Uğur Şahin, BioNTech CEO (Frank Rumpenhorst/dpa via AP Images)

Will ‘orig­i­nal anti­genic sin’ un­der­mine Omi­cron boost­ers? New re­search sug­gests ‘no’

Mod­er­na and Pfiz­er-BioN­Tech are now rac­ing to de­vel­op Omi­cron-spe­cif­ic boost­ers, hop­ing to be ready if the new im­mune-eva­sive vari­ant be­comes dom­i­nant glob­al­ly. But it wasn’t al­ways clear that vari­ant boost­ers could even work.

Af­ter the first Covid-19 vac­cines were au­tho­rized and talk be­gan of vari­ants and next-gen­er­a­tion vac­cines, sev­er­al vac­ci­nol­o­gists raised con­cerns in the me­dia and the sci­en­tif­ic press about a po­ten­tial­ly dele­te­ri­ous phe­nom­e­non that sounds as if it were born out of the Vat­i­can’s im­munol­o­gy wing: Orig­i­nal anti­genic sin.

OAS — or, as less bib­li­cal­ly in­clined re­searchers like to call it, im­print­ing — was first dis­cov­ered by re­searchers study­ing how old­er peo­ple re­spond to flu vac­cines.

There are about 20 dif­fer­ent flu virus­es. Dif­fer­ent strains are dom­i­nant in dif­fer­ent years and each evolves quick­ly. So every fall, man­u­fac­tur­ers try to in­clude the right virus — and the right ver­sion of each of those virus­es — in the an­nu­al shot, hop­ing to in­duce an­ti­bod­ies that match the virus peo­ple are most like­ly to en­counter.

Re­searchers found, though, that re­gard­less of the vac­cine’s de­sign, peo­ple pro­duced the best and longest-lived an­ti­bod­ies against the flu strains they were first ex­posed to as kids. It was if, like ba­by ducks per­ma­nent­ly mim­ic­k­ing the first duck or hu­man they saw, our im­mune sys­tems per­ma­nent­ly mold­ed around our first in­fec­tion and got stuck there.

Re­searchers feared the same could hap­pen with Covid-19 vac­cines and in­fec­tions. Al­though it’s rel­a­tive­ly straight­for­ward to de­sign an mR­NA vac­cine that codes for a new spike pro­tein, it wasn’t clear whether our im­mune sys­tems would be nim­ble enough to adapt to the new in­struc­tions.

In­ject­ed with a vari­ant-spe­cif­ic boost­er, maybe peo­ple would most­ly just churn out copies of the an­ti­bod­ies they made af­ter their first vac­ci­na­tion or in­fec­tion. That would give the world far less lat­i­tude to re­spond to an im­mune-eva­sive vari­ant like Omi­cron.

Da­ta, though, have since come sug­gest­ing that’s un­like­ly to be a prob­lem with this virus, en­cour­ag­ing vac­cine de­vel­op­ers that they can re­spond should the Omi­cron-spe­cif­ic boost­ers — or boost­ers for a fu­ture vari­ant — be need­ed.

Rather than a fixed im­mune re­sponse to coro­n­avirus­es, re­searchers have ob­served a far more flex­i­ble, tun­able one.

It’s “an im­por­tant sci­en­tif­ic ques­tion,” BioN­Tech CEO Uğur Şahin told re­porters Wednes­day. “And the da­ta that we have ob­served — and again this is pre­lim­i­nary — is en­cour­ag­ing that the im­mune re­sponse can be fine tuned.”

Sahin and oth­er re­searchers’ con­fi­dence come from test runs Mod­er­na and BioN­Tech ran against oth­er vari­ants. Last win­ter, af­ter the first vari­ant that could par­tial­ly evade an­ti­bod­ies from vac­cines, Be­ta, arose in South Africa, Mod­er­na de­signed a new vac­cine con­struct and test­ed it in Phase I.

Al­though Be­ta ul­ti­mate­ly van­ished and Mod­er­na aban­doned the can­di­date, the Phase I study showed that peo­ple giv­en the vari­ant-spe­cif­ic boost­er pro­duced high lev­els of Be­ta-spe­cif­ic an­ti­bod­ies.

“What we’ve seen sug­gests that anti­genic im­print­ing … is not go­ing to be a prob­lem,” said John Mas­co­la, head of the NIH’s vac­cine re­search cen­ter. “I shouldn’t say it’s not go­ing to be a prob­lem, but it hasn’t been a prob­lem so far.”

