret­ro­spec­tive­ly go back and ask whether COVID-22 was already float­ing around in 2021. It’s the kind of data that could be absolute­ly invalu­able dur­ing an emerg­ing pan­dem­ic. Which rais­es the obvi­ous ques­tion: so are there any frozen sewage sam­ples from 2019 or 2018 that can be sam­pled to look for signs of SARS-CoV­‑2? And it turns out, yes, at least in some cities, there are rou­tine­ly frozen sewage sam­ples and researchers have been look­ing at them and find­ing signs of SARS-CoV­‑2 in 2019, includ­ing researchers in Barcelona who got a pos­i­tive hit from a sin­gle sam­ple from March of 2019.

    Oth­er researchers not involved with the study are skep­ti­cal of the find­ing and sug­gest the pos­i­tive result was some sort of tech­ni­cal arti­fact and note that it did­n’t show up in sam­ples before or after that they test­ed. Just March of 2019. So was the virus in Barcelona in March of 2019? Unfor­tu­nate­ly because there was only a sin­gle frozen sam­ple and it was all used up for the ini­tial analy­sis we can’t go back and val­i­date their find­ings but the Barcelona researchers insist that they know how to car­ry­ing out these analy­ses cor­rect­ly with min­i­mal chance of a tech­ni­cal screw up caus­ing the pos­i­tive hit. So hope­ful­ly any future nation­al waste­water sur­veil­lance regimes will include keep­ing mul­ti­ple frozen sam­ples from each site for exact­ly this kind of sit­u­a­tion:

    The New York Times

    Study Sug­gests Coro­n­avirus Emerged Much Ear­li­er Than Thought. Some Are Skep­ti­cal.

    Sci­en­tists not involved in the study seri­ous­ly doubt the find­ings, which chal­lenge the cur­rent con­sen­sus on where and when the virus orig­i­nat­ed.

    By Carl Zim­mer and Raphael Min­der
    June 26, 2020

    In a study not yet pub­lished in a jour­nal, sci­en­tists have report­ed that the new coro­n­avirus was present in waste­water in Barcelona, Spain in March 2019, a find­ing that, if con­firmed, would show that the pathogen had emerged much ear­li­er than pre­vi­ous­ly thought.

    But inde­pen­dent experts who reviewed the find­ings said they doubt­ed the claim. The study was flawed, they said, and oth­er lines of evi­dence strong­ly sug­gest the virus emerged in Chi­na late last year.

    Up until now, the ear­li­est evi­dence of the virus any­where in the world has been from Decem­ber 2019 in Chi­na and it was only known to have hit main­land Spain in Feb­ru­ary 2020.

    “Barcelona is a city that is fre­quent­ed by Chi­nese peo­ple, in tourism and busi­ness, so prob­a­bly this hap­pened also else­where, and prob­a­bly at the same time,” said the lead author, Albert Bosch, a pro­fes­sor in the Depart­ment of Micro­bi­ol­o­gy of the Uni­ver­si­ty of Barcelona who has been study­ing virus­es in waste­water for more than 40 years.

    Sev­er­al experts not involved in the research point­ed out prob­lems with the new study, which has not yet been sub­ject­ed to the crit­i­cal review by out­side experts that occurs before pub­li­ca­tion in a sci­en­tif­ic jour­nal. They sug­gest­ed that the tests might very well have pro­duced false pos­i­tives because of con­t­a­m­i­na­tion or improp­er stor­age of the sam­ples.

    “I don’t trust the results,” said Irene Xago­rara­ki, an envi­ron­men­tal engi­neer at Michi­gan State Uni­ver­si­ty.

    Researchers at the Uni­ver­si­ty of Barcelona post­ed their find­ings online on June 13. Most of their report described research on waste­water treat­ments from ear­ly 2020. The sur­pris­ing find­ing about March 2019 was only men­tioned briefly at the end of the report.

    The research gained more atten­tion when the uni­ver­si­ty issued a news release on Fri­day.

    ...

    Researchers have stud­ied the muta­tions that have arisen in coro­n­avirus sam­ples col­lect­ed from across the world since then and have esti­mat­ed on the basis of their find­ings that the sam­ples shared a com­mon ances­tor that dat­ed to late 2019.

    More evi­dence for the ori­gin of the nov­el coro­n­avirus has come from oth­er virus­es that sci­en­tists have found in ani­mals. The clos­est rel­a­tives to the coro­n­avirus infect bats in Chi­na.

    Because the virus can be shed in feces, researchers have begun exam­in­ing waste­water to detect the pathogen’s genes.

    In Europe, Aus­tralia and the Unit­ed States, researchers dis­cov­ered ris­ing lev­els of the virus’s genes in waste­water days before con­firmed cas­es began to arise. These dis­cov­er­ies have led a num­ber of researchers to exam­ine frozen waste­water sam­ples from ear­li­er peri­ods, seek­ing evi­dence of the virus’s pres­ence before any­one knew to look for it.

    Last week, Ital­ian researchers report­ed find­ing the virus in Milan and Turin on Decem­ber 18, two months before north­ern Italy was besieged by Covid-19 cas­es.

    Sep­a­rate­ly, in Spain, Dr. Bosch and his col­leagues began tak­ing week­ly sam­ples of waste­water from two of Barcelona’s treat­ment plants in April. They found the virus in these sam­ples, prompt­ing them to look back at ear­li­er sam­ples.

    The researchers found the virus in a num­ber of sam­ples from ear­ly 2020, in the months before the pan­dem­ic struck Spain.

    Dr. Bosch and his col­leagues then went back even fur­ther, exam­in­ing nine sam­ples tak­en every few weeks or months between Jan­u­ary 2018 and Decem­ber 2019. In a sin­gle sam­ple, tak­en March 12, 2019, they got a pos­i­tive result from their tests for the virus.

    Dr. Bosch found it plau­si­ble that the virus could appear in March but not show up in more recent sam­ples.

    “Res­pi­ra­to­ry virus­es usu­al­ly have peaks around this time of the year,” Dr. Bosch said. “Prob­a­bly the virus then dis­ap­peared.”

    But Dr. Xago­rara­ki not­ed that the researchers used tests that search for bits of three dif­fer­ent genes. The only tests that came back pos­i­tive were for a gene called RdRp. One of the oth­er tests, for a gene called N, is known to be more sen­si­tive. “It should have shown a sig­nal as well,” Dr. Xago­rara­ki said.

    It was pos­si­ble that the pos­i­tive results were the result of con­t­a­m­i­na­tion from oth­er sam­ples that did have the virus, Dr. Xago­rara­ki said. She also doubt­ed whether the del­i­cate coro­n­avirus could have sur­vived for over a year with­out the sam­ple hav­ing been put in a deep freeze. “If the sam­ples were not stored in ‑80 degrees, you can’t trust the results,” she said.

    Gert­jan Mede­ma of the KWR Water Research Insti­tute in the Nether­lands said that the study came from a “knowl­edge­able research team,” and so should be tak­en seri­ous­ly. But, he added, “they need to con­firm this find­ing in mul­ti­ple ways.”

    Dr. Bosch said that his team would not be able to repeat the exper­i­ments in the pos­i­tive sam­ple from March 2019 because it was deplet­ed dur­ing the first test. “We proved it from this sam­ple but we can­not repeat it,” he said. But con­t­a­m­i­na­tion was unlike­ly, he said. “The way we work, when there is con­t­a­m­i­na­tion, we notice it.”

    Anoth­er way to con­firm the find­ing would be to search through stored sam­ples of blood from patients in Barcelona hos­pi­tals in March 2019. If the virus were cir­cu­lat­ing, even briefly, in Spain, some peo­ple would most like­ly have been hos­pi­tal­ized com­plain­ing of flu­like symp­toms.

    ————–

    “Study Sug­gests Coro­n­avirus Emerged Much Ear­li­er Than Thought. Some Are Skep­ti­cal.” by Carl Zim­mer and Raphael Min­der; The New York Times; 06/26/2020

    “Up until now, the ear­li­est evi­dence of the virus any­where in the world has been from Decem­ber 2019 in Chi­na and it was only known to have hit main­land Spain in Feb­ru­ary 2020.”

    Was this virus cir­cu­lat­ing in Spain for near­ly a year before it was detect­ed in Feb­ru­ary of this year? That’s what the find­ings from the Uni­ver­si­ty of Barcelona team sug­gests. Recall that Spain was one of the coun­tries with mil­i­tary ath­letes who report­ed feel­ing ill with COVID-like symp­toms dur­ing and after the Mil­i­tary World Games in Wuhan so the virus was like­ly cir­cu­lat­ing in Spain by at least Novem­ber. But could the virus have showed in in March and then dis­ap­peared again? Well, the researchers explain that it’s plau­si­ble that the virus would­n’t have been detect­ed in lat­er months because res­pi­ra­to­ry virus­es tend to peak in March and may have effec­tive­ly dis­ap­peared at that point:

    ...
    Dr. Bosch and his col­leagues then went back even fur­ther, exam­in­ing nine sam­ples tak­en every few weeks or months between Jan­u­ary 2018 and Decem­ber 2019. In a sin­gle sam­ple, tak­en March 12, 2019, they got a pos­i­tive result from their tests for the virus.

    Dr. Bosch found it plau­si­ble that the virus could appear in March but not show up in more recent sam­ples.

    “Res­pi­ra­to­ry virus­es usu­al­ly have peaks around this time of the year,” Dr. Bosch said. “Prob­a­bly the virus then dis­ap­peared.”
    ...

    Could this virus have sim­ply have dis­ap­peared with the wan­ing cold and flu sea­son? Giv­en that a high lev­el of infec­tious­ness has been one of the key fea­tures of these virus and it’s been spread­ing through­out the spring and sum­mer of 2020 it seems hard to imag­ine that the virus would have dis­si­pat­ed like that with the sea­sons. But it’s also worth recall­ing how ear­ly phy­lo­ge­net­ic analy­sis that exam­ined which strains of the virus were emerg­ing and spread­ing found that the virus seemed to mutate into a some­what more infec­tious form in Wuhan in Decem­ber of 2019 (the new “L‑type” vs old­er “S‑type” strains). A sin­gle muta­tion to the viral pro­tein sequence may have some­how made the virus even more capa­ble of spread­ing. Then there was a lat­er set of stud­ies that found anoth­er new strain (the new “G‑clade” vs old­er “D‑clade”) that either emerged in Wuhan or Ger­many in Jan­u­ary of 2020 has already com­plete­ly dom­i­nat­ed new cas­es because it’s bet­ter at spread­ing for some rea­son. So if the virus was already cir­cu­lat­ing (per­haps on mil­i­tary bases) ear­li­er in 2019 but it was the ear­li­er less infec­tious strain per­haps it could have fad­ed from Barcelona as the annu­al cold and flu sea­son.

    But as one out­side researcher points out, there’s anoth­er rea­son to sus­pect the March 2019 hit: there were three tests used to search for signs of the virus in the sam­ple and the one that got a pos­i­tive hit was not the most sen­si­tive of the three tests. The most sen­si­tive test did­n’t get that pos­i­tive hit and that’s why they sus­pect a con­t­a­m­i­na­tion. But the Barcelona researchers are stand­ing by the qual­i­ty of their assay:

    ...
    But Dr. Xago­rara­ki not­ed that the researchers used tests that search for bits of three dif­fer­ent genes. The only tests that came back pos­i­tive were for a gene called RdRp. One of the oth­er tests, for a gene called N, is known to be more sen­si­tive. “It should have shown a sig­nal as well,” Dr. Xago­rara­ki said.

    It was pos­si­ble that the pos­i­tive results were the result of con­t­a­m­i­na­tion from oth­er sam­ples that did have the virus, Dr. Xago­rara­ki said. She also doubt­ed whether the del­i­cate coro­n­avirus could have sur­vived for over a year with­out the sam­ple hav­ing been put in a deep freeze. “If the sam­ples were not stored in ‑80 degrees, you can’t trust the results,” she said.

    Gert­jan Mede­ma of the KWR Water Research Insti­tute in the Nether­lands said that the study came from a “knowl­edge­able research team,” and so should be tak­en seri­ous­ly. But, he added, “they need to con­firm this find­ing in mul­ti­ple ways.”

    Dr. Bosch said that his team would not be able to repeat the exper­i­ments in the pos­i­tive sam­ple from March 2019 because it was deplet­ed dur­ing the first test. “We proved it from this sam­ple but we can­not repeat it,” he said. But con­t­a­m­i­na­tion was unlike­ly, he said. “The way we work, when there is con­t­a­m­i­na­tion, we notice it.”
    ...

    So val­i­dat­ing that spe­cif­ic March 2019 sam­ple test real­ly is an open ques­tion that can’t be direct­ly answered. It was a one-shot test. But that does­n’t mean there’s no way to answer this ques­tion. Check­ing frozen sam­ples from sur­round­ing cities, if they’re avail­able, would be one way. And then there’s check­ing frozen blood sam­ples:

    ...
    Anoth­er way to con­firm the find­ing would be to search through stored sam­ples of blood from patients in Barcelona hos­pi­tals in March 2019. If the virus were cir­cu­lat­ing, even briefly, in Spain, some peo­ple would most like­ly have been hos­pi­tal­ized com­plain­ing of flu­like symp­toms.
    ...

    Keep in mind, of course, that while a pos­i­tive hit from frozen blood sam­ples tak­en in March would be a strong con­fir­ma­tion of these waste­water find­ings, not find­ing the virus in frozen blood sam­ples would­n’t nec­es­sar­i­ly inval­i­date the find­ing. Frozen blood is tak­en from just one per­son, after all, where­as waste­water is sam­pling the entire pop­u­la­tion. But it under­scores the fact that if we are gen­uine­ly inter­est­ed in find­ing the when and where this out­break may have start­ed we have options. At least as long as there are stored sam­ples kept some­where.

    And that’s all part of why it’s going to be very inter­est­ing to see how which coun­tries show an inter­est in set­ting up nation­al waste­water sur­veil­lance net­works. It’s the kind of infra­struc­ture that could answer a whole lot of ques­tions about when and where pan­demics start­ed. And in the age of an explo­sion of biowar­fare research facil­i­ties around the globe and the grow­ing use of ‘gain-of-func­tion’ exper­i­men­tal tech­niques, with all of the risks of oppor­tu­ni­ties that entails, the ques­tion of whether or not gov­ern­ments are nec­es­sar­i­ly going to want robust net­works that allow for mean­ing­ful ret­ro­spec­tive analy­sis of when and where pan­demics start­ed remains a very open ques­tion too.

    Posted by Pterrafractyl | July 22, 2020, 2:59 pm
  3. Here’s a set of arti­cles that raise intrigu­ing ques­tions about why it is that some peo­ple are min­i­mal­ly impact­ed by the SARS-CoV­‑2 virus while oth­ers are immuno­log­i­cal­ly dev­as­tat­ed by the virus that relates to the grow­ing aware­ness of the impor­tance of T‑cells, and not just anti­bod­ies, in pro­vid­ing some sort of immu­ni­ty to the virus along with the obser­va­tion that pri­or expo­sure to mild cold-like coro­n­avirus­es might con­fer some lev­el of resis­tance to SARS-CoV­‑2:

    First, as described in the fol­low­ing review arti­cle recent­ly pub­lished in Nature Reviews Immunol­o­gy, there are now mul­ti­ple stud­ies out that exam­ined the response of T‑cells drawn from peo­ple before the cur­rent out­break (so they pre­sum­ably weren’t exposed to SARS-CoV­‑2 when the blood was drawn) and, sure enough, these researchers are find­ing that these old­er T‑Cells can iden­ti­fy SARS-CoV­‑2 as a viral invad­er in a large num­ber of instances. In one study that looked at blood drawn from peo­ple in the US from 2015–2018, around 50% of the blood sam­ples had T‑cells that react­ed to SARS-CoV­‑2. But oth­er stud­ies from Europe and Sin­ga­pore also showed a high lev­el of reac­tiv­i­ty to the SARS-CoV­‑2 virus from old­er pre-pan­dem­ic blood sam­ples. Five pub­lished stud­ies in all so far have demon­strat­ed this and since more than 90% of the pop­u­la­tion is ser­pos­i­tive for at least three of these com­mon-cold coro­n­avirus­es (CCCs) — like HCoV-OC43, HCoV-HKU1, HCoV-NL63 and HCoV-229E — the ques­tion of what role that pri­or expo­sure is play­ing in the cur­rent pan­dem­ic is obvi­ous­ly a cru­cial and poten­tial­ly very help­ful ques­tion to ask. After all, would­n’t it be nice if we could just expose every­one to a bunch of com­mon-cold coro­n­avirus­es to con­fer par­tial immu­ni­ty?

    As the review arti­cle also reminds us, while there’s much hope that pri­or expo­sure to mild cold-like coro­n­avirus­es is pro­tec­tive, we can’t ignore the pos­si­bil­i­ty that pri­or expo­sure to these coro­n­avirus­es is actu­al­ly mak­ing the SARS-CoV­‑2 infec­tion worse in some cas­es. Recall how this kind of “anti­body-depen­dent enhance­ment” (ADE) sce­nario was observed by researchers when they were work­ing on a vac­cine for the orig­i­nal SARS vac­cine, lead­ing some researchers to spec­u­late that the high fatal­i­ty rate of SARS in Chi­na was due to pri­or expo­sure to com­mon-cold coro­n­avirus. It’s anoth­er rea­son the rela­tion­ship between past com­mon cold coro­n­avirus expo­sure and cur­rent SARS-CoV­‑2 immu­ni­ty is a cru­cial ques­tion to answer as the cur­rent pan­dem­ic plays out:

    Nature Reviews Immunol­o­gy
    vol­ume 20, pages457–458(2020)

    Pre-exist­ing immu­ni­ty to SARS-CoV­‑2: the knowns and unknowns

    Alessan­dro Sette & Shane Crot­ty

    Pub­lished: 07 July 2020

    T cell reac­tiv­i­ty against SARS-CoV­‑2 was observed in unex­posed peo­ple; how­ev­er, the source and clin­i­cal rel­e­vance of the reac­tiv­i­ty remains unknown. It is spec­u­lat­ed that this reflects T cell mem­o­ry to cir­cu­lat­ing ‘com­mon cold’ coro­n­avirus­es. It will be impor­tant to define speci­fici­ties of these T cells and assess their asso­ci­a­tion with COVID-19 dis­ease sever­i­ty and vac­cine respons­es.

