Spitfire List Web site and blog of anti-fascist researcher and radio personality Dave Emory.

For The Record  

FTR#‘s 1292 and 1293 The Oswald Institute of Virology, Part 14: The Northwoods Virus, Part 2 and Apocalypse, The Satanic Presidency of Joe Biden

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“Polit­i­cal language…is designed to make lies sound truth­ful and mur­der respectable, and to give an appear­ance of solid­i­ty to pure wind.”

— George Orwell, 1946

EVERYTHING MR. EMORY HAS BEEN SAYING ABOUT THE UKRAINE WAR IS ENCAPSULATED IN THIS VIDEO FROM UKRAINE 24

ANOTHER REVEALING VIDEO FROM UKRAINE 24

Mr. Emory has launched a new Patre­on site. Vis­it at: Patreon.com/DaveEmory

FTR#1292 This pro­gram was record­ed in one, 60-minute seg­ment.

FTR#1293 This pro­gram was record­ed in one, 60-minute seg­ment.

Intro­duc­tion: This descrip­tion opens with an unchar­ac­ter­is­tic qual­i­fi­ca­tion and apol­o­gy: There are two ele­ments of the titles of each of these pro­grams that were not ade­quate­ly explained in the broad­casts them­selves, although they are implic­it in the sub­ject mate­r­i­al.

The term “North­woods Virus” is more com­plete­ly pre­sent­ed in FTR#1215. Among the appar­ent goals of the “Covid Oper­a­tion” that pro­duced SARS CoV‑2 is the turn­ing of Amer­i­can pub­lic opin­ion against Chi­na. Oper­a­tion North­woods was a plan hatched by the Join Chiefs of Staff in the ear­ly 1960’s to stage appar­ent ter­ror­ist inci­dents against Amer­i­can civil­ian and mil­i­tary per­son­nel and infra­struc­ture in order to manip­u­late pub­lic opin­ion in this coun­try and gen­er­ate sen­ti­ment for an inva­sion of Cuba.

The sec­ond pro­gram refers to the Biden Pres­i­den­cy as “Satan­ic,” because behind a stu­dious­ly con­struct­ed façade of iden­ti­ty pol­i­tics, “Team Biden” is pur­su­ing an overt­ly war­like, impe­ri­al­ist agen­da that was accu­rate­ly char­ac­ter­ized by writer Hen­ry Miller in his nov­el Trop­ic of Can­cer: “Amer­i­ca is the very incar­na­tion of doom, and she will lead the rest of the world into the Bot­tom­less Pit.”

Per­haps the most insid­i­ous of Biden’s pro­grams is his “Can­cer Moon­shot.”

Omi­nous­ly, it may well be the suc­ces­sor to Richard Nixon’s “War on Can­cer,” which did not defeat can­cer, but did serve as the appar­ent plat­form for the devel­op­ment of bio­log­i­cal war­fare weapons, AIDS in par­tic­u­lar.

Mod­eled after DARPA, head­ed by a DARPA alum­na whose CV inter­sects with that Agency’s appar­ent involve­ment with the devel­op­ment of Covid-19 and with an act­ing direc­tor who is also a for­mer employ­ee of that benight­ed orga­ni­za­tion, this new health agencyARPA‑H, this agency will employ new, syn­thet­ic biol­o­gy tech­nol­o­gy.

Although that devel­op­ment is rep­re­sent­ed as human­i­tar­i­an, the struc­ture of the agency and the nation­al secu­ri­ty back­grounds of its lead­ing per­son­nel sug­gest strong­ly that this agency, too, will serve as a clan­des­tine plat­form for the next gen­er­a­tion of bio­log­i­cal weapon­ry.

We begin FTR#1292 with a reprise of the audio from a (now delet­ed) 55-sec­ond video of Dr. Jef­frey Sachs sum­ma­riz­ing his two-year stew­ard­ship of The Lancet’s com­mis­sion inves­ti­gat­ing the ori­gins of SARS CoV‑2.

Sachs stat­ed that he is “pret­ty con­vinced” it came from a U.S. bio­log­i­cal lab­o­ra­to­ry.

Next, we recap a study released by US Nation­al Acad­e­my of Sci­ences at the request of the Depart­ment of Defense about the threats of syn­thet­ic biol­o­gy con­clud­ed that the tech­niques to tweak and weaponize virus­es from known cat­a­logs of viral sequences is very fea­si­ble and rel­a­tive­ly easy to do.

One of the cen­tral points Mr. Emory has made about the gen­e­sis of the coro­n­avirus con­cerns the legal prin­ci­ple of “con­scious­ness of guilt.”

Going a long way toward prov­ing con­scious­ness of guilt are:

  1. The clas­si­fi­ca­tion of infor­ma­tion about the nature of the bio­log­i­cal agents involved with the CDC’s clo­sure of the Unit­ed States Army’s Med­ical Insti­tute of Infec­tious Dis­ease in ear­ly August of 2019, on the eve of the pan­dem­ic.
  2. The behav­ior of Peter Daszak and col­leagues in “gam­ing” the Lancet state­ment on the “nat­ur­al” ori­gin of the coro­n­avirus (Dasza­k’s Eco­Health Alliance–fund­ed and advised by the nation­al secu­ri­ty estab­lish­ment–is impli­cat­ed in the cre­ation of the SARS COV‑2.) Note that the Eco­Health Alliance was syn­the­siz­ing “nov­el coro­n­avirus­es” at this point in time, an impor­tant fac­tor to remem­ber when eval­u­at­ing the Metabiota/Munich Re busi­ness mod­el being pre­sent­ed in 2018. (See #4 pre­sent­ed below.)
  3. The reac­tion of gov­ern­ment offi­cials to Trump admin­is­tra­tion fig­ures into the ori­gins of the virus, advis­ing would be inves­ti­ga­tors that such inquiries would open a “can of worms,” or “a Pan­do­ra’s Box” because it would should light on U.S. fund­ing of the projects.
  4. Metabiota–partnered with Eco­Health Alliance–was net­worked with In-Q-Tel (the intel­li­gence com­mu­ni­ty’s ven­ture cap­i­tal arm) and Munich Re to pro­vide pan­dem­ic insur­ance. Their 2018 busi­ness mod­el direct­ly fore­shad­owed the pan­dem­ic. “ . . . . Just two years ear­li­er, the com­pa­ny had run a large set of sce­nar­ios fore­cast­ing the con­se­quences of a nov­el coro­n­avirus spread­ing around the globe. . . . Mea­sures that decreased per­son-to-per­son con­tact, includ­ing social dis­tanc­ing, quar­an­tine, and school clo­sures, had the great­est cost per death pre­vent­ed, most like­ly because of the amount of eco­nom­ic dis­rup­tion caused by those mea­sures . . . .”  In 2018, as well, Eco­Health Alliance pro­posed a nov­el coro­n­avirus” for syn­the­sis by DARPA. Although there is no evi­dence that DARPA syn­the­sized the virus, the U.S. did syn­the­size close­ly relat­ed virus­es. With the genome of that nov­el virus hav­ing been pub­lished, it may well have been syn­the­sized either by DARPA or some­one else, giv­en the con­tem­po­rary tech­nol­o­gy. Again, this, also was in 2018.
  5. Many aspects of the SARS COV‑2 virus, includ­ing its curi­ous FCS site and insti­tu­tion­al­ized obfus­ca­tion of aspects of the pan­dem­ic it caused sug­gest delib­er­ate cov­er-up. Why would the NIH redact 290 pages of a doc­u­ment request­ed by an FOIA suit!! Why were sequences of bat coro­n­avirus genomes removed from pub­lic view.

The pro­gram fea­tures a recap of some of the more impor­tant arti­cles in the long series on the coro­n­avirus, fol­lowed by dis­cus­sion of the Ener­gy Department’s con­clu­sion that the coro­n­avirus escaped from a Chi­nese lab­o­ra­to­ry.

Excel­lent analy­sis pre­sent­ed by the Moon of Alaba­ma blog notes that the Wall Street Jour­nal arti­cle break­ing the “news” about the Ener­gy Department’s con­clu­sion was co-authored by Michael R. Gor­don, who trum­pet­ed the “Lab Leak” meme in the spring of 2021.

In a pre­vi­ous jour­nal­is­tic incar­na­tion, Gor­don helped gen­er­ate enthu­si­asm for the inva­sion of Iraq by par­rot­ing the dis­in­for­ma­tion about Sad­dam Hus­sein hav­ing WMD’s.

Sur­pris­ing to Moon of Alaba­ma but not to us is Edward Snowden’s endorse­ment of the Lab Leak Hypoth­e­sis.

Far from being the “hero” Snow­den has made out to be, Snow­den is an extreme right-winger, whose work on cyber-secu­ri­ty appears to be the work of a con­scious dou­ble agent. (We have cov­ered Snowden’s escapades in numer­ous pro­grams over the years, par­tic­u­lar­ly FTR#’s 1078-1081.)

For the con­ve­nience of the lis­ten­er, we recap a 2001 arti­cle dis­cussing the all-encom­pass­ing scope of U.S. elec­tron­ic snooping—an arti­cle that reveals the depth of Snowden’s duplic­i­ty.

In addi­tion to touch­ing on a sto­ry of a recent­ly-released book about the Coro­n­avirus being syn­the­sized as part of a U.S. bio­log­i­cal war­fare pro­gram, the pro­gram recaps the Biden administration’s cre­ation of a “Med­ical DARPA.”

Fol­low­ing dis­cus­sion of Moderna’s delib­er­ate with­hold­ing of data from reg­u­la­tors about its new biva­lent mRNA vac­cine, we note a study that indi­cates that new, dead­ly vari­ants of Covid that could over­whelm the health­care sys­tem are a dis­tinct pos­si­bil­i­ty.

Of great sig­nif­i­cance is analy­sis of a diplo­mat­ic break­through engi­neered by Chi­na. Bro­ker­ing a rap­proche­ment between Iran and Sau­di Ara­bia in the Mid­dle East, Chi­na has helped to re-set the polit­i­cal land­scape of the Mid­dle East.

As not­ed by M.K. Bhadraku­mar, the realign­ment may sig­nal a demise of the dol­lar as the glob­al reserve cur­ren­cy of choice. IF such a devel­op­ment ensues, it will prove dev­as­tat­ing to America’s impe­r­i­al sta­tus, cur­tail­ing the mil­i­tary indus­tri­al com­plex in par­tic­u­lar.

Mr. Emory express­es his great fear that this will not be allowed to develop—the above-men­tioned “Can­cer Moon­shot” and lethal, syn­the­sized micro-organ­isms and pan­demics will very like­ly be the Amer­i­can answer to the long-term eco­nom­ic and polit­i­cal impli­ca­tions of the Chi­nese diplo­mat­ic coup.

1a. We begin with a reprise of the audio from a (now delet­ed) 55-sec­ond video of Dr. Jef­frey Sachs sum­ma­riz­ing his two-year stew­ard­ship of The Lancet’s com­mis­sion inves­ti­gat­ing the ori­gins of SARS CoV‑2.

Sachs stat­ed that he is “pret­ty con­vinced” it came from a U.S. bio­log­i­cal lab­o­ra­to­ry.

This same audio clip con­cludes FTR#1293.

1b. A study released by US Nation­al Acad­e­my of Sci­ences at the request of the Depart­ment of Defense about the threats of syn­thet­ic biol­o­gy con­clud­ed that the tech­niques to tweak and weaponize virus­es from known cat­a­logs of viral sequences is very fea­si­ble and rel­a­tive­ly easy to do:

“Syn­thet­ic biol­o­gy rais­es risk of new bioweapons, US report warns” by Ian Sam­ple; The Guardian; 06/19/2018

The rapid rise of syn­thet­ic biol­o­gy, a futur­is­tic field of sci­ence that seeks to mas­ter the machin­ery of life, has raised the risk of a new gen­er­a­tion of bioweapons, accord­ing a major US report into the state of the art. . . .

“ . . . Advances in the area mean that sci­en­tists now have the capa­bil­i­ty to recre­ate dan­ger­ous virus­es from scratch; make harm­ful bac­te­ria more dead­ly; and mod­i­fy com­mon microbes so that they churn out lethal tox­ins once they enter the body. . . In the report, the sci­en­tists describe how syn­thet­ic biol­o­gy, which gives researchers pre­ci­sion tools to manip­u­late liv­ing organ­isms, ‘enhances and expands’ oppor­tu­ni­ties to cre­ate bioweapons. . . . Today, the genet­ic code of almost any mam­malian virus can be found online and syn­the­sised. ‘The tech­nol­o­gy to do this is avail­able now,’ said [Michael] Impe­ri­ale. “It requires some exper­tise, but it’s some­thing that’s rel­a­tive­ly easy to do, and that is why it tops the list. . . .”

2a.  Going a long way toward prov­ing con­scious­ness of guilt are:

  1. The clas­si­fi­ca­tion of infor­ma­tion about the nature of the bio­log­i­cal agents involved with the CDC’s clo­sure of the Unit­ed States Army’s Med­ical Insti­tute of Infec­tious Dis­ease in ear­ly August of 2019, on the eve of the pan­dem­ic.
  2. The behav­ior of Peter Daszak and col­leagues in “gam­ing” the Lancet state­ment on the “nat­ur­al” ori­gin of the coro­n­avirus (Dasza­k’s Eco­Health Alliance–funded and advised by the nation­al secu­ri­ty establishment–is impli­cat­ed in the cre­ation of the SARS COV‑2.)
  3. The reac­tion of gov­ern­ment offi­cials to Trump admin­is­tra­tion fig­ures into the ori­gins of the virus, advis­ing would be inves­ti­ga­tors that such inquiries would open a “can of worms,” or “a Pan­do­ra’s Box” because it would should light on U.S. fund­ing of the projects.
  4. Metabiota–partnered with Eco­Health Alliance–was net­worked with In-Q-Tel (the intel­li­gence com­mu­ni­ty’s ven­ture cap­i­tal arm) and Munich Re to pro­vide pan­dem­ic insur­ance. Their 2018 busi­ness mod­el direct­ly fore­shad­owed the pan­dem­ic. “ . . . . Just two years ear­li­er, the com­pa­ny had run a large set of sce­nar­ios fore­cast­ing the con­se­quences of a nov­el coro­n­avirus spread­ing around the globe. . . . Mea­sures that decreased per­son-to-per­son con­tact, includ­ing social dis­tanc­ing, quar­an­tine, and school clo­sures, had the great­est cost per death pre­vent­ed, most like­ly because of the amount of eco­nom­ic dis­rup­tion caused by those mea­sures . . . .”  In 2018, as well, Eco­Health Alliance pro­posed a “nov­el coro­n­avirus” for syn­the­sis by DARPA. Although there is no evi­dence that DARPA syn­the­sized the virus, the U.S. did syn­the­size close­ly relat­ed virus­es. With the genome of that nov­el virus hav­ing been pub­lished, it may well have been syn­the­sized either by DARPA or some­one else, giv­en the con­tem­po­rary tech­nol­o­gy. Again, this, also was in 2018.
  5. Many aspects of the SARS COV‑2 virus, includ­ing its curi­ous FCS site and insti­tu­tion­al­ized obfus­ca­tion of aspects of the pan­dem­ic it caused sug­gest delib­er­ate cov­er-up. Why would the NIH redact 290 pages of a doc­u­ment request­ed by an FOIA suit!! Why were sequences of bat coro­n­avirus genomes removed from pub­lic view.

2b.

3a.“Ener­gy Dept. Sus­pects Virus Was From Lab” by Julian E. Barnes; The New York Times; 2/27/2023; pp. A1-A7 [West­ern Print Edi­tion].

3b.“U.S. Find­ing On Covid Draws Fire From Chi­na” by David Pier­son; The New York Times; 2/28/2023; p. A6  [West­ern Print Edi­tion].

. . . . Chi­na has also sought to deflect blame for the pan­dem­ic by spread­ing a con­spir­a­cy the­o­ry that the virus may have been the result of research at a U.S. mil­i­tary lab at Fort Det­rick, Md. The claim, which was first made in March 2020 was repeat­ed by a for­eign min­istry spokesman as recent­ly as this month.

At the Ener­gy Depart­ment, new intel­li­gence prompt­ed it to change its posi­tion from being unde­cid­ed about how the virus emerged. Offi­cials did not share that intel­li­gence but said the agency made its con­clu­sion with only “low con­fi­dence.” . . . . [Ital­ics are Mr. Emory’s]

4.“This Debate Hasn’t Made Us Safer” by David Wal­lace-Wells; The New York Times; 3/5/2023.

5.“Was the Pen­ta­gon and CIA Behind the COVID-19 Pan­dem­ic?” by Jere­my Kuz­marov; Covert Action Mag­a­zine; 2/27/2023.

Bioter­ror­ism expert and whistle­blow­er alleges that CIA secret­ly col­lab­o­rat­ed in sup­port­ing uneth­i­cal gain of func­tion research that result­ed in the man­u­fac­ture of the COVID-19 virus, which was then leaked from the Wuhan Insti­tute of Virol­o­gy.

Dr. Andrew G. Huff is an Iraq War vet­er­an and infec­tious dis­ease epi­demi­ol­o­gist with a Ph.D. from the Uni­ver­si­ty of Min­neso­ta who, in Sep­tem­ber 2014, went to work for Eco­Health Alliance, an NGO that received over $118 mil­lion in grants from fed­er­al agen­cies whose mis­sion was to pro­tect the pub­lic from infec­tious dis­eases.

In a new book, The Truth About Wuhan: How I Uncov­ered the Biggest Lie in His­to­ry (New York: Sky­horse Press, 2022), Huff claims that his boss at Eco­Health Alliance, Dr. Peter Daszak, was work­ing with the CIA and that begin­ning in 2012, he over­saw the devel­op­ment of the bio­log­i­cal agent known as SARS-CoV­‑2 that results in the dis­ease COVID-19.

The devel­op­ment occurred through Gain-of-Func­tion research fund­ed by the Unit­ed States Agency for Inter­na­tion­al Devel­op­ment (USAID) and the Nation­al Insti­tutes of Health (NIH).[1]

Accord­ing to Huff, Dr. Daszak and Dr. Antho­ny Fau­ci, Direc­tor of the Nation­al Insti­tute of Aller­gy and Infec­tious Dis­eases from 1984 until his retire­ment in Decem­ber 2022, along with oth­er col­leagues, “behaved like a pseu­do­science mafia entrenched in the halls of the med­ical mil­i­tary indus­tri­al com­plex.”[2]

They not only engi­neered the COVID-19 pan­dem­ic but “crim­i­nal­ly con­spired to smear” any­one who did not sup­port their narrative—including Huff who was sub­ject­ed to a cam­paign of FBI sur­veil­lance and harass­ment that near­ly result­ed in his death.

Engi­neer­ing a Dead­ly Virus—and a Vac­cine to Alleged­ly Com­bat It

One of the first tasks that Dr. Huff under­took while work­ing at Eco­Health Alliance was to review an NIH pro­pos­al titled “Under­stand­ing the Risk of Bat Coro­n­avirus Emer­gence,” writ­ten by Dr. Daszak with Zhengli Shi of the Wuhan Insti­tute of Virol­o­gy (WIV) and some oth­er sci­en­tists.

The study had the sup­port of “the grand­fa­ther of Gain-of-Func­tion research,” Dr. Ralph Bar­ic, a virol­o­gist at the Uni­ver­si­ty of North Carolina’s Gillings School of Pub­lic Health, which ranks third in NIH fund­ing. (Accord­ing to Huff, “Fau­ci has been [the school’s] de fac­to Don for decades.”[3])

The pro­pos­al advo­cat­ed for study­ing peo­ple in rur­al Chi­na who may have come into con­tact with bats that spread the Coro­n­avirus among humans and to screen for the virus with the goal of being able to bet­ter pre­dict Coro­n­avirus trans­mis­sion. It fur­ther aimed to devel­op new Coro­n­avirus strains and per­form exper­i­ments that would enhance the abil­i­ty of bat coro­n­avirus to infect human cells and lab­o­ra­to­ry ani­mals using tech­niques of genet­ic engi­neer­ing.[4]

This study fit the def­i­n­i­tion of Gain-of-Func­tion research, whose aim is to “pur­pose­ful­ly enhance the path­o­genic­i­ty, infec­tiv­i­ty, vir­u­lence, sur­viv­abil­i­ty or trans­mis­si­bil­i­ty of an infec­tious agent,” as Huff defines it, or put more sim­ply, “make an infec­tious agent more dan­ger­ous.”[5]

On Octo­ber 17, 2014, the Oba­ma admin­is­tra­tion declared a mora­to­ri­um on Gain-of-Func­tion research relat­ed to influen­za, Mid­dle East res­pi­ra­to­ry syn­drome (MERS) and severe acute res­pi­ra­to­ry syn­drome (SARS) after an acci­dent at the U.S. Cen­ter for Dis­ease Con­trol and Pre­ven­tion (CDC).

Dr. Fau­ci sub­se­quent­ly out­sourced the Gain-of-Func­tion research to China’s Wuhan lab and licensed the lab to con­tin­ue receiv­ing U.S. gov­ern­ment fund­ing. The mora­to­ri­um on Gain-of-Func­tion research was lift­ed by the Trump admin­is­tra­tion in Decem­ber 2017, and Dr. Fau­ci sent $3.7 mil­lion from the Nation­al Insti­tute of Aller­gy and Infec­tious Dis­eases to the Wuhan Insti­tute of Virol­o­gy to restart the coro­n­avirus bat project.

By try­ing to make bats capa­ble of infect­ing human cells, Huff came to believe that his employ­er was involved not only in uneth­i­cal Gain-of-Func­tion but also bioweapons research. Its end result was “the cre­ation of SARS-CoV­‑2,” which “caus­es the dis­ease known as COVID-19.”[6]

Accord­ing to Huff, the infec­tious agent SARS-CoV­‑2 and the COVID-19 mRNA vaccine—which Huff char­ac­ter­izes as gene therapy—were co-devel­oped under the same research pro­gram.[7]

Huff writes that Eco­Health Alliance used Dr. Baric’s work for test­ing exper­i­men­tal vac­cines, treat­ments and ther­a­peu­tics against the new­ly engi­neered SARS-CoV­‑2 strain years before COVID-19 was known to the pub­lic to deter­mine which coun­ter­mea­sures would be most effec­tive at mit­i­gat­ing the dis­ease in human­ized mice.[8] . . . . 

6. Among those par­rot­ing the Ener­gy Depart­men­t’s line on the Wuhan “Lab Leak” meme is Edward Snow­den. In, among oth­er pro­grams, FTR#‘s 1075 through 1081, we not­ed not only that the Inter­net was devel­oped for “coun­terin­sur­gency pur­pos­es”

“Edward Snow­den Signs On To Dis­trib­ute U.S. Gov Pro­pa­gan­da;” Moon of Alaba­ma; 2/27/2023.

Edward, you are an idiot.

Edward Snow­den @Snowden — 15:36 UTC · Feb 26, 2023

Do you remem­ber the “insti­tu­tion­al” and social media cor­po response in the first half of 2020 when some­one con­tra­dict­ed the con­sen­sus? They were pun­ished for the “crime” of “dis­in­for­ma­tion.”

Cor­po­ra­tions must nev­er again be per­mit­ted to police speech.

wsj.com
WSJ News Exclu­sive | Lab Leak Most Like­ly Ori­gin of Covid-19 Pan­dem­ic, U.S. Agency Now Says
The Ener­gy Department’s revised assess­ment of how the pan­dem­ic start­ed is based on new intel­li­gence.

Moon of Alaba­ma @MoonofA — 16:05 UTC · Feb 26, 2023

How is the U.S. Ener­gy Depart­ment (which is the ‘intel­li­gence’ here) qual­i­fied to make such con­clu­sions? Is Michael A. Gor­don, famous for Iraq WMD claims, an author qual­i­fied to write more than garbage?

Quot­ed Tweet
Edward Snow­den @Snowden · 14h
Do you remem­ber the “insti­tu­tion­al” and social media cor­po response in the first half of 2020 when some­one con­tra­dict­ed the con­sen­sus? They were pun­ished for the “crime” of “dis­in­for­ma­tion.”

Cor­po­ra­tions must nev­er again be per­mit­ted to police speech.
https://wsj.com/articles/covid-origin-china-lab-leak-807b7b0a

chi­na­hand @chinahand — 17:52 UTC · Feb 26, 2023

to recap the actu­al state of play: mean­ing­less DoE report gets leaked to journos so cre­den­tialed cretins can assist USG in mak­ing anti-Chi­na hay. Got­ta change the name to “less than zero media”

Caitlin John­stone @caitoz — 11:35 UTC · Feb 27, 2023

It’s the same guy. IT’S THE SAME FUCKING GUY.

Quot­ed Tweet
Mark Ames @MarkAmesExiled — 13h
DC’s Chi­na War lob­by dust­ing off their Iraq WMD tool to revive lab leak the­o­ry

The new ‘report’:

Lab Leak Most Like­ly Ori­gin of Covid-19 Pan­dem­ic, Ener­gy Depart­ment Now Says
U.S. agency’s revised assess­ment is based on new intel­li­gence
By Michael R. Gor­don and War­ren P. Stro­bel
Updat­ed Feb. 26, 2023 4:29 pm ET

The U.S. Ener­gy Depart­ment has con­clud­ed that the Covid pan­dem­ic most like­ly arose from a lab­o­ra­to­ry leak, accord­ing to a clas­si­fied intel­li­gence report recent­ly pro­vid­ed to the White House and key mem­bers of Con­gress.
...
The Ener­gy Depart­ment made its judg­ment with “low con­fi­dence,” accord­ing to peo­ple who have read the clas­si­fied report.
...
U.S. offi­cials declined to give details on the fresh intel­li­gence and analy­sis that led the Ener­gy Depart­ment to change its posi­tion.
...
The Nation­al Intel­li­gence Coun­cil, which con­ducts long-term strate­gic analy­sis, and four agen­cies, which offi­cials declined to iden­ti­fy, still assess with “low con­fi­dence” that the virus came about through nat­ur­al trans­mis­sion from an infect­ed ani­mal, accord­ing to the updat­ed report.

Pre­vi­ous­ly:

THREATS AND RESPONSES: THE IRAQIS; U.S. SAYS HUSSEIN INTENSIFIES QUEST FOR A‑BOMB PARTS
By Michael R. Gor­don and Judith Miller
Sept. 8, 2002

More than a decade after Sad­dam Hus­sein agreed to give up weapons of mass destruc­tion, Iraq has stepped up its quest for nuclear weapons and has embarked on a world­wide hunt for mate­ri­als to make an atom­ic bomb, Bush admin­is­tra­tion offi­cials said today.

In the last 14 months, Iraq has sought to buy thou­sands of spe­cial­ly designed alu­minum tubes, which Amer­i­can offi­cials believe were intend­ed as com­po­nents of cen­trifuges to enrich ura­ni­um. Amer­i­can offi­cials said sev­er­al efforts to arrange the ship­ment of the alu­minum tubes were blocked or inter­cept­ed but declined to say, cit­ing the sen­si­tiv­i­ty of the intel­li­gence, where they came from or how they were stopped.
...
While there is no indi­ca­tion that Iraq is on the verge of deploy­ing a nuclear bomb, Iraq’s pur­suit of nuclear weapons has been cit­ed by hard-lin­ers in the Bush admin­is­tra­tion to make the argu­ment that the Unit­ed States must act now, before Mr. Hus­sein acquires nuclear arms and thus alters the strate­gic bal­ance in the oil-rich Per­sian Gulf.
...
Hard-lin­ers are alarmed that Amer­i­can intel­li­gence under­es­ti­mat­ed the pace and scale of Iraq’s nuclear pro­gram before Bagh­dad’s defeat in the gulf war. Con­scious of this lapse in the past, they argue that Wash­ing­ton dare not wait until ana­lysts have found hard evi­dence that Mr. Hus­sein has acquired a nuclear weapon. The first sign of a ”smok­ing gun,” they argue, may be a mush­room cloud.