BioN­Tech has its own, less pub­li­cized stud­ies on vari­ant-spe­cif­ic boost­ers. In Au­gust, the Ger­man biotech launched a 1,245-per­son study to test four types of boost­ers: A boost­er of the orig­i­nal vac­cine; an Al­pha-spe­cif­ic boost­er; a Delta-spe­cif­ic boost­er; and a mul­ti-va­lent boost­er that codes for both the Al­pha spike pro­tein and the Delta spike pro­tein.

Un­re­leased da­ta from those stud­ies, Şahin said, have made the com­pa­ny con­fi­dent they could al­so make a boost­er that com­bines mul­ti­ple vari­ants and con­fers broad­er pro­tec­tion, should that even­tu­al­ly be need­ed.

“One op­tion, which I be­lieve is not very like­ly, could be an Omi­cron-Delta vari­ant,” he said.

Of­fi­cials and ex­ec­u­tives are still track­ing Omi­cron’s spread to see whether spe­cif­ic boost­ers will be need­ed. But if they are, it would be an­oth­er case where the world has man­aged to avoid a po­ten­tial im­muno­log­i­cal bul­let from a virus that, for all the ways it’s sur­prised re­searchers, has proven “stu­pid easy” to vac­ci­nate against.

Ear­ly in the pan­dem­ic, for in­stance, promi­nent im­mu­nol­o­gists and vac­ci­nol­o­gists warned about the risk of an­ti­body-de­pen­dent en­hance­ment, in which the an­ti­bod­ies pro­duced by vac­ci­na­tion or pri­or in­fec­tion ac­tu­al­ly help the virus in­fect more cells. There was ev­i­dence that SARS could do this, but for­tu­nate­ly the vac­cines ul­ti­mate­ly proved to do quite the op­po­site in Covid-19, pow­er­ful­ly sup­press­ing in­fec­tion and dis­ease.

Of course, no one is mak­ing any promis­es yet about Omi­cron boost­ers. Al­though the stud­ies so far point away from orig­i­nal anti­genic sin, they have been com­par­a­tive­ly small and on­ly cov­ered a cou­ple vari­ants.

If Omi­cron boost­ers are need­ed, com­pa­nies will need to run im­muno­log­i­cal stud­ies on the new shots be­fore they’ll be con­fi­dent they work.

“The Phase I tri­al da­ta, and NHP ex­per­i­ments, gen­er­al­ly in­di­cate that the vari­ant-spe­cif­ic boost­ers are not (se­ri­ous­ly) af­fect­ed by OAS. It may be part of the pic­ture, but there does still seem to be ben­e­fit,” John Moore, a vac­ci­nol­o­gist at Weill Cor­nell, said in an email.” Whether that changes re­gard­ing Omi­cron? Slaugh­ter a sheep and in­spect the en­trails … (Make sure you get an­i­mal study ap­provals first of course).”

The Big Phar­ma dis­card pile; Lay­offs all around while some biotechs bid farewell; New Roche CEO as­sem­bles top team; and more

Welcome back to Endpoints Weekly, your review of the week’s top biopharma headlines. Want this in your inbox every Saturday morning? Current Endpoints readers can visit their reader profile to add Endpoints Weekly. New to Endpoints? Sign up here.

With earnings seasons in full swing, we’ve listened in on all the calls so you don’t have to. But news is popping up from all corners, so make sure you check out our other updates, too.

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Photo: Julia Weeks/AP Images

FDA ax­es re­quire­ment for pos­i­tive Covid test be­fore Paxlovid use

FDA announced today that doctors and pharmacists can now prescribe Paxlovid to patients without a positive test for Covid-19.

CDER Director Patrizia Cavazzoni reissued Paxlovid’s authorization letter Wednesday, saying it has revised the authorization to “no longer require positive results of direct SARS-CoV-2 viral testing.” The EUA now requires instead that adults and kids 12 years of age and older have a “current diagnosis of mild-to-moderate COVID-19.”

Sen. Ron Wyden (D-OR) (Francis Chung/E&E News/Politico via AP Images)

In­fla­tion re­bates in­com­ing: Wyden calls on CMS to move quick­ly as No­var­tis CEO pledges re­ver­sal

Senate Finance Chair Ron Wyden (D-OR) this week sent a letter to the head of the Centers for Medicare & Medicaid Services seeking an update on how and when new inflation-linked rebates will take effect for drugs that see major price spikes.