    ******

    As data start to accu­mu­late on the detec­tion and char­ac­ter­i­za­tion of SARS-CoV­‑2 T cell respons­es in humans, a sur­pris­ing find­ing has been report­ed: lym­pho­cytes from 20–50% of unex­posed donors dis­play sig­nif­i­cant reac­tiv­i­ty to SARS-CoV­‑2 anti­gen pep­tide pools1,2,3,4.

    In a study by Gri­foni et al.1, reac­tiv­i­ty was detect­ed in 50% of donor blood sam­ples obtained in the USA between 2015 and 2018, before SARS-CoV­‑2 appeared in the human pop­u­la­tion. T cell reac­tiv­i­ty was high­est against pro­teins oth­er than the coro­n­avirus spike pro­tein, but T cell reac­tiv­i­ty was also detect­ed against spike. The SARS-CoV­‑2 T cell reac­tiv­i­ty was most­ly asso­ci­at­ed with CD4+ T cells, with a small­er con­tri­bu­tion by CD8+ T cells1. Sim­i­lar­ly, in a study of blood donors in the Nether­lands, Weiskopf et al.2 detect­ed CD4+ T cell reac­tiv­i­ty against SARS-CoV­‑2 spike pep­tides in 1 of 10 unex­posed sub­jects and against SARS-CoV­‑2 non-spike pep­tides in 2 of 10 unex­posed sub­jects. CD8+ T cell reac­tiv­i­ty was observed in 1 of 10 unex­posed donors. In a third study, from Ger­many, Braun et al.3 report­ed pos­i­tive T cell respons­es against spike pep­tides in 34% of SARS-CoV­‑2 seroneg­a­tive healthy donors (CD4+ and CD8+ T cells were not dis­tin­guished). Final­ly, a study of indi­vid­u­als in Sin­ga­pore, by Le Bert et al.4, report­ed T cell respons­es to nucle­o­cap­sid pro­tein nsp7 or nsp13 in 50% of sub­jects with no his­to­ry of SARS, COVID-19, or con­tact with patients with SARS or COVID-19. A study by Meck­iff using sam­ples from the UK also detect­ed reac­tiv­i­ty in unex­posed sub­jects5. Tak­en togeth­er, five stud­ies report evi­dence of pre-exist­ing T cells that rec­og­nize SARS-CoV­‑2 in a sig­nif­i­cant frac­tion of peo­ple from diverse geo­graph­i­cal loca­tions.

    These ear­ly reports demon­strate that sub­stan­tial T cell reac­tiv­i­ty exists in many unex­posed peo­ple; nev­er­the­less, data have not yet demon­strat­ed the source of the T cells or whether they are mem­o­ry T cells. It has been spec­u­lat­ed that the SARS-CoV-2-spe­cif­ic T cells in unex­posed indi­vid­u­als might orig­i­nate from mem­o­ry T cells derived from expo­sure to ‘com­mon cold’ coro­n­avirus­es (CCCs), such as HCoV-OC43, HCoV-HKU1, HCoV-NL63 and HCoV-229E, which wide­ly cir­cu­late in the human pop­u­la­tion and are respon­si­ble for mild self-lim­it­ing res­pi­ra­to­ry symp­toms. More than 90% of the human pop­u­la­tion is seropos­i­tive for at least three of the CCCs6. Thiel and col­leagues3 report­ed that the T cell reac­tiv­i­ty was high­est against a pool of SARS-CoV­‑2 spike pep­tides that had high­er homol­o­gy to CCCs, but the dif­fer­ence was not sig­nif­i­cant.

    What are the impli­ca­tions of these obser­va­tions? The poten­tial for pre-exist­ing cross­re­ac­tiv­i­ty against COVID-19 in a frac­tion of the human pop­u­la­tion has led to exten­sive spec­u­la­tion. Pre-exist­ing T cell immu­ni­ty to SARS-CoV­‑2 could be rel­e­vant because it could influ­ence COVID-19 dis­ease sever­i­ty. It is plau­si­ble that peo­ple with a high lev­el of pre-exist­ing mem­o­ry CD4+ T cells that rec­og­nize SARS-CoV­‑2 could mount a faster and stronger immune response upon expo­sure to SARS-CoV­‑2 and there­by lim­it dis­ease sever­i­ty. Mem­o­ry T fol­lic­u­lar helper (TFH) CD4+ T cells could poten­tial­ly facil­i­tate an increased and more rapid neu­tral­iz­ing anti­body response against SARS-CoV­‑2. Mem­o­ry CD4+ and CD8+ T cells might also facil­i­tate direct antivi­ral immu­ni­ty in the lungs and nasophar­ynx ear­ly after expo­sure, in keep­ing with our under­stand­ing of antivi­ral CD4+ T cells in lungs against the relat­ed SARS-CoV7 and our gen­er­al under­stand­ing of the val­ue of mem­o­ry CD8+ T cells in pro­tec­tion from viral infec­tions. Large stud­ies in which pre-exist­ing immu­ni­ty is mea­sured and cor­re­lat­ed with prospec­tive infec­tion and dis­ease sever­i­ty could address the pos­si­ble role of pre-exist­ing T cell mem­o­ry against SARS-CoV­‑2.

    If the pre-exist­ing T cell immu­ni­ty is relat­ed to CCC expo­sure, it will become impor­tant to bet­ter under­stand the pat­terns of CCC expo­sure in space and time. It is well estab­lished that the four main CCCs are cycli­cal in their preva­lence, fol­low­ing mul­ti­year cycles, which can dif­fer across geo­graph­i­cal loca­tions8. This leads to the spec­u­la­tive hypoth­e­sis that dif­fer­ences in CCC geo-dis­tri­b­u­tion might cor­re­late with bur­den of COVID-19 dis­ease sever­i­ty. Fur­ther­more, high­ly spec­u­la­tive hypothe­ses relat­ed to pre-exist­ing mem­o­ry T cells can be pro­posed regard­ing COVID-19 and age. Chil­dren are less sus­cep­ti­ble to COVID-19 clin­i­cal symp­toms. Old­er peo­ple are much more sus­cep­ti­ble to fatal COVID-19. The rea­sons for both are unclear. The age dis­tri­b­u­tion of CCC infec­tions is not well estab­lished and CCC immu­ni­ty should be exam­ined in greater detail. These con­sid­er­a­tions under­line how mul­ti­ple vari­ables may be involved in poten­tial pre-exist­ing par­tial immu­ni­ty to COVID-19 and mul­ti­ple hypothe­ses are wor­thy of fur­ther explo­ration, but cau­tion should be exer­cised to avoid over­gen­er­al­iza­tions or con­clu­sions in the absence of data.

    Pre-exist­ing CD4+ T cell mem­o­ry could also influ­ence vac­ci­na­tion out­comes, lead­ing to a faster or bet­ter immune response, par­tic­u­lar­ly the devel­op­ment of neu­tral­iz­ing anti­bod­ies, which gen­er­al­ly depend on T cell help. At the same time, pre-exist­ing T cell mem­o­ry could also act as a con­found­ing fac­tor, espe­cial­ly in rel­a­tive­ly small phase I vac­cine tri­als. For exam­ple, if sub­jects with pre-exist­ing reac­tiv­i­ty were assort­ed uneven­ly in dif­fer­ent vac­cine dose groups, this might lead to erro­neous con­clu­sions. Obvi­ous­ly, this could be avoid­ed by con­sid­er­ing pre-exist­ing immu­ni­ty as a vari­able to be con­sid­ered in tri­al design. Thus, we rec­om­mend mea­sur­ing pre-exist­ing immu­ni­ty in all COVID-19 vac­cine phase I clin­i­cal tri­als. Of note, such exper­i­ments would also offer an excit­ing oppor­tu­ni­ty to ascer­tain the poten­tial bio­log­i­cal sig­nif­i­cance of pre-exist­ing SARS-CoV-2-reac­tive T cells.

    It is fre­quent­ly assumed that pre-exist­ing T cell mem­o­ry against SARS-CoV­‑2 might be either ben­e­fi­cial or irrel­e­vant. How­ev­er, there is also the pos­si­bil­i­ty that pre-exist­ing immu­ni­ty might actu­al­ly be detri­men­tal, through mech­a­nisms such as ‘orig­i­nal anti­genic sin’ (the propen­si­ty to elic­it poten­tial­ly infe­ri­or immune respons­es owing to pre-exist­ing immune mem­o­ry to a relat­ed pathogen), or through anti­body-medi­at­ed dis­ease enhance­ment. While there is no direct evi­dence to sup­port these out­comes, they must be con­sid­ered. A detri­men­tal effect linked to pre-exist­ing immu­ni­ty is emi­nent­ly testable and would be revealed by the same COVID-19 cohort and vac­cine stud­ies pro­posed above.

    There is sub­stan­tial data from the influen­za lit­er­a­ture indi­cat­ing that pre-exist­ing cross-reac­tive T cell immu­ni­ty can be ben­e­fi­cial. In the case of the H1N1 influen­za pan­dem­ic of 2009, it was not­ed that an unusu­al ‘V’-shaped age dis­tri­b­u­tion curve exist­ed for dis­ease sever­i­ty, with old­er peo­ple far­ing bet­ter than younger adults. This cor­re­lat­ed with the cir­cu­la­tion of a dif­fer­ent H1N1 strain in the human pop­u­la­tion decades ear­li­er, which pre­sum­ably gen­er­at­ed pre-exist­ing immu­ni­ty in peo­ple old enough to have been exposed to it. This was ver­i­fied by show­ing that pre-exist­ing immu­ni­ty against H1N1 exist­ed in the gen­er­al human pop­u­la­tion9,10. It should be not­ed that if some degree of pre-exist­ing immu­ni­ty against SARS-CoV­‑2 exists in the gen­er­al pop­u­la­tion, this could also influ­ence epi­demi­o­log­i­cal mod­el­ling, and sug­gests that a slid­ing scale mod­el of COVID-19 sus­cep­ti­bil­i­ty may be con­sid­ered.

    ....

    ————

    “Pre-exist­ing immu­ni­ty to SARS-CoV­‑2: the knowns and unknowns” by Alessan­dro Sette & Shane Crot­ty; Nature Reviews Immunol­o­gy, vol­ume 20, pages457–458(2020); 07/07/2020

    “These ear­ly reports demon­strate that sub­stan­tial T cell reac­tiv­i­ty exists in many unex­posed peo­ple; nev­er­the­less, data have not yet demon­strat­ed the source of the T cells or whether they are mem­o­ry T cells. It has been spec­u­lat­ed that the SARS-CoV-2-spe­cif­ic T cells in unex­posed indi­vid­u­als might orig­i­nate from mem­o­ry T cells derived from expo­sure to ‘com­mon cold’ coro­n­avirus­es (CCCs), such as HCoV-OC43, HCoV-HKU1, HCoV-NL63 and HCoV-229E, which wide­ly cir­cu­late in the human pop­u­la­tion and are respon­si­ble for mild self-lim­it­ing res­pi­ra­to­ry symp­toms. More than 90% of the human pop­u­la­tion is seropos­i­tive for at least three of the CCCs6. Thiel and col­leagues3 report­ed that the T cell reac­tiv­i­ty was high­est against a pool of SARS-CoV­‑2 spike pep­tides that had high­er homol­o­gy to CCCs, but the dif­fer­ence was not sig­nif­i­cant.”

    We know a large per­cent of the pop­u­lace has some sort of immu­ni­ty to SARS-CoV­‑2, but we don’t know where exact­ly it came from and we don’t know if they hap­pen to the long-liv­ing “mem­o­ry” T‑cells that can con­fer long-term immu­ni­ty. But anoth­er major rea­son for clos­er study of which spe­cif­ic com­mon-cold coro­n­avirus­es might be con­tribut­ing to SARS-CoV­‑2 immu­ni­ty is that the four main com­mon-cold coro­n­avirus­es fol­low mul­ti-year geo­graph­ic cycles, sug­gest­ing it’s pos­si­ble that the dif­fer­ent observed fatal­i­ty rates of the virus in dif­fer­ent regions might be cor­re­lat­ed with the glob­al dis­tri­b­u­tion of these com­mon-cold coro­n­avirus­es in recent years. In oth­er words, did New York City, Wuhan, and Milan all hap­pen to have sim­i­lar com­mon-cold coro­n­avirus expo­sure in recent year that dif­fers from much of the rest of the world? If so, that might explain why those cities got hit so incred­i­bly hard com­pared to oth­er cities.
    On the oth­er hand, if some sort of anti­body-depen­dent enhance­ment sce­nario is impact­ing the mor­tal­i­ty rates of this virus it could be New York City, Wuhan, and Milan all got exposed (per­haps inten­tion­al­ly) to some sort of com­mon-cold coro­n­avirus (or per­haps a still uniden­ti­fied coro­n­avirus) in recent years that haven’t had time to spread around to the rest of the world:

    ...
    If the pre-exist­ing T cell immu­ni­ty is relat­ed to CCC expo­sure, it will become impor­tant to bet­ter under­stand the pat­terns of CCC expo­sure in space and time. It is well estab­lished that the four main CCCs are cycli­cal in their preva­lence, fol­low­ing mul­ti­year cycles, which can dif­fer across geo­graph­i­cal loca­tions8. This leads to the spec­u­la­tive hypoth­e­sis that dif­fer­ences in CCC geo-dis­tri­b­u­tion might cor­re­late with bur­den of COVID-19 dis­ease sever­i­ty. Fur­ther­more, high­ly spec­u­la­tive hypothe­ses relat­ed to pre-exist­ing mem­o­ry T cells can be pro­posed regard­ing COVID-19 and age. Chil­dren are less sus­cep­ti­ble to COVID-19 clin­i­cal symp­toms. Old­er peo­ple are much more sus­cep­ti­ble to fatal COVID-19. The rea­sons for both are unclear. The age dis­tri­b­u­tion of CCC infec­tions is not well estab­lished and CCC immu­ni­ty should be exam­ined in greater detail. These con­sid­er­a­tions under­line how mul­ti­ple vari­ables may be involved in poten­tial pre-exist­ing par­tial immu­ni­ty to COVID-19 and mul­ti­ple hypothe­ses are wor­thy of fur­ther explo­ration, but cau­tion should be exer­cised to avoid over­gen­er­al­iza­tions or con­clu­sions in the absence of data.

    ...

    It is fre­quent­ly assumed that pre-exist­ing T cell mem­o­ry against SARS-CoV­‑2 might be either ben­e­fi­cial or irrel­e­vant. How­ev­er, there is also the pos­si­bil­i­ty that pre-exist­ing immu­ni­ty might actu­al­ly be detri­men­tal, through mech­a­nisms such as ‘orig­i­nal anti­genic sin’ (the propen­si­ty to elic­it poten­tial­ly infe­ri­or immune respons­es owing to pre-exist­ing immune mem­o­ry to a relat­ed pathogen), or through anti­body-medi­at­ed dis­ease enhance­ment. While there is no direct evi­dence to sup­port these out­comes, they must be con­sid­ered. A detri­men­tal effect linked to pre-exist­ing immu­ni­ty is emi­nent­ly testable and would be revealed by the same COVID-19 cohort and vac­cine stud­ies pro­posed above.
    ...

    And then there’s the impor­tance of under­stand the role pre-exist­ing T‑cells might be play­ing when assess­ing the effec­tive­ness of vac­cines. If these T‑cells are play­ing a role in gen­er­at­ing an immune response from the vac­cine and a large per­cent of the pop­u­lace pos­sess­es these T‑cells that’s going to be quite a con­founder when try­ing to assess the effi­ca­cy of the vac­cine on peo­ple with­out those pre-exist­ing T‑cells and it’s that pop­u­la­tion that’s most like­ly to actu­al­ly need the vac­cine:

    ...
    Pre-exist­ing CD4+ T cell mem­o­ry could also influ­ence vac­ci­na­tion out­comes, lead­ing to a faster or bet­ter immune response, par­tic­u­lar­ly the devel­op­ment of neu­tral­iz­ing anti­bod­ies, which gen­er­al­ly depend on T cell help. At the same time, pre-exist­ing T cell mem­o­ry could also act as a con­found­ing fac­tor, espe­cial­ly in rel­a­tive­ly small phase I vac­cine tri­als. For exam­ple, if sub­jects with pre-exist­ing reac­tiv­i­ty were assort­ed uneven­ly in dif­fer­ent vac­cine dose groups, this might lead to erro­neous con­clu­sions. Obvi­ous­ly, this could be avoid­ed by con­sid­er­ing pre-exist­ing immu­ni­ty as a vari­able to be con­sid­ered in tri­al design. Thus, we rec­om­mend mea­sur­ing pre-exist­ing immu­ni­ty in all COVID-19 vac­cine phase I clin­i­cal tri­als. Of note, such exper­i­ments would also offer an excit­ing oppor­tu­ni­ty to ascer­tain the poten­tial bio­log­i­cal sig­nif­i­cance of pre-exist­ing SARS-CoV-2-reac­tive T cells.
    ...

    And as the fol­low­ing Bloomberg arti­cle makes clear, there’s anoth­er major rea­son vac­cine researchers need to keep in mind the pos­si­bil­i­ty that pre-exist­ing T‑cells are what make the vac­cine effec­tive: the recent announce­ments from SARS-CoV­‑2 vac­cine researchers are all falling back on the pres­ence of T‑cells that can rec­og­nize the SARS-CoV­‑2 virus as signs that their vac­cines might be work­ing despite a short-lived of non-exis­tent anti­body response in many of the peo­ple they are test­ing the vac­cines on. So if the vac­cines are indeed trig­ger­ing the devel­op­ing of new T‑cells that’s won­der­ful news. But if the vac­cines are instead just trig­ger­ing pre-exist­ing T‑cells that devel­oped pri­or to the SARS-CoV­‑2 pan­dem­ic that’s hor­ri­ble news that sug­gests the vac­cines aren’t real­ly gen­er­at­ing anti­bod­ies or new T‑cells and there­fore can’t help those with­out those pre-exist­ing T‑cells. So all of this seem­ing­ly good news about vac­cines that are acti­vat­ing T‑cells might actu­al­ly be bad news for the peo­ple who need it most:

    Bloomberg

    Unsung Immune Cells Take Over When Covid Anti­bod­ies Wane

    * Stud­ies show T cells’ cru­cial role in coro­n­avirus pro­tec­tion
    * Vac­cine mak­ers hail their pres­ence in tri­als of inoc­u­la­tions

    By Marthe Four­cade and Jason Gale
    July 22, 2020, 6:40 PM CDT Updat­ed on July 23, 2020, 7:49 AM CDT

    Anti­bod­ies have become a famil­iar word in the pan­dem­ic era, per­haps sug­gest­ing they’re the best hope for keep­ing the dead­ly coro­n­avirus at bay. But when cru­cial vac­cine data was released this week, the spot­light panned to an unsung immune play­er: T cells.