7. The year-long inves­ti­ga­tion con­clud­ed just before the 9/11/attacks. [The NSA/GCHQ vac­u­um clean­ing pre­dates 9/11–D.E.] The Euro­pean Par­lia­men­tary com­mis­sion con­clud­ed that many oth­er Euro­pean coun­tries had the same capa­bil­i­ty.

“World Brief­ing | Europe: Report On U.S. Spy Sys­tem” by Suzanne Daley; The New York Times; 9/6/2001.

[Notice when this was published–9/6/2001.–D.E.] . . . The Unit­ed States-led spy­ing sys­tem known as Ech­e­lon can mon­i­tor vir­tu­al­ly every com­mu­ni­ca­tion in the world — by e‑mail, phone or fax — that bounces off a satel­lite, the Euro­pean Par­lia­ment was told. But in report­ing on a year­long study of the sys­tem that was prompt­ed by con­cern that Amer­i­can com­pa­nies were using data from the sys­tem to gain a com­pet­i­tive edge, Ger­hard Schmid, a Ger­man mem­ber of the Par­lia­ment, said that many Euro­pean coun­tries had sim­i­lar abil­i­ties . . .

8. It appears that the FDA, CDC, and Mod­er­na all col­lud­ed to with­hold data from these advi­so­ry pan­els the Mod­er­na had already gath­ered indi­cat­ing that the biva­lent COVID boost­ers are pos­si­bly less effec­tive at pre­vent an infec­tion than the orig­i­nal mRNA vac­cine for­mu­la­tion.

Yep, first the FDA held a day-long meet­ing on June 28 with a pan­el of inde­pen­dent experts about the new boost­ers. The pres­i­dent of Mod­er­na was also invit­ed to present to the pan­el and shared the results of a new Mod­er­na study that had just been preprint­ed (non-peer reviewed) three days before the meet­ing. The study showed the new biva­lent vac­cine elicit­ed high­er anti­body lev­els. But also high­er infec­tion rates. The high­er anti­body lev­els were excit­ed­ly shared to the pan­el. Noth­ing about the high­er infec­tion rates was shared.

So why didn’t the FDA share this info about high­er infec­tion rates with the pan­el? The FDA was aware of Moderna’s preprint­ed study, after all. We’ll we’re told that the FDA just didn’t have enough time to review it. That’s the excuse giv­en for how Moderna’s pres­i­dent was allowed to selec­tive­ly share results with the pan­el and the FDA leav­ing the pan­elists in the dark.

The FDA ulti­mate­ly approved the biva­lent boost­ers on August 31. The next day, the CDC held an inde­pen­dent pan­el of its own to review the new biva­lent boost­ers. Again, peo­ple from Mod­er­na were there to selec­tive­ly present how the new boost­ers result­ed in high­er anti­body lev­els while leav­ing out the data about the high­er infec­tion rates entire­ly. On Sep­tem­ber 13, the FDA final­ly pub­lished the data it based its approval on, includ­ing the infec­tion data. So the FDA only pub­licly released the data from Mod­er­na show­ing pos­si­bly low­er effi­ca­cy for the new boost­ers only after the CDC’s pan­el gave its own stamp of approval with­out know­ing about the low­er effi­ca­cy find­ings.

So what was the CDC’s excuse for keep­ing the pan­el in the dark? Well, accord­ing to the CDC spokesper­son, the “CDC was aware” of the data that would lat­er be pub­lished in The New Eng­land Jour­nal of Med­i­cine. Also, they added that assess­ing infec­tions was an “explorato­ry objec­tive of the study,” which was “not designed to assess vac­cine effec­tive­ness.” It’s not exact­ly a com­pelling excuse. Final­ly, they point­ed out that in assess­ing infec­tions, “researchers used dif­fer­ent dura­tions and points in time among a very small group of peo­ple,” and because of the lim­i­ta­tions of the data, it was not fea­tured at the meet­ing. In oth­er words, the Mod­er­na study was poor­ly-pow­ered crap.

Which is was by all indi­ca­tions. And that’s part of the sto­ry here: Moderna’s poor­ly-pow­ered crap study was appar­ent­ly fine for use when it increased the chances of the vac­cines get­ting approved. But when it comes to the data show­ing reduced effec­tive­ness we can just ignore it because of the poor sta­tis­ti­cal pow­er. It’s all quite con­ve­nient. Con­ve­nient for Mod­er­na and any Mod­er­na super-fans that inhab­it the fed­er­al reg­u­la­to­ry bureau­cra­cy. As Dr. Paul Offit, one of the inde­pen­dent experts who is now livid over this scan­dal, put it, his faith in the whole approval process has been shak­en. Which should raise plen­ty of ques­tions for the rest of us:

“FDA vac­cine advis­ers ‘dis­ap­point­ed’ and ‘angry’ that ear­ly data about new Covid-19 boost­er shot wasn’t pre­sent­ed for review last year” by Eliz­a­beth Cohen and Nao­mi Thomas; CNN; 01/11/2023.

Some vac­cine advis­ers to the fed­er­al gov­ern­ment say they’re “dis­ap­point­ed” and “angry” that gov­ern­ment sci­en­tists and the phar­ma­ceu­ti­cal com­pa­ny Mod­er­na didn’t present a set of infec­tion data on the company’s new Covid-19 boost­er dur­ing meet­ings last year when the advis­ers dis­cussed whether the shot should be autho­rized and made avail­able to the pub­lic.

That data sug­gest­ed the pos­si­bil­i­ty that the updat­ed boost­er might not be any more effec­tive at pre­vent­ing Covid-19 infec­tions than the orig­i­nal shots.

The data was ear­ly and had many lim­i­ta­tions, but sev­er­al advis­ers told CNN that they were con­cerned about a lack of trans­paren­cy.

US tax­pay­ers spent near­ly $5 bil­lion on the new boost­er, which has been giv­en to more than 48.2 mil­lion peo­ple in the US.

“I was angry to find out that there was data that was rel­e­vant to our deci­sion that we didn’t get to see,” said Dr. Paul Offit, a mem­ber of the Vac­cines and Relat­ed Bio­log­i­cal Prod­ucts Advi­so­ry Com­mit­tee, a group of exter­nal advis­ers that helps the FDA make vac­cine deci­sions. “Deci­sions that are made for the pub­lic have to be made based on all avail­able infor­ma­tion – not just some infor­ma­tion, but all infor­ma­tion.”

At a meet­ing of this FDA advi­so­ry group in June and a meet­ing in Sep­tem­ber of a pan­el that advis­es the US Cen­ters for Dis­ease Con­trol and Pre­ven­tion, the experts were pre­sent­ed with reams of infor­ma­tion indi­cat­ing that the new vac­cine worked bet­ter than the one already on shelves, accord­ing to a review of videos and tran­scripts of those meet­ings and slide pre­sen­ta­tions made by Mod­er­na, CDC and FDA offi­cials.

That data – called immuno­genic­i­ty data – was based on blood work done on study par­tic­i­pants to assess how well each vac­cine elicit­ed anti­bod­ies that fight off the Omi­cron strain of the virus that caus­es Covid-19.

The data that was not pre­sent­ed to the experts looked at actu­al infec­tions: who caught Covid-19 and who did not.

It found that 1.9% of the study par­tic­i­pants who received the orig­i­nal boost­er became infect­ed. Among those who got the updat­ed biva­lent vac­cine – the one that sci­en­tists hoped would work bet­ter – a high­er per­cent­age, 3.2%, became infect­ed. Both ver­sions of the shot were found to be safe.

This infec­tion data was far from com­plete. The num­ber of study sub­jects who became infect­ed was very small, and both the patients and the researchers were aware of who was get­ting the orig­i­nal shot and who was get­ting the new boost­er.

Despite these imper­fec­tions, the data was includ­ed in a preprint study that was post­ed online in June, again in Sep­tem­ber in an FDA doc­u­ment and then lat­er that month in a top med­ical jour­nal – and advis­ers to the FDA and the CDC said the data should have been shared with them, too.

“It’s not a group of chil­dren. We under­stand how to inter­pret these results,” said Dr. Eric Rubin, a mem­ber of the FDA vac­cine advi­so­ry com­mit­tee.

The six FDA and CDC advis­ers inter­viewed by CNN said that this infec­tion data wouldn’t have changed how they vot­ed, because the data had such lim­i­ta­tions, but it still should have been pre­sent­ed to them.

“There should always be full trans­paren­cy,” said Dr. Arnold Mon­to, a pro­fes­sor of epi­demi­ol­o­gy at the Uni­ver­si­ty of Michi­gan School of Pub­lic Health and act­ing chair of the FDA advis­ers’ group. “These data should not be dis­missed. They are ear­ly, but they indi­cate that we need to look at them and see what their val­ue is.”

Dr. Pablo Sanchez, a mem­ber of the CDC’s pan­el, called the Advi­so­ry Com­mit­tee on Immu­niza­tion Prac­tices, said that if the data “was looked at as part of the study, it should have been pre­sent­ed to the advis­ers pri­or to their deci­sion.”

The FDA and the CDC con­vene their advi­so­ry board meet­ings and make pre­sen­ta­tions to the advis­ers. At last year’s meet­ings, Mod­er­na exec­u­tives made pre­sen­ta­tions, as well. The advis­ers then make their rec­om­men­da­tions to the agen­cies, and the agen­cies decide whether to autho­rize the shots and rec­om­mend them to the pub­lic.

Mod­er­na spokesman Christo­pher Rid­ley said in an email to CNN that the com­pa­ny shared the infec­tion data with the FDA and post­ed the study man­u­script before the agency’s pan­el meet­ing in June “in response to requests that we share an update from the ongo­ing study.”

That study preprint was post­ed online June 25, three days before the FDA advis­ers met.

Michael Fel­ber­baum, an FDA spokesman, told CNN in an email that “the FDA received the preprint less than a day pri­or to the advi­so­ry com­mit­tee meet­ing,” and “the infor­ma­tion was there­fore not pro­vid­ed in an ade­quate time­frame for it to be includ­ed in the agency’s meet­ing mate­ri­als, and gen­er­al­ly the FDA only dis­cuss­es data at advi­so­ry com­mit­tee meet­ings that the agency has had the oppor­tu­ni­ty to sub­stan­tive­ly review.”

“Numer­ous stud­ies sup­port the find­ing that the COVID-19 vac­cines remain the best defense against the most dev­as­tat­ing con­se­quences of COVID-19 such as hos­pi­tal­iza­tion and death, and that the updat­ed vac­cines may help pro­vide bet­ter pro­tec­tion against the cur­rent­ly cir­cu­lat­ing vari­ants,” Fel­ber­baum wrote.

He added that “through­out the pan­dem­ic, the FDA has remained as trans­par­ent as pos­si­ble regard­ing its process­es and deci­sion-mak­ing regard­ing the COVID-19 vac­cines” and that Mod­er­na could have cho­sen to present the data at the FDA advi­so­ry com­mit­tee meet­ing.

Kris­ten Nord­lund, a CDC spokes­woman, said that “due to the many lim­i­ta­tions involv­ing this clin­i­cal data, it was not fea­tured” in the CDC’s advi­so­ry com­mit­tee dis­cus­sion.

Empha­sis on trans­paren­cy

The advis­ers said there are three main rea­sons why it mat­ters that the infec­tion data was not pre­sent­ed to them.

One, they said, is the poten­tial impact of their deci­sion: If Amer­i­cans were going to be get­ting these shots, all avail­able data should be brought to the table for con­sid­er­a­tion.

Two, the advi­so­ry com­mit­tee meet­ings are streamed live online, and reg­u­la­to­ry agen­cies around the world use the infor­ma­tion to help make deci­sions about vac­cines in their coun­tries.

Three, they stressed that trans­paren­cy is impor­tant. The pub­lic doesn’t wit­ness con­ver­sa­tions among FDA offi­cials or between agency offi­cials and phar­ma­ceu­ti­cal com­pa­ny exec­u­tives, but they do get to watch the advi­so­ry pan­els’ pro­ceed­ings.

Infec­tion data not includ­ed in pre­sen­ta­tions by FDA and Mod­er­na

Last sum­mer, as the FDA’s and CDC’s out­side advis­ers con­sid­ered the updat­ed boost­ers, the stakes were high. They knew that in just a mat­ter of months, win­ter would be approach­ing, and Covid rates could spike. They also knew the orig­i­nal vac­cine was get­ting less effec­tive with each new vari­ant and that the addi­tion of the Omi­cron strain in the updat­ed boost­er might help bat­tle the virus.

The FDA advis­ers – 21 vot­ing mem­bers, includ­ing infec­tious dis­ease experts and vac­ci­nol­o­gists from Stan­ford, the Uni­ver­si­ty of Penn­syl­va­nia and Har­vard – met for a full day on June 28.

Dr. Stephen Hoge, the pres­i­dent of Mod­er­na, made a pre­sen­ta­tion to the advis­ers and fre­quent­ly referred to infor­ma­tion from the preprint study that had been post­ed three days before. The study was fund­ed by Mod­er­na and led by com­pa­ny sci­en­tists, and it had not been sub­ject­ed to peer review or pub­lished in a med­ical jour­nal.

The data Hoge shared with the advis­ers demon­strat­ed that blood tests on about 800 study par­tic­i­pants indi­cat­ed that the new biva­lent boost­er was “supe­ri­or” at increas­ing anti­bod­ies to the Omi­cron vari­ant com­pared with the orig­i­nal vac­cine.

Hoge did not men­tion anoth­er part of the study that cast a less-pos­i­tive light on the updat­ed shot.

In that part, the researchers gave some par­tic­i­pants the exist­ing vac­cine and oth­er par­tic­i­pants the updat­ed boost­er, and then they kept track of who became infect­ed with Covid-19.

Among the hun­dreds of par­tic­i­pants who received the orig­i­nal vac­cine and showed no evi­dence of a pri­or Covid-19 infec­tion, over the peri­od of the small study, 1.9% became infect­ed. Among the hun­dreds who received the new biva­lent vac­cine, a high­er per­cent­age, 3.2%, became infect­ed. The preprint did not indi­cate whether these find­ings were sta­tis­ti­cal­ly sig­nif­i­cant.

A 22-page FDA brief­ing doc­u­ment giv­en to the advis­ers did not men­tion this infec­tion data.

Dr. Jer­ry Weir, direc­tor of the Divi­sion of Viral Prod­ucts at the FDA’s Office of Vac­cines Research and Review, also did not men­tion the infec­tion data in his pre­sen­ta­tion to the advis­ers.

At the end of the June 28 meet­ing, the FDA advis­ers vot­ed 19–2 to rec­om­mend the inclu­sion of an Omi­cron vari­ant for the Covid-19 boost­er vac­cine. Offit, a pro­fes­sor of vac­ci­nol­o­gy at the Perel­man School of Med­i­cine at the Uni­ver­si­ty of Penn­syl­va­nia, and Dr. Hen­ry Bern­stein, a pro­fes­sor of pedi­atrics at the Zuck­er School of Med­i­cine at Hofstra/Northwell in New York, vot­ed in oppo­si­tion.

Over the next month, the US gov­ern­ment announced agree­ments to pur­chase the biva­lent boost­er from Pfiz­er and Mod­er­na: a con­tract for $3.2 bil­lion with Pfiz­er and for $1.74 bil­lion with Mod­er­na.

Lim­i­ta­tions of Moderna’s infec­tion data

The infec­tion data that wasn’t includ­ed in the Mod­er­na and FDA pre­sen­ta­tions has sev­er­al seri­ous lim­i­ta­tions, accord­ing to the six advis­ers who spoke to CNN.

First, the num­bers were very small: The study ana­lyzed only hun­dreds of patients, and only 16 became infect­ed. None of them end­ed up in the emer­gency room or were hos­pi­tal­ized.

Sec­ond, par­tic­i­pants were not ran­dom­ly assigned to receive either the orig­i­nal or new vac­cine, and the study was not dou­ble-blind, mean­ing the par­tic­i­pants and the researchers knew who was receiv­ing which shot. Lack of ran­dom­iza­tion and blind­ing can bias study results.

Third, the pri­ma­ry pur­pose of the study was not to study infec­tion rates but to do immuno­genic­i­ty analy­ses, tak­ing blood from par­tic­i­pants and exam­in­ing their anti­body respons­es to the vac­cine.

“The pri­ma­ry objec­tive of the study was to assess the safe­ty and immuno­genic­i­ty of the biva­lent vac­cine. The study was not ran­dom­ized and did not con­trol for infec­tion risk between arms, mak­ing com­par­i­son of a rel­a­tive­ly small num­ber of cas­es prob­lem­at­ic,” he wrote.

Near­ly $5 bil­lion for updat­ed boost­ers

On August 31, about two months after the FDA advis­ers’ meet­ing, the agency autho­rized the Mod­er­na biva­lent vac­cines. The Mod­er­na infec­tion data was includ­ed in the agency’s writ­ten deci­sion, but it wasn’t post­ed online until Sep­tem­ber 13, accord­ing to Fel­ber­baum, the FDA spokesman.

On Sep­tem­ber 1, the CDC advis­ers – 14 vot­ing mem­bers – met to con­sid­er whether to rec­om­mend the biva­lent boost­ers for Amer­i­cans to get in the fall. Sev­er­al CDC sci­en­tists pre­sent­ed data at that meet­ing but did not include the infec­tion data.

Nord­lund, the CDC spokes­woman, said in her email that the “CDC was aware” of the data that would lat­er be pub­lished in The New Eng­land Jour­nal of Med­i­cine but that assess­ing infec­tions was an “explorato­ry objec­tive of the study,” which was “not designed to assess vac­cine effec­tive­ness.” She added that in assess­ing infec­tions, “researchers used dif­fer­ent dura­tions and points in time among a very small group of peo­ple,” and because of the lim­i­ta­tions of the data, it was not fea­tured at the meet­ing.

“CDC vac­cine rec­om­men­da­tions are made fol­low­ing an eval­u­a­tion and pre­sen­ta­tion of high-qual­i­ty vac­cine effi­ca­cy or immuno­bridg­ing data,” Nord­lund wrote.

Dr. William Schaffn­er, a non-vot­ing mem­ber of the CDC’s advi­so­ry com­mit­tee, called Nordlund’s argu­ment “very weak.”

“The data are lim­it­ed, but they are infor­ma­tive, and I think one would have antic­i­pat­ed that a com­plete pre­sen­ta­tion would have includ­ed them,” said Schaffn­er, an infec­tious dis­ease spe­cial­ist at Van­der­bilt Uni­ver­si­ty Med­ical Cen­ter.

Dr. Jacque­line Miller, a senior vice pres­i­dent at Mod­er­na, pre­sent­ed to the advis­ers. Like her col­league Hoge, the com­pa­ny pres­i­dent, she showed mate­r­i­al sug­gest­ing that the biva­lent vac­cine was supe­ri­or and did not show slides detail­ing the sta­tis­tics about the infec­tion rates, accord­ing to a copy of the slides she pre­sent­ed.

Sev­er­al hours into the meet­ing, one of the CDC advis­ers, Dr. Sybil Cineas, an asso­ciate pro­fes­sor of med­i­cine at the War­ren Alpert Med­ical School of Brown Uni­ver­si­ty, asked Miller about cas­es of Covid-19 among study sub­jects who received the orig­i­nal vac­cine ver­sus the updat­ed biva­lent boost­er.

Miller said that among sub­jects with no evi­dence of pri­or infec­tion, as well as those with evi­dence of pri­or infec­tion, the dis­ease inci­dence rates were 2.4% for the group who received the orig­i­nal vac­cine and 2.5% for those who got the biva­lent boost­er.

That data would be pub­lished two weeks lat­er in The New Eng­land Jour­nal of Med­i­cine.

When she answered Cineas’ ques­tion, Miller did not men­tion oth­er aspects of the infec­tion data in the pub­lished study. That data indi­cat­ed that among hun­dreds of par­tic­i­pants with no pre­vi­ous Covid-19 infec­tions, infec­tion occurred in 1.9% of those who’d received the old vac­cine and in 3.2% of those who’d received the new biva­lent vac­cine. She also did not men­tion break­downs of whether par­tic­i­pants were sick with Covid or had asymp­to­matic ill­ness­es. The study, like the preprint, did not men­tion whether any of these find­ings were sta­tis­ti­cal­ly sig­nif­i­cant.

At the end of the meet­ing, the CDC advis­ers vot­ed 13–1 in favor of rec­om­mend­ing the biva­lent boost­er, with Sanchez, a pro­fes­sor of pedi­atrics at the Ohio State Uni­ver­si­ty Col­lege of Med­i­cine, vot­ing in oppo­si­tion. CDC Direc­tor Dr. Rochelle Walen­sky signed off on the rec­om­men­da­tion lat­er that day, and the vac­cines were made avail­able to the pub­lic. Cur­rent­ly, they are the only boost­er avail­able once some­one has had their pri­ma­ry series of a Covid-19 vac­cine.

More than six months after the FDA advis­ers met, Mod­er­na still has not released data from a ran­dom­ized Phase 3 tri­al com­par­ing infec­tions in par­tic­i­pants who received the new boost­er with those who received the old shot. The com­pa­ny expects to release such results “short­ly” with about 3,000 par­tic­i­pants, accord­ing to Rid­ley.

Pfiz­er does not “cur­rent­ly have data on inci­dence of infec­tion post biva­lent boost­er. How­ev­er, we con­tin­ue to mon­i­tor real-world data and col­lect data from our own stud­ies,” accord­ing to a state­ment from Jer­i­ca Pitts, senior direc­tor of glob­al media rela­tions.

Togeth­er, the new updat­ed boost­ers from Pfiz­er and Mod­er­na cost tax­pay­ers near­ly $5 bil­lion. To put that in per­spec­tive, that’s about the size of the annu­al bud­get for the state of Delaware.

For­mer FDA sci­en­tist: No excuse for exclud­ing infec­tion data

A for­mer FDA sci­en­tist who helped run the agency’s vac­cine divi­sion told CNN that if he were still at the agency, he would have advo­cat­ed for shar­ing the infec­tion infor­ma­tion with the advis­ers, even if it was made avail­able only a short time before the meet­ing.

“I don’t think there’s any excuse for exclud­ing it,” even with its imper­fec­tions, said Dr. Philip Krause, who served as deputy direc­tor of the FDA’s Office of Vac­cine Research and Review until he resigned in Octo­ber 2021.

“The company’s fail­ure to present this infor­ma­tion at the [FDA advis­ers meet­ing] and the omis­sion of dis­cus­sion about the data at that meet­ing rais­es ques­tions about the abil­i­ty of the process to pro­vide a full and trans­par­ent review of the data,” he added.

Krause said his main con­cern was pre­serv­ing – or regain­ing – the pub­lic trust in the FDA.

“That’s the crit­i­cal thing,” he said. “The FDA’s objec­tive review of the data is what is pro­vid­ing the great, great val­ue to the Amer­i­can peo­ple, because this way they know that some­body who doesn’t have a stake in the out­come has looked at the deep­est pos­si­ble lev­el at these data.”

FDA and CDC vac­cine advis­ers echoed Krause’s con­cerns about trans­paren­cy.

“I think that as much data that’s avail­able should be made pub­lic and avail­able for dis­cus­sion by advi­so­ry groups so that the pub­lic can see, yes, the avail­able sci­ence has been eval­u­at­ed as best as [pos­si­ble] at that par­tic­u­lar time,” said Bern­stein, the mem­ber of the FDA advi­so­ry com­mit­tee.

Bern­stein added that he was dis­ap­point­ed that the data had not been pre­sent­ed to him and the oth­er advis­ers.

Offit, the mem­ber from the Uni­ver­si­ty of Penn­syl­va­nia, said he was angry.

“I was angry to find out that there was data that was rel­e­vant to our deci­sion that I didn’t get to see. Angry because they should trust us to make the deci­sion based on all the data. These agen­cies, whether it’s the FDA or CDC, can’t make that deci­sion for us. That’s the point of hav­ing an inde­pen­dent advi­so­ry com­mit­tee,” he said.

‘It shook my faith’

About a month after the CDC advis­ers met, stud­ies were released from researchers at Har­vard and Colum­bia sug­gest­ing that the new vac­cines didn’t work any bet­ter than the orig­i­nal.

Those stud­ies, which were very small and only in preprint and not in a med­ical jour­nal, mea­sured immune respons­es after peo­ple got the biva­lent vac­cine com­pared with the orig­i­nal ver­sion of the vac­cine.

“We essen­tial­ly see no dif­fer­ence” between the old boost­ers and the new about a month after the shot, said Dr. David Ho, a pro­fes­sor of micro­bi­ol­o­gy and immunol­o­gy at Colum­bia whose team authored one of the stud­ies.

Pres­i­dent Joe Biden and oth­er admin­is­tra­tion offi­cials con­tin­ue to empha­size that the updat­ed boost­er is the best way to avoid hos­pi­tal­iza­tion or death from Covid-19. But near­ly four months after its release, only 15.4% of the US pop­u­la­tion age 5 and old­er has opt­ed to get the shot, accord­ing to CDC data.

On Jan­u­ary 26, the advis­ers are sched­uled to meet again to dis­cuss future Covid-19 vac­ci­na­tion reg­i­mens.

Offit, the FDA vac­cine advis­er, said the Colum­bia and Har­vard stud­ies con­vinced him even more that the infec­tion data and all the relat­ed caveats should have been giv­en to the advis­ers from the begin­ning.

“This was not accept­able. I under­stand we’re in the mid­dle of a pan­dem­ic. I under­stand we’re build­ing the plane while it’s still in the air, but you can’t do this,” he said. “It did shake my faith. It shook my faith in how these deci­sions were being made.”

——–

9. “Endemic­i­ty Is Not a Vic­to­ry: The Unmit­i­gat­ed Down­side Risks of Wide­spread SARS-CoV­‑2 Trans­mis­sion;” MDPI; Vol­ume 2, Issue 12.

Abstract

The strat­e­gy of rely­ing sole­ly on cur­rent SARS-CoV­‑2 vac­cines to halt SARS-CoV­‑2 trans­mis­sion has proven infea­si­ble. In response, many pub­lic-health author­i­ties have advo­cat­ed for using vac­cines to lim­it mor­tal­i­ty while per­mit­ting unchecked SARS-CoV­‑2 spread (“learn­ing to live with the dis­ease”). The fea­si­bil­i­ty of this strat­e­gy crit­i­cal­ly depends on the infec­tion fatal­i­ty rate (IFR) of SARS-CoV­‑2. An expec­ta­tion exists that the IFR will decrease due to selec­tion against vir­u­lence. In this work, we per­form a viral fit­ness esti­ma­tion to exam­ine the basis for this expec­ta­tion. Our find­ings sug­gest large increas­es in vir­u­lence for SARS-CoV­‑2 would result in min­i­mal loss of trans­mis­si­bil­i­ty, imply­ing that the IFR may vary freely under neu­tral evo­lu­tion­ary drift. We use an SEIRS mod­el frame­work to exam­ine the effect of hypo­thet­i­cal changes in the IFR on steady-state death tolls under COVID-19 endemic­i­ty. Our mod­el­ing sug­gests that endem­ic SARS-CoV­‑2 implies vast trans­mis­sion result­ing in year­ly US COVID-19 death tolls num­ber­ing in the hun­dreds of thou­sands under many plau­si­ble sce­nar­ios, with even mod­est increas­es in the IFR lead­ing to unsus­tain­able mor­tal­i­ty bur­dens. Our find­ings high­light the impor­tance of enact­ing a con­cert­ed strat­e­gy and con­tin­ued devel­op­ment of bio­med­ical inter­ven­tions to sup­press SARS-CoV­‑2 trans­mis­sion and slow its evo­lu­tion.

