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).”

Alexander Lefterov/Endpoints News

A new can­cer im­munother­a­py brings cau­tious hope for a field long await­ing the next big break­through

Bob Seibert sat silent across from his daughter at their favorite Spanish restaurant near his home in Charleston County, SC, their paella growing cold as he read through all the places in his body doctors found tumors.

He had texted his wife, a pediatric intensive care nurse, when he got the alert that his online chart was ready. Although he saw immediately it was bad, many of the terms — peritoneal, right iliac — were inscrutable. But she was five hours downstate, at a loud group dinner the night before another daughter’s cheer competition.

Endpoints Premium

Premium subscription required

Unlock this article along with other benefits by subscribing to one of our paid plans.

In a set­back, FDA or­ders Gilead to hit the brakes on their late-stage, $5B can­cer play

Gilead’s $5 billion drug magrolimab has run into a serious setback.

The FDA ordered Gilead to halt enrollment on their studies of the drug in combination with azacitidine after investigators reports revealed an “apparent imbalance” in the suspected unexpected serious adverse reactions between study arms. And the halt is raising questions about Gilead’s plans for a quick pitch to regulators.

Endpoints News

Keep reading Endpoints with a free subscription

Unlock this story instantly and join 129,700+ biopharma pros reading Endpoints daily — and it's free.

Graphic: Alexander Lefterov for Endpoints News

Small biotechs with big drug am­bi­tions threat­en to up­end the tra­di­tion­al drug launch play­book

Of the countless decisions Vlad Coric had to make as Biohaven’s CEO over the past seven years, there was one that felt particularly nerve-wracking: Instead of selling to a Big Pharma, the company decided it would commercialize its migraine drug itself.

“I remember some investors yelling and pounding on the table like, you can’t do this. What are you thinking? You’re going to get crushed by AbbVie,” he recalled.

Endpoints News

Keep reading Endpoints with a free subscription

Unlock this story instantly and join 129,700+ biopharma pros reading Endpoints daily — and it's free.

Mar­ket­ingRx roundup: Pfiz­er de­buts Pre­vnar 20 TV ads; Lil­ly gets first FDA 2022 pro­mo slap down let­ter

Pfizer debuted its first TV ad for its Prevnar 20 next-generation pneumococcal pneumonia vaccine. In the 60-second spot, several people (actor portrayals) with their ages listed as 65 or older are shown walking into a clinic as they turn to say they’re getting vaccinated with Prevnar 20 because they’re at risk.

The update to Pfizer’s blockbuster Prevnar 13 vaccine was approved in June, and as its name suggests is a vaccine for 20 serotypes — the original 13 plus seven more that cause pneumococcal disease. Pfizer used to spend heavily on TV ads to promote Prevnar 13 in 2018 and 2019 but cut back its TV budgets in the past two fall and winter seasonal spending cycles. Prevnar had been Pfizer’s top-selling drug, notching sales of just under $6 billion in 2020, and was the world’s top-selling vaccine before the Covid-19 vaccines came to market last year.

Endpoints News

Keep reading Endpoints with a free subscription

Unlock this story instantly and join 129,700+ biopharma pros reading Endpoints daily — and it's free.

Roy Baynes, Merck

FDA bats back Mer­ck’s ‘pipeline in a prod­uct,’ de­mands more ef­fi­ca­cy da­ta

Despite some heavy blowback from analysts, Merck execs maintained an upbeat attitude about the market potential of its chronic cough drug gefapixant. But the confidence may be fading somewhat today as Merck puts out news that the FDA is handing back its application with a CRL.

Dubbed by Merck’s development chief Roy Baynes as a “pipeline in a product” with a variety of potential uses, Merck had fielded positive late-stage data demonstrating the drug’s ability to combat chronic cough. The drug dramatically reduced chronic cough in Phase III, but so did placebo, leaving Merck’s research team with a marginal success on the p-value side of the equation.

Endpoints News

Keep reading Endpoints with a free subscription

Unlock this story instantly and join 129,700+ biopharma pros reading Endpoints daily — and it's free.

Albert Bourla (Photo by Steven Ferdman/Getty Images)

UP­DAT­ED: Pfiz­er fields a CRL for a $295M rare dis­ease play, giv­ing ri­val a big head start

Pfizer won’t be adding a new rare disease drug to the franchise club — for now, anyway.

The pharma giant put out word that their FDA application for the growth hormone therapy somatrogon got the regulatory heave-ho, though they didn’t even hint at a reason for the CRL. Following standard operating procedure, Pfizer said in a terse missive that they would be working with regulators on a followup.

Endpoints News

Keep reading Endpoints with a free subscription

Unlock this story instantly and join 129,700+ biopharma pros reading Endpoints daily — and it's free.

Covid-19 roundup: Pfiz­er/BioN­Tech launch Omi­cron-spe­cif­ic vac­cine tri­al; UK to re­cruit thou­sands more for mol­nupi­ravir study

Pfizer and BioNTech announced Tuesday that they’ve initiated a clinical study to evaluate the safety, tolerability and immunogenicity of an Omicron-targeted vaccine candidate in healthy adults 18 through 55 years of age, although it remains unclear when, if ever, that vaccine might be necessary.

Drawing on some of the participants from the companies’ Phase III booster study, the trial will enroll up to 1,420 participants and evaluate three groups of healthy adults up to the age of 55, including one group who received 2 doses of the Pfizer vaccine and will get one shot of the Omicron-specific booster, one group that received three doses of the Pfizer vaccine and will get one of the Omicron-based vaccines, and then a third group receiving three doses of the Omicron-based vaccine.

Florida Gov. Ron DeSantis (AP Photo/Wilfredo Lee, File)

Opin­ion: Flori­da is so mAb crazy, Ron De­San­tis wants to use mAbs that don't work

Florida Gov. Ron DeSantis is trying so hard to politicize the FDA and demonize the federal government that he entered into an alternate universe on Monday evening in describing a recent FDA action to restrict the use of two monoclonal antibody, or mAb, treatments for Covid-19 that don’t work against Omicron.

Without further ado, let’s break down his statement from last night, line by line, adjective by adjective.

Not cheap­er by the dozen: Bris­tol My­ers be­comes the 12th phar­ma com­pa­ny to re­strict 340B sales

Bristol Myers Squibb recently joined 11 of its peer pharma companies in limiting how many contract pharmacies can access certain drugs discounted by a federal program known as 340B.

Bristol Myers is just the latest in a series of high-profile pharma companies moving in their own direction as the Biden administration’s Health Resources and Services Administration struggles to rein in the drug discount program for the neediest Americans.