    AstraZeneca Plc, Pfiz­er Inc. and part­ner BioN­Tech SE, as well as China’s CanSi­no Bio­log­ics Inc. all hailed the pres­ence of these white blood cells in vac­cine recip­i­ents as a sign their exper­i­men­tal shots show promise.

    Thrust into focus by recent stud­ies, T cells are a reminder that the body’s defens­es rely on more than one weapon, and that much of the immune response to Covid-19 is still a mys­tery — espe­cial­ly after researchers revealed that the more laud­ed anti­bod­ies lack stay­ing pow­er.

    “Anti­bod­ies are only a very small part of the pic­ture,” said Paul Grif­fin, an asso­ciate pro­fes­sor of med­i­cine at the Uni­ver­si­ty of Queens­land in Bris­bane, who is lead­ing clin­i­cal stud­ies in Aus­tralia of two poten­tial Covid-19 vac­cines. But “we’re real­ly not there yet in terms of ful­ly under­stand­ing” people’s immu­ni­ty to the new coro­n­avirus.

    As the pan­dem­ic took the world by storm, sci­en­tists first focused on anti­bod­ies — pro­teins that stick to and dis­able for­eign invaders — because elic­it­ing them is the basis for most suc­cess­ful vac­cines. The immune pro­teins are also eas­i­er to mea­sure than T cells and can be used to gauge pri­or infec­tion.

    The study show­ing they wane quick­ly in patients with mild dis­ease dealt a blow to hopes that anti­bod­ies will pro­vide some last­ing form of immu­ni­ty.

    Unsung War­riors

    T cells, by con­trast, are able to kill virus-infect­ed cells, remem­ber past dis­eases for decades, and rouse fresh anti­body sol­diers long after the first have left the bat­tle­field. Peo­ple infect­ed with anoth­er coro­n­avirus that was respon­si­ble for the SARS epi­dem­ic in 2003, for exam­ple, still have a T‑cell response to the dis­ease 17 years lat­er.

    That sug­gests T cells may still, at least hypo­thet­i­cal­ly, be ready to pro­tect SARS sur­vivors against the infec­tion almost two decades lat­er, and might bol­ster their defense against Covid-19.

    “Anti­bod­ies wane after a cer­tain peri­od of time,” said Thomas Schi­neck­er, who heads the diag­nos­tics unit of Swiss drug­mak­er Roche Hold­ing AG. “This doesn’t mean that there is no immu­ni­ty, it just means that poten­tial­ly the mem­o­ry cells, T cells and oth­ers, will then be trig­gered to respond much bet­ter the sec­ond time so that you don’t have any severe response.”

    One study found that some patients with no symp­toms of Covid-19 had T‑cells that rec­og­nized the virus — even when they had no detectable anti­bod­ies. Anoth­er point­ed to a lev­el of immu­ni­ty in peo­ple who nev­er encoun­tered the pathogen, pos­si­bly because of expo­sure to one or more of the coro­n­avirus­es that cause the com­mon cold.

    Bal­anc­ing Act

    More research is need­ed to deter­mine whether pre-exist­ing T cells that cross-react with the SARS-CoV­‑2 virus may explain why some Covid patients are bare­ly affect­ed while oth­ers get very sick and even die. What’s clear is that a bal­ance of both anti­bod­ies and T cells is nec­es­sary for opti­mal defense, accord­ing to Grif­fin.

    Corey Smith, head of trans­la­tion­al and human immunol­o­gy at the QIMR Berghofer Med­ical Research Insti­tute in Bris­bane, says the find­ings about anti­bod­ies’ short dura­tion don’t mean immu­ni­ty wanes com­plete­ly, pre­cise­ly because of T cells.

    So-called helper T cells, as well as mem­o­ry T and B cells are able to prime anti­bod­ies to respond to a sub­se­quent infec­tion before it caus­es severe symp­toms, said Smith, who is study­ing the immune response to the SARS-CoV­‑2 virus.

    ...

    If could be that T cells are what ulti­mate­ly sub­due and blunt the pan­dem­ic virus that’s killed more than 600,000 peo­ple in less than sev­en months.

    “If we can’t erad­i­cate it, does it end up as a kind of a cir­cu­lat­ing virus, anoth­er cold virus?” Smith said. “I’m not sure, but it’s inter­est­ing.”

    ————

    “Unsung Immune Cells Take Over When Covid Anti­bod­ies Wane” by Marthe Four­cade and Jason Gale; Bloomberg; 07/22/2020

    “If could be that T cells are what ulti­mate­ly sub­due and blunt the pan­dem­ic virus that’s killed more than 600,000 peo­ple in less than sev­en months.”

    Are T‑cells going to be the heroes of the pan­dem­ic? It’s increas­ing­ly look­ing like that’s going to be the case based on the rel­a­tive suc­cess by the vac­cine researchers at detect­ing T‑cells that can inter­act with the SARS-CoV­‑2 virus in the vac­ci­nat­ed sub­jects. And yet it’s unclear if these vac­cine researchers were check­ing for the pres­ence of these T‑cells before the vac­ci­na­tion and if those T‑cells were already there their pres­ence post-vac­ci­na­tion does­n’t actu­al­ly tell us whether or not the vac­cine in work­ing. And the ques­tion of whether or not these peo­ple already had those T‑cells from past infec­tions remains a very open when mem­o­ry T‑cells from dif­fer­ent coro­n­avirus­es can last decades — with peo­ple infect­ed with SARS still show­ing a T‑cell response 17 years lat­er — and can cross-react with SARS-CoV­‑2:

    ...
    AstraZeneca Plc, Pfiz­er Inc. and part­ner BioN­Tech SE, as well as China’s CanSi­no Bio­log­ics Inc. all hailed the pres­ence of these white blood cells in vac­cine recip­i­ents as a sign their exper­i­men­tal shots show promise.

    ...

    T cells, by con­trast, are able to kill virus-infect­ed cells, remem­ber past dis­eases for decades, and rouse fresh anti­body sol­diers long after the first have left the bat­tle­field. Peo­ple infect­ed with anoth­er coro­n­avirus that was respon­si­ble for the SARS epi­dem­ic in 2003, for exam­ple, still have a T‑cell response to the dis­ease 17 years lat­er.

    That sug­gests T cells may still, at least hypo­thet­i­cal­ly, be ready to pro­tect SARS sur­vivors against the infec­tion almost two decades lat­er, and might bol­ster their defense against Covid-19.

    ...

    More research is need­ed to deter­mine whether pre-exist­ing T cells that cross-react with the SARS-CoV­‑2 virus may explain why some Covid patients are bare­ly affect­ed while oth­ers get very sick and even die. What’s clear is that a bal­ance of both anti­bod­ies and T cells is nec­es­sary for opti­mal defense, accord­ing to Grif­fin.
    ...

    Also keep in the pos­si­bil­i­ty that a num­ber of peo­ple might have already devel­oped T‑cells tar­get­ing SARS-CoV­‑2 from an ear­li­er unrec­og­nized out­break of SARS-CoV­‑2.

    And then there’s the pos­si­bil­i­ty that the virus is nev­er van­quished via a vac­cine and just keeps cir­cu­lat­ing for­ev­er. Will it just turn into anoth­er com­mon cold coro­n­avirus after we all even­tu­al­ly get exposed? Keep in mind that if this nev­er goes away most peo­ple are going to be exposed when they’re very young, so if this virus does con­tin­ue cir­cu­lat­ing indef­i­nite­ly at some point vir­tu­al­ly every­one alive (who isn’t killed by the virus) is going to have been exposed to it and will hope­ful­ly have this kind of pre-exist­ing T‑cell immu­ni­ty built up:

    ...
    “If we can’t erad­i­cate it, does it end up as a kind of a cir­cu­lat­ing virus, anoth­er cold virus?” Smith said. “I’m not sure, but it’s inter­est­ing.”
    ...

    Might we just have this virus cir­cu­lat­ing for­ev­er as some sort of com­mon cold? Well, as the fol­low­ing Nature arti­cle from ear­ly May (and there­fore two-and-a-half months behind the cur­rent SARS-CoV­‑2 research) sug­gest­ed, yes, that’s exact­ly what could hap­pen. And it could hap­pen despite the fact that coro­n­avirus­es are noto­ri­ous­ly slow at mutat­ing com­pared to oth­er viral fam­i­lies which makes it less like­ly the virus will mutate into a less vir­u­lent form, espe­cial­ly giv­en its wild suc­cess at spread­ing already that would blunt the evo­lu­tion­ary forces that might dri­ve the emer­gence of a less vir­u­lent form of the virus that’s more sim­i­lar to the com­mon cold. Instead, that rel­a­tive sta­bil­i­ty of the virus along with repeat­ed glob­al expo­sure could effec­tive­ly turn SARS-CoV­‑2 into a com­mon cold. It’s a sce­nario some researchers see as plau­si­ble in part because it’s thought that one of today’s exist­ing com­mon cold coro­n­avirus­es, OC43, under­went that same shift from a killer virus to a com­mon cold with­out actu­al­ly mutat­ing. As researchers found, the OC43 virus appears to have jumped from cows to humans around 1890 and may have been respon­si­ble for a pan­dem­ic that killed more than a mil­lion peo­ple glob­al­ly from 1889–1890. That same virus cir­cu­lates wide­ly today, but we’re all exposed to it repeat­ed­ly and now it’s just a com­mon cold:

    Nature 581, 22–26 (2020)

    Pro­file of a killer: the com­plex biol­o­gy pow­er­ing the coro­n­avirus pan­dem­ic
    Sci­en­tists are piec­ing togeth­er how SARS-CoV­‑2 oper­ates, where it came from and what it might do next — but press­ing ques­tions remain about the source of COVID-19.

    David Cyra­nos­ki
    04 May 2020
    Nature 581, 22–26 (2020)

    In 1912, Ger­man vet­eri­nar­i­ans puz­zled over the case of a fever­ish cat with an enor­mous­ly swollen bel­ly. That is now thought to be the first report­ed exam­ple of the debil­i­tat­ing pow­er of a coro­n­avirus. Vet­eri­nar­i­ans didn’t know it at the time, but coro­n­avirus­es were also giv­ing chick­ens bron­chi­tis, and pigs an intesti­nal dis­ease that killed almost every piglet under two weeks old.

    The link between these pathogens remained hid­den until the 1960s, when researchers in the Unit­ed King­dom and the Unit­ed States iso­lat­ed two virus­es with crown-like struc­tures caus­ing com­mon colds in humans. Sci­en­tists soon noticed that the virus­es iden­ti­fied in sick ani­mals had the same bristly struc­ture, stud­ded with spiky pro­tein pro­tru­sions. Under elec­tron micro­scopes, these virus­es resem­bled the solar coro­na, which led researchers in 1968 to coin the term coro­n­avirus­es for the entire group.

    It was a fam­i­ly of dynam­ic killers: dog coro­n­avirus­es could harm cats, the cat coro­n­avirus could rav­age pig intestines. Researchers thought that coro­n­avirus­es caused only mild symp­toms in humans, until the out­break of severe acute res­pi­ra­to­ry syn­drome (SARS) in 2003 revealed how eas­i­ly these ver­sa­tile virus­es could kill peo­ple.

    Now, as the death toll from the COVID-19 pan­dem­ic surges, researchers are scram­bling to uncov­er as much as pos­si­ble about the biol­o­gy of the lat­est coro­n­avirus, named SARS-CoV­‑2. A pro­file of the killer is already emerg­ing. Sci­en­tists are learn­ing that the virus has evolved an array of adap­ta­tions that make it much more lethal than the oth­er coro­n­avirus­es human­i­ty has met so far. Unlike close rel­a­tives, SARS-CoV­‑2 can read­i­ly attack human cells at mul­ti­ple points, with the lungs and the throat being the main tar­gets. Once inside the body, the virus makes use of a diverse arse­nal of dan­ger­ous mol­e­cules. And genet­ic evi­dence sug­gests that it has been hid­ing out in nature pos­si­bly for decades.

    But there are many cru­cial unknowns about this virus, includ­ing how exact­ly it kills, whether it will evolve into some­thing more — or less — lethal and what it can reveal about the next out­break from the coro­n­avirus fam­i­ly.

    “There will be more, either out there already or in the mak­ing,” says Andrew Ram­baut, who stud­ies viral evo­lu­tion at the Uni­ver­si­ty of Edin­burgh, UK.

    Bad fam­i­ly

    Of the virus­es that attack humans, coro­n­avirus­es are big. At 125 nanome­tres in diam­e­ter, they are also rel­a­tive­ly large for the virus­es that use RNA to repli­cate, the group that accounts for most new­ly emerg­ing dis­eases. But coro­n­avirus­es real­ly stand out for their genomes. With 30,000 genet­ic bases, coro­n­avirus­es have the largest genomes of all RNA virus­es. Their genomes are more than three times as big as those of HIV and hepati­tis C, and more than twice influenza’s.

    Coro­n­avirus­es are also one of the few RNA virus­es with a genom­ic proof­read­ing mech­a­nism — which keeps the virus from accu­mu­lat­ing muta­tions that could weak­en it. That abil­i­ty might be why com­mon antivi­rals such as rib­avirin, which can thwart virus­es such as hepati­tis C, have failed to sub­due SARS-CoV­‑2. The drugs weak­en virus­es by induc­ing muta­tions. But in the coro­n­avirus­es, the proof­read­er can weed out those changes.

    Muta­tions can have their advan­tages for virus­es. Influen­za mutates up to three times more often than coro­n­avirus­es do, a pace that enables it to evolve quick­ly and side­step vac­cines. But coro­n­avirus­es have a spe­cial trick that gives them a dead­ly dynamism: they fre­quent­ly recom­bine, swap­ping chunks of their RNA with oth­er coro­n­avirus­es. Typ­i­cal­ly, this is a mean­ing­less trad­ing of like parts between like virus­es. But when two dis­tant coro­n­avirus rel­a­tives end up in the same cell, recom­bi­na­tion can lead to for­mi­da­ble ver­sions that infect new cell types and jump to oth­er species, says Ram­baut.

    Recom­bi­na­tion hap­pens often in bats, which car­ry 61 virus­es known to infect humans; some species har­bour as many as 121. In most cas­es, the virus­es don’t harm the bats, and there are sev­er­al the­o­ries about why bats’ immune sys­tems can cope with these invaders. A paper pub­lished in Feb­ru­ary argues that bat cells infect­ed by virus­es rapid­ly release a sig­nal that makes them able to host the virus with­out killing it2.

    Esti­mates for the birth of the first coro­n­avirus vary wide­ly, from 10,000 years ago to 300 mil­lion years ago. Sci­en­tists are now aware of dozens of strains3, sev­en of which infect humans. Among the four that cause com­mon colds, two (OC43 and HKU1) came from rodents, and the oth­er two (229E and NL63) from bats. The three that cause severe dis­ease — SARS-CoV (the cause of SARS), Mid­dle East res­pi­ra­to­ry syn­drome MERS-CoV and SARS-CoV­‑2 — all came from bats. But sci­en­tists think there is usu­al­ly an inter­me­di­ary — an ani­mal infect­ed by the bats that car­ries the virus into humans. With SARS, the inter­me­di­ary is thought to be civet cats, which are sold in live-ani­mal mar­kets in Chi­na.

    ...

    Two open doors

    Although the known human coro­n­avirus­es can infect many cell types, they all main­ly cause res­pi­ra­to­ry infec­tions. The dif­fer­ence is that the four that cause com­mon colds eas­i­ly attack the upper res­pi­ra­to­ry tract, where­as MERS-CoV and SARS-CoV have more dif­fi­cul­ty gain­ing a hold there, but are more suc­cess­ful at infect­ing cells in the lungs.

    SARS-CoV­‑2, unfor­tu­nate­ly, can do both very effi­cient­ly. That gives it two places to get a foothold, says Shu-Yuan Xiao, a pathol­o­gist at the Uni­ver­si­ty of Chica­go, Illi­nois. A neighbour’s cough that sends ten viral par­ti­cles your way might be enough to start an infec­tion in your throat, but the hair-like cil­ia found there are like­ly to do their job and clear the invaders. If the neigh­bour is clos­er and coughs 100 par­ti­cles towards you, the virus might be able get all the way down to the lungs, says Xiao.

    These vary­ing capac­i­ties might explain why peo­ple with COVID-19 have such dif­fer­ent expe­ri­ences. The virus can start in the throat or nose, pro­duc­ing a cough and dis­rupt­ing taste and smell, and then end there. Or it might work its way down to the lungs and debil­i­tate that organ. How it gets down there, whether it moves cell by cell or some­how gets washed down, is not known, says Stan­ley Perl­man, an immu­nol­o­gist at the Uni­ver­si­ty of Iowa in Iowa City who stud­ies coro­n­avirus­es.

    Clemens-Mar­tin Wendt­ner, an infec­tious-dis­ease physi­cian at the Munich Clin­ic Schwabing in Ger­many, says it could be a prob­lem with the immune sys­tem that lets the virus sneak down into the lungs. Most infect­ed peo­ple cre­ate neu­tral­iz­ing anti­bod­ies that are tai­lored by the immune sys­tem to bind with the virus and block it from enter­ing a cell. But some peo­ple seem unable to make them, says Wendt­ner. That might be why some recov­er after a week of mild symp­toms, where­as oth­ers get hit with late-onset lung dis­ease. But the virus can also bypass the throat cells and go straight down into the lungs. Then patients might get pneu­mo­nia with­out the usu­al mild symp­toms such as a cough or low-grade fever that would oth­er­wise come first, says Wendt­ner. Hav­ing these two infec­tion points means that SARS-CoV­‑2 can mix the trans­mis­si­bil­i­ty of the com­mon cold coro­n­avirus­es with the lethal­i­ty of MERS-CoV and SARS-CoV. “It is an unfor­tu­nate and dan­ger­ous com­bi­na­tion of this coro­n­avirus strain,” he says.