10. “Chi­na steps up, a new era has dawned in world pol­i­tics” by M.K. Bhadraku­mar; Indi­an Punch­line; 3/11/2023. 

The agree­ment announced on Fri­day in Bei­jing regard­ing the nor­mal­i­sa­tion of diplo­mat­ic rela­tions between Sau­di Ara­bia and Iran and the reopen­ing of their embassies is a his­toric event. It goes way beyond an issue of Sau­di-Iran­ian rela­tions. China’s medi­a­tion sig­ni­fies that we are wit­ness­ing a pro­found shift of the tec­ton­ic plates in the geopol­i­tics of the 21st cen­tu­ry. 

The joint state­ment issued on Fri­day in Bei­jing begins by say­ing that the Sau­di-Iran­ian agree­ment was reached “in response to the noble ini­tia­tive of Pres­i­dent Xi Jin­ping.” The dra­mat­ic begin­ning goes on to state that Sau­di Ara­bia and Iran have expressed their “appre­ci­a­tion and grat­i­tude” to Xi Jin­ping and the Chi­nese gov­ern­ment “for host­ing and spon­sor­ing the talks, and the efforts it placed towards its suc­cess.” 

The joint com­mu­nique also men­tioned Iraq and Oman for fos­ter­ing the Sau­di-Iran­ian dia­logue dur­ing 2021–2022. But the salience is that the Unit­ed States, which has been tra­di­tion­al­ly the dom­i­nant pow­er in West Asian pol­i­tics for close to eight decades, is nowhere in the pic­ture.

Yet, this is about the rec­on­cil­i­a­tion between the two biggest region­al pow­ers in the Per­sian Gulf region. The US retrench­ment denotes a colos­sal break­down of Amer­i­can diplo­ma­cy. It will remain a black mark in Pres­i­dent Biden’s for­eign pol­i­cy lega­cy. 

But Biden must take the blame for it. Such a cat­a­clysmic fail­ure is large­ly to be traced to his fer­vour to impose his neo­con­ser­v­a­tive dog­mas as an adjunct of America’s mil­i­tary might and Biden’s own fre­quent insis­tence that the fate of humankind hinges on the out­come of a cos­mic strug­gle between democ­ra­cy and autoc­ra­cy. 

Chi­na has shown that Biden’s hyper­bole is delu­sion­al and it grates against real­i­ties. If Biden’s moral­is­tic, ill-con­sid­ered rhetoric alien­at­ed Sau­di Ara­bia, his attempts to sup­press Iran met with stub­born resis­tance from Tehran. And, in the final analy­sis, Biden lit­er­al­ly drove both Riyadh and Tehran to search for coun­ter­vail­ing forces that would help them to push back his oppres­sive, over­bear­ing atti­tude.

The US’ humil­i­at­ing exclu­sion from the cen­tre stage of West Asian pol­i­tics con­sti­tutes a “Suez moment” for the super­pow­er, com­pa­ra­ble to the cri­sis expe­ri­enced by the UK in 1956, which oblig­ed the British to sense that their impe­r­i­al project had reached a dead end and the old way of doing things—whipping weak­er nations into line as osten­si­ble oblig­a­tions of glob­al lead­er­ship —was no longer going to work and would only lead to dis­as­trous reck­on­ing. 

The stun­ning part here is the sheer brain pow­er and intel­lec­tu­al resources and ‘soft pow­er’ that Chi­na has brought into play to out­wit the US. The US has at least 30 mil­i­tary bases in West Asia — five in Sau­di Ara­bia alone — but it has lost the man­tle of lead­er­ship. Come to think of it, Sau­di Ara­bia, Iran and Chi­na made their land­mark announce­ment on the very same day Xi Jin­ping got elect­ed for a third term as pres­i­dent. 

What we are see­ing is a new Chi­na under the lead­er­ship of Xi Jin­ping trot­ting over the high knoll. Yet, it is adopt­ing a self-effac­ing pos­ture claim­ing no lau­rels for itself. There is no sign of the ‘Mid­dle King­dom syn­drome,’ which the US pro­pa­gan­dists had warned against. 

On the con­trary, for the world audi­ence — espe­cial­ly coun­tries like India or Viet­nam, Turkey, Brazil or South Africa — Chi­na has pre­sent­ed a salu­tary exam­ple of how a democ­ra­tised mul­ti­po­lar world can work in future — how it is pos­si­ble to anchor big pow­er diplo­ma­cy on con­sen­su­al, con­cil­ia­to­ry pol­i­tics, trade and inter­de­pen­dence and advance a ‘win-win’ out­come.  

Implic­it in this is anoth­er huge mes­sage here: Chi­na as a fac­tor of glob­al bal­ance and sta­bil­i­ty. It is not only Asia-Pacif­ic and West Asia who are watch­ing. The audi­ence also includes Africa and Latin Amer­i­ca — in fact, the entire non-West­ern world that forms the big major­i­ty of world com­mu­ni­ty who are known as the Glob­al South. 

What the pan­dem­ic and the Ukraine cri­sis have brought to the sur­face is the latent geopo­lit­i­cal real­i­ty that the Glob­al South rejects the poli­cies of neo-mer­can­talism pur­sued by the West in the garb of ‘lib­er­al inter­na­tion­al­ism.’ 

The West is pur­su­ing a hier­ar­chi­cal inter­na­tion­al order. None oth­er than the EU for­eign pol­i­cy chief Josep Bor­rell blurt­ed this out in an unguard­ed moment recent­ly with a touch of racist over­tone when he said from a pub­lic plat­form that ‘Europe Is a gar­den. The rest of the world Is a jun­gle, and the jun­gle could Invade the gar­den.’

Tomor­row, Chi­na could as well be chal­leng­ing the US hege­mo­ny over the West­ern Hemi­sphere. The recent paper by the Chi­nese For­eign Min­istry titled ‘US Hege­mo­ny and Its Per­ils’ tells us that Bei­jing will no longer be on the defen­sive. 

Mean­while, a realign­ment of forces on the world stage is tak­ing place with Chi­na and Rus­sia on one side and the US on the oth­er. Doesn’t it con­vey a big mes­sage that on the very eve of the his­toric announce­ment in Bei­jing on Fri­day, the Sau­di Ara­bi­an for­eign min­is­ter Prince Faisal bin Farhan Al Saud land­ed sud­den­ly in Moscow on a ‘work­ing vis­it’ and went into a hud­dle with For­eign Min­is­ter Sergey Lavrov who was vis­i­bly delight­ed? (herehere and  here  ) 

Of course, we will nev­er know what role Moscow would have played behind the scenes in coor­di­na­tion with Bei­jing to build bridges between Riyadh and Tehran. All we know that Rus­sia and Chi­na active­ly coor­di­nate their for­eign pol­i­cy moves. Inter­est­ing­ly, on March 6, Pres­i­dent Putin had a tele­phone con­ver­sa­tion with Iran’s Pres­i­dent Ebrahim Raisi.  

Audac­i­ty of hope 

To be sure, the geopol­i­tics of West Asia will nev­er be the same again. Real­is­ti­cal­ly, the first spar­row of spring has appeared but the ice was melt­ed for only three or four rods from the shore. Nonethe­less, the sun’s rays give hope, sig­nalling warmer days to come. 

Con­ceiv­ably, Riyadh won’t have any truck fur­ther with the dia­bol­i­cal plots hatched in Wash­ing­ton and Tel Aviv to resus­ci­tate an anti-Iran alliance in West Asia. Nor is it in the realms of pos­si­bil­i­ty that Sau­di Ara­bia will be par­ty to any US-Israeli attacks on Iran. 

This bad­ly iso­lates Israel in the region and ren­ders the US tooth­less. In sub­stan­tive terms, it scat­ters the Biden administration’s fever­ish efforts late­ly to cajole Riyadh to join Abra­ham Accords. 

How­ev­er, sig­nif­i­cant­ly, a com­men­tary in Glob­al Times not­ed some­what auda­cious­ly that the Sau­di-Iran­ian deal “set a pos­i­tive exam­ple for oth­er region­al hotspot issues, such as the eas­ing and set­tle­ment of the Israeli-Pales­tin­ian con­flict. And in the future, Chi­na could play an impor­tant role in build­ing a bridge for coun­tries to solve long-stand­ing thorny issues in the Mid­dle East just as what it did this time.” 

Indeed, the joint com­mu­nique issued in Bei­jing says, “The three coun­tries [Sau­di Ara­bia, Iran and Chi­na] expressed their keen­ness to exert all efforts towards enhanc­ing region­al and inter­na­tion­al peace and secu­ri­ty.” Can Chi­na pull a habit out of the hat? Time will tell.

For the present, though, the Sau­di-Iran­ian rap­proche­ment will cer­tain­ly have pos­i­tive fall­outs on the efforts toward a nego­ti­at­ed set­tle­ment in Yemen and Syr­ia as well as on the polit­i­cal insta­bil­i­ty in Lebanon.

Besides, the joint com­mu­nique empha­sis­es that Sau­di Ara­bia and Iran intend to revive the 1998 Gen­er­al Agree­ment for Coop­er­a­tion in the Fields of Econ­o­my, Trade, Invest­ment, Tech­nol­o­gy, Sci­ence, Cul­ture, Sports, and Youth. All in all, the Biden administration’s max­i­mum pres­sure strat­e­gy toward Iran has crashed and the West’s sanc­tions against Iran are being ren­dered inef­fec­tu­al. The US’ pol­i­cy options on Iran have shrunk. Put dif­fer­ent­ly, Iran gains strate­gic depth to nego­ti­ate with the US.  

The cut­ting edge of the US sanc­tions lies in the restric­tions on Iran’s oil trade and access to west­ern banks. It is entire­ly con­ceiv­able that a back­lash is about to begin as Rus­sia, Iran and Sau­di Ara­bia — three top oil/gas pro­duc­ing coun­tries start accel­er­at­ing their search for pay­ment mech­a­nisms bypass­ing the Amer­i­can dol­lar. 

Chi­na is already dis­cussing such an arrange­ment with Sau­di Ara­bia and Iran. Chi­na-Rus­sia trade and eco­nom­ic trans­ac­tions no longer use Amer­i­can dol­lar for pay­ments. It is well under­stood that any sig­nif­i­cant ero­sion in the sta­tus of the dol­lar as ‘world cur­ren­cy’ will not only spell doom for the Amer­i­can econ­o­my but will crip­ple the US’ capac­i­ty to wage ‘for­ev­er wars’ abroad and impose its glob­al hege­mo­ny. 

The bot­tom line is that the rec­on­cil­i­a­tion between Sau­di Ara­bia and Iran is also a pre­cur­sor to their induc­tion as BRICS mem­bers in a near future. To be sure, there is a Russ­ian-Chi­nese under­stand­ing already on this score. The BRICS mem­ber­ship for Sau­di Ara­bia and Iran will rad­i­cal­ly reset the pow­er dynam­ic in the inter­na­tion­al sys­tem.

11. “Biden Picks Biotech Exec­u­tive to Lead New Bio­med­ical Research Agency” By Sheryl Gay Stol­berg; The New York Times; 09/12/2022

Dr. Renee Wegrzyn is Pres­i­dent Biden’s choice to lead the Advanced Research Projects Agency for Health, which is aimed at dri­ving bio­med­ical inno­va­tion.

Pres­i­dent Biden, sketch­ing out a vision for “bold approach­es” to fight­ing can­cer and oth­er dis­eases, announced on Mon­day that he had select­ed Dr. Renee Wegrzyn, a Boston biotech exec­u­tive with gov­ern­ment expe­ri­ence, as the direc­tor of a new fed­er­al agency aimed at pur­su­ing risky, far-reach­ing ideas that will dri­ve bio­med­ical inno­va­tion. [!—D.E.]

Mr. Biden made the announce­ment at the John F. Kennedy Pres­i­den­tial Library and Muse­um in Boston, on the 60th anniver­sary of the for­mer president’s “moon­shot” speech that ush­ered in an era of space trav­el. He used the occa­sion to reit­er­ate his call to “end can­cer as we know it” — the tag line for his own “can­cer moon­shot” ini­tia­tive. . . .

. . . . Mod­eled after the Defense Advanced Research Projects Agency, the new agency is known as the Advanced Research Projects Agency for Health. (In the argot of Wash­ing­ton, where every agency has an acronym, the defense research agency is called DARPA and the health agency is ARPA‑H.) . . . .

. . . . Dr. Wegrzyn is a vice pres­i­dent for busi­ness devel­op­ment at Gink­go Bioworks and the head of inno­va­tion at Con­cen­tric by Gink­go, the company’s ini­tia­tive to advance coro­n­avirus test­ing and track the spread of the virus. She also worked at DARPA and its sis­ter agency, the Intel­li­gence Advanced Research Projects Activ­i­ty. . . .

. . . . The agency already has an act­ing deputy direc­tor, Adam H. Rus­sell, also a DARPA alum­nus, who has been lay­ing the tech­ni­cal infra­struc­ture and oth­er ground­work to get the new agency off the ground. . . .

. . . . In addi­tion to announc­ing his intent to appoint Dr. Wegrzyn, Mr. Biden issued an exec­u­tive order on Mon­day estab­lish­ing a biotech­nol­o­gy and bio­man­u­fac­tur­ing ini­tia­tive intend­ed to posi­tion the Unit­ed States as a leader in the field and to cen­ter drug man­u­fac­tur­ing in the coun­try. [This is aimed at China–D.E.]. . .

12. https://en.wikipedia.org/wiki/Renee_Wegrzyn

. . . . From 2003 to 2006, Wegrzyn worked as a post-doc­tor­al research fel­low at the Euro­pean Mol­e­c­u­lar Biol­o­gy Lab­o­ra­to­ry. From 2006 to 2008, she worked as the assay devel­op­ment group leader for Adlyfe, a biotech­nol­o­gy com­pa­ny based in Que­bec. In 2009, she was a senior sci­en­tist at Meso Scale Dis­cov­ery and in 2012, she was a fel­low at the Johns Hop­kins Cen­ter for Health Secu­ri­ty. From 2009 to 2016, she worked as a senior lead tech­nol­o­gist at Booz Allen Hamil­tonFrom 2016 to 2020, she served as a pro­gram man­ag­er in the Bio­log­i­cal Tech­nolo­gies Office of DARPA, where she spe­cial­ized in syn­thet­ic biol­o­gy and biose­cu­ri­ty. [This is the peri­od dur­ing which DARPA was doing the SARS CoV‑2 work—D.E.] 2018, she has been a senior advi­sor to the Nuclear Threat Ini­tia­tive.[3] In 2020, she joined Gink­go Bioworks as vice pres­i­dent of busi­ness devel­op­ment.[4]. . . .

 

Discussion

5 comments for “FTR#‘s 1292 and 1293 The Oswald Institute of Virology, Part 14: The Northwoods Virus, Part 2 and Apocalypse, The Satanic Presidency of Joe Biden”

  1. I’ve often won­dered about the Chi­nese for­eign min­is­ter, Wan Yi, declar­ing back in Decem­ber of 2019 that ‘the Unit­ed States is the trou­ble mak­er of the world.” At the time it was thought he was refer­ring to the ‘black hands’ he saw at work in Hong Kong and the right­eous com­ments about Xin­jiang province. I sus­pect that he was refer­ring to the deep state activ­i­ty which was only just being felt inside Chi­na at that time.

    Posted by Brad | March 21, 2023, 1:15 pm
  2. It was a night­mare sce­nario that shut­down the world. And yet, as we’ve seen as the COVID pan­dem­ic has played out, not all night­mare sce­nar­ios are equal. Some can be far more night­mar­ish than oth­ers. And that brings us to the fol­low­ing pair of arti­cles about the long-term night­mare impli­ca­tions of the SARS-CoV­‑2 virus that we have yet to real­ly under­stand. There’s the “known unknown” long-term impli­ca­tions of the impact that “long COVID” will ulti­mate­ly have on afflict­ed patients. But as the first arti­cle — a Nature Cell Biol­o­gy com­mu­ni­ca­tion — reminds us, we’re steadi­ly learn­ing more about those known unknowns of long COVID and the more we’re learn­ing the more dis­turb­ing it looks.

    Specif­i­cal­ly, it appears that DNA dam­age is one of the long-term impacts of a SARS-CoV­‑2 infec­tion. As researchers dis­cov­ered, the SARS-CoV­‑2 virus appears to dis­rupt the DNA dam­age response (DDR) cel­lu­lar path­ways in mul­ti­ple ways, lead­ing to cel­lu­lar senes­cence. It’s a night­mare. Senes­cent cells are basi­cal­ly aged dys­func­tion­al cells noto­ri­ous for chron­i­cal­ly send­ing out inflam­ma­to­ry sig­nals, with a long-term risk of can­cer. Yep, it’s look­ing like SARS-CoV­‑2 might be dri­ving both aging and, per­haps even­tu­al­ly, can­cer.

    It’s the kind of find­ings that should be rais­ing major alarm bells. The kind of alarm bells that trig­ger­ing a new “Oper­a­tion Warp Speed” inves­ti­ga­tion into whether or not a high­ly infec­tious air­borne aging+cancer virus was just unleashed across the globe. And that brings us to the sec­ond arti­cle below about an inves­ti­ga­tion recent­ly con­duct­ed by STAT News and Muck­rak­er into the US fed­er­al gov­ern­men­t’s $1.2 bil­lion RECOVER pro­gram set up to study both the long COVID dis­ease as well as treat­ments. As we’re going to see, not only has basi­cal­ly noth­ing come from that invest­ment but it’s not even clear who is ulti­mate­ly in charge and account­able for the pro­gram. Beyond that, these find­ings aren’t new. STAT News issues a sim­i­lar warn­ing about RECOV­ER’s lack of progress last year, prompt­ing con­gres­sion­al inquiries and pledges to pick up the pace. Instead, the delays have only com­pound­ed.

    At this point, only a sin­gle tri­al to study a drug treat­ment for long COVID has been approved — for Pfiz­er’s rel­a­tive­ly expen­sive new drug Paxlovid — but even that tri­al is well behind sched­ule. Tri­als for oth­er exist­ing much cheap­er drugs like met­formin and nal­trex­one have been inex­plic­a­bly ignored. And that brings us to a very inter­est­ing update on the Oya­Gen Oya‑1 mys­tery. Recall the intrigu­ing sto­ry of Oya­Gen, the Rochester, NY-based com­pa­ny that claimed to have found a well-estab­lished safe old drug was effec­tive­ly ster­il­iz­ing SARS-CoV­‑2. These find­ings were derived in part­ner­ship with US gov­ern­ment researchers as Fort Det­rick. The founder of Oya­Gen even went to the media call­ing for some sort of atten­tion to be drawn to these find­ings and per­mis­sion for emer­gency clin­i­cal tri­als. Noth­ing came of that. Instead, as we lat­er saw, Oya­Gen basi­cal­ly sold the rights to Oya‑1 to Tonix Phar­ma­ceu­ti­cals. We are now informed by Tonix that the fed­er­al gov­ern­ment has refused to help spon­sor tri­als of the drug. Again, we’re talk­ing about a drug that had its effi­ca­cy against SARS-CoV­‑2 estab­lished by US researchers at Fort Det­rick. A very cheap drug with known safe dosages for humans. For some rea­son, the US gov­ern­ment just has no inter­est in this drug. or any oth­er drug that does­n’t come from a major phar­ma­ceu­ti­cal com­pa­ny and can’t fetch an expen­sive “new drug” price, it seems.

    Oh, and it appears that long COVID’s symp­toms are alarm­ing­ly sim­i­lar to chron­ic-fatigue syn­drome (CSF). And yet, as we’re going to see, one of the only clin­i­cal tri­als the RECOVER pro­gram has actu­al­ly announced at this point for a pos­si­ble treat­ment for long COVID focus­es on exer­cise as a ther­a­py, that’s despite the fact that exer­cise ther­a­py has been shown to be poten­tial­ly dan­ger­ous for CFS patients. As a result, the CFS com­mu­ni­ty is also now alarmed by the RECOVER pro­gram’s deci­sion-mak­ing. This is a good time to recall the sor­did his­to­ry tying the emer­gence of CFS to Lyme dis­ease, its direct ties US biowar­fare research, and the decades of appar­ent coverup of that research in rela­tion to Lyme dis­ease and CFS.

    So at the same time we’re learn­ing that SARS-CoV­‑2 could ulti­mate­ly be far more dam­ag­ing to the long-term health of the human species than pre­vi­ous­ly rec­og­nized, we’re also learn­ing that the NIH — an enti­ty that has been thor­ough­ly cap­tured by pri­vate inter­ests at this point — seems to have an inter­est in NOT learn­ing about this dis­ease. It’s all part of the night­mare.

    Ok, first, here’s a Nature Cell Biol­o­gy com­mu­ni­ca­tion from the team that dis­cov­ered that high­ly alarm­ing evi­dence for long-term DNA dam­age induced by SARS-CoV-2’s attack on the cells own DNA dam­age response path­way. It’s the kind of dam­age with major long-term impli­ca­tions, rang­ing from accel­er­at­ed aging to poten­tial­ly can­cer:

    Nature Cell Biol­o­gy
    vol­ume 25, pages 526–527 (2023)

    SARS-CoV­‑2 caus­es DNA dam­age, cel­lu­lar senes­cence and inflam­ma­tion

    Fab­rizio d’Adda di Fagagna
    Pub­lished: 09 March 2023

    We dis­cov­ered that SARS-CoV­‑2 infec­tion caus­es DNA dam­age both in cul­tured cells and in vivo. Mech­a­nis­ti­cal­ly, SARS-CoV­‑2 degrades the enzyme CHK1, which leads to a reduc­tion in dNTPs and impaired DNA repli­ca­tion. More­over, inhi­bi­tion of the for­ma­tion of bind­ing pro­tein 53BP1 foci by the SARS-CoV­‑2 nucle­o­cap­sid pro­tein hin­ders the repair of dam­aged DNA. The ensu­ing accu­mu­la­tion of DNA dam­age caus­es cel­lu­lar senes­cence and inflam­ma­tion.

    The ques­tions

    SARS-CoV­‑2 — the virus respon­si­ble for the COVID-19 pan­dem­ic — has a greater impact on human health than oth­er res­pi­ra­to­ry virus­es have, although the mech­a­nisms of this are not ful­ly under­stood. Fur­ther ques­tions are the mol­e­c­u­lar basis of the long-term con­se­quences of COVID-19, known as ‘long COVID’, and why SARS-CoV­‑2 seems to accel­er­ate human aging. One poten­tial expla­na­tion for these obser­va­tions is that SARS-CoV­‑2 caus­es dam­age to nuclear DNA — the only irre­place­able cell com­po­nent. We there­fore aimed to test the hypoth­e­sis that dam­age to nuclear DNA might be the under­ly­ing cause of the many severe con­se­quences of SARS-CoV­‑2 infec­tion.

    The dis­cov­ery

    To estab­lish whether SARS-CoV­‑2 infec­tion results in acti­va­tion of the DNA dam­age response (DDR), we infect­ed human cell lines with SARS-CoV­‑2 and per­formed immunoblot analy­sis of DDR mark­ers. We showed that SARS-CoV­‑2 infec­tion acti­vat­ed the DDR, and we con­firmed the pres­ence of DNA frag­men­ta­tion through the use of comet assays. These events were accom­pa­nied by pro-inflam­ma­to­ry sig­nal­ing and the estab­lish­ment of cel­lu­lar senes­cence (a form of cel­lu­lar aging).

    We next probed the mol­e­c­u­lar mech­a­nisms that caused the DNA dam­age. We dis­cov­ered that SARS-CoV­‑2 express­es pro­teins that, by dis­tinct mech­a­nisms, hijack cell nucleotide metab­o­lism. Specif­i­cal­ly, the viral fac­tors ORF6 and NSP13 pro­mot­ed the degra­da­tion of check­point kinase 1 (CHK1), an enzyme involved in coor­di­nat­ing the DDR. A reduc­tion in CHK1 lev­els is thought to result in the accu­mu­la­tion of rNTPs, which we pro­pose is need­ed to fuel viral repli­ca­tion (SARS-CoV­‑2 being a RNA virus). How­ev­er, the accu­mu­la­tion of rNTPs seemed to occur at the expense of dNTPs, which we detect­ed at low­er lev­els after SARS-CoV­‑2 infec­tion and which result­ed in impaired DNA repli­ca­tion and DNA dam­age.

    In addi­tion, we found evi­dence that DNA breaks accu­mu­lat­ed because they were not effi­cient­ly repaired. Indeed, we dis­cov­ered that the SARS-Cov­‑2 nucle­o­cap­sid pro­tein impaired focal recruit­ment of the bind­ing pro­tein 53BP1 and decreased DNA repair by com­pet­ing with 53BP1 for asso­ci­a­tion with dam­age-induced long non-cod­ing RNAs. Over­all, these find­ings sug­gest that SARS-CoV­‑2 both induces DNA dam­age and impairs its repair, ulti­mate­ly caus­ing cells to age and spread inflam­ma­tion (Fig. 1). Final­ly, we demon­strat­ed that these events hap­pened in vivo in SARS-CoV-2-infect­ed mice and in patients with COVID-19.

    The impli­ca­tions

    Our find­ings reveal the pro­found impact that SARS-CoV­‑2 infec­tion has on cel­lu­lar biol­o­gy, threat­en­ing the most impor­tant cel­lu­lar con­stituent: nuclear DNA. The accu­mu­la­tion of DNA dam­age is known to be asso­ci­at­ed with can­cer and aging1. Although the long-term con­se­quences of severe COVID-19 on lung can­cer inci­dence are unknown at present, accel­er­at­ed aging phe­no­types have been report­ed2,3. Our results may pro­vide a mech­a­nis­tic expla­na­tion for post-COVID-19 syn­dromes with has­tened aging fea­tures, to which the estab­lish­ment of cel­lu­lar senes­cence and the trig­ger­ing of inflam­ma­to­ry process­es might be a cru­cial con­tribut­ing fac­tor. Indeed, chron­ic inflam­ma­tion is thought to be the under­ly­ing cause of lung fibro­sis4, brain degen­er­a­tion5 and over­all frailty. Thus, local events ini­tial­ly restrict­ed to the res­pi­ra­to­ry sys­tem may have sys­temic con­se­quences.