The newly signed Inflation Reduction Act requires manufacturers to pay a rebate to Medicare when they increase drug prices faster than the rate of inflation.

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Trodelvy notch­es a win in most com­mon form of breast can­cer

Following a promise last year to go “big and fast in breast cancer,” Gilead has secured a win for Trodelvy in the most common form.

The drug was approved to treat HR-positive, HER2-negative breast cancer patients who’ve already received endocrine-based therapy and at least two other systemic therapies for metastatic cancer, Gilead announced on Friday.

Trodelvy won its first indication in metastatic triple-negative breast cancer back in 2020, and has since added urothelial cancer to the list. HR-positive HER2-negative breast cancer accounts for roughly 70% of new breast cancer cases worldwide per year, according to senior VP of oncology clinical development Bill Grossman, and many patients develop resistance to endocrine-based therapies or worsen on chemotherapy.

Raymond Stevens, Structure Therapeutics CEO

Be­hind Fri­day's $161M IPO: A star sci­en­tist, GPCR drug dis­cov­ery and a plan to chal­lenge phar­ma in di­a­betes

What does it take to pull off a $161 million biotech IPO these days?

In Structure Therapeutics’ case, it means having a star scientist co-founder paired with the computational drug discovery company Schrödinger, $198 million in private funding from blue-chip investors, almost six years of research work on G protein-coupled receptors and a slate of oral, small-molecule drugs, with an eye on the huge and growing diabetes and weight-loss market.

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Af­ter 13 years, Ramy Mah­moud steps in­to CEO seat at Opti­nose; Ru­pert Vessey set to ex­it Bris­tol My­ers in Ju­ly

After 13 years as president and COO at Optinose, Ramy Mahmoud has stepped into a new role as its CEO. He is taking the place of Peter Miller, who stepped down earlier this week, though Miller is still staying with the company as a consultant.

In 2010, the two business partners joined Optinose to take it in a new direction, transforming it from a delivery platform to product company. They previously worked together at Johnson & Johnson, when Miller was president at Janssen and Mahmoud headed medical affairs. Miller said after he learned about Optinose, “I did what I always do, which is find people smarter than me to talk with about the idea. And the first person I called was Ramy … and I said, ‘Hey, Ramy, what do you think of this technology?’”

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Ma­gen­ta halts stem cell work and may sell it­self fol­low­ing pa­tient death, clin­i­cal hold

Magenta Therapeutics said it is halting work on its stem cell transplant drug pipeline and may sell itself, a week after the company reported the death of a patient in an early stage trial of its antibody-drug conjugate.

The Cambridge, MA-based company said it will conduct a “review of strategic alternatives,” and that could include an “acquisition, merger, business combination, or other transaction.”

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Giovanni Caforio, Bristol Myers Squibb CEO (Nicolas Messyasz/Sipa via AP Images)

Bris­tol My­ers turns at­ten­tion to new prod­ucts in wake of Revlim­id patent loss

Bristol Myers Squibb CEO Giovanni Caforio is shifting his focus to newer products as generic sales continue to gnaw at the company’s blockbuster myeloma drug Revlimid.

Both Revlimid and Abraxane sales took a dive last year thanks to generic rivals, BMS reported in its Q4 and full-year results on Thursday. As a result, Q4 sales dipped 5% and full-year sales remained flat. However, Caforio sees a silver lining — or rather, two of them.

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Lina Khan, FTC chair (Graeme Jennings/Pool via AP)

FTC makes an ex­am­ple of GoodRx, bans dis­counter from shar­ing pri­vate health da­ta with ad­ver­tis­ers

Prescription drug discount provider GoodRx will no longer be allowed to share its users’ sensitive health data with advertisers after the Federal Trade Commission charged the online coupon provider with failing to notify consumers of such disclosures to Facebook, Google, and other companies.

GoodRx agreed to pay a $1.5 million civil penalty for violating the FTC’s Health Breach Notification Rule after the FTC said it repeatedly violated a 2017 promise to not share sensitive personal health information. The FTC alleged that the company shared users’ prescription medications and personal health conditions with third party advertisers and platforms like Facebook, Google, Criteo, Branch and Twilio.