    The virus’s abil­i­ty to infect and active­ly repro­duce in the upper res­pi­ra­to­ry tract was some­thing of a sur­prise, giv­en that its close genet­ic rel­a­tive, SARS-CoV, lacks that abil­i­ty. Last month, Wendt­ner pub­lished results8 of exper­i­ments in which his team was able to cul­ture virus from the throats of nine peo­ple with COVID-19, show­ing that the virus is active­ly repro­duc­ing and infec­tious there. That explains a cru­cial dif­fer­ence between the close rel­a­tives. SARS-CoV­‑2 can shed viral par­ti­cles from the throat into sali­va even before symp­toms start, and these can then pass eas­i­ly from per­son to per­son. SARS-CoV was much less effec­tive at mak­ing that jump, pass­ing only when symp­toms were full-blown, mak­ing it eas­i­er to con­tain.

    These dif­fer­ences have led to some con­fu­sion about the lethal­i­ty of SARS-CoV­‑2. Some experts and media reports describe it as less dead­ly than SARS-CoV because it kills about 1% of the peo­ple it infects, where­as SARS-CoV killed at rough­ly ten times that rate. But Perl­man says that’s the wrong way to look at it. SARS-CoV­‑2 is much bet­ter at infect­ing peo­ple, but many of the infec­tions don’t progress to the lungs. “Once it gets down in the lungs, it’s prob­a­bly just as dead­ly,” he says.

    What it does when it gets down to the lungs is sim­i­lar in some respects to what res­pi­ra­to­ry virus­es do, although much remains unknown. Like SARS-CoV and influen­za, it infects and destroys the alve­oli, the tiny sacs in the lungs that shut­tle oxy­gen into the blood­stream. As the cel­lu­lar bar­ri­er divid­ing these sacs from blood ves­sels break down, liq­uid from the ves­sels leaks in, block­ing oxy­gen from get­ting to the blood. Oth­er cells, includ­ing white blood cells, plug up the air­way fur­ther. A robust immune response will clear all this out in some patients, but over­re­ac­tion of the immune sys­tem can make the tis­sue dam­age worse. If the inflam­ma­tion and tis­sue dam­age are too severe, the lungs nev­er recov­er and the per­son dies or is left with scarred lungs, says Xiao. “From a patho­log­i­cal point of view, we don’t see a lot of unique­ness here.”

    And as with SARS-CoV, MERS-CoV and ani­mal coro­n­avirus­es, the dam­age doesn’t stop with the lungs. A SARS-CoV­‑2 infec­tion can trig­ger an exces­sive immune response known as a cytokine storm, which can lead to mul­ti­ple organ fail­ure and death. The virus can also infect the intestines, the heart, the blood, sperm (as can MERS-CoV), the eye and pos­si­bly the brain. Dam­age to the kid­ney, liv­er and spleen observed in peo­ple with COVID-19 sug­gests that the virus can be car­ried in the blood and infect var­i­ous organs or tis­sues, says Guan Wei-jie, a pul­mo­nolo­gist at the Guangzhou Insti­tute of Res­pi­ra­to­ry Health at Guangzhou Med­ical Uni­ver­si­ty, Chi­na, an insti­tu­tion laud­ed for its role in com­bat­ing SARS and COVID-19. The virus might be able to infect var­i­ous organs or tis­sues wher­ev­er the blood sup­ply reach­es, says Guan.

    But although genet­ic mate­r­i­al from the virus is show­ing up in these var­i­ous tis­sues, it is not yet clear whether the dam­age there is being done by the virus or by a cytokine storm, says Wendt­ner. “Autop­sies are under way in our cen­tre. More data will come soon,” he says.

    ...

    Pow­er spikes

    SARS-CoV­‑2 is unique­ly equipped for forc­ing entry into cells. Both SARS-CoV and SARS-CoV­‑2 bind with ACE2, but the recep­tor-bind­ing domain of SARS-CoV­‑2 is a par­tic­u­lar­ly snug fit. It is 10–20 times more like­ly to bind ACE2 than is SARS-CoV9. Wendt­ner says that SARS-CoV­‑2 is so good at infect­ing the upper res­pi­ra­to­ry tract that there might even be a sec­ond recep­tor that the virus could use to launch its attack.

    Even more trou­bling is the fact that SARS-COV‑2 seems to make use of the enzyme furin from the host to cleave the viral spike pro­tein. This is wor­ry­ing, researchers say, because furin is abun­dant in the res­pi­ra­to­ry tract and found through­out the body. It is used by oth­er for­mi­da­ble virus­es, includ­ing HIV, influen­za, dengue and Ebo­la to enter cells. By con­trast, the cleav­age mol­e­cules used by SARS-CoV are much less com­mon and not as effec­tive.

    Sci­en­tists think that the involve­ment of furin could explain why SARS-CoV­‑2 is so good at jump­ing from cell to cell, per­son to per­son and pos­si­bly ani­mal to human. Robert Gar­ry, a virol­o­gist at Tulane Uni­ver­si­ty in New Orleans, Louisiana, esti­mates that it gives SARS-CoV­‑2 a 100–1,000 times greater chance than SARS-CoV of get­ting deep into the lungs. “When I saw SARS-CoV­‑2 had that cleav­age site, I did not sleep very well that night,” he says.

    The mys­tery is where the genet­ic instruc­tions for this par­tic­u­lar cleav­age site came from. Although the virus prob­a­bly gained them through recom­bi­na­tion, this par­tic­u­lar set-up has nev­er been found in any oth­er coro­n­avirus in any species. Pin­ning down its ori­gin might be the last piece in the puz­zle that will deter­mine which ani­mal was the step­ping stone that allowed the virus to reach humans.

    End game

    Some researchers hope that the virus will weak­en over time through a series of muta­tions that adapt it to per­sist in humans. By this log­ic, it would become less dead­ly and have more chances to spread. But researchers have not yet found any sign of such weak­en­ing, prob­a­bly because of the virus’s effi­cient genet­ic repair mech­a­nism. “The genome of COVID-19 virus is very sta­ble, and I don’t see any change of path­o­genic­i­ty that is caused by virus muta­tion,” says Guo Deyin, who research­es coro­n­avirus­es at Sun Yat-sen Uni­ver­si­ty in Guangzhou.

    Ram­baut, too, doubts that the virus will become milder over time and spare its host. “It doesn’t work that way,” he says. As long as it can suc­cess­ful­ly infect new cells, repro­duce and trans­mit to new ones, it doesn’t mat­ter whether it harms the host, he says.

    But oth­ers think there is a chance for a bet­ter out­come. It might give peo­ple anti­bod­ies that will offer at least par­tial pro­tec­tion, says Klaus Stöhr, who head­ed the World Health Organization’s SARS research and epi­demi­ol­o­gy divi­sion. Stöhr says that immu­ni­ty will not be per­fect — peo­ple who are rein­fect­ed will still devel­op minor symp­toms, the way they do now from the com­mon cold, and there will be rare exam­ples of severe dis­ease. But the virus’s proof­read­ing mech­a­nism means it will not mutate quick­ly, and peo­ple who were infect­ed will retain robust pro­tec­tion, he says.

    “By far the most like­ly sce­nario is that the virus will con­tin­ue to spread and infect most of the world pop­u­la­tion in a rel­a­tive­ly short peri­od of time,” says Stöhr, mean­ing one to two years. “After­wards, the virus will con­tin­ue to spread in the human pop­u­la­tion, like­ly for­ev­er.” Like the four gen­er­al­ly mild human coro­n­avirus­es, SARS-CoV­‑2 would then cir­cu­late con­stant­ly and cause main­ly mild upper res­pi­ra­to­ry tract infec­tions, says Stöhr. For that rea­son, he adds, vac­cines won’t be nec­es­sary.

    Some pre­vi­ous stud­ies sup­port this argu­ment. One10 showed that when peo­ple were inoc­u­lat­ed with the com­mon-cold coro­n­avirus 229E, their anti­body lev­els peaked two weeks lat­er and were only slight­ly raised after a year. That did not pre­vent infec­tions a year lat­er, but sub­se­quent infec­tions led to few, if any, symp­toms and a short­er peri­od of viral shed­ding.

    The OC43 coro­n­avirus offers a mod­el for where this pan­dem­ic might go. That virus also gives humans com­mon colds, but genet­ic research from the Uni­ver­si­ty of Leu­ven in Bel­gium sug­gests that OC43 might have been a killer in the past11. That study indi­cates that OC43 spilled over to humans in around 1890 from cows, which got it from mice. The sci­en­tists sug­gest that OC43 was respon­si­ble for a pan­dem­ic that killed more than one mil­lion peo­ple world­wide in 1889–90 — an out­break pre­vi­ous­ly blamed on influen­za. Today, OC43 con­tin­ues to cir­cu­late wide­ly and it might be that con­tin­u­al expo­sure to the virus keeps the great major­i­ty of peo­ple immune to it.

    But even if that process made OC43 less dead­ly, it is not yet clear whether some­thing sim­i­lar would hap­pen with SARS-CoV­‑2. A study in mon­keys showed that they retained anti­bod­ies to SARS-CoV­‑2, but the researchers only report­ed on the first 28 days after infec­tion, so it is unclear how long the immu­ni­ty last­ed12. Con­cen­tra­tions of anti­bod­ies against SARS-CoV also dropped sig­nif­i­cant­ly over a two- to three-year peri­od13. Whether those low­ered lev­els would be enough to pre­vent infec­tion or reduce sever­i­ty has not been test­ed. Cats, cows, dogs and chick­ens do not seem to become immune to the some­times dead­ly coro­n­avirus­es that infect them, leav­ing vet­eri­nar­i­ans over the years to scram­ble for vac­cines. Despite all the ques­tions about whether peo­ple retain any immu­ni­ty to SARS-CoV­‑2, some coun­tries are pro­mot­ing the idea of giv­ing sur­vivors ‘immu­ni­ty pass­ports’ to allow them to ven­ture out with­out fear of being infect­ed or infect­ing oth­ers.

    Many sci­en­tists are reserv­ing judge­ment on whether the tamer coro­n­avirus­es were once as vir­u­lent as SARS-CoV­‑2. Peo­ple like to think that “the oth­er coro­n­avirus­es were ter­ri­ble and became mild”, says Perl­man. “That’s an opti­mistic way to think about what’s going on now, but we don’t have evi­dence.”

    ———–

    “Pro­file of a killer: the com­plex biol­o­gy pow­er­ing the coro­n­avirus pan­dem­ic” by David Cyra­nos­ki; Nature; 05/04/2020

    ““By far the most like­ly sce­nario is that the virus will con­tin­ue to spread and infect most of the world pop­u­la­tion in a rel­a­tive­ly short peri­od of time,” says Stöhr, mean­ing one to two years. “After­wards, the virus will con­tin­ue to spread in the human pop­u­la­tion, like­ly for­ev­er.” Like the four gen­er­al­ly mild human coro­n­avirus­es, SARS-CoV­‑2 would then cir­cu­late con­stant­ly and cause main­ly mild upper res­pi­ra­to­ry tract infec­tions, says Stöhr. For that rea­son, he adds, vac­cines won’t be nec­es­sary.

    No vac­cines will be nec­es­sary because this is just going to become a slow­ly evolv­ing com­mon cold after we’re all exposed to it. That was the view of Klaus Stöhr, the for­mer head of the World Health Organization’s SARS research and epi­demi­ol­o­gy divi­sion. And it’s human­i­ty’s expe­ri­ence with OC43 that gives Stöhr this kind of opti­mism:

    ...
    Ram­baut, too, doubts that the virus will become milder over time and spare its host. “It doesn’t work that way,” he says. As long as it can suc­cess­ful­ly infect new cells, repro­duce and trans­mit to new ones, it doesn’t mat­ter whether it harms the host, he says.

    But oth­ers think there is a chance for a bet­ter out­come. It might give peo­ple anti­bod­ies that will offer at least par­tial pro­tec­tion, says Klaus Stöhr, who head­ed the World Health Organization’s SARS research and epi­demi­ol­o­gy divi­sion. Stöhr says that immu­ni­ty will not be per­fect — peo­ple who are rein­fect­ed will still devel­op minor symp­toms, the way they do now from the com­mon cold, and there will be rare exam­ples of severe dis­ease. But the virus’s proof­read­ing mech­a­nism means it will not mutate quick­ly, and peo­ple who were infect­ed will retain robust pro­tec­tion, he says.

    ...

    Some pre­vi­ous stud­ies sup­port this argu­ment. One10 showed that when peo­ple were inoc­u­lat­ed with the com­mon-cold coro­n­avirus 229E, their anti­body lev­els peaked two weeks lat­er and were only slight­ly raised after a year. That did not pre­vent infec­tions a year lat­er, but sub­se­quent infec­tions led to few, if any, symp­toms and a short­er peri­od of viral shed­ding.

    The OC43 coro­n­avirus offers a mod­el for where this pan­dem­ic might go. That virus also gives humans com­mon colds, but genet­ic research from the Uni­ver­si­ty of Leu­ven in Bel­gium sug­gests that OC43 might have been a killer in the past11. That study indi­cates that OC43 spilled over to humans in around 1890 from cows, which got it from mice. The sci­en­tists sug­gest that OC43 was respon­si­ble for a pan­dem­ic that killed more than one mil­lion peo­ple world­wide in 1889–90 — an out­break pre­vi­ous­ly blamed on influen­za. Today, OC43 con­tin­ues to cir­cu­late wide­ly and it might be that con­tin­u­al expo­sure to the virus keeps the great major­i­ty of peo­ple immune to it.
    ...

    Is Stöhr going to be cor­rect? Let’s hope so because hav­ing the virus just fade into com­mon-cold sta­tus would be a real­ly nice back­up ‘plan’ should the vac­cines fail. It also rais­es the ques­tion of whether or not we should be just expos­ing peo­ple to these com­mon cold coro­n­avirus­es as a kind of vac­cine, along with the dis­turb­ing pos­si­bil­i­ty that social dis­tanc­ing mea­sures might be lim­it­ing the ben­e­fits of com­mon cold coro­n­avirus expo­sure right now. One of the inter­est­ing ques­tions raised by this the­o­ry is why the elder­ly, who would have had the most com­mon cold coro­n­avirus expo­sure over the course of their lives, are the most vul­nen­able to the dis­ease. Are they los­ing their mem­o­ry T‑cells from past com­mon cold coro­n­avirus expo­sures? Would new expo­sures bring those T‑cells back at lev­els high enough to pro­tect against SARS-CoV­‑2? These are the kinds of ques­tions we’re going to have to ask if the vac­cines don’t pan out as hoped.

    But as Klaus Stöhr makes clear in anoth­er recent Bloomberg arti­cle, there’s anoth­er we might have to rely on T‑cell immu­ni­ty and hope that this virus even­tu­al­ly does just become anoth­er com­mon cold coro­n­avirus: most of the devel­op­ing world is unlike­ly to get access to a vac­cine even if one is devel­oped, at least for a long time. And in the mean time, the virus is going to keep spread­ing. In oth­er words, it’s pos­si­ble that the vac­cine is the solu­tion for wealth­i­er coun­tries but for most of the rest of the world they’re going to have lit­tle choice but to even­tu­al­ly just let the virus run through the pop­u­lace until they acquire ‘herd immu­ni­ty’ so we had bet­ter hope the tran­si­tion-to-com­mon-cold sce­nario real­ly does play out:

    Bloomberg

    Most of the World May Face Covid With­out a Vac­cine

    “There will be anoth­er wave, and it will be very seri­ous.”

    By James Paton
    July 18, 2020, 1:00 AM CDT

    Klaus Stohr has urged gov­ern­ments for many years to pre­pare for the grim pos­si­bil­i­ty of a pan­dem­ic.

    In 2003, he played a key role in a World Health Orga­ni­za­tion inves­ti­ga­tion that swift­ly iden­ti­fied a coro­n­avirus as the cause of SARS. Stohr also sound­ed the alarm on the pan­dem­ic poten­tial of avian flu, bring­ing coun­tries and com­pa­nies to the table to increase pro­duc­tion of vac­cines in case it began spread­ing wide­ly in peo­ple.

    ...

    Bloomberg: How do you see the pan­dem­ic advanc­ing before a vac­cine poten­tial­ly is avail­able?

    Stohr: The epi­demi­o­log­i­cal behav­ior of this virus will not be that much dif­fer­ent from oth­er res­pi­ra­to­ry dis­eases. Dur­ing win­ter, they come back.

    There will be anoth­er wave, and it will be very seri­ous. More than 90% of the pop­u­la­tion is sus­cep­ti­ble. If we do not tight­en again to a seri­ous lock­down or sim­i­lar mea­sures, the virus is going to cause a sig­nif­i­cant out­break. Win­ter is com­ing before the vac­cine. There will be an increase in cas­es, and there will be prob­lems con­tain­ing it because peo­ple seem not very amenable to more con­straints in their move­ment and free­dom.

    Bloomberg: When do you pre­dict vac­cines may arrive?

    Stohr: Coun­tries like Ger­many may have a sig­nif­i­cant amount of vac­cine by the begin­ning of next year and a roll­out that may take four, five, six months for the elder­ly. The strat­e­gy may be dif­fer­ent for a coun­try like Brazil, Argenti­na or Chile, which may nev­er get a sin­gle dose of a vac­cine and still has to cope.

    The world will be divid­ed into two groups, those with vac­cines and those with no vac­cines.

    Bloomberg: How do you see world­wide immu­ni­ty ramp­ing up as vac­cines are intro­duced and the dis­ease spreads?

    Stohr: I would assume that by the mid­dle of next year a sig­nif­i­cant por­tion of the world will have anti­bod­ies. That will increase grad­u­al­ly over time. Then there will be a third wave, and when that is over, I would think that 80% of the world may have anti­bod­ies if lock­downs are not insti­tut­ed, which I doubt.

    Bloomberg: What does that mean for vac­cines under devel­op­ment?

    Stohr: We’re in a big, big quandary. We have to throw all the resources we can afford toward the devel­op­ment of a vac­cine. On the oth­er hand, I believe com­mon sense tells us vac­cines will not be avail­able for the major­i­ty of the world.

    There may be, by the end of this year or begin­ning of next year, a half a bil­lion dos­es avail­able. The world pop­u­la­tion is 7.5 bil­lion. Par­tic­u­lar­ly in those coun­tries which have insuf­fi­cient infra­struc­ture and strug­gle with their health-care sys­tems and have huge pop­u­la­tions, what vac­cine are they going to have?