    ...
    ———–

    “SARS-CoV­‑2 caus­es DNA dam­age, cel­lu­lar senes­cence and inflam­ma­tion” by Fab­rizio d’Adda di Fagagna; Nature Cell Biol­o­gy, vol­ume 25, pages 526–527 (2023); 03/09/2023

    Our find­ings reveal the pro­found impact that SARS-CoV­‑2 infec­tion has on cel­lu­lar biol­o­gy, threat­en­ing the most impor­tant cel­lu­lar con­stituent: nuclear DNA. The accu­mu­la­tion of DNA dam­age is known to be asso­ci­at­ed with can­cer and aging1. Although the long-term con­se­quences of severe COVID-19 on lung can­cer inci­dence are unknown at present, accel­er­at­ed aging phe­no­types have been report­ed2,3. Our results may pro­vide a mech­a­nis­tic expla­na­tion for post-COVID-19 syn­dromes with has­tened aging fea­tures, to which the estab­lish­ment of cel­lu­lar senes­cence and the trig­ger­ing of inflam­ma­to­ry process­es might be a cru­cial con­tribut­ing fac­tor. Indeed, chron­ic inflam­ma­tion is thought to be the under­ly­ing cause of lung fibro­sis4, brain degen­er­a­tion5 and over­all frailty. Thus, local events ini­tial­ly restrict­ed to the res­pi­ra­to­ry sys­tem may have sys­temic con­se­quences.”

    It’s one of the most omi­nous con­se­quences we could dis­cov­er from SAR-CoV­‑2: DNA dam­age accu­mu­la­tion. It’s like an air­borne can­cer + aging virus. Maybe. We don’t real­ly know yet. More stud­ies are obvi­ous­ly nec­es­sary. But accord­ing to this study, SAR-CoV­‑2 appears to induce DNA dam­age through mul­ti­ple mech­a­nisms that dis­rupt­ed the cel­lu­lar DNA dam­age response (DDR) path­ways. First, it appears at least two viral pro­teins pro­mote the degra­da­tion of check­point kinase 1 (CHK1), an enzyme involved in coor­di­nat­ing the DDR. In addi­tion, the SARS-Cov­‑2 nucle­o­cap­sid pro­tein impaired focal recruit­ment of the bind­ing pro­tein 53BP1 and decreased DNA repair by com­pet­ing with 53BP1 for asso­ci­a­tion with dam­age-induced long non-cod­ing RNAs. In oth­er words, one of the virus­es pro­teins acts like a sponge sop­ping up the DNA dam­age sig­nals, fur­ther dis­rupt­ing the DDR. Final­ly, and per­haps most impor­tant­ly, they dis­cov­ered this not just in cell cul­tures but in infect­ed mice and human patients. This isn’t just hypo­thet­i­cal dam­age:

    ...
    To estab­lish whether SARS-CoV­‑2 infec­tion results in acti­va­tion of the DNA dam­age response (DDR), we infect­ed human cell lines with SARS-CoV­‑2 and per­formed immunoblot analy­sis of DDR mark­ers. We showed that SARS-CoV­‑2 infec­tion acti­vat­ed the DDR, and we con­firmed the pres­ence of DNA frag­men­ta­tion through the use of comet assays. These events were accom­pa­nied by pro-inflam­ma­to­ry sig­nal­ing and the estab­lish­ment of cel­lu­lar senes­cence (a form of cel­lu­lar aging).

    We next probed the mol­e­c­u­lar mech­a­nisms that caused the DNA dam­age. We dis­cov­ered that SARS-CoV­‑2 express­es pro­teins that, by dis­tinct mech­a­nisms, hijack cell nucleotide metab­o­lism. Specif­i­cal­ly, the viral fac­tors ORF6 and NSP13 pro­mot­ed the degra­da­tion of check­point kinase 1 (CHK1), an enzyme involved in coor­di­nat­ing the DDR. A reduc­tion in CHK1 lev­els is thought to result in the accu­mu­la­tion of rNTPs, which we pro­pose is need­ed to fuel viral repli­ca­tion (SARS-CoV­‑2 being a RNA virus). How­ev­er, the accu­mu­la­tion of rNTPs seemed to occur at the expense of dNTPs, which we detect­ed at low­er lev­els after SARS-CoV­‑2 infec­tion and which result­ed in impaired DNA repli­ca­tion and DNA dam­age.

    In addi­tion, we found evi­dence that DNA breaks accu­mu­lat­ed because they were not effi­cient­ly repaired. Indeed, we dis­cov­ered that the SARS-Cov­‑2 nucle­o­cap­sid pro­tein impaired focal recruit­ment of the bind­ing pro­tein 53BP1 and decreased DNA repair by com­pet­ing with 53BP1 for asso­ci­a­tion with dam­age-induced long non-cod­ing RNAs. Over­all, these find­ings sug­gest that SARS-CoV­‑2 both induces DNA dam­age and impairs its repair, ulti­mate­ly caus­ing cells to age and spread inflam­ma­tion (Fig. 1). Final­ly, we demon­strat­ed that these events hap­pened in vivo in SARS-CoV-2-infect­ed mice and in patients with COVID-19.
    ...

    It’s more or less a night­mare sce­nario. The kind of night­mare sce­nario that becomes more and more night­mar­ish the longer it does, espe­cial­ly for long COVID patients. Or at least it’s ear­ly evi­dence sug­gest­ing we could be look­ing at that long-term night­mare sce­nario. It sure would be nice if there was a robust research pro­gram into the nature long COVID. And that brings us to anoth­er night­mare sce­nario also play­ing out: the NIH’s $1.2 bil­lion RECOVER pro­gram ded­i­cat­ed to the study of long COVID has appar­ent­ly been a com­plete bust. An ongo­ing bust, with mon­ey still be spent but no one appar­ent­ly able to answer where it’s going, why there are so many delays, or who is ulti­mate­ly account­able. And while Con­gress explic­it­ly ear­marked that $1.2 bil­lion for the study of both long COVID and treat­ments, the RECOVER project appears to have neglect­ed the treat­ments almost entire­ly. The only drug tri­al announced is for Pfiz­er’s Paxlovid and even that is run­ning way behind sched­ule. Also, none of this is new. Alarm bells were raised about these delays last year and yet the delays have only com­pound­ed:

    Stat News

    The NIH has poured $1 bil­lion into long Covid research — with lit­tle to show for it

    By Rachel Cohrs and Bet­sy Ladyzhets
    April 20, 2023

    WASHINGTON — The fed­er­al gov­ern­ment has burned through more than $1 bil­lion to study long Covid, an effort to help the mil­lions of Amer­i­cans who expe­ri­ence brain fog, fatigue, and oth­er symp­toms after recov­er­ing from a coro­n­avirus infec­tion.

    There’s basi­cal­ly noth­ing to show for it.

    The Nation­al Insti­tutes of Health hasn’t signed up a sin­gle patient to test any poten­tial treat­ments — despite a clear man­date from Con­gress to study them. And the few tri­als it is plan­ning have already drawn a firestorm of crit­i­cism, espe­cial­ly one inter­ven­tion that experts and advo­cates say may actu­al­ly make some patients’ long Covid symp­toms worse.

    Instead, the NIH spent the major­i­ty of its mon­ey on broad­er, obser­va­tion­al research that won’t direct­ly bring relief to patients. But it still hasn’t pub­lished any find­ings from the patients who joined that study, almost two years after it start­ed.

    There’s no sense of urgency to do more or to speed things up, either. The agency isn’t ask­ing Con­gress for any more fund­ing for long Covid research, and STAT and Muck­Rock obtained doc­u­ments show­ing the NIH refus­es to use its own mon­ey to change course.

    “So far, I don’t think we’ve got­ten any­thing for a bil­lion dol­lars,” said Ezekiel Emanuel, a physi­cian, vice provost for glob­al ini­tia­tives, and co-direc­tor of the Health­care Trans­for­ma­tion Insti­tute at the Uni­ver­si­ty of Penn­syl­va­nia. “That is just unac­cept­able, and it’s a seri­ous dys­func­tion.”

    Eric Topol, the founder and direc­tor of the Scripps Research Trans­la­tion­al Insti­tute, said he expect­ed the NIH would have launched many large-scale tri­als by now, and that test­ing treat­ments should have been an urgent pri­or­i­ty when Con­gress first gave the agency mon­ey in late 2020.

    “I don’t know that they’ve con­tributed any­thing except more con­fu­sion,” Topol said.

    Patients and researchers have already raised alarms about the glacial pace of the NIH’s ear­ly long Covid efforts. But a new inves­ti­ga­tion from STAT and the non­prof­it news orga­ni­za­tion Muck­Rock, based on inter­views with near­ly two dozen gov­ern­ment offi­cials, experts, patients, and advo­cates, and inter­nal NIH cor­re­spon­dence, let­ters, and pub­lic doc­u­ments, under­scores that the NIH hasn’t picked up the pace — instead, the delays have com­pound­ed.

    It’s dif­fi­cult to pin­point exact­ly why progress is so stalled, experts and patients involved in the project empha­sized, because the NIH has obscured both who is in charge of the long Covid efforts and how it spent the mon­ey. The broad­er Biden admin­is­tra­tion has also missed oppor­tu­ni­ties for over­sight and account­abil­i­ty of the effort — despite the president’s lofty promis­es to focus on the dis­ease.

    The NIH’s blun­ders have mas­sive ram­i­fi­ca­tions for the more than 16 mil­lion Amer­i­cans suf­fer­ing from long Covid, in addi­tion to those with oth­er, sim­i­lar chron­ic dis­eases. As the biggest gov­ern­ment-fund­ed study on this top­ic, the NIH ini­tia­tive, dubbed RECOVER, sets prece­dents for future research and clin­i­cal guide­lines. It will dic­tate how doc­tors across the coun­try treat their patients — and, in turn, impact people’s abil­i­ty to access work accom­mo­da­tions, dis­abil­i­ty ben­e­fits, and more.

    ...

    In response to STAT and MuckRock’s ques­tions, the NIH and an insti­tute at Duke Uni­ver­si­ty man­ag­ing the clin­i­cal tri­als defend­ed the ini­tia­tive, with­out pro­vid­ing a clear expla­na­tion for the delays.

    The NIH said it chose to fund a large-scale research pro­gram instead of small-scale stud­ies to make sure data and process­es could be shared across dif­fer­ent groups of patients, adding that clin­i­cal tri­als will be launch­ing soon. In these tri­als, stan­dard­ized study designs will allow the agency to test mul­ti­ple treat­ments across mul­ti­ple sites. If there are sig­nals a drug works, the agency said it can piv­ot to devote more resources there.

    A Depart­ment of Health and Human Ser­vices spokesper­son said the agency has made progress over the last year in respond­ing to long Covid, and that there are research efforts under­way in addi­tion to the RECOVER pro­gram.

    ...

    In 2020, Con­gress made an invest­ment of $1.2 bil­lion to learn more about the mys­te­ri­ous ongo­ing symp­toms that were afflict­ing some peo­ple infect­ed with Covid-19. That sort of mon­ey to fund research into a chron­ic con­di­tion like long Covid was vir­tu­al­ly unheard of.

    The mon­ey was explic­it­ly ear­marked to fund both research to under­stand the dis­ease and clin­i­cal tri­als to test treat­ments that could bring patients relief. But more than two years in, the agency hasn’t start­ed test­ing a sin­gle treat­ment. Nor is it plan­ning to test many in the future. Instead, it’s focused on obser­va­tion­al research — and that, too, has pro­duced few insights.

    The NIH is plan­ning five clin­i­cal tri­als, each of which will test treat­ments that may help with a major cat­e­go­ry of long Covid symp­toms. Some of these treat­ments will be drugs, while oth­ers will be behav­ioral ther­a­pies, such as cog­ni­tive retrain­ing. Each tri­al will include 300 to 900 patients, select­ed based on their symp­toms, accord­ing to details shared dur­ing a webi­nar in mid-April.

    The only tri­al to be for­mal­ly announced so far will focus on Paxlovid, test­ing whether the drug alle­vi­ates symp­toms by mit­i­gat­ing any ongo­ing viral infec­tion in patients’ bod­ies. The study was sup­posed to start recruit­ing in Jan­u­ary.

    But as of April, RECOVER hasn’t signed up a sin­gle patient for any of those clin­i­cal tri­als. And the time­line has slipped over and over again.

    Ini­tial­ly, in a let­ter to mem­bers of Con­gress prompt­ed by STAT’s March 2022 report­ing on the initiative’s slow start, the NIH told law­mak­ers that the agency expect­ed to launch clin­i­cal tri­als by that fall. But by August, the esti­mat­ed launch had slipped to “by the end of 2022.” Then, anoth­er delay became pub­lic in Decem­ber, when one of the NIH offi­cials lead­ing RECOVER told advis­ers that clin­i­cal tri­als would begin by the first quar­ter of 2023. Now, Duke Uni­ver­si­ty, which is over­see­ing the clin­i­cal tri­al infra­struc­ture, told STAT and Muck­Rock it expects the first patients to sign up for tri­als this sum­mer.

    [Click to read the entire doc­u­ment.]

    Emanuel said the pace of tri­als shows lit­tle urgency on the part of NIH.

    “If you don’t have the patho­bi­ol­o­gy fig­ured out, you try things. You don’t just slow, slow, slow, walk it,” he said.

    All five clin­i­cal tri­al pro­to­cols are going through safe­ty reviews, and the Food and Drug Admin­is­tra­tion is review­ing the tri­als that will test Paxlovid and oth­er drugs, the Duke Clin­i­cal Research Insti­tute said. The insti­tute plans to share these pro­to­cols pub­licly when reviews are com­plete, but did not pro­vide an esti­mate for when that will hap­pen.

    Faster progress is pos­si­ble. A sim­i­lar study at Stan­ford, which received fund­ing direct­ly from Pfiz­er, was also announced in Octo­ber 2022 but has already begun recruit­ing patients. This tri­al was “able to be more flex­i­ble and get the study start­ed faster” in com­par­i­son to RECOVER because it’s small­er, said Upin­der Singh, the study’s prin­ci­pal inves­ti­ga­tor. Singh and her col­leagues are only test­ing Paxlovid and doing so at only one loca­tion, rather than com­par­ing dif­fer­ent treat­ments.

    Duke was also sup­posed to cre­ate a patient reg­istry to col­lect infor­ma­tion about long Covid patients, but that ini­tia­tive hasn’t been launched, either.

    ...

    Rather than pri­or­i­tiz­ing treat­ments from the start, the NIH used much of its long Covid fund­ing on a large-scale study to track long Covid symp­toms and learn how the dis­ease works. This choice has frus­trat­ed patients because thou­sands of oth­er stud­ies have already answered many major ques­tions about the con­di­tion.

    “We didn’t need to recre­ate” exist­ing stud­ies that already answered these ques­tions, said Cole, the long Covid patient. Researchers have been com­pil­ing lists of com­mon symp­toms since sum­mer 2020, she said. For Cole, fatigue and brain fog are the most debil­i­tat­ing aspects of the con­di­tion.

    And even the symp­tom study is mov­ing slow­ly, in part because the ini­tia­tive has failed to bring in healthy peo­ple who could be com­pared against long Covid patients. RECOVER quick­ly filled its slots for peo­ple who had Covid more than 30 days pri­or to their recruit­ment, but is still look­ing for peo­ple who were infect­ed recent­ly, study lead Leo­ra Hor­witz said in a state­ment. Most study sites closed enroll­ment for long Covid patients at the end of August 2022.

    The major­i­ty of the sci­en­tif­ic find­ings to emerge from RECOVER so far have been based on small groups of patients or on elec­tron­ic health records, rather than on the thou­sands of peo­ple who signed up to par­tic­i­pate.

    The crawl­ing pace of the government’s long Covid efforts stand in stark con­trast with the government’s wild­ly suc­cess­ful part­ner­ship with the phar­ma­ceu­ti­cal indus­try to get Covid-19 vac­cines to mar­ket in less than 12 months. There are no ongo­ing efforts to sup­port inde­pen­dent pri­vate-sec­tor com­pa­nies or researchers try­ing to study treat­ments for long Covid through the NIH, even though some have proved promis­ing. Just this month, the White House left long Covid out of a $5 bil­lion effort to research next-gen­er­a­tion Covid-19 treat­ments and vac­cines.

    Long Covid researchers feel there needs to be greater urgency. Singh com­pared the pres­sure that she’s cur­rent­ly under to the pres­sure many sci­en­tists faced ear­li­er in the pan­dem­ic when study­ing vac­cines and treat­ments. “We as a sci­en­tif­ic com­mu­ni­ty need to focus on long Covid and find solu­tions for long Covid,” she said.

    Topol echoed this sen­ti­ment, cit­ing a recent opin­ion piece in Sci­en­tif­ic Amer­i­can that called for an Oper­a­tion Warp Speed for long Covid treat­ments. “That’s what should have hap­pened,” he said.

    It’s almost impos­si­ble to tell where the NIH’s $1.2 bil­lion pot of long Covid mon­ey has gone.

    There is no sin­gle NIH offi­cial respon­si­ble for lead­ing RECOVER, and the ini­tia­tive has failed to share basic infor­ma­tion that would typ­i­cal­ly be avail­able for a gov­ern­ment research project of this scale.

    Unlike Oper­a­tion Warp Speed and oth­er Covid efforts, the NIH has out­sourced much of the work of run­ning RECOVER to out­side orga­ni­za­tions. New York Uni­ver­si­ty, RTI Inter­na­tion­al, Mayo Clin­ic, Mass­a­chu­setts Gen­er­al Hos­pi­tal, and Duke Uni­ver­si­ty are respon­si­ble for var­i­ous parts of the ini­tia­tive.

    Many of the research projects asso­ci­at­ed with RECOVER have been fund­ed through these orga­ni­za­tions rather than direct­ly from the NIH. This process makes it hard to track how deci­sions are made or how mon­ey is spent through pub­lic data­bas­es, said Michael Siev­erts, a mem­ber of the long Covid Patient-Led Research Col­lab­o­ra­tive who has a back­ground in fed­er­al bud­get­ing for sci­en­tif­ic research.

    Pub­lic records requests that Muck­Rock filed to the agency in late 2022, intend­ed to answer ques­tions about RECOVER’s fund­ing, are still incom­plete as of mid-April. Siev­erts has sim­i­lar­ly asked ques­tions to NIH offi­cials and received no respons­es.

    The orga­ni­za­tion of RECOVER itself is con­vo­lut­ed, and dif­fi­cult to fig­ure out even for patient advo­cates who are direct­ly involved, they said. It’s advised by a com­plex series of com­mit­tees, some of which aren’t even post­ed on the initiative’s web­site. There’s no one per­son ulti­mate­ly respon­si­ble for coor­di­nat­ing among the dif­fer­ent insti­tutes — and requests for infor­ma­tion about the lead­er­ship hier­ar­chy have been ignored.

    “They don’t have an org chart for the entire thing that exists, after two-plus years,” said Diana Güthe, the founder of Sur­vivor Corps and a RECOVER advis­er who has asked at near­ly every meet­ing she’s attend­ed.

    Lau­ren Stiles, a patient advo­cate and Pres­i­dent and CEO of Dysau­tono­mia Inter­na­tion­al who serves on sev­er­al RECOVER com­mit­tees, shared sim­i­lar con­cerns.

    “There’s a com­plete lack of trans­paren­cy. When we ask who made this deci­sion … they won’t tell us,” Stiles said.

    As a result, when RECOVER says it’s run­ning out of funds, it’s hard to iden­ti­fy who is respon­si­ble for major deci­sions.

    In response to ques­tions about the initiative’s bud­get, the NIH said it has no mon­ey avail­able for addi­tion­al pro­gram­ming. The agency said $811 mil­lion has been legal­ly com­mit­ted to var­i­ous activ­i­ties, and the rest is ear­marked to sup­port future research activ­i­ties.

    The bud­get restric­tions are hav­ing prac­ti­cal impacts already.

    A RECOVER advi­so­ry com­mit­tee respon­si­ble for rank­ing and eval­u­at­ing poten­tial treat­ment options was put on hia­tus “due to a lack of funds,” the committee’s leader told mem­bers in late Jan­u­ary, per an email exchange shared with STAT and Muck­Rock that has not been pre­vi­ous­ly report­ed.

    The NIH told STAT and Muck­Rock that the com­mit­tee was paused because the clin­i­cal tri­al med­i­cines, devices, and treat­ment pro­grams have been cho­sen. How­ev­er, the agency said that the RECOVER clin­i­cal tri­als are “adap­tive plat­form tri­als,” which means they are designed with the inten­tion of remov­ing and adding treat­ments as new infor­ma­tion becomes avail­able.

    This cur­rent bud­get squeeze didn’t come with­out warn­ing: The NIH was well-aware last sum­mer that the agency wouldn’t have enough mon­ey to run clin­i­cal tri­als that matched the initiative’s goals of reach­ing patients with diverse symp­toms.

    One of RECOVER’s co-chairs wrote to Con­gress in June that “addi­tion­al resources are nec­es­sary” to test the full range of treat­ments need­ed.

    But the Biden admin­is­tra­tion isn’t tak­ing any action to get more fund­ing with­in the agency, or from law­mak­ers.

    NIH act­ing Direc­tor Lawrence Tabak told patient advo­cates that the agency isn’t plan­ning on direct­ing any fur­ther fund­ing for RECOVER with­in the agency. The agency said that such a request would poten­tial­ly under­cut a failed request for sup­ple­men­tal fund­ing that Con­gress ignored last year.

    [Click to read the entire doc­u­ment.]

    The Biden admin­is­tra­tion didn’t request any new funds for RECOVER in its 2024 bud­get, a large­ly aspi­ra­tional doc­u­ment that reflects the administration’s finan­cial pri­or­i­ties.

    The bud­get did include $130 mil­lion in long Covid-relat­ed asks for oth­er agen­cies, includ­ing for the Health Resources and Ser­vices Admin­is­tra­tion to sup­port care for long Covid patients with com­plex needs and to edu­cate pri­ma­ry care providers, and for the Agency for Health­care Research and Qual­i­ty to research the deliv­ery of long Covid care and to estab­lish long Covid care hubs.

    There’s also lit­tle account­abil­i­ty for NIH lead­ers to dis­close how funds are spent or respond to oth­er con­cerns with RECOVER because an enti­ty intend­ed to over­see long Covid research across the fed­er­al gov­ern­ment hasn’t been cre­at­ed.

    In April 2022, Pres­i­dent Biden issued a pres­i­den­tial mem­o­ran­dum call­ing on fed­er­al agen­cies to “har­ness the full poten­tial” of the gov­ern­ment, in part­ner­ship with pri­vate sec­tor part­ners, to respond to long Covid.

    The fol­low-through has been lack­ing on the initiative’s high­est-pro­file goal.

    In August, in a con­gres­sion­al­ly man­dat­ed nation­al long Covid research plan, the Biden admin­is­tra­tion said it would cre­ate an Office of Long Covid Research and Prac­tice at HHS. This month, HHS put out a fact sheet tout­ing the administration’s progress in reach­ing its goals — and omit­ted any men­tion of the office.

    An HHS spokesper­son said that the depart­ment is work­ing to devel­op the office, and request­ed fund­ing in next year’s White House’s bud­get for the Office of the Assis­tant Sec­re­tary for Health to coor­di­nate response efforts to long Covid.

    “It seems to have been like, well, if we don’t do any­thing, maybe no one will notice,” said Güthe. “It’s so impor­tant to do an eval­u­a­tion of what was promised. What’s been accom­plished, and what hasn’t?”

    A huge chunk of fund­ing to study a chron­ic ill­ness like long Covid is rare, so any clin­i­cal tri­als that the NIH choos­es to run are cru­cial choic­es — and some doc­tors and advo­ca­cy groups have voiced seri­ous con­cerns about the selec­tion of one clin­i­cal tri­al in par­tic­u­lar.

    That tri­al would test exer­cise as a poten­tial long Covid treat­ment, despite years of research sug­gest­ing that exer­cise could harm patients and set back fur­ther study.

    Many peo­ple with long Covid have sim­i­lar symp­toms to peo­ple with myal­gic encephalomyelitis or chron­ic fatigue syn­drome (ME/CFS), a debil­i­tat­ing con­di­tion that often fol­lows viral infec­tion. The defin­ing fea­ture of ME/CFS is intense fatigue and wors­en­ing of oth­er health issues after phys­i­cal or men­tal activ­i­ty. This symp­tom, known as post-exer­tion­al malaise, often occurs with a lag, which can make it tough for doc­tors to diag­nose — and even for patients to rec­og­nize them­selves.

    “What often hap­pens is, peo­ple will go for a walk, they may not feel it for a day or two, and then sud­den­ly, they feel ill on the third day,” said Adam Lowe, an ME/CFS patient and one of the founders of MEAc­tion UK, the U.K. branch of the Myal­gic Encephalomyelitis Action Net­work. Patients might sud­den­ly become bed-bound and have trou­ble focus­ing, he said.

    This wors­en­ing of symp­toms hap­pens because a patient isn’t pro­duc­ing and using ener­gy in the same way as a healthy per­son, said Todd Dav­en­port, a pro­fes­sor at Uni­ver­si­ty of the Pacif­ic who hasstud­ied exer­cise and this con­di­tion. It’s an inter­nal change sim­i­lar to the whole-body exhaus­tion that a marathon run­ner might expe­ri­ence at the fin­ish line of their race.

    A num­ber of past stud­ies and sur­veys of patients have demon­strat­ed how dan­ger­ous exer­cise can be for peo­ple with ME/CFS. Many patients told to exer­cise by their doc­tors lat­er dropped out of stud­ies or treat­ment reg­i­mens, cit­ing wors­en­ing symp­toms. One infa­mous tri­al that point­ed to exer­cise as a poten­tial treat­ment was lat­er dis­cred­it­ed as deeply flawed.

    Study­ing exer­cise as a treat­ment could “frame long Covid as some­thing that can be over­come with grit and hard work,” said Jaime Seltzer, the direc­tor of sci­en­tif­ic and med­ical out­reach at MEAc­tion, argu­ing that such fram­ing is “unsound and eth­i­cal­ly trou­bling.”

    Not all patients with long Covid expe­ri­ence post-exer­tion­al malaise, and those who don’t could find exer­cise help­ful, Dav­en­port said. In those cas­es, slow and care­ful exer­cise through a reha­bil­i­ta­tion or phys­i­cal ther­a­py pro­gram might help repair ener­gy sys­tems that have fall­en out of shape.

    But it may be dif­fi­cult to dis­tin­guish between these dif­fer­ent groups of patients, unless a clin­i­cal tri­al is set up with the utmost cau­tion. “Ide­al­ly, what you would want is a very coher­ent, very spe­cif­ic set of inclu­sion and exclu­sion cri­te­ria,” Dav­en­port said. Oth­er­wise, the study would risk pro­duc­ing results that over­sim­pli­fy long Covid, he added, lead­ing doc­tors to wide­ly pre­scribe a treat­ment that doesn’t work for some or many.

    Sci­en­tists and patient advo­cates respon­si­ble for advis­ing RECOVER have warned that an exer­cise tri­al could harm patients, but received mixed respons­es. Patients involved in the study sent emails and social media posts demand­ing that RECOVER stop the planned tri­al, while MEAc­tion sent a pub­lic let­ter to NIH lead­ers.

    [Click to read the entire doc­u­ment.]

    Sci­en­tists and clin­i­cians on an NIH advi­so­ry com­mit­tee focused on reha­bil­i­ta­tion sim­i­lar­ly sug­gest­ed that post-exer­tion­al malaise could be a dan­ger­ous result of the tri­al, accord­ing to inter­nal emails shared with STAT and Muck­Rock. In response, NIH pro­gram offi­cer Antonel­lo Pun­turi­eri pushed back on the con­cerns. Pun­turi­eri cit­ed clin­i­cal guide­lines from the World Health Orga­ni­za­tion and a U.K. agency, even though both rec­om­mend against exer­cise for peo­ple with ME/CFS.