    Bloomberg: A num­ber of groups, includ­ing the WHO, are focus­ing on equi­table access. Won’t that help tack­le those con­cerns?

    Stohr: It would be irre­spon­si­ble not to do any­thing. Nev­er­the­less, the major­i­ty of the world pop­u­la­tion will not receive a vac­cine. The virus will con­tin­ue to spread, and it could take two to three years before the virus has affect­ed a large major­i­ty of the pop­u­la­tion.

    It’s not the vac­cine that’s going to end the pan­dem­ic. The virus will end this pan­dem­ic by burn­ing every piece of dry wood it will find. The fire will not go out before the last sus­cep­ti­ble per­son has been affect­ed.

    Then the ques­tion is what role will any vac­cine play after­ward.

    Bloomberg: You seem opti­mistic researchers will suc­ceed in com­ing up with vac­cines. How do you assess the prospects and poten­tial risks?

    Stohr: The coro­n­avirus is not a par­tic­u­lar­ly dif­fi­cult virus to han­dle. Even the con­ven­tion­al vac­cines could make a dif­fer­ence, and we have dif­fer­ent approach­es, vec­tor vac­cines, mRNA. That is very promis­ing.

    In the past, when a vac­cine is intro­duced, you have a grad­ual increase in its use, in the num­ber of peo­ple immu­nized, and if any­thing comes up, even very rare events, they will be noticed pret­ty ear­ly. But here, a vac­cine will be used in large amounts, pos­si­bly hun­dreds of mil­lions of dos­es, in a rel­a­tive­ly short peri­od of time, six months to a year. So the ques­tion is if there is any­thing pos­si­bly lin­ger­ing in the vac­cine that can­not be detect­ed in the large-scale safe­ty test­ing dur­ing the approval process.

    It could hit many, many peo­ple. If you immu­nize 500 mil­lion, and it’s only 1 in a mil­lion who is affect­ed, you still have a sig­nif­i­cant num­ber of peo­ple who may have safe­ty prob­lems, so that is some­thing that has to be addressed. But one has to bal­ance the con­cern about the impact of the dis­ease against the con­cern of the pos­si­ble impact of the use of the vac­cine.

    Bloomberg: You’ve said coun­tries need to adjust their strate­gies. What is the best approach gov­ern­ments can take?

    Stohr: We have to find a way to open our com­mu­ni­ty in a way that sup­ports our long-term med­ical goal, which is the least num­ber of casu­al­ties over time, know­ing that you can­not avoid the spread of infec­tion. There is no oth­er tool avail­able. If you’ve got a med­ical prob­lem, you go ski­ing, you break your leg, your knee lig­a­ment is torn, no prob­lem, go to the doc­tor and get it fixed. We have no fix here.

    We have to live with this virus and we have to find a prop­er way to ensure that when we are through with this we look back and say we did the best to pre­vent death and dis­ease. But we can­not do the ostrich pol­i­cy here and hope that some mir­a­cle will hap­pen and the virus will dis­ap­pear. The per­fect strat­e­gy isn’t avail­able.

    Bloomberg: You’ve tack­led oth­er virus­es from SARS to bird flu, are there any lessons from the past that are rel­e­vant today?

    Stohr: Since 2003 we’ve been talk­ing about pan­dem­ic plan­ning. Some coun­tries devel­oped these plans and used them. I believe those who had a decent pan­dem­ic plan were a cou­ple of steps ahead. But there are still coun­tries with no plans. The learn­ing is get your pan­dem­ic plan ready.

    It may be clear that only those who will have vac­cine pro­duc­tion on their soil will have access to vac­cines dur­ing the pan­dem­ic. I hope it’s not going to turn out this way, but I fear it will. That hope­ful­ly will result in more invest­ment into pan­dem­ic pre­pared­ness and vac­cine pre­pared­ness in the com­ing years, so that the next pan­dem­ic will be addressed bet­ter than this one.

    ————

    “Most of the World May Face Covid With­out a Vac­cine” by James Paton; Bloomberg; 07/18/2020

    “It’s not the vac­cine that’s going to end the pan­dem­ic. The virus will end this pan­dem­ic by burn­ing every piece of dry wood it will find. The fire will not go out before the last sus­cep­ti­ble per­son has been affect­ed.

    That was the very recent pre­dic­tion by for­mer WHO head of SARS vac­cine devel­op­ment: there’s no way a vac­cine is stop­ping this. The only thing that’s stop­ping it is basi­cal­ly ‘herd immu­ni­ty’. And he appears to pre­dict that this herd immu­ni­ty — around 80% of the world hav­ing anti­bod­ies — will be achieved fol­low­ing a “third wave” that may take two to three years to achieve. And there’s noth­ing to pre­vent that sce­nario because even if a vac­cine is devel­oped it’s high­ly unlike­ly the entire world is going to get access to it in time before the virus has already hit that ‘herd immu­ni­ty’ lev­el. Only renewed lock­downs could avoid the sce­nario he’s describ­ing and he doubts new lock­downs are going to hap­pen:

    ...
    Bloomberg: How do you see world­wide immu­ni­ty ramp­ing up as vac­cines are intro­duced and the dis­ease spreads?

    Stohr: I would assume that by the mid­dle of next year a sig­nif­i­cant por­tion of the world will have anti­bod­ies. That will increase grad­u­al­ly over time. Then there will be a third wave, and when that is over, I would think that 80% of the world may have anti­bod­ies if lock­downs are not insti­tut­ed, which I doubt.

    ...

    There may be, by the end of this year or begin­ning of next year, a half a bil­lion dos­es avail­able. The world pop­u­la­tion is 7.5 bil­lion. Par­tic­u­lar­ly in those coun­tries which have insuf­fi­cient infra­struc­ture and strug­gle with their health-care sys­tems and have huge pop­u­la­tions, what vac­cine are they going to have?

    ...

    Stohr: It would be irre­spon­si­ble not to do any­thing. Nev­er­the­less, the major­i­ty of the world pop­u­la­tion will not receive a vac­cine. The virus will con­tin­ue to spread, and it could take two to three years before the virus has affect­ed a large major­i­ty of the pop­u­la­tion.

    ...

    Stohr: We have to find a way to open our com­mu­ni­ty in a way that sup­ports our long-term med­ical goal, which is the least num­ber of casu­al­ties over time, know­ing that you can­not avoid the spread of infec­tion. There is no oth­er tool avail­able. If you’ve got a med­ical prob­lem, you go ski­ing, you break your leg, your knee lig­a­ment is torn, no prob­lem, go to the doc­tor and get it fixed. We have no fix here.

    We have to live with this virus and we have to find a prop­er way to ensure that when we are through with this we look back and say we did the best to pre­vent death and dis­ease. But we can­not do the ostrich pol­i­cy here and hope that some mir­a­cle will hap­pen and the virus will dis­ap­pear. The per­fect strat­e­gy isn’t avail­able.
    ...

    So unless the strat­e­gy of glob­al lock­downs intend­ed to min­i­mize the spread of the virus is kept in place glob­al­ly for the next two to three years (if we’re lucky enough for a safe vac­cine to be devel­oped by then), it’s almost inevitable that the devel­op­ing world is just going to see this virus blow through the pop­u­lace until ‘herd immu­ni­ty’ is achieved. And that immu­ni­ty will, hope­ful­ly, be main­tained over time as the virus just con­tin­ues to cir­cu­late the world for­ev­er and is effec­tive­ly turned into a com­mon cold coro­n­avirus. Stöhr seems pret­ty adamant that this is how this pan­dem­ic will play out.

    It’s also worth recall­ing that very dis­turb­ing study that found the SARS-CoV­‑2 virus was capa­ble of infect­ing T‑cells and killing them in the process. And the virus’s entry into the cell was medi­at­ed through a means oth­er than the ACE2 recep­tor rais­ing the pos­si­bil­i­ty that the virus can infect all sorts of oth­er cell types than cur­rent­ly sus­pect­ed. Part of what makes that find­ing so dis­turb­ing in the con­text of T‑cell-based immu­ni­ty and pos­si­bil­i­ty that SARS-CoV­‑2 could just cir­cu­late the globe for years as a com­mon cold coro­n­avirus is a sce­nario where it con­tin­ues to cir­cu­late the globe each year and ends up killing those pre­cious mem­o­ry T cells in the process. So instead of the rou­tine cir­cu­la­tion of SARS-CoV­‑2 help­ing us all build up our immu­ni­ty to the virus (and relat­ed coro­n­avirus­es) and turn­ing it into a com­mon cold virus it could become like an uncom­mon cold that’s mild but still steadi­ly kills off your earned immu­ni­ty from past infec­tions. We don’t know that’s what’s going to hap­pen but it would cer­tain­ly be the­mat­i­cal­ly con­sis­tent with the gen­er­al night­mare sit­u­a­tion.

    All in all, it’s quite a bit to chew on. Klaus Stöhr, some­one very famil­iar with coro­n­avirus vac­cine devel­op­ment, does­n’t see min­i­miz­ing expo­sure or vac­cines as fea­si­ble glob­al strate­gies for con­tain­ing the virus. It also rais­es a chal­lenge asso­ci­at­ed with the upcom­ing cold and flu sea­son: if social dis­tanc­ing lim­its the spread of com­mon cold coro­n­avirus­es we could end up mak­ing a bad sit­u­a­tion worse. ‘Tis the sea­son of “com­mon cold coro­n­avirus par­ties”?

    Posted by Pterrafractyl | July 23, 2020, 4:06 pm
  4. Here’s an inter­est­ing arti­cle from 2004 about a con­tro­ver­sial exper­i­ment that’s sim­i­lar to “gain-of-func­tion” exper­i­ments: reas­sort­ment stud­ies. That’s when you inten­tion­al­ly try to cre­ate hybrids of two exist­ing virus­es by infect­ing cells or an organ­ism with both virus­es at once and wait­ing to see if a new hybrid virus emerges.

    It turns out this sto­ry relates to the whole SARS-CoV­‑2 coro­n­avirus sit­u­a­tion in a num­ber of ways. First, recall how the pre­vail­ing the­o­ry of the ori­gins of the SARS-CoV­‑2 virus — that it emerged nat­u­ral­ly — has increas­ing­ly relied on the assump­tion that the virus arose from a recom­bi­na­tion event. This is because, while parts of the SARS-CoV­‑2 genome has a high sim­i­lar­i­ty to a strain of bat coro­n­avirus that was iden­ti­fied by researchers in 2013 in a cave in Yun­nan Chi­na, the part of the spike pro­tein that actu­al­ly binds to the ACE2 recep­tor — the Recep­tor Bind­ing Domain (RBD) — was more close­ly relat­ed to a known Pan­golin coro­n­avirus, although the SARS-CoV­‑2 canon­i­cal furin cleav­age site was­n’t found in either of the two Pan­golin or Bat coro­n­avirus­es. Also recall a lat­er study that com­pared the abil­i­ty of SARS-CoV­‑2 to bind to the ACE2 recep­tor to oth­er coro­n­avirus­es and found that SARS-CoV­‑2 binds bet­ter than them all, includ­ing the Pan­golin coro­n­avirus, lead­ing the researchers to sug­gest that a Pan­golin was­n’t actu­al­ly the like­ly inter­me­di­ary species that the virus evolved in before jump­ing to humans and there must be some oth­er undis­cov­ered inter­me­di­ary species.

    These are the kinds of obser­va­tions that made a recom­bi­na­tion event a stan­dard assump­tion now for how the virus could have emerged nat­u­ral­ly. So if recom­bi­na­tion events were being arti­fi­cial­ly gen­er­at­ed in the lab in these reas­sort­ment stud­ies that would obvi­ous­ly be some­thing we would want to keep in mind when inves­ti­gat­ing the ori­gins of the virus. Now, keep in mind that with gain-of-func­tion exper­i­ments those recom­bi­na­tion events can be basi­cal­ly built into the exper­i­ment as the first step because the exper­i­ments can involve direct­ly cre­at­ing new chimeric virus­es by comb­ing dif­fer­ent parts of dif­fer­ent virus­es using recom­bi­nant genom­ic meth­ods. That was the case with the now-noto­ri­ous 2015 exper­i­ment when Ralph Bar­ic’s lab cre­at­ed a chimera out of a Horse­shoe bat coro­n­avirus with the back­bone of the 2003 SARS virus.

    So reas­sort­ment stud­ies are like sim­pler “gain-of-func­tion” exper­i­ments, focused on ask­ing the ques­tion of whether two exist­ing virus­es can recom­bine at all. As the arti­cle notes, the CDC actu­al­ly start­ed such stud­ies with H5N1 in 2000 in response to the 1997 bird flu out­break. They man­aged to cre­ate hybrid strains but had­n’t had a chance to study them yet as of 2004 because the SARS out­break swamped the researchers so the hybrid virus­es were still sit­ting in freez­ers. It’s the kind of anec­dote that rais­es the ques­tion of how many hybrid strains, stud­ied and not-yet-stud­ied, are sit­ting in freez­ers some­where.

    Also of inter­est in the fol­low­ing 2004 sto­ry about the debate over reas­sort­ment stud­ies is the fact that the per­son who appeared to be the biggest advo­cate of them at the time was Klaus Stöhr, the for­mer head of the World Health Orga­ni­za­tion’s SARS research and epi­demi­ol­o­gy pro­gram at the time who recent­ly came out and declared that a vac­cine was unlike­ly to end the pan­dem­ic the only way it was going to end was by infect­ing the world and run­ning out of new peo­ple to infect. He’s described as the WHO’s prin­ci­ple flu expert at the time so Stöhr was a very influ­en­tial fig­ure in shap­ing the con­tem­po­rary glob­al approach to prepar­ing for pan­demics.

    As we’ll see, back in 2004 when the world was in the mid­dle of a giant H5N1 bird flu scare, Stöhr was open­ly call­ing for coun­tries to rapid­ly begin reas­sort­ment stud­ies specif­i­cal­ly with H5N1. The rea­son­ing was quite sim­ple: giv­en the repeat­ed out­breaks of avian flu that could infect humans but could­n’t yet car­ry out human-to-human trans­mis­sion, human­i­ty was one awful recom­bi­na­tion event away from the emer­gence of a hybrid ver­sion of bird flu that could jump from human-to-human and cre­ate the much feared super pan­dem­ic that could kill hun­dreds of mil­lions or bil­lions. Reas­sort­ment stud­ies would act as an ear­ly warn­ing sys­tem for the pos­si­bil­i­ty of such a recom­bi­na­tion event tak­ing place nat­u­ral­ly.

    Now here’s a part of this sto­ry that relates to the inter­est­ing his­to­ry of for­mer Gilead Chair­man Don­ald Rums­feld becom­ing Sec­re­tary of Defense dur­ing the peri­od of the post‑9/11 explo­sion in biode­fense spend­ing and the mas­sive prof­its Gilead made dur­ing this time from the gov­ern­ment stock­pil­ing of Tam­i­flu, the pri­ma­ry drug used to fight the bird flu at the time: When Klaus Stöhr was advo­cat­ing for reas­sort­ment stud­ies as a new pan­dem­ic warn­ing sys­tem tool, he was clear that the pur­pose of these stud­ies was­n’t to devel­op new drugs to treat the hybrid virus­es because exist­ing drugs were ade­quate. No, the pur­pose of the reas­sort­ment stud­ies was to let gov­ern­ments know whether or not they should stock­pile even more of these exist­ing drugs. Keep in mind that Stöhr was mak­ing these state­ments at a time when Tam­i­flu was the drug get­ting stock­piled by gov­ern­ments around the world.

    Now, on the one hand, hav­ing large stock­piles of an effec­tive drug is indeed quite help­ful if you’re fac­ing a glob­al pan­dem­ic of a high­ly dead­ly virus like H5N1. But on the oth­er hand, it’s kind of odd to just assume that the new hybrid virus is going to work with exist­ing ther­a­pies as the cur­rent pan­dem­ic should make abun­dant­ly clear which is why this push for reas­sort­ment stud­ies almost seem like being part of the Gilead Tam­i­flu bonan­za going on at that moment. Of course, once you cre­ate the hybrid virus you could test exist­ing ther­a­peu­tics against it, so it’s not like there could­n’t be any new drug devel­op­ment that emerges from such exper­i­ments. But Stöhr felt the need to point out that the pur­pose was­n’t about devel­op­ing new drugs but instead about assess­ing whether or not gov­ern­ments need­ed to stock­pile more exist­ing drugs, which is why the call for more reas­sort­ment stud­ies is almost like a gim­mick to encour­age even more stock­pil­ing of Tam­i­flu.

    So that gives us a sense of the World Health Orga­ni­za­tion’s stance on these reas­sort­ment stud­ies back in 2004 that were sort of like ear­ly “gain-of-func­tion” stud­ies: it was an enthu­si­as­tic backer of the stud­ies because they would leave the world bet­ter pre­pared for future pan­demics by scar­ing gov­ern­ments into stock­pil­ing more drugs like Tam­i­flu:

    Sci­ence

    Tip­toe­ing Around Pan­do­ra’s Box

    Researchers say cross­ing avian and human flu virus­es is cru­cial to under­stand­ing the threat of a new influen­za pan­dem­ic, but they admit that they might cre­ate a mon­ster

    Mar­tin Enserink
    July 30, 2004, Vol. 305, No. 5684, pp. 594–595

    Once again, the world is cross­ing its fin­gers. The avian influen­za out­break in Asia, already one of the worst ani­mal-health dis­as­ters in his­to­ry, has flared up in four coun­tries; tens of thou­sands of birds are being killed in des­per­ate attempts to halt the virus’s spread. And again, the unnerv­ing ques­tion aris­es: Could the out­break of the H5N1 strain spi­ral into a human flu pan­dem­ic, a glob­al cat­a­clysm that could kill mil­lions in a mat­ter of months and shake soci­eties to their core?

    There is a way to find out, flu sci­en­tists say—but it’s con­tro­ver­sial.

    Leav­ing nature to take its course, a pan­dem­ic could be ignit­ed if avian and human influen­za strains recombine—say, in the lungs of an Asian farmer infect­ed with both—producing a brand-new hybrid no human is immune to. By mix­ing H5N1 and human flu virus­es in the lab, sci­en­tists can find out how like­ly this is, and how dan­ger­ous a hybrid it would be.