    In response to these con­cerns, RECOVER set up inter­nal meet­ings includ­ing researchers in charge of the exer­cise study, patient rep­re­sen­ta­tives, and the initiative’s top advi­so­ry com­mit­tee. “Work is now under­way to fur­ther revise that pro­to­col” based on these meet­ings, the Duke Clin­i­cal Research Insti­tute said.

    [Click to read the entire doc­u­ment.]

    The study’s planned revi­sions will address con­cerns about patient safe­ty, such as mon­i­tor­ing for post-exer­tion­al malaise after exer­cise. But it’s unclear how the researchers will do this screen­ing, or whether ME/CFS doc­tors will be involved.

    Even with revi­sion, experts and patient advo­cates remain con­cerned that the exer­cise study takes resources away from oth­er research and could lead to harm­ful rec­om­men­da­tions from doc­tors. If RECOVER finds exer­cise is help­ful for some patients, asked JD Davids, an advo­cate with Long COVID Jus­tice and author of a peti­tion ask­ing the NIH to stop this tri­al, “What are the chances that doc­tors would cor­rect­ly under­stand how lim­it­ed this rec­om­men­da­tion is? I think it’s very low.”

    It’s not like there aren’t plen­ty of poten­tial treat­ment options worth study­ing.

    Topol and oth­er researchers com­piled a full table of oth­er treat­ment can­di­dates for a review paper pub­lished in Nature in Jan­u­ary. Experts on one of RECOVER’s advi­so­ry com­mit­tees com­piled a sim­i­lar list, for a paper pub­lished in March.

    Giv­en “the num­ber of oth­er can­di­date treat­ments out there, I can’t imag­ine why you would choose grad­ed exer­cise ther­a­py,” said Julia Moore Vogel, a researcher at the Scripps Trans­la­tion­al Insti­tute liv­ing with long Covid, and co-author of the Nature review paper. Vogel is lead­ing a study of wear­able devices for long Covid, which will start with about 500 par­tic­i­pants despite plan­ning for up to 100,000.

    One study has even report­ed results already, via a preprint shared by The Lancet in ear­ly March. The tri­al found that met­formin, a com­mon treat­ment for dia­betes that also has antivi­ral prop­er­ties, low­ered Covid patients’ risk of devel­op­ing long-term symp­toms by about 42%.

    This research group actu­al­ly didn’t set out to study long Covid, said David Boul­ware, one of the sci­en­tists and an infec­tious dis­ease physi­cian at the Uni­ver­si­ty of Min­neso­ta Med­ical School. The ini­tial goal was to eval­u­ate poten­tial treat­ments for acute Covid-19, but the team added long Covid track­ing part­way through the tri­al.

    And it’s unlike­ly to get fur­ther study with­out some kind of gov­ern­ment assis­tance. The ini­tial study relied on phil­an­thropic fund­ing, and addi­tion­al grants would be need­ed to keep study­ing this gener­ic drug.

    “It’s a great drug, it’s cheap, it’s avail­able world­wide,” Boul­ware said, “but there’s no prof­it mar­gin for any­one to study it.”

    There may be sim­i­lar con­cerns for research into low-dose nal­trex­one, an off-label use of the addic­tion drug that has become com­mon for long Covid and oth­er chron­ic dis­eases. In low dos­es, nal­trex­one can help reduce inflam­ma­tion in the immune and neu­ro­log­i­cal sys­tems, poten­tial­ly alle­vi­at­ing long Covid symp­toms.

    But because the drug has been wide­ly avail­able for decades, phar­ma­ceu­ti­cal com­pa­nies aren’t moti­vat­ed to fund large tri­als. A few small clin­i­cal tri­als are under­way, accord­ing to report­ing by Rolling Stone.

    The lack of help from NIH has left biotech exec­u­tives frus­trat­ed.

    “You have to under­stand what you’re try­ing to tack­le, so we sup­port that, of course. But as patients will tell you, we want inter­ven­tion, not obser­va­tion,” said Axcel­la CEO Bill Hin­shaw. His Mass­a­chu­setts-based com­pa­ny has gone all in on test­ing a drug can­di­date to treat long Covid symp­toms, with­out any help from NIH.

    Tonix Phar­ma­ceu­ti­cals, which is devel­op­ing a fibromyal­gia med­ica­tion that the com­pa­ny is hop­ing could be an effec­tive treat­ment for long Covid symp­toms, didn’t receive any fund­ing from NIH either, despite putting in an appli­ca­tion.

    “I hope there are more ther­a­peu­tics tri­als. And I think that the ther­a­peu­tics tri­als can go hand in hand with the nat­ur­al his­to­ry kind of stud­ies like RECOVER,” Tonix CEO Seth Led­er­man said.

    Patients and experts fear that if RECOVER is the extent of fed­er­al effort to study long Covid, the con­di­tion could fall into the long­stand­ing pat­tern of apa­thy and lack of urgency that has made break­throughs in chron­ic ill­ness treat­ment chal­leng­ing.

    “It’s clear that there are a lot of peo­ple at the NIH who are ded­i­cat­ed and deter­mined, try­ing to fig­ure this out,” said Char­lie McCone, a patient rep­re­sen­ta­tive at RECOVER. As a result, “patients are con­fused” why only a hand­ful of clin­i­cal tri­als have been planned and none of those have launched yet, he said.

    ...

    ————-

    “The NIH has poured $1 bil­lion into long Covid research — with lit­tle to show for it” By Rachel Cohrs and Bet­sy Ladyzhets; Stat News; 04/20/2023

    “There’s no sense of urgency to do more or to speed things up, either. The agency isn’t ask­ing Con­gress for any more fund­ing for long Covid research, and STAT and Muck­Rock obtained doc­u­ments show­ing the NIH refus­es to use its own mon­ey to change course.”

    Over $1 bil­lion invest­ed into...what exact­ly? Where did the mon­ey go? That’s part of the mys­tery here. But only part. There’s also gen­er­al mys­tery of who is even run­ning the fed­er­al­ly-fund­ed RECOVER pro­gram, which is espe­cial­ly prob­lem­at­ic when you want to get an answer as to why the pro­gram has­n’t done any of the things it was man­dat­ed to do but instead appears to just be putting up new obsta­cles and delays. Some­how this pro­gram was set up in a man­ner where no one appears to be account­able:

    ...
    The Nation­al Insti­tutes of Health hasn’t signed up a sin­gle patient to test any poten­tial treat­ments — despite a clear man­date from Con­gress to study them. And the few tri­als it is plan­ning have already drawn a firestorm of crit­i­cism, espe­cial­ly one inter­ven­tion that experts and advo­cates say may actu­al­ly make some patients’ long Covid symp­toms worse.

    Instead, the NIH spent the major­i­ty of its mon­ey on broad­er, obser­va­tion­al research that won’t direct­ly bring relief to patients. But it still hasn’t pub­lished any find­ings from the patients who joined that study, almost two years after it start­ed.

    ...

    “So far, I don’t think we’ve got­ten any­thing for a bil­lion dol­lars,” said Ezekiel Emanuel, a physi­cian, vice provost for glob­al ini­tia­tives, and co-direc­tor of the Health­care Trans­for­ma­tion Insti­tute at the Uni­ver­si­ty of Penn­syl­va­nia. “That is just unac­cept­able, and it’s a seri­ous dys­func­tion.”

    Eric Topol, the founder and direc­tor of the Scripps Research Trans­la­tion­al Insti­tute, said he expect­ed the NIH would have launched many large-scale tri­als by now, and that test­ing treat­ments should have been an urgent pri­or­i­ty when Con­gress first gave the agency mon­ey in late 2020.

    “I don’t know that they’ve con­tributed any­thing except more con­fu­sion,” Topol said.

    Patients and researchers have already raised alarms about the glacial pace of the NIH’s ear­ly long Covid efforts. But a new inves­ti­ga­tion from STAT and the non­prof­it news orga­ni­za­tion Muck­Rock, based on inter­views with near­ly two dozen gov­ern­ment offi­cials, experts, patients, and advo­cates, and inter­nal NIH cor­re­spon­dence, let­ters, and pub­lic doc­u­ments, under­scores that the NIH hasn’t picked up the pace — instead, the delays have com­pound­ed.

    It’s dif­fi­cult to pin­point exact­ly why progress is so stalled, experts and patients involved in the project empha­sized, because the NIH has obscured both who is in charge of the long Covid efforts and how it spent the mon­ey. The broad­er Biden admin­is­tra­tion has also missed oppor­tu­ni­ties for over­sight and account­abil­i­ty of the effort — despite the president’s lofty promis­es to focus on the dis­ease.

    The NIH’s blun­ders have mas­sive ram­i­fi­ca­tions for the more than 16 mil­lion Amer­i­cans suf­fer­ing from long Covid, in addi­tion to those with oth­er, sim­i­lar chron­ic dis­eases. As the biggest gov­ern­ment-fund­ed study on this top­ic, the NIH ini­tia­tive, dubbed RECOVER, sets prece­dents for future research and clin­i­cal guide­lines. It will dic­tate how doc­tors across the coun­try treat their patients — and, in turn, impact people’s abil­i­ty to access work accom­mo­da­tions, dis­abil­i­ty ben­e­fits, and more.
    ...

    And, again, note that the $1.2 bil­lion ear­marked by Con­gress for the RECOVER pro­gram was explic­it­ly ear­marked to fund both stud­ies that exam­ine the dis­ease pathol­o­gy of long COVID but also treat­ments. And yet, at this point there has­n’t been a sin­gle treat­ment test­ed. And the only treat­ment approved so far will focus on Pfiz­er’s Paxlovid. This is a good time to recall how the rel­a­tive­ly expen­sive new drug Paxlovid appeared to work in a sim­i­lar man­ner to the much cheap­er exist­ing drug lopinavir, and yet, as we saw, no tri­als of lopinavir’s effi­ca­cy against SARS-CoV­‑2 was ever con­duct­ed at the time of Paxlovid’s roll out. And even that Paxlovid tri­al is behind sched­ule, but keep in mind that Paxlovid is already approved so it’s not like this delay is harm­ing Pfiz­er’s bot­tom line. It’s a per­va­sive pat­tern:

    ...
    In 2020, Con­gress made an invest­ment of $1.2 bil­lion to learn more about the mys­te­ri­ous ongo­ing symp­toms that were afflict­ing some peo­ple infect­ed with Covid-19. That sort of mon­ey to fund research into a chron­ic con­di­tion like long Covid was vir­tu­al­ly unheard of.

    The mon­ey was explic­it­ly ear­marked to fund both research to under­stand the dis­ease and clin­i­cal tri­als to test treat­ments that could bring patients relief. But more than two years in, the agency hasn’t start­ed test­ing a sin­gle treat­ment. Nor is it plan­ning to test many in the future. Instead, it’s focused on obser­va­tion­al research — and that, too, has pro­duced few insights.

    The NIH is plan­ning five clin­i­cal tri­als, each of which will test treat­ments that may help with a major cat­e­go­ry of long Covid symp­toms. Some of these treat­ments will be drugs, while oth­ers will be behav­ioral ther­a­pies, such as cog­ni­tive retrain­ing. Each tri­al will include 300 to 900 patients, select­ed based on their symp­toms, accord­ing to details shared dur­ing a webi­nar in mid-April.

    The only tri­al to be for­mal­ly announced so far will focus on Paxlovid, test­ing whether the drug alle­vi­ates symp­toms by mit­i­gat­ing any ongo­ing viral infec­tion in patients’ bod­ies. The study was sup­posed to start recruit­ing in Jan­u­ary.

    But as of April, RECOVER hasn’t signed up a sin­gle patient for any of those clin­i­cal tri­als. And the time­line has slipped over and over again.
    ...

    And as the arti­cle notes, this is all in stark con­trast with the US gov­ern­men­t’s “wild­ly suc­cess­ful part­ner­ship with the phar­ma­ceu­ti­cal indus­try to get Covid-19 vac­cines to mar­ket”. Indeed, it’s been quite the con­trast when it comes to cheap­er exist­ing drug alter­na­tives like met­formin or nal­trex­one, where the NIH just could­n’t be both­ered to help. Except it’s not real­ly in con­trast if you oper­at­ing on the assump­tion that max­i­miz­ing the phar­ma­ceu­ti­cal indus­try’s prof­it mar­gins is the top pri­or­i­ty. It’s all quite con­sis­tent with reg­u­la­to­ry cap­ture, whether we’re talk­ing about vac­cines or drug treat­ments:

    ...
    The crawl­ing pace of the government’s long Covid efforts stand in stark con­trast with the government’s wild­ly suc­cess­ful part­ner­ship with the phar­ma­ceu­ti­cal indus­try to get Covid-19 vac­cines to mar­ket in less than 12 months. There are no ongo­ing efforts to sup­port inde­pen­dent pri­vate-sec­tor com­pa­nies or researchers try­ing to study treat­ments for long Covid through the NIH, even though some have proved promis­ing. Just this month, the White House left long Covid out of a $5 bil­lion effort to research next-gen­er­a­tion Covid-19 treat­ments and vac­cines.

    ...

    One study has even report­ed results already, via a preprint shared by The Lancet in ear­ly March. The tri­al found that met­formin, a com­mon treat­ment for dia­betes that also has antivi­ral prop­er­ties, low­ered Covid patients’ risk of devel­op­ing long-term symp­toms by about 42%.

    This research group actu­al­ly didn’t set out to study long Covid, said David Boul­ware, one of the sci­en­tists and an infec­tious dis­ease physi­cian at the Uni­ver­si­ty of Min­neso­ta Med­ical School. The ini­tial goal was to eval­u­ate poten­tial treat­ments for acute Covid-19, but the team added long Covid track­ing part­way through the tri­al.

    And it’s unlike­ly to get fur­ther study with­out some kind of gov­ern­ment assis­tance. The ini­tial study relied on phil­an­thropic fund­ing, and addi­tion­al grants would be need­ed to keep study­ing this gener­ic drug.

    “It’s a great drug, it’s cheap, it’s avail­able world­wide,” Boul­ware said, “but there’s no prof­it mar­gin for any­one to study it.”

    There may be sim­i­lar con­cerns for research into low-dose nal­trex­one, an off-label use of the addic­tion drug that has become com­mon for long Covid and oth­er chron­ic dis­eases. In low dos­es, nal­trex­one can help reduce inflam­ma­tion in the immune and neu­ro­log­i­cal sys­tems, poten­tial­ly alle­vi­at­ing long Covid symp­toms.

    But because the drug has been wide­ly avail­able for decades, phar­ma­ceu­ti­cal com­pa­nies aren’t moti­vat­ed to fund large tri­als. A few small clin­i­cal tri­als are under­way, accord­ing to report­ing by Rolling Stone.

    The lack of help from NIH has left biotech exec­u­tives frus­trat­ed.

    “You have to under­stand what you’re try­ing to tack­le, so we sup­port that, of course. But as patients will tell you, we want inter­ven­tion, not obser­va­tion,” said Axcel­la CEO Bill Hin­shaw. His Mass­a­chu­setts-based com­pa­ny has gone all in on test­ing a drug can­di­date to treat long Covid symp­toms, with­out any help from NIH.
    ...

    And that brings us to this remark­able claim by Tonix Phar­ma­ceu­ti­cals: Tonix ulti­mate­ly received NO FEDERAL fund­ing for its POTENTIALLY BLOCKBUSTER DRUG. Recall the intrigu­ing sto­ry of Oya­Gen, the Rochester, NY-based com­pa­ny that claimed to have found a well-estab­lished safe old drug was effec­tive­ly ster­il­iz­ing SARS-CoV­‑2. These find­ings were derived in part­ner­ship with US gov­ern­ment researchers as Fort Det­rick. The founder of Oya­Gen even went to the media call­ing for some sort of atten­tion to be drawn to these find­ings and per­mis­sion for emer­gency clin­i­cal tri­als. Noth­ing came of that. Instead, as we lat­er saw, Oya­Gen basi­cal­ly sold the rights to Oya‑1 to Tonix Phar­ma­ceu­ti­cals. And now we’re learn­ing that the US gov­ern­ment has con­tin­ued to refuse to sup­port the devel­op­ment of this drug...an old drug that the phar­ma­ceu­ti­cal indus­try sim­ply won’t be able to charge exor­bi­tant prices to use:

    ...
    Tonix Phar­ma­ceu­ti­cals, which is devel­op­ing a fibromyal­gia med­ica­tion that the com­pa­ny is hop­ing could be an effec­tive treat­ment for long Covid symp­toms, didn’t receive any fund­ing from NIH either, despite putting in an appli­ca­tion.

    “I hope there are more ther­a­peu­tics tri­als. And I think that the ther­a­peu­tics tri­als can go hand in hand with the nat­ur­al his­to­ry kind of stud­ies like RECOVER,” Tonix CEO Seth Led­er­man said.

    Patients and experts fear that if RECOVER is the extent of fed­er­al effort to study long Covid, the con­di­tion could fall into the long­stand­ing pat­tern of apa­thy and lack of urgency that has made break­throughs in chron­ic ill­ness treat­ment chal­leng­ing.

    “It’s clear that there are a lot of peo­ple at the NIH who are ded­i­cat­ed and deter­mined, try­ing to fig­ure this out,” said Char­lie McCone, a patient rep­re­sen­ta­tive at RECOVER. As a result, “patients are con­fused” why only a hand­ful of clin­i­cal tri­als have been planned and none of those have launched yet, he said.
    ...

    But it’s not sim­ply that RECOVER is pri­or­i­tiz­ing the study the long COVID dis­ease over the study of treat­ments. Even the stud­ies of the dis­ease are run­ning behind sched­ule. It’s like we have a $1.2 bil­lion smoke­screen:

    ...
    Rather than pri­or­i­tiz­ing treat­ments from the start, the NIH used much of its long Covid fund­ing on a large-scale study to track long Covid symp­toms and learn how the dis­ease works. This choice has frus­trat­ed patients because thou­sands of oth­er stud­ies have already answered many major ques­tions about the con­di­tion.

    “We didn’t need to recre­ate” exist­ing stud­ies that already answered these ques­tions, said Cole, the long Covid patient. Researchers have been com­pil­ing lists of com­mon symp­toms since sum­mer 2020, she said. For Cole, fatigue and brain fog are the most debil­i­tat­ing aspects of the con­di­tion.

    And even the symp­tom study is mov­ing slow­ly, in part because the ini­tia­tive has failed to bring in healthy peo­ple who could be com­pared against long Covid patients. RECOVER quick­ly filled its slots for peo­ple who had Covid more than 30 days pri­or to their recruit­ment, but is still look­ing for peo­ple who were infect­ed recent­ly, study lead Leo­ra Hor­witz said in a state­ment. Most study sites closed enroll­ment for long Covid patients at the end of August 2022.

    The major­i­ty of the sci­en­tif­ic find­ings to emerge from RECOVER so far have been based on small groups of patients or on elec­tron­ic health records, rather than on the thou­sands of peo­ple who signed up to par­tic­i­pate.
    ...

    Final­ly, we get to this very inter­est­ing tie in to anoth­er long-stand­ing med­ical scan­dal: the refusal to rec­og­nize chron­ic-fatigue syn­drome (CFS). Keep in mind the sor­did his­to­ry tying the emer­gence of CFS to Lyme dis­ease, its direct ties US biowar­fare research, and the decades of appar­ent coverup of that research in rela­tion to Lyme dis­ease and CFS. And here we find the CFS com­mu­ni­ty rais­ing major alarm bells about the lack of any CFS-relat­ed con­sid­er­a­tions in the long COVID pop­u­la­tion despite the enor­mous symp­to­matic over­lap. Are we look­ing at anoth­er biowar­fare-relat­ed CFS coverup in action?

    ...
    Many peo­ple with long Covid have sim­i­lar symp­toms to peo­ple with myal­gic encephalomyelitis or chron­ic fatigue syn­drome (ME/CFS), a debil­i­tat­ing con­di­tion that often fol­lows viral infec­tion. The defin­ing fea­ture of ME/CFS is intense fatigue and wors­en­ing of oth­er health issues after phys­i­cal or men­tal activ­i­ty. This symp­tom, known as post-exer­tion­al malaise, often occurs with a lag, which can make it tough for doc­tors to diag­nose — and even for patients to rec­og­nize them­selves.

    ...

    This wors­en­ing of symp­toms hap­pens because a patient isn’t pro­duc­ing and using ener­gy in the same way as a healthy per­son, said Todd Dav­en­port, a pro­fes­sor at Uni­ver­si­ty of the Pacif­ic who hasstud­ied exer­cise and this con­di­tion. It’s an inter­nal change sim­i­lar to the whole-body exhaus­tion that a marathon run­ner might expe­ri­ence at the fin­ish line of their race.

    A num­ber of past stud­ies and sur­veys of patients have demon­strat­ed how dan­ger­ous exer­cise can be for peo­ple with ME/CFS. Many patients told to exer­cise by their doc­tors lat­er dropped out of stud­ies or treat­ment reg­i­mens, cit­ing wors­en­ing symp­toms. One infa­mous tri­al that point­ed to exer­cise as a poten­tial treat­ment was lat­er dis­cred­it­ed as deeply flawed.

    Study­ing exer­cise as a treat­ment could “frame long Covid as some­thing that can be over­come with grit and hard work,” said Jaime Seltzer, the direc­tor of sci­en­tif­ic and med­ical out­reach at MEAc­tion, argu­ing that such fram­ing is “unsound and eth­i­cal­ly trou­bling.”

    ...

    Sci­en­tists and clin­i­cians on an NIH advi­so­ry com­mit­tee focused on reha­bil­i­ta­tion sim­i­lar­ly sug­gest­ed that post-exer­tion­al malaise could be a dan­ger­ous result of the tri­al, accord­ing to inter­nal emails shared with STAT and Muck­Rock. In response, NIH pro­gram offi­cer Antonel­lo Pun­turi­eri pushed back on the con­cerns. Pun­turi­eri cit­ed clin­i­cal guide­lines from the World Health Orga­ni­za­tion and a U.K. agency, even though both rec­om­mend against exer­cise for peo­ple with ME/CFS.

    In response to these con­cerns, RECOVER set up inter­nal meet­ings includ­ing researchers in charge of the exer­cise study, patient rep­re­sen­ta­tives, and the initiative’s top advi­so­ry com­mit­tee. “Work is now under­way to fur­ther revise that pro­to­col” based on these meet­ings, the Duke Clin­i­cal Research Insti­tute said.

    [Click to read the entire doc­u­ment.]

    The study’s planned revi­sions will address con­cerns about patient safe­ty, such as mon­i­tor­ing for post-exer­tion­al malaise after exer­cise. But it’s unclear how the researchers will do this screen­ing, or whether ME/CFS doc­tors will be involved.

    ...

    Topol and oth­er researchers com­piled a full table of oth­er treat­ment can­di­dates for a review paper pub­lished in Nature in Jan­u­ary. Experts on one of RECOVER’s advi­so­ry com­mit­tees com­piled a sim­i­lar list, for a paper pub­lished in March.

    Giv­en “the num­ber of oth­er can­di­date treat­ments out there, I can’t imag­ine why you would choose grad­ed exer­cise ther­a­py,” said Julia Moore Vogel, a researcher at the Scripps Trans­la­tion­al Insti­tute liv­ing with long Covid, and co-author of the Nature review paper. Vogel is lead­ing a study of wear­able devices for long Covid, which will start with about 500 par­tic­i­pants despite plan­ning for up to 100,000.
    ...

    It looks like the CFS com­mu­ni­ty is going to be grow­ing quite a bit in com­ing decades. Let’s hope this now-COVID-fueled patient pop­u­la­tion is able to have more suc­cess than the Lyme Dis­ease CFS suf­fer­ers in wran­gling the truth of this dis­ease and its ori­gins. Of course, there’s a poten­tial dark flip-side to this: the need to cov­er up the biowar­fare ori­gins of Lyme Dis­ease are even more urgent now that we have this whole new COVID CFS mega-scan­dal and relat­ed biowar­fare his­to­ry. Might we already be see­ing that cov­er up in action? It sure would explain the near com­plete lack of progress. It’s also a grim reminder that when we’re talk­ing about inex­plic­a­ble delays and obsta­cles put in front of cru­cial research need­ed to answer vital ques­tions, we should­n’t nec­es­sar­i­ly assume the answers to those cru­cial ques­tions aren’t already qui­et­ly known. And already qui­et­ly iden­ti­fied as too scan­dalous to pub­licly answer.

    Posted by Pterrafractyl | May 4, 2023, 4:32 pm
  3. It’s hard to think of a scari­er update about the nature of the SARS-CoV­‑2 virus than the recent study reveal­ing the exten­sive DNA dam­age caused by the virus. But as we seem­ing­ly always dis­cov­er, things can always get worse and scari­er. And that brings us to the fol­low­ing pair of stud­ies that fur­ther elu­ci­date both the scope of the dam­age inflict­ed upon cel­lu­lar DNA and the unusu­al nature of this dam­age.

    First, it turns out the DNA dam­age caused by SARS-CoV­‑2 was iden­ti­fied back in Sep­tem­ber in a study that com­pared the hearts of patients who died from COVID vs those who died from influen­za. As we should now expect, they found exten­sive signs of DNA dam­age in the hearts of the SARS-CoV­‑2 patients. As the researchers put it, the DNA dam­age pre­sent­ed was sim­i­lar to the way chron­ic dis­eases such as dia­betes or even can­cer pre­sent­ed. Inter­est­ing­ly, this DNA dam­age was much low­er in the influen­za patients.

    Anoth­er intrigu­ing find­ing was that the inflam­ma­to­ry sig­nals in the hearts of the COVID patients appeared to be sup­pressed. Keep in mind that we’ve seen an asso­ci­a­tion between myocardi­tis — inflam­ma­tion of the heart — in both COVID patients and also peo­ple who have just received the vac­cine. Also keep in mind that the peo­ple used in this study obvi­ous­ly had severe cas­es of COVID since they died and may not be rep­re­sen­ta­tive of the impact of the virus on rel­a­tive­ly healthy peo­ple. It’s part of what will make this all a very inter­est­ing avenue of fur­ther inves­ti­ga­tion.

    Next, there was a study pub­lished back in March that looks at a dif­fer­ent form of dam­age inflict­ed upon the cel­l’s nucle­us: a dra­mat­ic repro­gram­ming of the cel­l’s 3d-struc­tu “epigenome”. Put sim­ply, while all cells pos­sess all of your genes, only some genes are made “avail­able” in each cell-type and SARS-CoV­‑2 appears to change which genes are “avail­able” or not in a high­ly chaot­ic man­ner. It’s, again, the kind of phe­nom­e­na we expect to see in can­cer. Oh, and it turns out this epi­ge­net­ic repro­gram­ming isn’t seen in the oth­er com­mon-cold coro­n­avirus­es they test­ed. We just keep find­ing SARS-CoV­‑2 nov­el ‘fea­tures’.

    Ok, first, here’s as look at that Sep­tem­ber 2022 paper find­ing exten­sive DNA dam­age in the hearts of SARS-CoV­‑2 patients, but not in influen­za patients, sug­gest­ing that there’s some­thing unusu­al about how SARS-CoV­‑2 attacks the cel­l’s DNA. But not entire­ly unusu­al. It’s the same kind of DNA dam­age sig­nal seen in dia­betes and can­cer:

    Bris­bane Times

    Unlike flu, COVID-19 attacks DNA in the heart: new research

    By Stu­art Layt
    Sep­tem­ber 29, 2022 — 8.07pm

    Direct research on the hearts of COVID-19 patients who have died from the dis­ease has revealed they sus­tained DNA dam­age in a way com­plete­ly unlike how influen­za affects the body.