    Such exper­i­ments can give the world a bet­ter han­dle on the risks, but they could also cre­ate dan­ger­ous new virus­es that would have to be destroyed or locked up for­ev­er in a sci­en­tif­ic high-secu­ri­ty prison. An acci­den­tal release—not so far-fetched a sce­nario giv­en that the severe acute res­pi­ra­to­ry syn­drome (SARS) virus man­aged to escape from three Asian labs in the past year—could lead to glob­al dis­as­ter. Giv­en their sci­en­tif­ic mer­it, the World Health Orga­ni­za­tion (WHO) is enthu­si­as­ti­cal­ly pro­mot­ing the exper­i­ments. But wor­ried crit­ics point out that there is no glob­al mech­a­nism to ensure that they are done safe­ly.

    Despite the con­cerns, such stud­ies have already begun. In 2000, the U.S. Cen­ters for Dis­ease Con­trol and Pre­ven­tion (CDC) in Atlanta, Geor­gia, start­ed exper­i­ments to cre­ate crossovers between the H5N1 strain iso­lat­ed dur­ing a 1997 out­break in Hong Kong and a human flu virus adapt­ed for the lab. The study was sus­pend­ed when CDC’s flu researchers became over­whelmed by SARS and the new H5N1 out­break, both in 2003, says CDC flu expert Nan­cy Cox, who led the work. But the agency plans to resume the work short­ly with the H5N1 strain now rag­ing in Asia.

    Oth­ers are explor­ing the options as well. Virol­o­gist Albert Oster­haus of Eras­mus Uni­ver­si­ty in Rot­ter­dam, the Nether­lands, is eager to try not just H5N1 but also oth­er bird flu strains, such as H7N7. The Nether­lands won’t have the required high-lev­el biosafe­ty lab until late 2005, so Oster­haus is talk­ing to researchers in France who do. In the Unit­ed King­dom, researchers at the Health Pro­tec­tion Agency, the Nation­al Insti­tute for Bio­log­i­cal Stan­dards and Con­trol, and uni­ver­si­ties are also dis­cussing the idea. There are no con­crete plans yet—in part because of a lack of funds—but there’s a con­sen­sus that the stud­ies are impor­tant and that Britain is well suit­ed to do them, says influen­za researcher Maria Zam­bon of the Health Pro­tec­tion Agency.

    The aim of reas­sort­ment stud­ies, as they’re called, would not be to devel­op new coun­ter­mea­sures, says WHO’s prin­ci­pal flu sci­en­tist, Klaus Stöhr, because researchers believe cur­rent drugs and an H5N1 vac­cine in devel­op­ment would work against a pan­dem­ic strain as well. But the exper­i­ments would pro­vide a bad­ly need­ed way to assess the risk of a pan­dem­ic. If they indi­cate that a pan­dem­ic virus is just around the cor­ner, health offi­cials would fur­ther inten­si­fy their fight in Asia and go full-throt­tle in stash­ing vac­cines and drugs; if not, they could breathe a lit­tle eas­i­er. “It’s an extreme­ly impor­tant ques­tion, and we have a respon­si­bil­i­ty to answer it,” insists Stöhr.

    The safe­ty wor­ries are legit­i­mate, Stöhr con­cedes, and the work should be done only by labs with ample flu exper­tise and excel­lent safe­ty systems—not the ones that let SARS out. “We don’t want peo­ple just fid­dling around,” he says. He also down­plays con­cerns that the results, when pub­lished, might help those who would unleash a pan­dem­ic on pur­pose. Any­one with the sci­en­tif­ic smarts to do so can already find plen­ty of ideas in the lit­er­a­ture, Stöhr asserts. More­over, the stud­ies are unlike­ly to pro­duce any­thing that could not arise nat­u­ral­ly, says Oster­haus: “You could cre­ate a mon­ster. But it’s a mon­ster that nature could pro­duce as well.”

    But crit­ics beg to dif­fer. “We’ve been debat­ing whether to destroy the small­pox virus for years—and now we’re plan­ning to cre­ate some­thing that’s almost as dan­ger­ous?” asks Mark Wheel­is, an arms-con­trol researcher at the Uni­ver­si­ty of Cal­i­for­nia, Davis. Wheel­is also points out that there’s no way to keep coun­tries with poor safe­ty records from get­ting in on the game. At the very least, there should be some glob­al con­sen­sus on how to pro­ceed, adds Elisa Har­ris, a researcher at the Cen­ter for Inter­na­tion­al and Secu­ri­ty Stud­ies at the Uni­ver­si­ty of Mary­land, Col­lege Park—although no for­mal mech­a­nism for reach­ing it exists.

    Mix and match

    The H5N1 strain has been vicious to its human vic­tims, killing 23 of 34 patients in Viet­nam and Thai­land this year. So far, how­ev­er, every known patient had been in con­tact with infect­ed birds; there’s no evi­dence that the virus can jump from one per­son to the next—for now. But the virus could evolve inside one of its human hosts, acquir­ing muta­tions that make it pos­si­ble to infect humans direct­ly, Stöhr says. Anoth­er scenario—one researchers believe sparked sev­er­al pre­vi­ous influen­za pandemics—is reas­sort­ment with a human flu virus in a per­son infect­ed with both.

    ...

    To cre­ate a world­wide out­break, a new­com­er must cause dis­ease in humans and be trans­mis­si­ble between them, and its coat must look so new that no human immune sys­tem rec­og­nizes it. This is deter­mined pri­mar­i­ly by the two gly­co­pro­teins on the viral sur­face, hemag­glu­tinin and neuraminidase—the “H” and “N” in names like H5N1. (Hemag­glu­tinin comes in at least 16 dif­fer­ent types, N in nine.) The cur­rent fear is that the Asian flu will keep its H5—which humans have nev­er seen before—but swap enough of the remain­ing sev­en gene seg­ments with those of a human strain to become more adept at repli­ca­tion in its new host.

    Dur­ing H5N1’s first major out­break in Hong Kong poul­try in 1997, 18 peo­ple got sick and six died. But the out­break was stamped out effi­cient­ly, and lit­tle was heard of H5N1 for 6 years—until it came roar­ing back last year. Giv­en the mag­ni­tude of the cur­rent out­break, the rid­dle is why reas­sort­ment has not yet tak­en place, says Stöhr. Reas­sort­ment stud­ies could help explain whether the world has sim­ply been lucky, or whether there’s some bar­ri­er to reas­sort­ment of H5N1.

    The exper­i­ments are straight­for­ward. Researchers take a cell line such as MDCK or Vero cells, often used for virus iso­la­tion, and add both H5N1 and a cur­rent­ly cir­cu­lat­ing human strain, such as H3N2 or H1N1. Or they can use a slight­ly less nat­ur­al tech­nique called reverse genet­ics, with which vir­tu­al­ly any com­bi­na­tion of genes can be put into a flu virus. Any viable hybrid strains would be inoc­u­lat­ed into mice; those that cause dis­ease would move on to fer­rets, a species very sim­i­lar to humans in its sus­cep­ti­bil­i­ty to influen­za. Any strain that is path­o­gen­ic in fer­rets and also jumps, say, from a sick ani­mal to a healthy one in an adja­cent cage could be humankind’s next night­mare.

    Dur­ing its first round of exper­i­ments with the H5N1 strain, CDC man­aged to cre­ate sev­er­al reas­sor­tants, Cox says, but it did­n’t get around to char­ac­ter­iz­ing them; they’re still sit­ting in a locked freez­er in Atlanta.

    Glob­al risks, glob­al review?

    Most agree that such exper­i­ments are in a league of their own. Con­tro­ver­sial flu stud­ies were con­duct­ed in the past; for instance, researchers sequenced parts of the genome of the “Span­ish flu” strain from 1918 (Sci­ence, 21 March 1997, p. 1793) and insert­ed its genes into oth­er strains to find out why it was so dead­ly. But that did­n’t amount to a whole­sale fish­ing expe­di­tion for pan­dem­ic strains. And because the 1918 strain was an H1 virus, just like one of the cur­rent­ly active ones, you’d expect at least some immu­ni­ty to it in the human pop­u­la­tion, says Yoshi­hi­ro Kawao­ka of the Uni­ver­si­ty of Tokyo and the Uni­ver­si­ty of Wis­con­sin, Madi­son, who stud­ies the 1918 strain. With an H5 virus, in con­trast, every­one would be vul­ner­a­ble.

    Yet although most coun­tries have sys­tems to review the safe­ty and eth­i­cal aspects of run-of-the-mill sci­en­tif­ic stud­ies, none have for­mal pan­els to weigh stud­ies that could, say, put the entire world at risk or be of poten­tial help to bioter­ror­ists. [The U.S. gov­ern­ment has announced plans for a nation­al biose­cu­ri­ty pan­el and a review sys­tem to fill that gap (Sci­ence, 12 March, p. 1595), but they have yet to be imple­ment­ed.] So although CDC’s first round of stud­ies cleared all the usu­al review hur­dles at the agency, Cox says, noth­ing beyond that was con­sid­ered nec­es­sary.

    Since then, “the times have changed,” Cox says. The H5N1 strain now plagu­ing Asia, with which CDC wants to work this time, appears to be more vir­u­lent than the 1997 ver­sion, and the specter of nefar­i­ous use of pathogens looms much larg­er. More­over, the mishaps with SARS have made peo­ple jit­tery about labs’ abil­i­ties to keep bugs on the inside. That’s why Cox says she has con­sult­ed more exten­sive­ly with col­leagues inside and out­side CDC, includ­ing experts such as Nobel lau­re­ate Joshua Leder­berg and WHO. She also plans to seek approval from col­leagues at the U.S. Nation­al Insti­tutes of Health and the U.S. Food and Drug Admin­is­tra­tion.

    But flu researcher Karl Nichol­son of the Uni­ver­si­ty of Leices­ter, U.K., says there should be a more for­mal, glob­al con­sen­sus on the neces­si­ty of the stud­ies, who should con­duct them, and how. For any coun­try to under­take them on its own, he says, “is like a deci­sion to start test­ing nuclear weapons uni­lat­er­al­ly.” WHO would be the best orga­ni­za­tion to start such a process, says Har­ris: The destruc­tion of the small­pox virus has been debat­ed at WHO, and an inter­na­tion­al pan­el there is over­see­ing exper­i­ments with it at CDC and in Rus­sia.

    But Stöhr believes exist­ing safe­guards suf­fice. The stud­ies have been dis­cussed wide­ly with sci­en­tists in WHO’s glob­al flu lab net­work and at a recent flu meet­ing in Lis­bon, he says, and have met with noth­ing but “over­whelm­ing agree­ment.” “If there are oth­er voic­es, we will take them seri­ous­ly,” Stöhr adds—but for now, it’s up to the labs to have their plans rig­or­ous­ly vet­ted by nation­al author­i­ties and get start­ed.

    Even­tu­al­ly, any strain with pan­dem­ic poten­tial should be destroyed, he says. But there’s no way to enforce this, and skep­tics point out that the small­pox virus was slat­ed for destruc­tion, too—until the threat of bioter­ror­ism cre­at­ed a move­ment to keep it alive, per­haps indef­i­nite­ly, for defen­sive stud­ies. In a way this dis­cus­sion is moot, says Richard Web­by of St. Jude Chil­dren’s Research Hos­pi­tal in Mem­phis, Ten­nessee. With flu strains read­i­ly avail­able, any­one with a good knowl­edge of mol­e­c­u­lar biol­o­gy could recre­ate a pan­dem­ic virus once it’s dis­cov­ered, he says. “You can destroy this virus,” Web­by says, “but it will nev­er real­ly be gone.”

    ———-

    “Tip­toe­ing Around Pan­do­ra’s Box” by Mar­tin Enserink; Sci­ence; 07/30/2004

    “The exper­i­ments are straight­for­ward. Researchers take a cell line such as MDCK or Vero cells, often used for virus iso­la­tion, and add both H5N1 and a cur­rent­ly cir­cu­lat­ing human strain, such as H3N2 or H1N1. Or they can use a slight­ly less nat­ur­al tech­nique called reverse genet­ics, with which vir­tu­al­ly any com­bi­na­tion of genes can be put into a flu virus. Any viable hybrid strains would be inoc­u­lat­ed into mice; those that cause dis­ease would move on to fer­rets, a species very sim­i­lar to humans in its sus­cep­ti­bil­i­ty to influen­za. Any strain that is path­o­gen­ic in fer­rets and also jumps, say, from a sick ani­mal to a healthy one in an adja­cent cage could be humankind’s next night­mare.

    A “humankind’s next night­mare” machine. Build the night­mare in a lab as a way of test­ing whether or not the night­mare might emerge nat­u­ral­ly. It’s a sim­ple con­cept. A sim­ple scary con­cept that was enthu­si­as­ti­cal­ly cham­pi­oned by the WHO at the time. But it was­n’t like the WHO need­ed to give its bless­ings to the reas­sort­ment exper­i­ments for coun­tries to car­ry them out, as evi­denced by the fact that the CDC start­ed these exper­i­ments in 2000 before putting them lit­er­al­ly on ice fol­low­ing the 2003 SARS out­break. But hybrids were cre­at­ed:

    ...
    Such exper­i­ments can give the world a bet­ter han­dle on the risks, but they could also cre­ate dan­ger­ous new virus­es that would have to be destroyed or locked up for­ev­er in a sci­en­tif­ic high-secu­ri­ty prison. An acci­den­tal release—not so far-fetched a sce­nario giv­en that the severe acute res­pi­ra­to­ry syn­drome (SARS) virus man­aged to escape from three Asian labs in the past year—could lead to glob­al dis­as­ter. Giv­en their sci­en­tif­ic mer­it, the World Health Orga­ni­za­tion (WHO) is enthu­si­as­ti­cal­ly pro­mot­ing the exper­i­ments. But wor­ried crit­ics point out that there is no glob­al mech­a­nism to ensure that they are done safe­ly.

    Despite the con­cerns, such stud­ies have already begun. In 2000, the U.S. Cen­ters for Dis­ease Con­trol and Pre­ven­tion (CDC) in Atlanta, Geor­gia, start­ed exper­i­ments to cre­ate crossovers between the H5N1 strain iso­lat­ed dur­ing a 1997 out­break in Hong Kong and a human flu virus adapt­ed for the lab. The study was sus­pend­ed when CDC’s flu researchers became over­whelmed by SARS and the new H5N1 out­break, both in 2003, says CDC flu expert Nan­cy Cox, who led the work. But the agency plans to resume the work short­ly with the H5N1 strain now rag­ing in Asia.

    ...

    Dur­ing its first round of exper­i­ments with the H5N1 strain, CDC man­aged to cre­ate sev­er­al reas­sor­tants, Cox says, but it did­n’t get around to char­ac­ter­iz­ing them; they’re still sit­ting in a locked freez­er in Atlanta.
    ...

    But despite the con­cerns about these hybrid virus­es acci­den­tal­ly leak­ing out of a lab, Klaus Stöhr, speak­ing on behalf of the WHO, down­played such con­cerns by point­ing out that any­one with mali­cious intent and the skills to do so would have plen­ty of hor­ri­ble night­mare ideas already avail­able to deploy based on exist­ing sci­en­tif­ic lit­er­a­ture. So, yes, safe­ty con­cerns are valid but dwarfed by the exist­ing safe­ty risks. That was how Stöhr down­played these con­cerns:

    ...
    The safe­ty wor­ries are legit­i­mate, Stöhr con­cedes, and the work should be done only by labs with ample flu exper­tise and excel­lent safe­ty systems—not the ones that let SARS out. “We don’t want peo­ple just fid­dling around,” he says. He also down­plays con­cerns that the results, when pub­lished, might help those who would unleash a pan­dem­ic on pur­pose. Any­one with the sci­en­tif­ic smarts to do so can already find plen­ty of ideas in the lit­er­a­ture, Stöhr asserts. More­over, the stud­ies are unlike­ly to pro­duce any­thing that could not arise nat­u­ral­ly, says Oster­haus: “You could cre­ate a mon­ster. But it’s a mon­ster that nature could pro­duce as well.”

    But crit­ics beg to dif­fer. “We’ve been debat­ing whether to destroy the small­pox virus for years—and now we’re plan­ning to cre­ate some­thing that’s almost as dan­ger­ous?” asks Mark Wheel­is, an arms-con­trol researcher at the Uni­ver­si­ty of Cal­i­for­nia, Davis. Wheel­is also points out that there’s no way to keep coun­tries with poor safe­ty records from get­ting in on the game. At the very least, there should be some glob­al con­sen­sus on how to pro­ceed, adds Elisa Har­ris, a researcher at the Cen­ter for Inter­na­tion­al and Secu­ri­ty Stud­ies at the Uni­ver­si­ty of Mary­land, Col­lege Park—although no for­mal mech­a­nism for reach­ing it exists.

    ...

    But Stöhr believes exist­ing safe­guards suf­fice. The stud­ies have been dis­cussed wide­ly with sci­en­tists in WHO’s glob­al flu lab net­work and at a recent flu meet­ing in Lis­bon, he says, and have met with noth­ing but “over­whelm­ing agree­ment.” “If there are oth­er voic­es, we will take them seri­ous­ly,” Stöhr adds—but for now, it’s up to the labs to have their plans rig­or­ous­ly vet­ted by nation­al author­i­ties and get start­ed.

    Even­tu­al­ly, any strain with pan­dem­ic poten­tial should be destroyed, he says. But there’s no way to enforce this, and skep­tics point out that the small­pox virus was slat­ed for destruc­tion, too—until the threat of bioter­ror­ism cre­at­ed a move­ment to keep it alive, per­haps indef­i­nite­ly, for defen­sive stud­ies. In a way this dis­cus­sion is moot, says Richard Web­by of St. Jude Chil­dren’s Research Hos­pi­tal in Mem­phis, Ten­nessee. With flu strains read­i­ly avail­able, any­one with a good knowl­edge of mol­e­c­u­lar biol­o­gy could recre­ate a pan­dem­ic virus once it’s dis­cov­ered, he says. “You can destroy this virus,” Web­by says, “but it will nev­er real­ly be gone.”
    ...

    But the pur­pose of these reas­sort­ment stud­ies isn’t to devel­op new coun­ter­mea­sures for the iden­ti­fied viable hybrid virus­es. The pur­pose is to let gov­ern­ments know whether or not they should stock­pile more exist­ing drugs. At least that was the case in 2004, when Gilead­’s Tam­i­flu was the drug gov­ern­ments was stock­pil­ing:

    ...
    The aim of reas­sort­ment stud­ies, as they’re called, would not be to devel­op new coun­ter­mea­sures, says WHO’s prin­ci­pal flu sci­en­tist, Klaus Stöhr, because researchers believe cur­rent drugs and an H5N1 vac­cine in devel­op­ment would work against a pan­dem­ic strain as well. But the exper­i­ments would pro­vide a bad­ly need­ed way to assess the risk of a pan­dem­ic. If they indi­cate that a pan­dem­ic virus is just around the cor­ner, health offi­cials would fur­ther inten­si­fy their fight in Asia and go full-throt­tle in stash­ing vac­cines and drugs; if not, they could breathe a lit­tle eas­i­er. “It’s an extreme­ly impor­tant ques­tion, and we have a respon­si­bil­i­ty to answer it,” insists Stöhr.
    ...

    So that’s part of the his­to­ry of “gain-of-func­tion” exper­i­ments and the role the WHO played in pro­mot­ing these kinds of exper­i­ments. It’s a his­to­ry that rais­es an obvi­ous ques­tion giv­en that we’re told that SARS-CoV­‑2 like­ly arose nat­u­ral­ly from a recom­bi­na­tion event: so have there been any reas­sort­ment stud­ies involv­ing Hor­shoe bat and Pan­golin coro­n­avirus­es late­ly? Maybe around 2018 or 2019?

    Posted by Pterrafractyl | July 24, 2020, 12:54 pm
  5. The New York Times has a new piece out exam­in­ing a grow­ing pat­tern of behav­ior with­in the exec­u­tive boards of the grow­ing num­ber of biotech com­pa­nies that are involved in the race for a coro­n­avirus vac­cine. It’s a pat­tern of behav­ior that is com­plete­ly pre­dictable, in part because much of it is legal even if its unseem­ly:

    As the race to find a coro­n­avirus vac­cine con­tin­ues it turns out the insid­ers at the biotech com­pa­nies involved in that race are mak­ing tons of mon­ey from the soar­ing share prices of their com­pa­nies. And while it’s not exact­ly a rev­e­la­tion that com­pa­ny insid­ers are sell­ing their shares after mak­ing pos­i­tive announce­ments that cause their stock prices to pop, it does become a more mean­ing­ful sto­ry if it turns out com­pa­nies are basi­cal­ly prey­ing on the pub­lic’s des­per­a­tion for a vac­cine to first issue a bunch of stock options to them­selves, then make a vague­ly pos­i­tive announce­ment about the vac­cine and watch the stock price dou­ble over night only to exe­cute those options and make an imme­di­ate mas­sive wind­fall. And it’s even worse if the com­pa­nies are issu­ing spe­cial stock options to their exec­u­tives that can be exec­u­tive in the short-term instead of only being exe­cutable after a num­ber of years like most stock options. And that’s exact­ly what’s hap­pen­ing across the indus­try as this vac­cine hunt plays in accord­ing to this inves­ti­ga­tion. In many cas­es exec­u­tives are oppor­tunis­ti­cal­ly exe­cut­ing exist­ing stock options to take advan­tage of this sud­den surge in biotech shares, but we’re also see­ing spe­cial unusu­al stock options get­ting issued that can be exe­cut­ed in the short-term which is noth­ing oth­er than insid­ers try­ing to cash in on this spec­u­la­tive boom. All in all, insid­ers from 11 vac­cine com­pa­nies, most of them small­er com­pa­nies, have sold well over $1 bil­lion in shares imme­di­ate­ly fol­low­ing pos­i­tive announce­ments about their vac­cine devel­op­ment efforts since March:

    The New York Times

    Cor­po­rate Insid­ers Pock­et $1 Bil­lion in Rush for Coro­n­avirus Vac­cine

    Well-timed stock bets have gen­er­at­ed big prof­its for senior exec­u­tives and board mem­bers at com­pa­nies devel­op­ing vac­cines and treat­ments.

    By David Gelles and Jesse Druck­er

    July 25, 2020
    Updat­ed 9:28 a.m. ET

    On June 26, a small South San Fran­cis­co com­pa­ny called Vaxart made a sur­prise announce­ment: A coro­n­avirus vac­cine it was work­ing on had been select­ed by the U.S. gov­ern­ment to be part of Oper­a­tion Warp Speed, the flag­ship fed­er­al ini­tia­tive to quick­ly devel­op drugs to com­bat Covid-19.

    Vaxart’s shares soared. Com­pa­ny insid­ers, who weeks ear­li­er had received stock options worth a few mil­lion dol­lars, saw the val­ue of those awards increase six­fold. And a hedge fund that part­ly con­trolled the com­pa­ny walked away with more than $200 mil­lion in instant prof­its.

    The race is on to devel­op a coro­n­avirus vac­cine, and some com­pa­nies and investors are bet­ting that the win­ners stand to earn vast prof­its from sell­ing hun­dreds of mil­lions — or even bil­lions — of dos­es to a des­per­ate pub­lic.

    Across the phar­ma­ceu­ti­cal and med­ical indus­tries, senior exec­u­tives and board mem­bers are cap­i­tal­iz­ing on that dynam­ic.

    They are mak­ing mil­lions of dol­lars after announc­ing pos­i­tive devel­op­ments, includ­ing sup­port from the gov­ern­ment, in their efforts to fight Covid-19. After such announce­ments, insid­ers from at least 11 com­pa­nies — most of them small­er firms whose for­tunes often hinge on the suc­cess or fail­ure of a sin­gle drug — have sold shares worth well over $1 bil­lion since March, accord­ing to fig­ures com­piled for The New York Times by Equi­lar, a data provider.

    In some cas­es, com­pa­ny insid­ers are prof­it­ing from reg­u­lar­ly sched­uled com­pen­sa­tion or auto­mat­ic stock trades. But in oth­er sit­u­a­tions, senior offi­cials appear to be pounc­ing on oppor­tu­ni­ties to cash out while their stock prices are sky high. And some com­pa­nies have award­ed stock options to exec­u­tives short­ly before mar­ket-mov­ing announce­ments about their vac­cine progress.

    The sud­den wind­falls high­light the pow­er­ful finan­cial incen­tives for com­pa­ny offi­cials to gen­er­ate pos­i­tive head­lines in the race for coro­n­avirus vac­cines and treat­ments, even if the drugs might nev­er pan out.

    Some com­pa­nies are attract­ing gov­ern­ment scruti­ny for poten­tial­ly using their asso­ci­a­tions with Oper­a­tion Warp Speed as mar­ket­ing ploys.

    For exam­ple, the head­line on Vaxart’s news release declared: “Vaxart’s Covid-19 Vac­cine Select­ed for the U.S. Government’s Oper­a­tion Warp Speed.” But the real­i­ty is more com­plex.

    Vaxart’s vac­cine can­di­date was includ­ed in a tri­al on pri­mates that a fed­er­al agency was orga­niz­ing in con­junc­tion with Oper­a­tion Warp Speed. But Vaxart is not among the com­pa­nies select­ed to receive sig­nif­i­cant finan­cial sup­port from Warp Speed to pro­duce hun­dreds of mil­lions of vac­cine dos­es.

    “The U.S. Depart­ment of Health and Human Ser­vices has entered into fund­ing agree­ments with cer­tain vac­cine man­u­fac­tur­ers, and we are nego­ti­at­ing with oth­ers. Nei­ther is the case with Vaxart,” said Michael R. Caputo, the department’s assis­tant sec­re­tary for pub­lic affairs. “Vaxart’s vac­cine can­di­date was select­ed to par­tic­i­pate in pre­lim­i­nary U.S. gov­ern­ment stud­ies to deter­mine poten­tial areas for pos­si­ble Oper­a­tion Warp Speed part­ner­ship and sup­port. At this time, those stud­ies are ongo­ing, and no deter­mi­na­tions have been made.”

    Some offi­cials at the Depart­ment of Health and Human Ser­vices have grown con­cerned about whether com­pa­nies includ­ing Vaxart are try­ing to inflate their stock prices by exag­ger­at­ing their roles in Warp Speed, a senior Trump admin­is­tra­tion offi­cial said. The depart­ment has relayed those con­cerns to the Secu­ri­ties and Exchange Com­mis­sion, said the offi­cial, who spoke on the con­di­tion of anonymi­ty.

    It isn’t clear if the com­mis­sion is look­ing into the mat­ter. An S.E.C. spokes­woman declined to com­ment.

    “Vaxart abides by good cor­po­rate gov­er­nance guide­lines and poli­cies and makes deci­sions in accor­dance with the best inter­ests of the com­pa­ny and its share­hold­ers,” Vaxart’s chief exec­u­tive, Andrei Floroiu, said in a state­ment on Fri­day. Refer­ring to Oper­a­tion Warp Speed, he added, “We believe that Vaxart’s Covid-19 vac­cine is the most excit­ing one in O.W.S. because it is the only oral vac­cine (a pill) in O.W.S.”

    Well-timed stock trans­ac­tions are gen­er­al­ly legal. But investors and cor­po­rate gov­er­nance experts say they can cre­ate the appear­ance that exec­u­tives are prof­it­ing from inside infor­ma­tion, and could erode pub­lic con­fi­dence in the phar­ma­ceu­ti­cal indus­try when the world is look­ing to these com­pa­nies to cure Covid-19.

    “It is inap­pro­pri­ate for drug com­pa­ny exec­u­tives to cash in on a cri­sis,” said Ben Wakana, exec­u­tive direc­tor of Patients for Afford­able Drugs, a non­prof­it advo­ca­cy group. “Every day, Amer­i­cans wake up and make sac­ri­fices dur­ing this pan­dem­ic. Drug com­pa­nies see this as a pay­day.”

    Exec­u­tives at a long list of com­pa­nies have reaped sev­en- or eight-fig­ure prof­its thanks to their work on coro­n­avirus vac­cines and treat­ments.

    Shares of Regen­eron, a biotech com­pa­ny in Tar­ry­town, N.Y., have climbed near­ly 80 per­cent since ear­ly Feb­ru­ary, when it announced a col­lab­o­ra­tion with the Depart­ment of Health and Human Ser­vices to devel­op a Covid-19 treat­ment. Since then, the company’s top exec­u­tives and board mem­bers have sold near­ly $700 mil­lion in stock. The chief exec­u­tive, Leonard Schleifer, sold $178 mil­lion of shares on a sin­gle day in May.

    Alexan­dra Bowie, a spokes­woman for Regen­eron, said most of those sales had been sched­uled in advance through pro­grams that auto­mat­i­cal­ly sell exec­u­tives’ shares if the stock hits a cer­tain price.

    Mod­er­na, a 10-year-old vac­cine devel­op­er based in Cam­bridge, Mass., that has nev­er brought a prod­uct to mar­ket, announced in late Jan­u­ary that it was work­ing on a coro­n­avirus vac­cine. It has issued a stream of news releas­es hail­ing its vac­cine progress, and its stock has more than tripled, giv­ing the com­pa­ny a mar­ket val­ue of almost $30 bil­lion.

    Mod­er­na insid­ers have sold about $248 mil­lion of shares since that Jan­u­ary announce­ment, most of it after the com­pa­ny was select­ed in April to receive fed­er­al fund­ing to sup­port its vac­cine efforts.

    While some of those sales were sched­uled in advance, oth­ers were more spur of the moment. Flag­ship Ven­tures, an invest­ment fund run by the company’s founder and chair­man, Noubar Afeyan, sold more than $68 mil­lion worth of Mod­er­na shares on May 21. Those trans­ac­tions were not sched­uled in advance, accord­ing to secu­ri­ties fil­ings.

    Exec­u­tives and board mem­bers at Luminex, Quidel and Emer­gent BioSo­lu­tions have sold shares worth a com­bined $85 mil­lion after announc­ing they were work­ing on vac­cines, treat­ments or test­ing solu­tions.

    At oth­er com­pa­nies, exec­u­tives and board mem­bers received large grants of stock options short­ly before the com­pa­nies announced good news that lift­ed the val­ue of those options.

    Novavax, a drug­mak­er in Gaithers­burg, Md., began work­ing on a vac­cine ear­ly this year. This spring, the com­pa­ny report­ed promis­ing pre­lim­i­nary test results and a $1.6 bil­lion deal with the Trump admin­is­tra­tion.

    In April, with its shares below $24, Novavax issued a batch of new stock awards to all its employ­ees “in acknowl­edg­ment of the extra­or­di­nary work of our employ­ees to imple­ment a new vac­cine pro­gram.” Four senior exec­u­tives, includ­ing the chief exec­u­tive, Stan­ley Erck, received stock options that were worth less than $20 mil­lion at the time.

    Since then, Novavax’s stock has rock­et­ed to more than $130 a share. At least on paper, the four exec­u­tives’ stock options are worth more than $100 mil­lion.

    So long as the com­pa­ny hits a mile­stone with its vac­cine test­ing, which it is expect­ed to achieve soon, the exec­u­tives will be able to use the options to buy dis­count­ed Novavax shares as ear­ly as next year, regard­less of whether the com­pa­ny devel­ops a suc­cess­ful vac­cine.

    Sil­via Tay­lor, a Novavax spokes­woman, said the stock awards were designed “to incen­tivize and retain our employ­ees dur­ing this crit­i­cal time.” She added that “there is no guar­an­tee they will retain their val­ue.”

    Two oth­er drug­mak­ers, Trans­late Bio and Inovio, award­ed large batch­es of stock options to exec­u­tives and board mem­bers short­ly before they announced progress on their coro­n­avirus vac­cines, send­ing shares high­er. Rep­re­sen­ta­tives of the com­pa­nies said the options were reg­u­lar­ly sched­uled annu­al grants.

    Vaxart, though, is where the most mon­ey was made the fastest.

    At the start of the year, its shares were around 35 cents. Then in late Jan­u­ary, Vaxart began work­ing on an oral­ly admin­is­tered coro­n­avirus vac­cine, and its shares start­ed ris­ing.

    Vaxart’s largest share­hold­er was a New York hedge fund, Armistice Cap­i­tal, which last year acquired near­ly two-thirds of the company’s shares. Two Armistice exec­u­tives, includ­ing the hedge fund’s founder, Steven Boyd, joined Vaxart’s board of direc­tors. The hedge fund also pur­chased rights, known as war­rants, to buy 21 mil­lion more Vaxart shares at some point in the future for as lit­tle as 30 cents each.

    Vaxart has nev­er brought a vac­cine to mar­ket. It has just 15 employ­ees. But through­out the spring, Vaxart announced pos­i­tive pre­lim­i­nary data for its vac­cine, along with a part­ner­ship with a com­pa­ny that could man­u­fac­ture it. By late April, with investors sens­ing the poten­tial for big prof­its, the company’s shares had reached $3.66 — a ten­fold increase from Jan­u­ary.

    On June 8, Vaxart changed the terms of its war­rants agree­ment with Armistice, mak­ing it eas­i­er for the hedge fund to rapid­ly acquire the 21 mil­lion shares, rather than hav­ing to buy and sell in small­er batch­es.

    One week lat­er, Vaxart announced that its chief exec­u­tive was step­ping down, though he would remain chair­man. The new C.E.O., Mr. Floroiu, had pre­vi­ous­ly worked with Mr. Boyd, Armistice’s founder, at the hedge fund and the con­sult­ing firm McK­in­sey.

    On June 25, Vaxart announced that it had signed a let­ter of intent with anoth­er com­pa­ny that might help it mass-pro­duce a coro­n­avirus vac­cine. Vaxart’s shares near­ly dou­bled that day.

    The next day, Vaxart issued its news release say­ing it had been select­ed for Oper­a­tion Warp Speed. Its shares instant­ly dou­bled again, at one point­ing hit­ting $14, their high­est lev­el in years.

    “We are very pleased to be one of the few com­pa­nies select­ed by Oper­a­tion Warp Speed, and that ours is the only oral vac­cine being eval­u­at­ed,” Mr. Floroiu said.

    Armistice took advan­tage of the stock’s expo­nen­tial increase — at that point up more than 3,600 per­cent since Jan­u­ary. On June 26, a Fri­day, and the next Mon­day, the hedge fund exer­cised its war­rants to buy near­ly 21 mil­lion Vaxart shares for either 30 cents or $1.10 a share — pur­chas­es it would not have been able to make as quick­ly had its agree­ment with Vaxart not been mod­i­fied weeks ear­li­er.

    Armistice then imme­di­ate­ly sold the shares at prices from $6.58 to $12.89 a share, accord­ing to secu­ri­ties fil­ings. The hedge fund’s prof­its were immense: more than $197 mil­lion.

    “It looks like the war­rants may have been recon­fig­ured at a time when they knew good news was com­ing,” said Robert Daines, a pro­fes­sor at Stan­ford Law School who is an expert on cor­po­rate gov­er­nance. “That’s a valu­able change, made right as the company’s stock price was about to rise.”

    At the same time, the hedge fund also unloaded some of the Vaxart shares it had pre­vi­ous­ly bought, notch­ing tens of mil­lions of dol­lars in addi­tion­al prof­its.

    By the end of that Mon­day, June 29, Armistice had sold almost all of its Vaxart shares.

    ...

    Mr. Floroiu said the change to the Armistice agree­ment “was in the best inter­ests of Vaxart and its stock­hold­ers” and helped it raise mon­ey to work on the Covid-19 vac­cine.

    He and oth­er Vaxart board mem­bers also were posi­tioned for big per­son­al prof­its. When he became chief exec­u­tive in mid-June, Mr. Floroiu received stock options that were worth about $4.3 mil­lion. A month lat­er, those options were worth more than $28 mil­lion.

    Nor­mal­ly when com­pa­nies issue stock options to exec­u­tives, the options can’t be exer­cised for months or years. Because of the unusu­al terms and the run-up in Vaxart’s stock price, most of Mr. Floroiu’s can be cashed in now.

    Vaxart’s board mem­bers also received large grants of stock options, giv­ing them the right to buy shares in the com­pa­ny at prices well below where the stock is now trad­ing. The high­er the shares fly, the big­ger the prof­its.

    “Vaxart is dis­rupt­ing the vac­cine world,” Mr. Floroiu boast­ed dur­ing a vir­tu­al investor con­fer­ence on Thurs­day. He added that his impres­sion was that “it’s OK to make a prof­it from Covid vac­cines, as long as you’re not prof­i­teer­ing.”