    ...

    The work was an inter­na­tion­al col­lab­o­ra­tion led by researchers from Aus­tralia, with Dr Arutha Kulas­inghe from the Uni­ver­si­ty of Queensland’s Dia­man­ti­na Insti­tute and Ning Liu from Victoria’s Wal­ter and Eliza Hall Insti­tute of Med­ical Research co-lead authors.

    Kulas­inghe said the research is only a pre­lim­i­nary step because the sam­ple size was so small – the hearts of just sev­en COVID-19 patients from Brazil were stud­ied for the paper, along with hearts from peo­ple who had died from influen­za and a con­trol group.

    But he said their find­ings gave them insight for the first time as to why the heart was being affect­ed by COVID-19 but not but severe influen­za.

    “We found a lot of DNA dam­age that was unique to the COVID-19 patients which wasn’t present in the flu patients,” he said.

    “So in this study, COVID-19 and flu look very dif­fer­ent in the way they affect the heart.”

    The fact that COVID-19 affects people’s hearts has been observed both anec­do­tal­ly and in a num­ber of stud­ies since the start of the pan­dem­ic, but the under­ly­ing cause is still yet to be deter­mined.

    One rea­son is that it is extreme­ly dif­fi­cult to get tis­sue sam­ples from a liv­ing heart, so researchers have to wait for peo­ple to die from the dis­ease and for their heart to be able to be stud­ied.

    Kulas­inghe said he and his col­leagues found that rather than extreme inflam­ma­tion which they had expect­ed to find, inflam­ma­tion sig­nals had been sup­pressed in the hearts of the COVID-19 patients, while mark­ers for DNA dam­age and repair were much high­er than in peo­ple who had died from the flu.

    “So the indi­ca­tions here are that there’s DNA dam­age here, it’s not inflam­ma­tion, there’s some­thing else going on that we need to fig­ure out,” Kulas­inghe said.

    He said the way the DNA dam­age pre­sent­ed was sim­i­lar to the way chron­ic dis­eases such as dia­betes or even can­cer pre­sent­ed, with the tis­sues of the heart putting out DNA dam­age sig­nals.

    ...

    A fed­er­al sen­ate inquiry into the issue is cur­rent­ly tak­ing sub­mis­sions, with the inquiry’s Chair, south-west­ern Syd­ney Labor MP Dr Mike Free­lander, say­ing say­ing ear­li­er this month that he was “very con­cerned” about high­er-than-nor­mal deaths in the pan­dem­ic and that more research was need­ed to ascer­tain why.

    Kulas­inghe said they hoped their find­ings could be built upon to devel­op meth­ods to estab­lish who was at risk of seri­ous com­pli­ca­tions from COVID-19, so they could be treat­ed ear­ly.

    “Ide­al­ly in the future if you have car­dio­vas­cu­lar dis­ease, if you’re obese or have oth­er com­pli­ca­tions, and you’ve got a sig­na­ture in your blood that indi­cates you are at risk of severe dis­ease, then we can risk-strat­i­fy patients when they are diag­nosed,” he said.

    “Our chal­lenge now is to draw a clin­i­cal find­ing from this, which we can’t at this stage, but it’s a real­ly fun­da­men­tal bio­log­i­cal dif­fer­ence we’re observ­ing [between COVID-19 and flu] which we need to val­i­date with larg­er stud­ies.”

    The research has been pub­lished in the jour­nal Immunol­o­gy.

    ————

    “Unlike flu, COVID-19 attacks DNA in the heart: new research” By Stu­art Layt; Bris­bane Times; 09/29/2022

    “The fact that COVID-19 affects people’s hearts has been observed both anec­do­tal­ly and in a num­ber of stud­ies since the start of the pan­dem­ic, but the under­ly­ing cause is still yet to be deter­mined.”

    A con­nec­tion between COVID and heart trou­bles isn’t new. We’ve repeat­ed­ly heard such anec­dotes. What is new is the dis­cov­ery that this heart dam­age is not seen in influen­za patients and is direct­ly relat­ed to DNA dam­age. It’s fur­ther evi­dence that DNA dam­age is part of what is dri­ving a num­ber of COVID’s unusu­al fea­tures. At least unusu­al for a viral infec­tion. It’s the same kind of DNA dam­age seen in chron­ic dis­eases asso­ci­at­ed with chron­ic inflam­ma­tion like dia­betes and can­cer:

    ...
    Kulas­inghe said the research is only a pre­lim­i­nary step because the sam­ple size was so small – the hearts of just sev­en COVID-19 patients from Brazil were stud­ied for the paper, along with hearts from peo­ple who had died from influen­za and a con­trol group.

    But he said their find­ings gave them insight for the first time as to why the heart was being affect­ed by COVID-19 but not but severe influen­za.

    “We found a lot of DNA dam­age that was unique to the COVID-19 patients which wasn’t present in the flu patients,” he said.

    “So in this study, COVID-19 and flu look very dif­fer­ent in the way they affect the heart.”

    ...

    One rea­son is that it is extreme­ly dif­fi­cult to get tis­sue sam­ples from a liv­ing heart, so researchers have to wait for peo­ple to die from the dis­ease and for their heart to be able to be stud­ied.

    Kulas­inghe said he and his col­leagues found that rather than extreme inflam­ma­tion which they had expect­ed to find, inflam­ma­tion sig­nals had been sup­pressed in the hearts of the COVID-19 patients, while mark­ers for DNA dam­age and repair were much high­er than in peo­ple who had died from the flu.

    “So the indi­ca­tions here are that there’s DNA dam­age here, it’s not inflam­ma­tion, there’s some­thig else going on that we need to fig­ure out,” Kulas­inghe said.

    He said the way the DNA dam­age pre­sent­ed was sim­i­lar to the way chron­ic dis­eases such as dia­betes or even can­cer pre­sent­ed, with the tis­sues of the heart putting out DNA dam­age sig­nals.

    ...

    “Our chal­lenge now is to draw a clin­i­cal find­ing from this, which we can’t at this stage, but it’s a real­ly fun­da­men­tal bio­log­i­cal dif­fer­ence we’re observ­ing [between COVID-19 and flu] which we need to val­i­date with larg­er stud­ies.”
    ...

    How many oth­er tis­sues is SARS-CoV­‑2 induc­ing this kind of DNA dam­age? Don’t for­get that one of the dis­turb­ing fea­tures of SARS-CoV­‑2 was how wide­spread the infec­tion could get across a wide vari­ety of tis­sues. DNA dam­age in the heart might kill you in the short run, but that does­n’t mean there isn’t all sorts of long-term DNA dam­age in oth­er tis­sues tak­ing place. How about in the tes­ti­cles and ovaries? Any DNA dam­age tak­ing place there? Let’s hope some­one is inves­ti­gat­ing that.

    But as the fol­low­ing arti­cle about research pub­lished back in March reminds us, there’s more than one way for SARS-CoV­‑2 to dam­age your cel­l’s DNA. Because it turns out SARS-CoV­‑2 has anoth­er DNA-dam­ag­ing trait: dra­mat­ic epige­nom­ic repro­gram­ming. Yes, SARS-CoV­‑2 appears to sig­nif­i­cant­ly dis­rupt the 3D chro­matin struc­ture inside the cell nucle­us that deter­mines which genes are “avail­able” inside a cell. Keep in mind that ALL cells pos­sess ALL genes, but WHICH gene is ‘avail­able’ is deter­mined by the cell type. In oth­er words, if you dra­mat­i­cal­ly change which genes are ‘turned on’ in a cell you’re effec­tive­ly scram­bling its mode of oper­a­tion and turn it into anoth­er kind of dys­func­tion­al cell. Some­thing much clos­er to a can­cer cell, which has epige­nom­ic repro­gram­ming as one of its hall­mark fea­tures. So as we learn more and more about the dam­age SARS-CoV­‑2 is going to the genet­ic con­tents of the cells it attacks, keep in mind that it’s not just induc­ing DNA muta­tions. It’s also scram­bling the high­er-lev­el reg­u­la­to­ry genet­ic struc­ture:

    News-Medical.net

    Epigenome repro­gram­ming after SARS-CoV­‑2 infec­tion

    By Neha Math­ur Mar 27 2023
    Reviewed by Lily Ram­sey, LLM

    In a recent arti­cle in pub­lished in the jour­nal Nature Micro­bi­ol­o­gy, researchers in Texas, Unit­ed States (US) per­formed a three-dimen­sion­al (3D) eval­u­a­tion of severe acute res­pi­ra­to­ry syn­drome coro­n­avirus 2 (SARS-CoV­‑2) infect­ed human cells to show a direct cell-autonomous effect elicit­ed by SARS-CoV­‑2 on the host chro­matin.

    The study aimed at improv­ing the under­stand­ing of coro­n­avirus dis­ease 2019 (COVID-19)-related per­tur­ba­tions in the genome and epigenome of a host cell.

    Back­ground

    The 3D fold­ing of chro­matin in mam­mals, includ­ing humans, influ­ences deoxyri­bonu­cle­ic acid (DNA) repli­ca­tion, recom­bi­na­tion, DNA dam­age repair, and tran­scrip­tion. It is a key deter­mi­nant of how human cells act and func­tion. Virus­es, includ­ing SARS-CoV­‑2, antag­o­nize host defense by rewiring their chro­matin archi­tec­ture, which typ­i­cal­ly has sev­er­al lay­ers, e.g., A/B com­part­ments, chro­matin loops, and topo­log­i­cal asso­ci­at­ing domains (TADs).

    The A and B com­part­ments super­im­pose tran­scrip­tion­al­ly active euchro­matin and rel­a­tive­ly inac­tive het­e­rochro­matin, respec­tive­ly. How­ev­er, stud­ies have bare­ly inves­ti­gat­ed these effects.

    In addi­tion, epi­ge­net­ic alter­ations impact gene expres­sion and result­ing phe­no­types in the long term. Thus, a sneak peek into the inter­ac­tions between the virus, host chro­matin, and epigenome could help find nov­el meth­ods to fight SARS-CoV­‑2 in the acute phase. In addi­tion, it could unrav­el the mol­e­c­u­lar basis of post-acute SARS-CoV­‑2 seque­lae or long COVID and sub­se­quent­ly mit­i­gate it.

    About the study

    At 24 hours post-infec­tion (24 hpi), human A549 cells express­ing angiotensin-con­vert­ing enzyme 2 (ACE2), infect­ed with SARS-CoV­‑2 at a mul­ti­plic­i­ty of infec­tion (MOI) of 0.1, had high lev­els of infec­tion. This was shown by ribonu­cle­ic acid-sequenc­ing (RNA-seq). Immuno­flu­o­res­cence of the SARS-CoV­‑2 spike (S) gly­co­pro­tein also sub­stan­ti­at­ed an ele­vat­ed infec­tion ratio.

    ...

    Results

    The Hi‑C analy­sis showed exten­sive alter­ations in the hosts’ 3D genome after SARS-CoV­‑2 infec­tion. The researchers also plot­ted a Pear­son cor­re­la­tion map of their Hi‑C analy­sis that reaf­firmed these changes along­side indi­cat­ing mod­i­fied chro­matin com­part­men­tal­iza­tion.

    A focused view of the ~0.7 Mb region showed a weak­en­ing of the rec­tan­gle-shaped chro­matin domains and dereg­u­la­tion of chro­matin loops. While SARS-CoV­‑2 prompt­ed a glob­al decline in near-diag­o­nal short-range chro­matin con­tacts (28 megabas­es) were often dereg­u­lat­ed.

    Fur­ther, a P(s) curve showed that SARS-CoV­‑2 elicit­ed mod­est and enhanced inter­ac­tions in mid­dle-to-long-dis­tance con­tacts (~560 kb to 8.9 Mb) and far-posi­tioned regions, respec­tive­ly.

    Fold changes in inter-chro­mo­so­mal inter­ac­tions or trans-vs-cis con­tact ratios also depict­ed the effect of SARS-CoV­‑2 infec­tion on inter-chro­mo­so­mal con­tacts. The enhance­ment of inter- and intra-chro­mo­so­mal inter­ac­tions indi­cat­ed changes in chro­matin com­part­men­tal­iza­tion. Con­se­quent­ly, prin­ci­pal com­po­nent analy­sis (PCA) of a 100-kb bin on Hi‑C back­ground showed notice­able defects of chro­matin com­part­men­tal­iza­tion in virus-infect­ed cells.

    The total PCA E1 scores quan­ti­fy­ing E1 changes in ~30% of genom­ic regions showed a wide­spread dimin­ish­ing of the A com­part­ment, A‑to‑B switch­ing, or strength­en­ing of the B com­part­ment post-SARS-CoV­‑2 infec­tion.

    Among all, A to weak­er A changes were the most com­mon and occurred in ~18% of the genome, which indi­cat­ed that SARS-CoV­‑2 exten­sive­ly weak­ened the host euchro­matin.

    Fur­ther analy­sis showed that the ‘B‑ing’ and ‘A‑ing’ genom­ic regions were his­tor­i­cal­ly enriched in active chro­matin mark­ers (e.g., H3K27ac) and repres­sive his­tone mark­ers, espe­cial­ly H3K27me3. Unex­pect­ed­ly, SARS-CoV­‑2 infec­tion selec­tive­ly mod­i­fied the H3K4me3 mark­er of phy­tochrome inter­act­ing fac­tors (PIF) gene pro­mot­ers, sug­gest­ing unap­pre­ci­at­ed mech­a­nisms at these pro­mot­ers that con­fer devi­at­ing inflam­ma­tion in COVID-19.

    A flawed chro­matin com­part­men­tal­iza­tion like­ly caused the his­tor­i­cal­ly well-par­ti­tioned A or B com­part­ments to lose their iden­ti­ty. A sad­dle plot illus­trat­ing inter-com­part­ment chro­matin inter­ac­tions across the genome showed these glob­al changes.

    The authors also not­ed weak­ened com­part­men­tal­iza­tion between chro­mo­somes. For instance, in chro­mo­somes 17 & 18, while A–B inter­ac­tions were ampli­fied, A–A/B–B homo­typ­ic inter­ac­tions appeared to have become com­pro­mised.

    More­over, SARS-CoV­‑2 infec­tion mech­a­nis­ti­cal­ly deplet­ed the cohesin com­plex in a per­va­sive but selec­tive man­ner from intra-TAD regions. These changes pro­vid­ed a mol­e­c­u­lar expla­na­tion for the weak­en­ing of intra-TAD inter­ac­tions.

    It sup­port­ed the notion that defec­tive cohesin loop extru­sion inside TADs releas­es this chro­matin to engage in long-dis­tance asso­ci­a­tions. Intrigu­ing­ly, chro­matin in SARS-CoV-2-infect­ed cells exhib­it­ed a high­er fre­quen­cy of long-dis­tance intra-chro­mo­so­mal and inter-chro­mo­so­mal inter­ac­tions.

    Con­clu­sions

    SARS-CoV­‑2 infec­tion marked­ly restruc­tured 3D host chro­matin, fea­tur­ing wide­spread com­part­ment A weak­en­ing and A–B mix­ing and glob­al reduc­tion in intra-TAD chro­matin con­tacts.

    How­ev­er, it is still unknown exact­ly how SARS-COV‑2 infec­tion restruc­tures host chro­matin. Like­ly, open read­ing frame 8 (ORF8) dis­rupts the host epigenome, sug­gest­ing that some viral fac­tors are involved in host chro­matin rewiring.

    It also altered the host epigenome, includ­ing a glob­al reduc­tion in active chro­matin mark H3K27ac and a spe­cif­ic increase in H3K4me3 at pro-inflam­ma­to­ry gene pro­mot­ers. Intrigu­ing­ly, all these host chro­matin alter­ations were unique to SARS-CoV­‑2 infec­tion, and oth­er com­mon-cold coro­n­avirus­es or immune stim­uli did not elic­it these changes.

    Jour­nal ref­er­ence:

    Wang, R. et al. (2023) “SARS-CoV­‑2 restruc­tures host chro­matin archi­tec­ture”, Nature Micro­bi­ol­o­gy. doi: 10.1038/s41564-023–01344‑8. https://www.nature.com/articles/s41564-023–01344‑8

    ———–

    “Epigenome repro­gram­ming after SARS-CoV­‑2 infec­tion” By Neha Math­ur; News-Medical.net; 03/27/2023

    The 3D fold­ing of chro­matin in mam­mals, includ­ing humans, influ­ences deoxyri­bonu­cle­ic acid (DNA) repli­ca­tion, recom­bi­na­tion, DNA dam­age repair, and tran­scrip­tion. It is a key deter­mi­nant of how human cells act and func­tion. Virus­es, includ­ing SARS-CoV­‑2, antag­o­nize host defense by rewiring their chro­matin archi­tec­ture, which typ­i­cal­ly has sev­er­al lay­ers, e.g., A/B com­part­ments, chro­matin loops, and topo­log­i­cal asso­ci­at­ing domains (TADs).”

    It’s not just dam­age to the DNA sequences. SARS-CoV­‑2 also induces mas­sive alter­ations to the cel­l’s epigenome by essen­tial­ly repro­gram­ming the chro­matin that deter­mines what DNA in a cell is “avail­able” to be con­vert­ed into pro­teins or oth­er­wise inter­act with the cel­l’s reg­u­la­to­ry path­ways. In oth­er words, SARS-CoV­‑2 intro­duces a kind of reg­u­la­to­ry chaos at the cel­lu­lar lev­el:

    ...
    Results

    The Hi‑C analy­sis showed exten­sive alter­ations in the hosts’ 3D genome after SARS-CoV­‑2 infec­tion. The researchers also plot­ted a Pear­son cor­re­la­tion map of their Hi‑C analy­sis that reaf­firmed these changes along­side indi­cat­ing mod­i­fied chro­matin com­part­men­tal­iza­tion.

    ...

    Fur­ther analy­sis showed that the ‘B‑ing’ and ‘A‑ing’ genom­ic regions were his­tor­i­cal­ly enriched in active chro­matin mark­ers (e.g., H3K27ac) and repres­sive his­tone mark­ers, espe­cial­ly H3K27me3. Unex­pect­ed­ly, SARS-CoV­‑2 infec­tion selec­tive­ly mod­i­fied the H3K4me3 mark­er of phy­tochrome inter­act­ing fac­tors (PIF) gene pro­mot­ers, sug­gest­ing unap­pre­ci­at­ed mech­a­nisms at these pro­mot­ers that con­fer devi­at­ing inflam­ma­tion in COVID-19.

    ...

    The authors also not­ed weak­ened com­part­men­tal­iza­tion between chro­mo­somes. For instance, in chro­mo­somes 17 & 18, while A–B inter­ac­tions were ampli­fied, A–A/B–B homo­typ­ic inter­ac­tions appeared to have become com­pro­mised.

    More­over, SARS-CoV­‑2 infec­tion mech­a­nis­ti­cal­ly deplet­ed the cohesin com­plex in a per­va­sive but selec­tive man­ner from intra-TAD regions. These changes pro­vid­ed a mol­e­c­u­lar expla­na­tion for the weak­en­ing of intra-TAD inter­ac­tions.

    It sup­port­ed the notion that defec­tive cohesin loop extru­sion inside TADs releas­es this chro­matin to engage in long-dis­tance asso­ci­a­tions. Intrigu­ing­ly, chro­matin in SARS-CoV-2-infect­ed cells exhib­it­ed a high­er fre­quen­cy of long-dis­tance intra-chro­mo­so­mal and inter-chro­mo­so­mal inter­ac­tions.
    ...

    Intrigu­ing­ly, this restruc­tur­ing of the cel­l’s epigenome isn’t seen as a con­se­quence for the com­mon-cold coro­n­avirus­es they also test­ed. So like the DNA dam­age, this epigenome restruc­tur­ing appears to be anoth­er unusu­al ‘fea­ture’ of this virus:

    ...
    Con­clu­sions

    SARS-CoV­‑2 infec­tion marked­ly restruc­tured 3D host chro­matin, fea­tur­ing wide­spread com­part­ment A weak­en­ing and A–B mix­ing and glob­al reduc­tion in intra-TAD chro­matin con­tacts.

    How­ev­er, it is still unknown exact­ly how SARS-COV‑2 infec­tion restruc­tures host chro­matin. Like­ly, open read­ing frame 8 (ORF8) dis­rupts the host epigenome, sug­gest­ing that some viral fac­tors are involved in host chro­matin rewiring.

    It also altered the host epigenome, includ­ing a glob­al reduc­tion in active chro­matin mark H3K27ac and a spe­cif­ic increase in H3K4me3 at pro-inflam­ma­to­ry gene pro­mot­ers. Intrigu­ing­ly, all these host chro­matin alter­ations were unique to SARS-CoV­‑2 infec­tion, and oth­er com­mon-cold coro­n­avirus­es or immune stim­uli did not elic­it these changes.
    ...

    This is a good time to recall how one of the big hopes from the out­set of this pan­dem­ic was that we might even­tu­al­ly see this virus evolve into a rel­a­tive­ly harm­less com­mon-cold coro­n­avirus as has hap­pened in the past. Also keep in mind that when we’re assess­ing the results of these stud­ies we should dif­fer­en­ti­ate between severe­ly ill patients and those with just a mild infec­tion. in oth­er words, it’s not clear at this point if the kind of pro­found DNA dam­age we’re see­ing in these stud­ies is spe­cif­ic to severe cas­es of COVID. And it’s cer­tain­ly pos­si­ble that the DNA dam­age real­ly is lim­it­ed to severe cas­es. Let’s hope that’s the case. But if not, it’s going to real­ly hard to get a sense of the long-term dam­age cre­at­ed by this virus. Again, are testis and ovaries impact­ed too? Because we real­ly don’t want to see DNA dam­age in those tis­sues. More stud­ies are clear­ly nec­es­sary. And, depend­ing on the find­ings, per­haps a few more ‘can­cer moon­shots’.

    Posted by Pterrafractyl | May 5, 2023, 4:43 pm
  4. @Pterrafractyl–

    Bril­liant and ter­ri­fy­ing!

    Keep up the mag­nif­i­cent work!

    Best,

    Dave

    Posted by Dave Emory | May 5, 2023, 5:45 pm
  5. We just got anoth­er myocardi­tis-relat­ed COVID update. The head­line find­ings are great. But as we should expect, upon clos­er exam­i­na­tion not only are the find­ings not great but appear to be fur­ther con­fir­ma­tion of anoth­er COVID-relat­ed night­mare sce­nario. A night­mare sce­nario not dri­ven by the SARS-CoV­‑2 virus itself but rather the lipid nanopar­ti­cle (LNP) deliv­ery vehi­cles used in the Pfiz­er and Mod­er­na mRNA vac­cines:

    Researchers at Yale just pub­lished a study based on 23 young men who expe­ri­ence myocardi­tis — inflam­ma­tion of the heart — fol­low­ing their COVID vac­ci­na­tions. Accord­ing to their find­ings, no signs of an autoim­mune response attack­ing the heart was seen. That’s the good news. Based on those find­ings, it is now being report­ed as a con­fir­ma­tion that the mRNA vac­cines aren’t the cause of the myocardi­tis

    And indeed it is good to not find signs of an autoim­mune response attack­ing the heart. But as we’re going to see, it’s not like the study did­n’t see signs of a vac­cine-induced inflam­ma­to­ry response in the hearts of these patients. They just did­n’t see a spe­cif­ic autoim­mune response gen­er­at­ed by the vac­cine. They still saw an gen­er­al innate immune response and in fact that’s what they attrib­uted the myocardi­tis to: an over­ac­tive innate immune response some­how trig­gered by the vac­cine.

    Beyond that, as we’re going to see when we look close­ly at the Dis­cus­sion sec­tion of this new study, we find that the authors explic­it­ly spec­u­late that some sort of “com­pound role of the adju­vant deliv­ery plat­form in syn­er­gy with vac­cine-vec­tored anti­gens is more like­ly the dri­ver of an exag­ger­at­ed immune cytokine response dri­ving car­diac pathol­o­gy after vac­ci­na­tion in sus­cep­ti­ble indi­vid­u­als.” A “com­pound role of the adju­vant deliv­ery plat­form in syn­er­gy with vac­cine-vec­tored anti­gens” is anoth­er way of say­ing that the com­bined effects of the immune sys­tem response to both the vac­cine-spe­cif­ic tar­get (the COVID spike pro­tein, in this case) and the immune response to the LNP deliv­ery vehi­cle. So this new study that is being tout­ed as a val­i­da­tion of the safe­ty of mRNA vac­cines mere­ly found that the side effects aren’t exclu­sive­ly trig­gered by an autoim­mune response but are instead also heav­i­ly dri­ven by some sort of “adju­vant” innate immune response trig­gered by the LNPs.

    This is a good time to recall that 2016 STAT News arti­cle describ­ing the shift in Mod­er­na’s mRNA ther­a­peu­tics research towards vac­cine devel­op­ment. As we saw, a num­ber of indus­try observers com­ment­ed on how the shift like­ly reflect­ed long-stand­ing indus­try frus­tra­tions with the side-effects of mRNA deliv­ery mak­ing vac­cines — where the side effects of an immune response are desired and hypo­thet­i­cal­ly as lit­tle as a sin­gle shot — mak­ing vac­cines an obvi­ous path to final­ly bring­ing an mRNA prod­uct to mar­ket. This is also a good time to recall how the US gov­ern­ment cur­rent­ly ONLY allows the mRNA vac­cines for any boost­er shots after your first boost­er.

    Final­ly, as we’re also going to see, the sig­nal pro­file of innate inflam­ma­to­ry sig­nals that this Yale team found in the these patients — ele­vat­ed lev­els of cir­cu­lat­ing inter­leukins (IL-1ß, IL-1RA, and IL-15), chemokines (CCL4, CXCL1, and CXCL10), and matrix met­al­lo­pro­teas­es (MMP1, MMP8, MMP9, and TIMP1) — sure looks an awful lot like the sig­nal pro­file of inflam­ma­to­ry respons­es induced by LNPs alone found in mice pub­lished in a study back in Decem­ber of 2021. That’s part of the con­text of this lat­est study: it’s fol­low­ing a grow­ing num­ber of stud­ies show­ing the pow­er­ful inflam­ma­to­ry response to LNPs alone. When the Yale authors refer to the “adju­vant deliv­ery plat­form”, that pow­er­ful immune response to LNPs is what they are talk­ing about.

    So if you want to pro­tect your­self from the DNA-dam­ag­ing effects of COVID and you hap­pen to be in the US, you can roll the immuno­log­i­cal dice with the mRNA vac­cines or you can go with­out pro­tec­tion. Those are the only two options cur­rent­ly avail­able. Best of luck with that:

    STAT News

    What explains rare heart con­di­tion among young men after Covid vac­cines? A new study offers clues

    By Elaine Chen May 5, 2023

    A new study sheds light on what may be caus­ing very rare cas­es of heart inflam­ma­tion in young men after receiv­ing an mRNA Covid vac­cine.