    ————

    “Cor­po­rate Insid­ers Pock­et $1 Bil­lion in Rush for Coro­n­avirus Vac­cine” by David Gelles and Jesse Druck­er; The New York Times; 07/25/2020

    “They are mak­ing mil­lions of dol­lars after announc­ing pos­i­tive devel­op­ments, includ­ing sup­port from the gov­ern­ment, in their efforts to fight Covid-19. After such announce­ments, insid­ers from at least 11 com­pa­nies — most of them small­er firms whose for­tunes often hinge on the suc­cess or fail­ure of a sin­gle drug — have sold shares worth well over $1 bil­lion since March, accord­ing to fig­ures com­piled for The New York Times by Equi­lar, a data provider.”

    It’s a great time to be an exec­u­tive at a vac­cine devel­op­ment com­pa­ny. That’s not a sur­prise giv­en the sit­u­a­tion. The prob­lem is that it’s turn­ing out to be a great time to be an exec­u­tive at a vac­cine devel­op­ment com­pa­ny whether or not the com­pa­ny has any hope of actu­al­ly cre­at­ing a viable vac­cine and bring­ing it to mar­ket. Some sort of vague­ly pos­i­tive announce­ment, that can be as sim­ple as an announce­ment of a part­ner­ship with the US fed­er­al gov­ern­ment, can trig­ger a stock price pop fol­lowed by a flur­ry of insid­er sales. It real­ly is the per­fect envi­ron­ment for a sec­tor-wide ‘pump and dump’ dynam­ic.

    Even worse is that this is kind of legal and kind of not legal. Exec­u­tives can oppor­tunis­ti­cal­ly sell shares and exec­u­tive avail­able stock options when stock prices are high. But when com­pa­nies are award­ing stock options to exec­u­tives short­ly before mar­ket-mov­ing announce­ments about their vac­cine devel­op­ment it’s the kind of sit­u­a­tion that just looks like a giant pump and dump scheme. Because that’s prob­a­bly what it is in many cas­es:

    ...
    In some cas­es, com­pa­ny insid­ers are prof­it­ing from reg­u­lar­ly sched­uled com­pen­sa­tion or auto­mat­ic stock trades. But in oth­er sit­u­a­tions, senior offi­cials appear to be pounc­ing on oppor­tu­ni­ties to cash out while their stock prices are sky high. And some com­pa­nies have award­ed stock options to exec­u­tives short­ly before mar­ket-mov­ing announce­ments about their vac­cine progress.

    The sud­den wind­falls high­light the pow­er­ful finan­cial incen­tives for com­pa­ny offi­cials to gen­er­ate pos­i­tive head­lines in the race for coro­n­avirus vac­cines and treat­ments, even if the drugs might nev­er pan out.

    ...

    Well-timed stock trans­ac­tions are gen­er­al­ly legal. But investors and cor­po­rate gov­er­nance experts say they can cre­ate the appear­ance that exec­u­tives are prof­it­ing from inside infor­ma­tion, and could erode pub­lic con­fi­dence in the phar­ma­ceu­ti­cal indus­try when the world is look­ing to these com­pa­nies to cure Covid-19.

    “It is inap­pro­pri­ate for drug com­pa­ny exec­u­tives to cash in on a cri­sis,” said Ben Wakana, exec­u­tive direc­tor of Patients for Afford­able Drugs, a non­prof­it advo­ca­cy group. “Every day, Amer­i­cans wake up and make sac­ri­fices dur­ing this pan­dem­ic. Drug com­pa­nies see this as a pay­day.”

    Exec­u­tives at a long list of com­pa­nies have reaped sev­en- or eight-fig­ure prof­its thanks to their work on coro­n­avirus vac­cines and treat­ments.
    ...

    And note how, in the case of Vaxart, the com­pa­ny trig­gered a stock surge when it announced that it was select­ed to be part of “Oper­a­tion Warp Speed”. And while it was tech­ni­cal­ly cho­sen to par­tic­i­pate in a non-human pri­mate study that was being orga­nized by Oper­a­tion Warp Speed, the com­pa­ny had­n’t actu­al­ly been select­ed to received large gov­ern­ment grants like oth­er com­pa­nies that have received awards exceed­ing a bil­lion dol­lars from Oper­a­tion Warp Speed. So the Vaxart announce­ment about being select­ed by Oper­a­tion Warp Speed real­ly was a decep­tion. A decep­tion that worked, which is part of why some gov­ern­ment offi­cials have report­ed­ly raised con­cerns with the Secu­ri­ties and Exchange Com­mis­sion (SEC) but there’s no sign this is actu­al­ly being inves­ti­gat­ed:

    ...
    Some com­pa­nies are attract­ing gov­ern­ment scruti­ny for poten­tial­ly using their asso­ci­a­tions with Oper­a­tion Warp Speed as mar­ket­ing ploys.

    For exam­ple, the head­line on Vaxart’s news release declared: “Vaxart’s Covid-19 Vac­cine Select­ed for the U.S. Government’s Oper­a­tion Warp Speed.” But the real­i­ty is more com­plex.

    Vaxart’s vac­cine can­di­date was includ­ed in a tri­al on pri­mates that a fed­er­al agency was orga­niz­ing in con­junc­tion with Oper­a­tion Warp Speed. But Vaxart is not among the com­pa­nies select­ed to receive sig­nif­i­cant finan­cial sup­port from Warp Speed to pro­duce hun­dreds of mil­lions of vac­cine dos­es.

    “The U.S. Depart­ment of Health and Human Ser­vices has entered into fund­ing agree­ments with cer­tain vac­cine man­u­fac­tur­ers, and we are nego­ti­at­ing with oth­ers. Nei­ther is the case with Vaxart,” said Michael R. Caputo, the department’s assis­tant sec­re­tary for pub­lic affairs. “Vaxart’s vac­cine can­di­date was select­ed to par­tic­i­pate in pre­lim­i­nary U.S. gov­ern­ment stud­ies to deter­mine poten­tial areas for pos­si­ble Oper­a­tion Warp Speed part­ner­ship and sup­port. At this time, those stud­ies are ongo­ing, and no deter­mi­na­tions have been made.”

    Some offi­cials at the Depart­ment of Health and Human Ser­vices have grown con­cerned about whether com­pa­nies includ­ing Vaxart are try­ing to inflate their stock prices by exag­ger­at­ing their roles in Warp Speed, a senior Trump admin­is­tra­tion offi­cial said. The depart­ment has relayed those con­cerns to the Secu­ri­ties and Exchange Com­mis­sion, said the offi­cial, who spoke on the con­di­tion of anonymi­ty.

    It isn’t clear if the com­mis­sion is look­ing into the mat­ter. An S.E.C. spokes­woman declined to com­ment.
    ...

    It’s also worth not­ing that Fort Det­rick announced back in May that it was going to be car­ry­ing out ani­mal stud­ies stud­ies as part of Oper­a­tion Warp Speed so there’s a good chance the pri­mate study Vaxart is par­tic­i­pat­ing in is being car­ried out at Fort Det­rick. Hope­ful­ly they got all those safe­ty issues worked out at the facil­i­ty where non-human pri­mate stud­ies were being con­duct­ed, although at least if any­thing escapes from those stud­ies it will be a virus that’s already out there.

    So it’s going to be very inter­est­ing to see if the SEC actu­al­ly looks into these con­cerns about com­pa­nies mak­ing exag­ger­at­ed claims to inflate their stock prices. Those exag­ger­at­ed claims are polit­i­cal­ly con­ve­nient claims, after all, that help but­tress the broad­er finan­cial mar­kets with a gen­er­al opti­mism that a vac­cine real­ly might be right around the cor­ner. That’s part of what makes this such an inter­est­ing sto­ry: yes, there appears to be wide­spread hyp­ing of the progress made on COVID ther­a­peu­tics — from vac­cines to drug devel­op­ment — but that hyp­ing real­ly is like­ly help­ing to keep the broad­er stock mar­ket ele­vat­ed. Do Trump admin­is­tra­tion offi­cials nec­es­sar­i­ly want to burst that opti­mism bub­ble? They haven’t so far and it’s hard to see what’s going to change that sit­u­a­tion. Plus, this is the Trump admin­is­tra­tion. Decep­tive­ly exploit­ing hype is one of the few things it does well.

    Posted by Pterrafractyl | July 25, 2020, 3:36 pm
  6. Here’s a quick pair of updates on remde­sivir: First, here’s an update on the assess­ments of remde­sivir’s effec­tive­ness against COVID-19. A pan­el of inter­na­tion­al experts con­vened by the British Med­ical Jour­nal reviewed the avail­able evi­dence on remde­sivir and con­clud­ed that it’s worth pre­scrib­ing to patients with sev­er COVID-19 despite its effec­tive­ness remain­ing incon­clu­sive due to the fact that most of the tri­als were small and have had lim­i­ta­tions. Recall how the study design of the remde­sivir clin­i­cal tri­als run by Gilead itself has been a tar­get of fre­quent crit­i­cism. So this expert pan­el appears to have large­ly con­curred with those crit­i­cisms and are rec­om­mend­ing remde­sivir large­ly because it’s prob­a­bly bet­ter than noth­ing even though we don’t know if it’s actu­al­ly bet­ter than noth­ing.

    The pan­el also address­es remde­sivir’s rather high price tag of $3,120 a course for most US patients, warn­ing that the use of such cost­ly drugs notes, using cost­ly drugs like remde­sivir may divert funds, time, atten­tion and work­force away from oth­er poten­tial­ly worth­while treat­ments. So the pan­el is tepid­ly endors­ing the use of the drug despite lim­it­ed evi­dence that it actu­al­ly helps patients — because there’s no oth­er options — at the same time it notes that the use of cost­ly drugs like remde­sivir may be lim­it­ing the search from oth­er treat­ments:

    Bloomberg

    Remde­sivir Gets Luke­warm Endorse­ment From Experts in Covid Fight

    By Jade Wil­son
    July 30, 2020, 6:01 PM CDT

    * Tri­als of remde­sivir have had lim­i­ta­tions, jour­nal says
    * Pan­el calls for more study of Gilead drug in Covid patients

    Gilead Sci­ences Inc.’s remde­sivir is worth pre­scrib­ing for patients with severe Covid-19 though evi­dence of its ben­e­fits remains incon­clu­sive, accord­ing to a pan­el of inter­na­tion­al experts con­vened by the British Med­ical Jour­nal.

    The effec­tive­ness of most inter­ven­tions with remde­sivir is uncer­tain because most of the tri­als so far have been small and have lim­i­ta­tions, the authors said in a review for the jour­nal.

    ...

    Remde­sivir may be effec­tive in reduc­ing recov­ery time in patients with severe Covid-19, though more tri­als are need­ed to con­firm this, the experts said. The drug prob­a­bly has no impor­tant effect on the need for mechan­i­cal ven­ti­la­tion and may have lit­tle or no effect on the length of hos­pi­tal stay.

    Gilead said in June that it will charge U.S. hos­pi­tals rough­ly $3,120 for a course of treat­ment of remde­sivir for most patients. The drug received an emer­gency use autho­riza­tion from U.S. reg­u­la­tors in May, after a big tri­al found it sped recov­ery by about four days in hos­pi­tal­ized patients.

    The authors said use of a cost­ly drug like remde­sivir may divert funds, time, atten­tion and work­force away from oth­er poten­tial­ly worth­while treat­ments. They sug­gest­ed future research should focus on areas such as opti­mal dose of the drug, dura­tion of ther­a­py, and whether there are spe­cif­ic groups of patients most like­ly to ben­e­fit.

    ————-

    “Remde­sivir Gets Luke­warm Endorse­ment From Experts in Covid Fight” by Jade Wil­son; Bloomberg; 07/30/2020

    The authors said use of a cost­ly drug like remde­sivir may divert funds, time, atten­tion and work­force away from oth­er poten­tial­ly worth­while treat­ments. They sug­gest­ed future research should focus on areas such as opti­mal dose of the drug, dura­tion of ther­a­py, and whether there are spe­cif­ic groups of patients most like­ly to ben­e­fit.”

    An expen­sive diver­sion that’s hope­ful­ly bet­ter than noth­ing but we can’t be sure because the effi­ca­cy stud­ies were so inad­e­quate. That was the gen­er­al take of this expert pan­el. It’s less an endorse­ment than a capit­u­la­tion to cir­cum­stance.

    And now here’s an arti­cle about the update Gilead just gave on its 2020 sales out­look. Despite a near­ly 9.6% drop in base­line sales of Gilead­’s exist­ing drugs — which appears to be large­ly dri­ven by the pan­dem­ic lead­ing to a fall in demand for Gilead­’s HIV drugs — the com­pa­ny is rais­ing its pre­vi­ous sales guid­ance of $21.8 -$22.2 bil­lion made back in Feb­ru­ary to $23-$25 bil­lion due entire­ly to sales of remde­sivir:

    Fierce Phar­ma

    Gilead banks on block­buster remde­sivir with sun­nier 2020 out­look

    by Angus Liu | Jul 31, 2020 11:51am

    Gilead is part of a long list of drug­mak­ers that have suf­fered from busi­ness slow­downs caused by COVID-19. But unlike its peers, the Big Biotech has an unex­pect­ed block­buster source of rev­enue that led it to ele­vate its full-year out­look: COVID-19 ther­a­py remde­sivir.

    The com­pa­ny on Thurs­day increased its 2020 sales guid­ance to the range of $23 bil­lion to $25 bil­lion, from a pre­vi­ous $21.8 bil­lion to $22.2 bil­lion, even after it was hit with a big­ger-than-expect­ed year-over-year top-line decline of 9.6% in the sec­ond quar­ter.

    The rea­son? It now expects to sell 1 mil­lion to 1.5 mil­lion treat­ment cours­es of remde­sivir in COVID-19, Chief Finan­cial Offi­cer Andrew Dick­in­son told investors dur­ing a con­fer­ence call on Thurs­day. By RBC Cap­i­tal Mar­kets ana­lyst Bri­an Abra­hams’ cal­cu­la­tion, that rough­ly equates to $3.5 bil­lion in addi­tion­al sec­ond-half 2020 sales of the antivi­ral.

    Gilead­’s pre­vi­ous guid­ance, mean­while didn’t include any con­tri­bu­tions from remde­sivir. It was only in late April—on the eve of Gilead’s first-quar­ter earn­ings report—that the Nation­al Insti­tutes of Health unveiled the first data from a place­bo-con­trolled clin­i­cal tri­al, show­ing the drug cut recov­ery time by 31% for hos­pi­tal­ized COVID-19 patients. And it wasn’t until two months lat­er that the com­pa­ny unveiled its com­mer­cial plan, set­ting the list price at $3,120 for a stan­dard five-day treat­ment course for pri­vate insur­ance plans and $2,340 per course for gov­ern­ment pur­chas­es from devel­oped coun­tries.

    In a con­tro­ver­sial move, the U.S. Depart­ment of Health and Human Ser­vices has secured over 500,000 treat­ment cours­es of remde­sivir for U.S. use through Sep­tem­ber. That rep­re­sents near­ly all of Gilead’s pro­ject­ed yield dur­ing the peri­od. As it works to ramp up man­u­fac­tur­ing, the com­pa­ny now expects to have enough sup­plies to “meet real-time glob­al demand” from Octo­ber, Gilead CEO Daniel O’Day said dur­ing the call.

    Gilead exec­u­tives acknowl­edged that there remain many uncer­tain­ties around how the pan­dem­ic will evolve in the sec­ond half of the year, which explains why the com­pa­ny is leav­ing a wide $2 bil­lion dif­fer­ence between the two ends of its full-year sales expec­ta­tions. But in a Fri­day note to clients, SVB Leerink ana­lyst Geof­frey Porges said he expects there will be “sig­nif­i­cant demand” for remde­sivir giv­en the disease’s unre­lent­ing grip on the world, and that gov­ern­ment nego­ti­a­tions on stock­pil­ing will start in the fourth quar­ter.

    ...

    ————-

    “Gilead banks on block­buster remde­sivir with sun­nier 2020 out­look” by Angus Liu; Fierce Phar­ma; 07/31/2020

    The com­pa­ny on Thurs­day increased its 2020 sales guid­ance to the range of $23 bil­lion to $25 bil­lion, from a pre­vi­ous $21.8 bil­lion to $22.2 bil­lion, even after it was hit with a big­ger-than-expect­ed year-over-year top-line decline of 9.6% in the sec­ond quar­ter.”

    A big­ger-than-expect­ed drop off in the base­line sales of its drugs is going to be more than off­set by a pro­ject­ed $3.5 bil­lion in remde­sivir sales. That’s the new guid­ance for Gilead now that it has a much bet­ter sense of how much of the drug it’s going to sell this year and how much it can charge for it.

    So while we still have no idea whether or not remde­sivir actu­al­ly helps COVID-19 patients we are get­ting much greater clar­i­ty on the impact of remde­sivir or Gilead­’s bot­tom line. As for­mer Gilead chair­man Don­ald Rums­feld once said, “You go to war with the army you have, not the army you might want or wish to have at a lat­er time.” The same is true of pan­demics and pri­or­i­ties.

    Posted by Pterrafractyl | July 31, 2020, 2:22 pm
  7. Very clever use of the NYT stand­by “right wing pop­ulist”. They let the counter-pro­tes­tors call the marchers “Nazis”, but their own writer calls them “Right wing pop­ulists”. Oh, Times, nev­er change..

    https://www.nytimes.com/aponline/2020/08/01/world/europe/ap-virus-outbreak-germany.html

    Thou­sands protest­ed Ger­many’s coro­n­avirus restric­tions Sat­ur­day in a Berlin demon­stra­tion mark­ing what orga­niz­ers called “the end of the pan­dem­ic” — a dec­la­ra­tion that comes just as author­i­ties are voic­ing increas­ing con­cerns about an uptick in new infec­tions.

    ...Police esti­mat­ed about 17,000 peo­ple turned out. The demon­stra­tors were kept apart from coun­ter­pro­test­ers, some of whom chant­ed “Nazis out!”

    Pro­test­ers con­tin­ued to a sub­se­quent ral­ly on a boule­vard run­ning through the city’s Tier­garten park, which police esti­mat­ed drew 20,000 peo­ple. Police declared that event over as orga­niz­ers again failed to get demon­stra­tors to wear masks or keep their dis­tance.

    Protests against anti-virus restric­tions in Ger­many have drawn a vari­ety of atten­dees, includ­ing con­spir­a­cy the­o­rists and right-wing pop­ulists.

    Posted by CinqueAnon | August 3, 2020, 3:32 pm

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