    Ear­ly hypothe­ses as to what was dri­ving the heart inflam­ma­tion, called myocardi­tis, includ­ed an aller­gic response to the vac­cine, vac­cine-induced anti­bod­ies, or an autoim­mune response in which the immune sys­tem attacks the body’s own healthy tis­sue by mis­take. But the study, pub­lished Fri­day in Sci­ence Immunol­o­gy, doesn’t find evi­dence for any of these mech­a­nisms.

    Instead, when look­ing at cas­es in 23 patients, the researchers found signs of a revved-up immune sys­tem dri­ven by inflam­ma­to­ry pro­teins.

    “We were a lit­tle relieved that what we found was the inflam­ma­tion-induced myocardi­tis,” said Akiko Iwasa­ki, one of the authors and a pro­fes­sor of immuno­bi­ol­o­gy at Yale Uni­ver­si­ty. In par­tic­u­lar, if the cas­es were dri­ven by an autoim­mune response, they “would be a lit­tle bit more dif­fi­cult to treat and deal with.”

    ...

    The researchers behind the study explored each of the lead­ing pos­si­bil­i­ties as to the root cause of myocardi­tis after vac­ci­na­tion. When they looked at blood sam­ples, the researchers didn’t see greater anti­body or neu­tral­iz­ing anti­body lev­els in patients who had devel­oped myocardi­tis com­pared with a con­trol group, sug­gest­ing the heart con­di­tion wasn’t dri­ven by vac­cine-induced anti­bod­ies.

    The researchers then looked for signs of an autoim­mune response. They didn’t find any autoan­ti­bod­ies, and the pat­tern of immune cells that pro­lif­er­at­ed also didn’t look like the pat­tern typ­i­cal­ly seen in an autoim­mune response.

    They then pro­ceed­ed to do more detailed analy­sis of the patients’ blood sam­ples. They found ele­vat­ed lev­els of inflam­ma­to­ry pro­teins, such as ones called inter­leukin-15, and also found a pro­lif­er­a­tion of tis­sue-dam­ag­ing immune cells that looked to be acti­vat­ed by inflam­ma­to­ry pro­teins. Tak­en togeth­er, the find­ings sup­port the idea that the myocardi­tis cas­es were dri­ven by an over­ac­tive immune sys­tem.

    ...

    But it’s still unclear why the rare cas­es of myocardi­tis are con­cen­trat­ed in young men, said Daniela Cihako­va, a pro­fes­sor of pathol­o­gy at Johns Hop­kins Uni­ver­si­ty who is unaf­fil­i­at­ed with the study. “What we need to under­stand in a broad way is — how is the response of that age cat­e­go­ry and that sex cat­e­go­ry dif­fer­ent from oth­er cat­e­gories in vac­ci­na­tion?”

    ————

    “What explains rare heart con­di­tion among young men after Covid vac­cines? A new study offers clues” by Elaine Chen; STAT News; 05/05/2023

    ““We were a lit­tle relieved that what we found was the inflam­ma­tion-induced myocardi­tis,” said Akiko Iwasa­ki, one of the authors and a pro­fes­sor of immuno­bi­ol­o­gy at Yale Uni­ver­si­ty. In par­tic­u­lar, if the cas­es were dri­ven by an autoim­mune response, they “would be a lit­tle bit more dif­fi­cult to treat and deal with.””

    It’s a relief! That’s the head­line find­ing in this new­ly pub­lished Yale study based on 23 patients. They did­n’t find signs of an autoim­mune response gen­er­at­ed by the mRNA vac­cines. Nope. Instead, they found signs of a revved up immune sys­tem dri­ven by inflam­ma­to­ry pro­teins. So they did find an immune response, just not an autoim­mune response. That’s the basis for the col­lec­tive “phew!”

    ...
    Ear­ly hypothe­ses as to what was dri­ving the heart inflam­ma­tion, called myocardi­tis, includ­ed an aller­gic response to the vac­cine, vac­cine-induced anti­bod­ies, or an autoim­mune response in which the immune sys­tem attacks the body’s own healthy tis­sue by mis­take. But the study, pub­lished Fri­day in Sci­ence Immunol­o­gy, doesn’t find evi­dence for any of these mech­a­nisms.

    Instead, when look­ing at cas­es in 23 patients, the researchers found signs of a revved-up immune sys­tem dri­ven by inflam­ma­to­ry pro­teins.

    ...

    >The researchers behind the study explored each of the lead­ing pos­si­bil­i­ties as to the root cause of myocardi­tis after vac­ci­na­tion. When they looked at blood sam­ples, the researchers didn’t see greater anti­body or neu­tral­iz­ing anti­body lev­els in patients who had devel­oped myocardi­tis com­pared with a con­trol group, sug­gest­ing the heart con­di­tion wasn’t dri­ven by vac­cine-induced anti­bod­ies.

    The researchers then looked for signs of an autoim­mune response. They didn’t find any autoan­ti­bod­ies, and the pat­tern of immune cells that pro­lif­er­at­ed also didn’t look like the pat­tern typ­i­cal­ly seen in an autoim­mune response.

    They then pro­ceed­ed to do more detailed analy­sis of the patients’ blood sam­ples. They found ele­vat­ed lev­els of inflam­ma­to­ry pro­teins, such as ones called inter­leukin-15, and also found a pro­lif­er­a­tion of tis­sue-dam­ag­ing immune cells that looked to be acti­vat­ed by inflam­ma­to­ry pro­teins. Tak­en togeth­er, the find­ings sup­port the idea that the myocardi­tis cas­es were dri­ven by an over­ac­tive immune sys­tem.
    ...

    But what was it that cre­at­ed the over­ac­tive innate immune response in the first place? Was it just some­thing about these patients? Or was the vac­cine also play­ing a role? That’s all dis­missed in the report­ing we’re see­ing on this study. And yet, when we look more close­ly at the study, we find they do actu­al­ly address the immune respons­es trig­gered by LNPs as pos­si­bly play­ing a role in myocardi­tis. As they put it in the study’s Dis­cus­sion sec­tion, “a com­pound role of the adju­vant deliv­ery plat­form in syn­er­gy with vac­cine-vec­tored anti­gens is more like­ly the dri­ver of an exag­ger­at­ed immune cytokine response dri­ving car­diac pathol­o­gy after vac­ci­na­tion in sus­cep­ti­ble indi­vid­u­als”:

    Sci­ence Immunol­o­gy

    Cytokinopa­thy with aber­rant cyto­tox­ic lym­pho­cytes and profi­brot­ic myeloid response in SARS-CoV­‑2 mRNA vaccine–associated myocardi­tis

    Anis Bar­ma­da, Jon Klein, Anjali Ramaswamy, Nina N. Brod­sky, Jil­lian R. Jay­cox, Has­san Sheikha, Kate M. Jones, Vic­to­ria Habet, Melis­sa Camp­bell, Tomokazu S. Sum­i­da, Amy Kon­torovich, Dusan Bogunovic, Car­los R. Oliveira, Jere­my Steele, E. Kevin Hall, Mario Pena-Her­nan­dez, Val­ter Mon­teiro, Car­oli­na Lucas, Aaron M. Ring, Saad B. Omer, Akiko Iwasa­ki, Inci Yildirim, and Car­rie L. Lucas

    05/05/2023 Vol 8, Issue 83

    Abstract

    Rare immune-medi­at­ed car­diac tis­sue inflam­ma­tion can occur after vac­ci­na­tion, includ­ing after SARS-CoV­‑2 mRNA vac­cines. How­ev­er, the under­ly­ing immune cel­lu­lar and mol­e­c­u­lar mech­a­nisms dri­ving this pathol­o­gy remain poor­ly under­stood. Here, we inves­ti­gat­ed a cohort of patients who devel­oped myocardi­tis and/or peri­cardi­tis with ele­vat­ed tro­ponin, B‑type natri­uret­ic pep­tide, and C‑reactive pro­tein lev­els as well as car­diac imag­ing abnor­mal­i­ties short­ly after SARS-CoV­‑2 mRNA vac­ci­na­tion. Con­trary to ear­ly hypothe­ses, patients did not demon­strate fea­tures of hyper­sen­si­tiv­i­ty myocardi­tis, nor did they have exag­ger­at­ed SARS-CoV‑2–specific or neu­tral­iz­ing anti­body respons­es con­sis­tent with a hyper­im­mune humoral mech­a­nism. We addi­tion­al­ly found no evi­dence of car­diac-tar­get­ed autoan­ti­bod­ies. Instead, unbi­ased sys­tem­at­ic immune serum pro­fil­ing revealed ele­va­tions in cir­cu­lat­ing inter­leukins (IL-1ß, IL-1RA, and IL-15), chemokines (CCL4, CXCL1, and CXCL10), and matrix met­al­lo­pro­teas­es (MMP1, MMP8, MMP9, and TIMP1). Sub­se­quent deep immune pro­fil­ing using sin­gle-cell RNA and reper­toire sequenc­ing of periph­er­al blood mononu­clear cells dur­ing acute dis­ease revealed expan­sion of acti­vat­ed CXCR3+ cyto­tox­ic T cells and NK cells, both phe­no­typ­i­cal­ly resem­bling cytokine-dri­ven killer cells. In addi­tion, patients dis­played sig­na­tures of inflam­ma­to­ry and profi­brot­ic CCR2+ CD163+ mono­cytes, cou­pled with ele­vat­ed serum-sol­u­ble CD163, that may be linked to the late gadolin­i­um enhance­ment on car­diac MRI, which can per­sist for months after vac­ci­na­tion. Togeth­er, our results demon­strate up-reg­u­la­tion in inflam­ma­to­ry cytokines and cor­re­spond­ing lym­pho­cytes with tis­sue-dam­ag­ing capa­bil­i­ties, sug­gest­ing a cytokine-depen­dent pathol­o­gy, which may fur­ther be accom­pa­nied by myeloid cell–associated car­diac fibro­sis. These find­ings like­ly rule out some pre­vi­ous­ly pro­posed mech­a­nisms of mRNA vaccine–-associated myoperi­cardi­tis and point to new ones with rel­e­vance to vac­cine devel­op­ment and clin­i­cal care.

    ...

    Dis­cus­sion

    ...

    Although the LNP com­po­nent of the vac­cine alone was found to be high­ly inflam­ma­to­ry, such respons­es cen­tered on IL‑6 and IL-1ß (41, 123). IL-1ß was ele­vat­ed in our cohort of patients and togeth­er with upstream NLRP3 inflam­ma­some acti­va­tion and asso­ci­at­ed cytokines may play a role in the patho­gen­e­sis of myocardi­tis (32, 39). How­ev­er, IL-1ß induc­tion by lipid-for­mu­lat­ed RNA vac­cines, which can then stim­u­late var­i­ous proin­flam­ma­to­ry cytokines, was also shown to be depen­dent on both the RNA and lipid for­mu­la­tion in human immune cells (124). Thus, a com­pound role of the adju­vant deliv­ery plat­form in syn­er­gy with vac­cine-vec­tored anti­gens is more like­ly the dri­ver of an exag­ger­at­ed immune cytokine response dri­ving car­diac pathol­o­gy after vac­ci­na­tion in sus­cep­ti­ble indi­vid­u­als. What caus­es cer­tain indi­vid­u­als, notably ado­les­cent and young adult males, to be more sus­cep­ti­ble to these car­diac-relat­ed adverse events is not clear but like­ly not unique to vac­cine-induced patho­gen­e­sis. A bias toward younger males is sim­i­lar­ly seen in com­mu­ni­ty-acquired myocarditis/pericarditis, where many large-scale epi­demi­o­log­i­cal and clin­i­cal stud­ies have demon­strat­ed that patients are much more fre­quent­ly males (65 to 84% of patients) and sig­nif­i­cant­ly younger than female patients (125136), poten­tial­ly sug­gest­ing height­ened immune and/or inflam­ma­to­ry respons­es in these demo­graph­ic groups.

    ...

    ———–

    “Cytokinopa­thy with aber­rant cyto­tox­ic lym­pho­cytes and profi­brot­ic myeloid response in SARS-CoV­‑2 mRNA vaccine–associated myocardi­tis” by Anis Bar­ma­da, et al; Sci­ence Immunol­o­gy; 05/05/2023 Vol 8, Issue 83

    “Instead, unbi­ased sys­tem­at­ic immune serum pro­fil­ing revealed ele­va­tions in cir­cu­lat­ing inter­leukins (IL-1ß, IL-1RA, and IL-15), chemokines (CCL4, CXCL1, and CXCL10), and matrix met­al­lo­pro­teas­es (MMP1, MMP8, MMP9, and TIMP1).”

    Take note of that list of cytokines, chemokines, and inter­luekins they found at ele­vat­ed lev­els in these myocardi­tis patients, along with their rea­son­able spec­u­la­tion that “a com­pound role of the adju­vant deliv­ery plat­form” is play­ing a role here. Because that “adju­vant deliv­ery plat­form” is anoth­er way of describ­ing the LNPs and the innate immune response they elic­it. And as we’re going to see in the fol­low­ing arti­cle pub­lished in Decem­ber of 2021 explor­ing that innate response on mouse mod­els, the LNP’s alone are capa­ble of illic­it a very sim­i­lar look­ing immune response:

    iScience

    The mRNA-LNP plat­for­m’s lipid nanopar­ti­cle com­po­nent used in pre­clin­i­cal vac­cine stud­ies is high­ly inflam­ma­to­ry

    Sonia Nde­u­pen, Zhen Qin, Sanya Jacob­sen, Aure­lie Bouteau, Hen­ri Estanbouli, Botond Z. Igyártó

    Vol­ume 24, Issue 12, 17 Decem­ber 2021, 103479

    High­lights

    • Lipid nanopar­ti­cles (LNPs) used for pre­clin­i­cal stud­ies are high­ly inflam­ma­to­ry
    • The LNPs acti­vate mul­ti­ple inflam­ma­to­ry path­ways and induce IL-1ß and IL‑6
    • The LNPs’ inflam­ma­to­ry prop­er­ties stem from their ion­iz­able lipid com­po­nent
    • The LNPs could be respon­si­ble for adju­van­tic­i­ty and some of the side effects

    Sum­ma­ry

    Vac­cines based on mRNA-con­tain­ing lipid nanopar­ti­cles (LNPs) are a promis­ing new plat­form used by two lead­ing vac­cines against COVID-19. Clin­i­cal tri­als and ongo­ing vac­ci­na­tions present with vary­ing degrees of pro­tec­tion lev­els and side effects. How­ev­er, the dri­vers of the report­ed side effects remain poor­ly defined. Here we present evi­dence that Acuitas’ LNPs used in pre­clin­i­cal nucle­o­side-mod­i­fied mRNA vac­cine stud­ies are high­ly inflam­ma­to­ry in mice. Intra­der­mal and intra­mus­cu­lar injec­tion of these LNPs led to rapid and robust inflam­ma­to­ry respons­es, char­ac­ter­ized by mas­sive neu­trophil infil­tra­tion, acti­va­tion of diverse inflam­ma­to­ry path­ways, and pro­duc­tion of var­i­ous inflam­ma­to­ry cytokines and chemokines. The same dose of LNP deliv­ered intranasal­ly led to sim­i­lar inflam­ma­to­ry respons­es in the lung and result­ed in a high mor­tal­i­ty rate, with mech­a­nism unre­solved. Thus, the mRNA-LNP plat­forms’ poten­cy in sup­port­ing the induc­tion of adap­tive immune respons­es and the observed side effects may stem from the LNPs’ high­ly inflam­ma­to­ry nature.

    Intro­duc­tion

    The nucle­o­side-mod­i­fied mRNA-LNP vac­cine plat­form used by Pfizer/BioNTech and Mod­er­na in their SARS-CoV­‑2 vac­cines has been wide­ly test­ed in pre­clin­i­cal stud­ies, and its effec­tive­ness in sup­port­ing Tfh cells and pro­tec­tive humoral immune respons­es match­es or sur­pass­es oth­er vac­cines (Alameh et al., 2020). These vac­cines’ mRNA com­po­nent is nucle­o­side mod­i­fied to decrease poten­tial innate immune recog­ni­tion (Karikó et al., 2005; Karikó et al., 2008). The LNP was cho­sen as a car­ri­er vehi­cle to pro­tect the mRNA from degra­da­tion and aid intra­cel­lu­lar deliv­ery and endo­so­mal escape. The LNPs con­sist of a mix­ture of phos­pho­lipids, cho­les­terol, PEGy­lat­ed lipids, and cation­ic or ion­iz­able lipids. The phos­pho­lipids and cho­les­terol have struc­tur­al and sta­bi­liz­ing roles, where­as the PEGy­lat­ed lipids sup­port pro­longed cir­cu­la­tion. The cationic/ionizable lipids are includ­ed to allow the com­plex­ing of the neg­a­tive­ly charged mRNA mol­e­cules and enable the exit of the mRNA from the endo­some to the cytosol for trans­la­tion (Samari­dou et al., 2020). The ion­iz­able lipids were devel­oped to decrease the high­ly inflam­ma­to­ry and cyto­tox­ic effects of some of the per­ma­nent­ly charged cation­ic lipids (Kulka­rni et al., 2018). A pre­clin­i­cal study showed that nucle­o­side-mod­i­fied mRNA com­plexed with Acuitas Ther­a­peu­tics’ LNPs con­tain­ing pro­pri­etary ion­iz­able lipid has adju­vant activ­i­ty (Par­di et al., 2018a). How­ev­er, the poten­tial inflam­ma­to­ry nature of these LNPs was not assessed (Alameh et al., 2020; Par­di et al., 2018a).

    The human clin­i­cal tri­als of the Pfizer/BioNTech and Mod­er­na vac­cines have report­ed side effects such as pain, swelling, fever, and sleepi­ness (Jack­son et al., 2020; Sahin et al., 2020; Walsh et al., 2020). Under the pre­sump­tion that this vac­cine plat­form is non­in­flam­ma­to­ry, some of the clin­i­cians and pub­lic health com­mu­ni­ca­tors inter­pret­ed these report­ed acute side effects as the vac­cine being potent and gen­er­at­ing an adap­tive immune response. These side effects, how­ev­er, are more in line with acute inflam­ma­to­ry respons­es induced by the vac­cine. Still, no stud­ies have been under­tak­en to char­ac­ter­ize the imme­di­ate innate inflam­ma­to­ry reac­tions induced by this vac­cine plat­form that could poten­tial­ly cause the local and sys­temic side effects. There­fore, in this study, we took a sys­tem­at­ic approach, focus­ing our atten­tion on the injec­tion site and ana­lyz­ing the inflam­ma­to­ry reac­tions caused by the LNPs used for pre­clin­i­cal vac­cine stud­ies (Awasthi et al., 2019; Laczkó et al., 2020; Led­er­er et al., 2020; Par­di et al., 2017, Par­di et al., 2018a, Par­di et al., 2018b). Using com­ple­men­tary tech­niques, we show that in mice intra­der­mal, intra­mus­cu­lar, or intranasal deliv­ery of LNPs used in pre­clin­i­cal stud­ies trig­gers inflam­ma­tion char­ac­ter­ized by leuko­cyt­ic infil­tra­tion, acti­va­tion of dif­fer­ent inflam­ma­to­ry path­ways, and secre­tion of a diverse pool of inflam­ma­to­ry cytokines and chemokines. Thus, the inflam­ma­to­ry milieu induced by the LNPs could be par­tial­ly respon­si­ble for report­ed side effects of mRNA-LNP-based SARS-CoV­‑2 vac­cines in humans and are pos­si­bly con­trib­u­to­ry to their report­ed high poten­cy for elic­it­ing anti­body respons­es.

    Results

    Intra­der­mal and intra­mus­cu­lar inoc­u­la­tion with LNPs induces robust inflam­ma­tion

    mRNAs com­bined with LNPs were used in many pre­clin­i­cal stud­ies and are key com­po­nents of the recent Pfizer/BioNTech and Mod­er­na SARS-CoV­‑2 vac­cine (Alameh et al., 2020; Jack­son et al., 2020; Sahin et al., 2020; Walsh et al., 2020). The mech­a­nism of action of this mRNA-LNP plat­form is not well defined. The mRNA com­po­nent is mod­i­fied to decrease the engage­ment of innate immune sen­sors (Karikó et al., 2005; Karikó et al., 2008), but the mRNA com­plexed with LNPs was shown to have adju­vant activ­i­ty (Par­di et al., 2018a). The mRNA-LNP plat­form pro­motes robust humoral immune respons­es, and humans receiv­ing the vac­cine often pre­sent­ed with typ­i­cal acute side effects of inflam­ma­tion, such as pain, swelling, and fever (Jack­son et al., 2020). Based on these obser­va­tions, we hypoth­e­sized that mRNA-LNP adju­vant activ­i­ty and the report­ed side effects in humans could stem from the LNPs’ inflam­ma­to­ry prop­er­ties. mRNAs com­plexed with LNPs were used in pre­clin­i­cal stud­ies at dos­es rang­ing from 3 to 30 µg/mouse (Laczkó et al., 2020; Par­di et al., 2018a). We inject­ed 10 µg (4 spots; 2.5 µg/spot) of these emp­ty LNPs for­mu­lat­ed in phos­phate buffered saline (PBS) or con­trol PBS intra­der­mal­ly into adult wild-type (WT) C57BL/6 (B6) mice. We sac­ri­ficed the mice at dif­fer­ent time points post-injec­tion, and ~1 cm² skin sam­ples from the injec­tion sites were col­lect­ed. The LNP-inject­ed skin sam­ples macro­scop­i­cal­ly showed signs of intense inflam­ma­tion, such as red­ness and swelling (Fig­ure 1A). Sin­gle-cell sus­pen­sions were pre­pared from these sam­ples and ana­lyzed for infil­trates using flow cytom­e­try (Fig­ures 1B and S1A). Flow cytom­e­try revealed mas­sive and rapid leuko­cyt­ic infil­trates dom­i­nat­ed by neu­trophils that slow­ly resolved by day 14 (Fig­ure 1B). Removal of the ion­iz­able lipid com­po­nent from the LNPs abol­ished vis­i­ble skin inflam­ma­tion Fig­ure 1C) and the leuko­cyt­ic infil­tra­tion (Fig­ure 1D). Thus, LNPs used in pre­clin­i­cal stud­ies pro­mote swift inflam­ma­to­ry respons­es at the injec­tion site, which depends on the ion­iz­able lipid com­po­nent.

    [see Fig­ure 1]

    *****

    The pre­clin­i­cal ani­mal vac­cine stud­ies with this mRNA-LNP plat­form were car­ried out through intra­mus­cu­lar and intra­der­mal inoc­u­la­tions. Both deliv­ery routes led to robust humoral immune respons­es (Laczkó et al., 2020; Par­di et al., 2018a). The cur­rent mRNA-LNP-based human SARS-CoV­‑2 vac­cines are deliv­ered intra­mus­cu­lar­ly, which might be moti­vat­ed by clin­i­cal prac­ti­cal­i­ty (Ols et al., 2020). To test whether intra­mus­cu­lar deliv­ery also leads to inflam­ma­tion, we inject­ed ani­mals intra­mus­cu­lar­ly with 10 µg of LNPs in 30 µL of PBS or PBS alone. Twen­ty-four hours lat­er, the inject­ed mus­cles were col­lect­ed for analy­sis. Sim­i­lar to the skin, we observed robust neu­trophil infil­tra­tion to the mus­cle sam­ples that received LNPs (Fig­ures 1E and S1B). The mus­cles inject­ed with LNPs also showed a sig­nif­i­cant increase in weight (Fig­ure 1F). Thus, these find­ings col­lec­tive­ly indi­cate mas­sive local inflam­ma­tion that could account for some of the report­ed local side effects.

    To acquire a more in-depth under­stand­ing of the glob­al changes trig­gered by the injec­tion of the LNPs, we repeat­ed the intra­der­mal exper­i­ments pre­sent­ed above with LNPs com­plexed with con­trol, non­cod­ing poly-cyto­sine mRNA. Skin sam­ples har­vest­ed one day after injec­tion were split into two and ana­lyzed using Luminex and bulk RNA-seq (Fig­ure 2A). The Luminex data cor­rob­o­rat­ed the flow cytom­e­try find­ings and demon­strat­ed the pres­ence of a vari­ety of inflam­ma­to­ry cytokines and chemokines (Fig­ures 2B, 2C and S2), in com­par­i­son to con­trol sam­ples. Chemokines that attract neu­trophils and mono­cytes and pro­mote their func­tions, such as CCL2, CCL3, CCL4, CCL7, CCL12, CXCL1, and CXCL2, dom­i­nat­ed the pan­el (Fig­ure 2B). We fur­ther found large amounts of inter­leukin-1ß (IL-1ß), gran­u­lo­cyte-macrophage colony-stim­u­lat­ing fac­tor (GM-CSF), and IL‑6, the sig­na­ture cytokines of inflam­ma­to­ry respons­es (Fig­ure 2C). Our RNA-seq analy­sis revealed that thou­sands of genes were upreg­u­lat­ed (Fig­ure 2D) upon LNP injec­tion. With p < 0.05 and FDR<0.05, 9,508 genes and 8,883 genes, respec­tive­ly, were dif­fer­en­tial­ly expressed. More impor­tant­ly, con­firm­ing our flow cytom­e­try and Luminex data, the genes asso­ci­at­ed with monocyte/granulocyte devel­op­ment, recruit­ment, and func­tion (Cxcl1, Cxcl2, Cxcl5, Cxcl10, Ccl2, Ccl3, Ccl4, Ccl7, Ccl12, Csf2, and Csf3) and inflam­ma­tion (Il1b and Il6) showed the high­est fold increas­es over the con­trol sam­ples (Fig­ure 2E). We also observed sig­nif­i­cant upreg­u­la­tion of gene tran­scripts asso­ci­at­ed with acti­va­tion of inflam­ma­somes, such as Il1b and Nlrp3, and down­reg­u­la­tion of Nlrp10, which is known to inhib­it inflam­ma­somes (Fig­ure 2E). Gene set enrich­ment analy­ses (GSEA) showed the acti­va­tion of many dif­fer­ent inflam­ma­to­ry path­ways, includ­ing, but not lim­it­ed to, viral infec­tions, RIG‑I, NOD-like, and Toll-like recep­tor sig­nal­ing (Fig­ure 2F). Pro-apop­tot­ic and necrop­tot­ic gene sets were also sig­nif­i­cant­ly upreg­u­lat­ed, as well as inter­fer­on sig­nal­ing Fig­ure 2F).

    [see Fig­ure 2]

    ****

    In sum­ma­ry, using dif­fer­ent tech­niques, we show that LNPs, alone or com­plexed with con­trol non­cod­ing poly-cyto­sine mRNA, are high­ly inflam­ma­to­ry in mice, like­ly through the engage­ment and acti­va­tion of var­i­ous dis­tinct and con­ver­gent inflam­ma­to­ry path­ways.

    Intranasal inoc­u­la­tion with LNPs leads to robust inflam­ma­to­ry respons­es in the lung

    Res­pi­ra­to­ry infec­tions, includ­ing with SARS-CoV­‑2, induce a dom­i­nant mucosa-pro­tec­tive anti­body response and local T‑cell-medi­at­ed immu­ni­ty (Grau-Expósi­to et al., 2021; Rus­sell et al., 2020; Ster­lin et al., 2021). There­fore, to achieve an immune response that mim­ic nat­ur­al infec­tion and might con­fer more pro­tec­tion against SARS-CoV­‑2 at the lev­els of the res­pi­ra­to­ry tract (Lund and Ran­dall, 2021; Rus­sell et al., 2020; Zens et al., 2019), researchers are active­ly work­ing on devel­op­ing SARS-CoV­‑2 vac­cines that could be admin­is­tered intranasal­ly (Buschmann et al., 2021; Chav­da et al., 2021; van Dore­malen et al., 2021). There­fore, we first test­ed whether the LNPs can reach the lungs upon intranasal deliv­ery. For this pur­pose, we inoc­u­lat­ed mice intranasal­ly with PBS or 10 µg of DiI-labeled LNPs. Six hours lat­er his­tol­ogy showed a homo­ge­neous dis­tri­b­u­tion of the LNPs in the lung tis­sue (Fig­ure 3A). Next, we test­ed whether intranasal deliv­ery leads to inflam­ma­tion in the lungs. For this, we intranasal­ly inoc­u­lat­ed adult WT B6 mice with PBS or 10 µg of LNPs in PBS/mouse. Lung sam­ples from PBS- and 10 µg LNP-treat­ed mice were pre­pared for macro­scop­ic analy­ses 9 and 24 h post-inoc­u­la­tion and for flow cytom­e­try 9 h post-inoc­u­la­tion. In a mat­ter of hours, the lungs turned red in col­or in the LNP-inoc­u­lat­ed group (Fig­ure 3B). As was observed for the skin and mus­cle, flow cyto­met­ric analy­ses revealed sig­nif­i­cant leuko­cyt­ic infil­tra­tion dom­i­nat­ed by neu­trophils and eosinophils and a decrease in macrophages and cer­tain den­drit­ic cell (DC) sub­sets Fig­ure 3C and S3). Thus, intranasal deliv­ery of LNPs leads to mas­sive inflam­ma­tion in the lungs.

    [see Fig­ure 3]

    ******

    With the exper­i­ments pre­sent­ed ear­li­er, we observed a high mor­tal­i­ty rate among the mice inoc­u­lat­ed with LNPs. These find­ings prompt­ed us to per­form a dose-response exper­i­ment to deter­mine the amounts of LNPs that might be safe to use for mucos­al vac­ci­na­tion. We intranasal­ly inoc­u­lat­ed adult WT B6 mice with LNPs rang­ing from 2.5 µg to 10 µg/mouse and mon­i­tored their health and weight for up to 8 days. We found that ~80% of mice treat­ed with 10 µg of LNP died in less than 24 h (Fig­ure 3D). The 5 µg dose killed ~20% of the mice by that time, where­as all the 2.5 µg-treat­ed mice sur­vived and showed no weight drop (Fig­ure 3D) and no sig­nif­i­cant clin­i­cal signs of dis­tress (Fig­ure 3E). For the 5 and 10 µg dos­es, the sur­viv­ing mice showed notable clin­i­cal scores of dis­tress, such as shaking/shivering, and they lost weight sig­nif­i­cant­ly dur­ing the first 2 days of treat­ment (Fig­ure 3E and 3F). After the first ~3 days, these mice did not con­tin­ue to show sig­nif­i­cant clin­i­cal scores any­more, and their weight slow­ly start­ed to nor­mal­ize (Fig­ure 3E). These data sug­gest that care­ful opti­miza­tion of the LNP dose might allow the use of the mRNA-LNP plat­form for intranasal vac­ci­na­tion.

    Dis­cus­sion

    Here we show that the LNPs used for many pre­clin­i­cal stud­ies (Freyn et al., 2020; Laczkó et al., 2020; Led­er­er et al., 2020; Par­di et al., 2017, Par­di et al., 2018a, Par­di et al., 2018b) are high­ly inflam­ma­to­ry. This could explain their potent adju­vant activ­i­ty and their supe­ri­or­i­ty, com­pared with oth­er adju­vants, in sup­port­ing the induc­tion of adap­tive immune respons­es.

    Pre­vi­ous pre­clin­i­cal mouse data sug­gest­ed that mRNA com­plexed with LNPs have adju­vant activ­i­ty (Par­di et al., 2018a). The mRNA is nucle­o­side mod­i­fied and puri­fied to decrease acti­va­tion of cer­tain innate inflam­ma­to­ry path­ways (Karikó et al., 2005; Karikó et al., 2008, 2011). Our injec­tion-site-focused analy­ses revealed the inflam­ma­to­ry nature of these LNPs, which like­ly pro­vides a basis for their adju­vant prop­er­ties. The cation­ic lipid com­po­nent of the lipid car­ri­ers is often inflam­ma­to­ry and cyto­tox­ic (Fil­ion and Phillips, 1997, 1998; Lv et al., 2006; Samari­dou et al., 2020; Sedic et al., 2018; Tao et al., 2011). The ion­iz­able lipids were devel­oped to over­come the inflam­ma­to­ry nature of the per­ma­nent­ly charged cation­ic lipids (Kulka­rni et al., 2018). How­ev­er, we found that the pro­pri­etary ion­iz­able lipid com­po­nent of these LNPs is inflam­ma­to­ry (Fig­ures 1C and 1D). The inflam­ma­to­ry respons­es trig­gered by the LNPs alone or com­plexed with mRNAs were inde­pen­dent of the deliv­ery route and were dom­i­nat­ed by neu­trophil infil­tra­tion. Despite the induc­tion of phe­no­typ­i­cal­ly sim­i­lar innate inflam­ma­to­ry respons­es, unlike intra­der­mal and intra­mus­cu­lar inoc­u­la­tions, intranasal deliv­ery of 2.5 µg of mRNA-LNP cod­ing for PR8 HA did not lead to detectable lev­els of adap­tive immune respons­es (unpub­lished obser­va­tion). Thus, slight dif­fer­ences are like­ly to exist between the route of admin­is­tra­tion, which war­rants fur­ther inves­ti­ga­tion to opti­mize this plat­form for intranasal use. Under­stand­ing the cel­lu­lar and mol­e­c­u­lar dif­fer­ences between intradermal/intramuscular and intranasal deliv­ery sites that under­line this dis­sim­i­lar­i­ty in adap­tive immune respons­es might also help to deci­pher why cer­tain peo­ple do not react to the intra­mus­cu­lar­ly deliv­ered mRNA-LNP vac­cines.

    Humans present var­i­ous side effects, most often pain, swelling, fever, and chills, after intra­mus­cu­lar vac­ci­na­tion with the Pfizer/BioNTech or Mod­er­na vac­cines (Jack­son et al., 2020; Sahin et al., 2020; Walsh et al., 2020). These are typ­i­cal symp­toms asso­ci­at­ed with inflam­ma­tion trig­gered by cytokines such as IL-1ß and IL‑6 (Dinarel­lo, 2018; Tana­ka et al., 2014). Along with caus­ing local inflam­ma­to­ry respons­es, these cytokines also act as major endoge­nous pyro­gens (Con­ti, 2004) and instruct the hypo­thal­a­mus to increase the body’s tem­per­a­ture (fever) to help over­come pos­si­ble infec­tions. In con­cor­dance with this, the intra­der­mal inoc­u­la­tion of LNPs in mice led to the secre­tion of large amounts of major and minor pyro­gens, IL-1ß/IL‑6 and macrophage inflam­ma­to­ry protein‑a (CCL3) and macrophage inflam­ma­to­ry protein‑ß (CCL4), respec­tive­ly (Fig­ures 2B and 2C). Fur­ther­more, the observed acti­va­tion of oth­er inflam­ma­to­ry path­ways and cell death could fur­ther accen­tu­ate the expe­ri­enced side effects. How­ev­er, fur­ther stud­ies will be need­ed to deter­mine the exact nature of the inflam­ma­to­ry respons­es trig­gered by mRNA-LNP vac­cines in humans and how much over­lap there might be with the inflam­ma­to­ry sig­na­tures doc­u­ment­ed here for mice.

    It remains to be deter­mined how these LNPs or their ion­iz­able lipid com­po­nent acti­vate dis­tinct inflam­ma­to­ry path­ways. In the­o­ry, LNPs could acti­vate mul­ti­ple path­ways or alter­na­tive­ly engage only one that would ini­ti­ate an inflam­ma­to­ry cas­cade. Some cationic/ionizable lipids bind and acti­vate TLRs (Lonez et al., 2012, 2014; Samari­dou et al., 2020; Tana­ka et al., 2008). Our GSEA analy­ses are con­sis­tent with TLR engage­ment by these pro­pri­etary LNPs, among oth­ers (Fig­ure 2F). We also observed upreg­u­la­tion of inflam­ma­some com­po­nents such Nlrp3 and enrich­ment of genes involved in necrop­to­sis. Inflam­ma­to­ry cell death, such as necrop­to­sis and pyrop­to­sis, could cause the release of DAMPs and the fur­ther enhance­ment of inflam­ma­tion. The syn­thet­ic ion­iz­able lipid in the Pfiz­er SARS-CoV­‑2 vac­cine has been spec­u­lat­ed to have approx­i­mate­ly 20–30 days of half-life in humans (Comir­naty, 2021). Whether the long-term pres­ence of ion­iz­able lipid could lead to low lev­els of chron­ic inflam­ma­tion and immune exhaus­tion (Wher­ry and Kurachi, 2015) remain to be deter­mined.

    Intranasal inoc­u­la­tion with high­er dos­es of LNPs led to a sig­nif­i­cant mor­tal­i­ty rate. Hypo­thet­i­cal­ly, the mas­sive innate inflam­ma­to­ry respons­es induced in the lung (Fig­ure 3) and chem­i­cal dis­rup­tion of the pul­monary sur­fac­tant by cation­ic lipids (Bon­cuk et al., 1997), i.e., reduced gas exchange, cyto­tox­i­c­i­ty to alve­o­lar cells, or oth­er mech­a­nisms, could all have con­tributed to ani­mal death (Dok­ka et al., 2000). Thus, fur­ther exper­i­men­ta­tion is need­ed to inves­ti­gate the mech­a­nism of the tox­i­c­i­ty. Mate­ri­als of dif­fer­ent nature includ­ing nanopar­ti­cles inoc­u­lat­ed intranasal­ly read­i­ly enter the cen­tral ner­vous sys­tem (CNS), and it is the pre­ferred method to over­come the blood-brain bar­ri­er and deliv­er active sub­stances to the brain (Cos­ta et al., 2021; Elder et al., 2006; Gao et al., 2006; Han­son et al., 2013; Lock­man et al., 2004). LNPs as lipid par­ti­cles can quick­ly dif­fuse (Fig­ure 3A) (Par­di et al., 2015) and, through intranasal deliv­ery, could poten­tial­ly gain access to the CNS at high enough lev­els to induce sig­nif­i­cant inflam­ma­tion. Whether these LNPs reach the CNS and induce lev­els of inflam­ma­tion that could have con­tributed to the ani­mal death observed at high­er dos­es remains to be deter­mined. Inter­est­ing­ly, it has been report­ed that the mRNA from Mod­er­na’s mRNA-LNP vac­cine inject­ed intra­mus­cu­lar­ly could be detect­ed in very low lev­els in the brain, poten­tial­ly indi­cat­ing that the mRNA-LNP plat­form might cross the blood-brain bar­ri­er and reach the CNS (Mod­er­na, 2021). How­ev­er, in this case, the scant amounts detect­ed in the CNS would like­ly not induce sig­nif­i­cant inflam­ma­tion but might trig­ger hypo­thal­a­mus-dri­ven side effects such as fever, nau­sea, and sleepi­ness. Fur­ther stud­ies will be need­ed to deter­mine whether these min­i­mal amounts of vac­cine com­po­nents detect­ed in the CNS are phys­i­o­log­i­cal­ly rel­e­vant and define whether they could exac­er­bate pre­ex­ist­ing inflam­ma­to­ry respons­es report­ed in a small case report with MS autoim­mune patients (Khay­at-Khoei et al., 2021). It is impor­tant to note that a medi­um-sized obser­va­tion­al study did not find an increased risk of relapse activ­i­ty after mRNA-LNP vac­ci­na­tion in MS patients (Ach­i­ron et al., 2021), where­as oth­ers have not­ed a slight but increased risk of hem­or­rhag­ic stroke. How­ev­er, the risk of these com­pli­ca­tions was greater fol­low­ing a pos­i­tive SARS-CoV­‑2 test (Patone et al., 2021).

    Peo­ple often present with more severe and sys­temic side effects after the boost­er shot. This rais­es the pos­si­bil­i­ty that the adap­tive immune response might some­how ampli­fy side effects induced by the vac­cine. One cul­prit iden­ti­fied so far is PEG, which is immuno­genic. Anti­bod­ies formed against PEG have been report­ed to sup­port a so-called ana­phy­lac­toid, com­ple­ment acti­va­tion-relat­ed pseudoal­ler­gy (CARPA) reac­tion (Koz­ma et al., 2020; Szebeni, 2005, Szebeni, 2014). Of note, because PEG is a com­pound fre­quent­ly used in cos­met­ics and tooth­paste, many indi­vid­u­als could have anti-PEG anti­bod­ies. We have dis­cussed oth­er pos­si­ble mech­a­nisms in our recent opin­ion arti­cle (Igyártó et al., 2021). Briefly, although mRNA main­ly trans­fects cells near the injec­tion site, it could hypo­thet­i­cal­ly reach any cell in the body (Maugeri et al., 2019; Par­di et al., 2015). The result­ing trans­lat­ed pro­tein could be pre­sent­ed on MHC‑I in the form of pep­tides or dis­played as a whole pro­tein in the cell mem­brane. In both cas­es, cells with the vac­cine peptide/protein on their sur­faces could be tar­get­ed and killed by cells of the adap­tive and innate immune sys­tem, CD8+ T and nat­ur­al killer (NK) cells (via anti­body-depen­dent cel­lu­lar tox­i­c­i­ty [ADCC]), respec­tive­ly. In line with this, the so-called “Covid-arm,” a delayed-type hyper­sen­si­tiv­i­ty reac­tion that devel­ops in some patients sev­er­al days after vac­ci­na­tion (Blu­men­thal et al., 2021), or the myocarditis/pericarditis recent­ly report­ed with some of the vac­ci­nat­ed peo­ple (Abu Mouch et al., 2021; Diaz et al., 2021; Mar­shall et al., 2021; Mont­gomery et al., 2021; Shay et al., 2021), or the CNS inflam­ma­tion observed in a small num­ber of vac­ci­nat­ed MS patients (Khay­at-Khoei et al., 2021) could be indeed an indi­ca­tion of immune respons­es tar­get­ing the cells express­ing the vac­cine-derived peptides/proteins.

    In sum­ma­ry, the first vac­ci­na­tion’s side effects, except for CARPA, are like­ly asso­ci­at­ed with robust innate inflam­ma­tion induced by the LNPs. In con­trast, after the sec­ond vac­ci­na­tion, side effects could be fur­ther exac­er­bat­ed by immune respons­es tar­get­ing cells express­ing the vac­cine pro­tein or its pep­tide deriv­a­tives. Whether innate mem­o­ry respons­es (Netea et al., 2011) to LNPs also con­tribute to ampli­fy­ing the side effects remains to be deter­mined (Fig­ure 4). Over­all, the robust inflam­ma­to­ry milieu induced by LNPs, com­bined with pre­sen­ta­tion of the vac­cine-derived peptides/protein out­side of anti­gen-pre­sent­ing cells, might cause tis­sue dam­age and exac­er­bate side effects. Because self-anti­gen pre­sen­ta­tion in an inflam­ma­to­ry envi­ron­ment has been linked to autoim­mune dis­ease devel­op­ment (Janeway et al., 2001), this mer­its fur­ther inves­ti­ga­tion.

    [see Fig­ure 4]

    The side effects observed with the SARS-CoV­‑2 vac­cine’s first dose are like­ly asso­ci­at­ed with the LNPs’ inflam­ma­to­ry prop­er­ties. LNPs acti­vate dif­fer­ent inflam­ma­to­ry path­ways that will lead to the pro­duc­tion of inflam­ma­to­ry cytokines, such as IL-1ß and IL‑6, that can ini­ti­ate and sus­tain local and sys­temic inflam­ma­tions and side effects. The dashed line indi­cates the pos­si­bil­i­ty that the LNPs might also dif­fuse from the periph­ery and reach any organs in the body, includ­ing CNS (hypo­thal­a­mus) where they could direct­ly induce side effects. PEG is wide­ly used as a food and med­i­cine addi­tive, and many of us devel­op anti­bod­ies to PEG. There­fore, the LNPs’ PEGy­lat­ed lipids can induce CARPA in humans with pre­ex­ist­ing PEG-spe­cif­ic anti­bod­ies. Humans often expe­ri­ence more severe side effects with the sec­ond dose. Here we posit that might be due to mul­ti­ple rea­sons. First­ly, innate immune mem­o­ry against the LNPs might form after the first vac­ci­na­tion and that could lead to even more robust inflam­ma­to­ry respons­es upon the sec­ond vac­ci­na­tion. Sec­ond­ly, after the first vac­ci­na­tion, adap­tive immune respons­es are formed tar­get­ing the viral pro­tein cod­ed by the mRNA. As such, cells (shown as red shape) express­ing the viral pro­tein-derived pep­tides or pro­tein itself can become the tar­get of CD8+ T- or NK-cell-medi­at­ed killing (ADCC), respec­tive­ly. Because the LNPs could dif­fuse through­out the body and trans­fect any cell in their path with the mRNA, and the mRNA could also be fur­ther dis­trib­uted through extra­cel­lu­lar vesi­cles (Maugeri et al., 2019), the tar­get pop­u­la­tion could poten­tial­ly be vast and diverse.

    ...

    ———–

    “The mRNA-LNP plat­for­m’s lipid nanopar­ti­cle com­po­nent used in pre­clin­i­cal vac­cine stud­ies is high­ly inflam­ma­to­ry” by Sonia Nde­u­pen, Zhen Qin, Sanya Jacob­sen, Aure­lie Bouteau, Hen­ri Estanbouli, Botond Z. Igyártó; iScience; Vol­ume 24, Issue 12, 17 Decem­ber 2021

    “The human clin­i­cal tri­als of the Pfizer/BioNTech and Mod­er­na vac­cines have report­ed side effects such as pain, swelling, fever, and sleepi­ness (Jack­son et al., 2020; Sahin et al., 2020; Walsh et al., 2020). Under the pre­sump­tion that this vac­cine plat­form is non­in­flam­ma­to­ry, some of the clin­i­cians and pub­lic health com­mu­ni­ca­tors inter­pret­ed these report­ed acute side effects as the vac­cine being potent and gen­er­at­ing an adap­tive immune response. These side effects, how­ev­er, are more in line with acute inflam­ma­to­ry respons­es induced by the vac­cine. Still, no stud­ies have been under­tak­en to char­ac­ter­ize the imme­di­ate innate inflam­ma­to­ry reac­tions induced by this vac­cine plat­form that could poten­tial­ly cause the local and sys­temic side effects. There­fore, in this study, we took a sys­tem­at­ic approach, focus­ing our atten­tion on the injec­tion site and ana­lyz­ing the inflam­ma­to­ry reac­tions caused by the LNPs used for pre­clin­i­cal vac­cine stud­ies (Awasthi et al., 2019; Laczkó et al., 2020; Led­er­er et al., 2020; Par­di et al., 2017, Par­di et al., 2018a, Par­di et al., 2018b). Using com­ple­men­tary tech­niques, we show that in mice intra­der­mal, intra­mus­cu­lar, or intranasal deliv­ery of LNPs used in pre­clin­i­cal stud­ies trig­gers inflam­ma­tion char­ac­ter­ized by leuko­cyt­ic infil­tra­tion, acti­va­tion of dif­fer­ent inflam­ma­to­ry path­ways, and secre­tion of a diverse pool of inflam­ma­to­ry cytokines and chemokines. Thus, the inflam­ma­to­ry milieu induced by the LNPs could be par­tial­ly respon­si­ble for report­ed side effects of mRNA-LNP-based SARS-CoV­‑2 vac­cines in humans and are pos­si­bly con­trib­u­to­ry to their report­ed high poten­cy for elic­it­ing anti­body respons­es.

    As the authors point out, the assump­tion that the report­ed side effects from the mRNA vac­cines were all a con­se­quence of the adap­tive respons­es induced by the mRNA in the vac­cine is just that, an assump­tion. A wide­ly held assump­tion but a rather ques­tion­able one giv­en that the side effect symp­toms — pain, swelling, fever, and sleepi­ness, etc — are more in line with the non-adap­tive imme­di­ate innate immune response to the LNP vac­cine plat­form itself. In oth­er words, is it the chunk of the SARS-CoV­‑2 spike pro­tein embed­ded in the mRNA stuffed into the LNP bub­bles that is dri­ving these side effects or is it the LNP bub­bles them­selves dri­ving this? That’s the ques­tion these authors set out to address in this study pub­lished in Decem­ber of 2021. Mice had LNP expose their skin, inject­ed into their mus­cles, and exposed intranasal­ly in order to explore the inflam­ma­to­ry impact of the LNP par­ti­cles alone. They also exam­ined LNPs with mRNA spiked in (mRNA that does­n’t code for any pro­tein), to sim­u­late the gen­er­ate expo­sure of mRNA and LNPs non-spe­cif­ic to the SARS-CoV­‑2 spike pro­tein’s immuno­log­i­cal effects. And as we can see in their pub­lished results, the observed inflam­ma­tion induced by the LNPs in these mice was pro­found, whether the LNPs were exposed to the skin, inject­ed into mus­cle, or deliv­ered through the nose where inflam­ma­tion of the lungs was wide­spread short­ly after expo­sure.

    And here we get to the very inter­est­ing results that direct­ly tie in to the recent Yale study’s find­ings: When they spiked in non-pro­tein mRNA into the LNPs to more close­ly sim­u­late the mRNA vac­cines, they found a vari­ety of inflam­a­to­ry cytokines and chemokines such as CCL2, CCL3, CCL4, CCL7, CCL12, CXCL1, and CXCL2 and large amounts of inter­leukin-1ß (IL-1ß), gran­u­lo­cyte-macrophage colony-stim­u­lat­ing fac­tor (GM-CSF), and IL‑6, the sig­na­ture cytokines of inflam­ma­to­ry respons­es. Recall what the Yale authors found: “Con­trary to ear­ly hypothe­ses, patients did not demon­strate fea­tures of hyper­sen­si­tiv­i­ty myocardi­tis, nor did they have exag­ger­at­ed SARS-CoV‑2–specific or neu­tral­iz­ing anti­body respons­es con­sis­tent with a hyper­im­mune humoral mech­a­nism. We addi­tion­al­ly found no evi­dence of car­diac-tar­get­ed autoan­ti­bod­ies. Instead, unbi­ased sys­tem­at­ic immune serum pro­fil­ing revealed ele­va­tions in cir­cu­lat­ing inter­leukins (IL-1ß, IL-1RA, and IL-15), chemokines (CCL4, CXCL1, and CXCL10), and matrix met­al­lo­pro­teas­es (MMP1, MMP8, MMP9, and TIMP1).” Now, those two lists of cytokines and chemokines don’t over­lap exact­ly, but they are both point­ing towards the same gen­er­ate innate immune response. All of this research demon­strat­ing how LNPs induce the same kind of immune response that the Yale team was observ­ing was just left out of their analy­sis:

    ...
    To acquire a more in-depth under­stand­ing of the glob­al changes trig­gered by the injec­tion of the LNPs, we repeat­ed the intra­der­mal exper­i­ments pre­sent­ed above with LNPs com­plexed with con­trol, non­cod­ing poly-cyto­sine mRNA. Skin sam­ples har­vest­ed one day after injec­tion were split into two and ana­lyzed using Luminex and bulk RNA-seq (Fig­ure 2A). The Luminex data cor­rob­o­rat­ed the flow cytom­e­try find­ings and demon­strat­ed the pres­ence of a vari­ety of inflam­ma­to­ry cytokines and chemokines (Fig­ures 2B, 2C and S2), in com­par­i­son to con­trol sam­ples. Chemokines that attract neu­trophils and mono­cytes and pro­mote their func­tions, such as CCL2, CCL3, CCL4, CCL7, CCL12, CXCL1, and CXCL2, dom­i­nat­ed the pan­el (Fig­ure 2B). We fur­ther found large amounts of inter­leukin-1ß (IL-1ß), gran­u­lo­cyte-macrophage colony-stim­u­lat­ing fac­tor (GM-CSF), and IL‑6, the sig­na­ture cytokines of inflam­ma­to­ry respons­es (Fig­ure 2C). Our RNA-seq analy­sis revealed that thou­sands of genes were upreg­u­lat­ed (Fig­ure 2D) upon LNP injec­tion. ...

    ...

    It’s also inter­est­ing that, as the authors note, peo­ple often expe­ri­ence their most severe side effects fol­low­ing a boost­er shot, and not the first shot, which might indeed point towards an inter­play with the adap­tive immune response and the fact that, while inject­ed mRNA vac­cine are pri­mar­i­ly trans­fect the cells near the injec­tion site, they can hypo­thet­i­cal­ly reach any cell in the body. And this could, in turn, explain the observed inci­dents of myocardi­tis fol­low­ing vac­ci­na­tions. In oth­er words, if the LNPs inject­ed into your arm are mak­ing their way to your heart, an adap­tive response could hypo­thet­i­cal­ly tar­get the trans­fect­ed heart cells:

    ...
    ... Briefly, although mRNA main­ly trans­fects cells near the injec­tion site, it could hypo­thet­i­cal­ly reach any cell in the body (Maugeri et al., 2019; Par­di et al., 2015). The result­ing trans­lat­ed pro­tein could be pre­sent­ed on MHC‑I in the form of pep­tides or dis­played as a whole pro­tein in the cell mem­brane. In both cas­es, cells with the vac­cine peptide/protein on their sur­faces could be tar­get­ed and killed by cells of the adap­tive and innate immune sys­tem, CD8+ T and nat­ur­al killer (NK) cells (via anti­body-depen­dent cel­lu­lar tox­i­c­i­ty [ADCC]), respec­tive­ly. In line with this, the so-called “Covid-arm,” a delayed-type hyper­sen­si­tiv­i­ty reac­tion that devel­ops in some patients sev­er­al days after vac­ci­na­tion (Blu­men­thal et al., 2021), or the myocarditis/pericarditis recent­ly report­ed with some of the vac­ci­nat­ed peo­ple (Abu Mouch et al., 2021; Diaz et al., 2021; Mar­shall et al., 2021; Mont­gomery et al., 2021; Shay et al., 2021), or the CNS inflam­ma­tion observed in a small num­ber of vac­ci­nat­ed MS patients (Khay­at-Khoei et al., 2021) could be indeed an indi­ca­tion of immune respons­es tar­get­ing the cells express­ing the vac­cine-derived peptides/proteins.
    ...

    Do you take the shot? Or roll the dice with the virus? Which immune sys­tem gam­ble is right for you? That’s the trag­ic health dilem­ma fac­ing the pop­u­lace. Again, no non-mRNA vac­cines are approved in the US after you’ve had your first boost­er. If you want fur­ther boosts you HAVE to get one of these mRNA shots, despite the exis­tence of both the J&J and Novavax that some­how just can’t ever get full approval. Why is that? And how is it that we can have stud­ies pub­lished in peer reviewed jour­nals rais­ing major ques­tions about the safe­ty of LNPs and it’s like it nev­er hap­pened? More ques­tions to add to the ever-grow­ing pile of unan­swered ques­tions. Or, in some cas­es, ques­tions with answers no one wants to hear.

    Posted by Pterrafractyl | May 6, 2023, 4:38 pm

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