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The Food and Drug Administration faces an important decision in coming days — whether to instruct companies that make Covid-19 vaccines to update the viral strain or strains of SARS-CoV-2 those products target.

It seems almost a given that the FDA will tell manufacturers that it is time to change the composition of Covid vaccines, with an eye to a rollout of updated vaccines to be administered in the autumn. But how and to what are questions that still need answering.

The agency is seeking the advice of its independent panel of vaccine experts, the Vaccines and Related Biological Products Advisory Committee, or VRBPAC, to help it decide how, in the words of senior FDA official Peter Marks, to predict the future. VRBPAC meets Tuesday to discuss the issue.


“This is actually one of the more challenging scientific and scientifically nuanced decisions that FDA has to make because, in a sense, we are trying to predict the future based on probability and odds and the best scientific data that we have, knowing full well that this virus has surprised us previously,” Marks, director of FDA’s Center for Biologics Evaluation and Research, told STAT in an interview late last week.

To date, Covid vaccines target the original strain of SARS-2 that first started sickening people in Wuhan, China, in late 2019. As new versions of the virus have emerged with mutations that help it evade immune responses we’ve developed through vaccination, infection, or a combination of the two, manufacturers have made and tested updated versions of the vaccine.


Prior to the emergence of the Omicron variant in late November, it didn’t seem like updating the vaccine strain would lead to enough of a gain, protection-wise, to warrant the work involved. But the calculus appears to have changed with Omicron — which has evolved into a series of subvariants over time. Omicron is so different than the strains that came before it that it is able, more commonly, to evade the immune response the vaccines generate. Since the emergence of the variant, there has been an increase in breakthrough infections, even among people who have had booster shots.

In fact, a committee that advises the World Health Organization, the Technical Advisory Group on Covid-19 Vaccine Composition, recently recommended that vaccines be updated to include an Omicron-based viral target, as a means of broadening the protection the vaccines induce.

“I think most people think that continuing to vaccinate with the same product is not the optimum way to get a breadth of response,” Kate O’Brien, the WHO’s technical lead for vaccines, said in an interview.

Marks said it now seems clear that targeting Omicron will improve the performance of the vaccines. But the question remains: Should the vaccines be updated to include two strains — the original virus and a version of Omicron, a bivalent vaccine — or just Omicron itself?

“We have to have a dialogue at this meeting about what you might buy by moving to a new vaccine composition and what you might lose and whether there’s some balance,” he said. “In other words, do you fully shift to a new vaccine composition, all Omicron? Do you potentially shift to 50-50 — our current vaccine 50%, plus Omicron 50%? And so that will be the discussion that’s going to occur to try to come to the best place we can to protect the population as we go forward.”

The FDA’s decision will influence the products vaccine manufacturers can bring to the American market. But the importance of this market means that its decision may impact what will be available to people far beyond the country’s borders as well.

The WHO’s committee has suggested that including a version of the Omicron variant in Covid vaccines will broaden the immune system’s capacity to recognize and fight off SARS-2 viruses, because Omicron, of all the variants that have emerged so far, is the most different from the original or index virus.

The committee suggested vaccines should either be reformulated to include two versions of the SARS-2 virus — a bivalent vaccine targeting the index virus and an Omicron version, BA.1 — or that a booster-only vaccine be created that targets Omicron alone.

It did not support the idea that an Omicron-only shot could be used as a first vaccination, a primary series vaccine that would be given to anyone who hasn’t yet been vaccinated, or, going forward, babies 6 months or older who are being vaccinated against SARS-2 for the first time.

“That doesn’t broaden the response,” O’Brien said of a monovalent vaccine only targeting the Omicron variant. “So if you’re coming with a monovalent product, then probably that product would only be used as a booster dose.”

The WHO has been working for months with regulatory agencies from around the world to try to develop a unified approach to updating Covid-19 vaccines, similar but not identical to the system used to change the composition of flu vaccines.

Will the U.S. follow the WHO’s advice here? Marks seemed to indicate there may be an interest in using a monovalent Omicron vaccine as a primary series. Data released by Pfizer and BioNTech over the weekend suggested the antibody levels induced by an Omicron-only vaccine were greater than what was seen with a version that included the index virus and Omicron.

The FDA in general tries to follow the WHO’s advice on influenza vaccine composition, Marks said, “but I think there will be a discussion here.”

Likewise, the FDA is asking its advisory committee to discuss whether using the BA.1 version of Omicron — which has been replaced by other subvariants of Omicron in the United States — is appropriate, or whether using BA.4 or BA.5 makes more sense. Those two subvariants are making up a growing share of infections in this country and elsewhere.

There are pros and cons to the various options. For instance, using different formulations for a primary series vaccine and booster shots creates delivery challenges — doctors’ offices and pharmacies would need to keep stocks of both on hand. Targeting Omicron alone would protect people against the strain of viruses that is actually circulating, Marks said.

But the WHO’s position is that the goal of updating the vaccines isn’t to try to keep up with the evolving virus — an approach that is used with flu vaccines — but rather to expose the immune system to another very different version of SARS-2 to teach it to better recognize and respond to both current and hopefully future strains of the virus. Think of it as making a wanted poster using multiple photos of a fugitive, taken from different angles.

“We’re not trying to say: Put Omicron in it because we think Omicron is what’s going to be around for the rest of time,” O’Brien said. “What the composition committee is saying is: We think that what will protect people best against whatever is going to come in the future is a broad immune response. And for the vaccines, the variant that is most different on the evolutionary tree from the ancestor strain, the index variant, is Omicron. That’s why they’re recommending Omicron.”

O’Brien noted that if another variant of concern replaces Omicron, the vaccines might not require updating, if testing shows that their protection holds up against the new strain. In this way, she said, the system being devised to update Covid vaccines is not like the one used to modify the composition of flu shots — which must include viral targets that are as close as possible to circulating strains to be effective.

“The point is not to copy and paste what has been done with flu but it’s more to get inspiration, basically, from the flu process,” O’Brien’s WHO colleague, Sylvie Briand, agreed. Briand is director of the global health agency’s epidemic and pandemic prevention and preparedness department.

One area in which the proposed updating of vaccines will likely follow the influenza model — and where the FDA will likely follow the WHO’s advice — relates to the way updated vaccines will be authorized for use. When the viral targets in flu vaccines are updated, the vaccines are not deemed to be new products and they do not have to undergo wide-scale efficacy testing. Instead, strain changes follow an accelerated regulatory pathway.

Updated vaccines will be authorized for use based on small safety trials and what is known as immunobridging — comparing the antibody levels induced by the updated vaccines to those generated by earlier versions. If they are similar, the assumption will be that antibody levels that protected against earlier versions of the virus will be protective again.

Marks said the FDA is aided in this task by the fact that as each variant of concern has emerged, Pfizer and Moderna have developed and tested prototypes against the new strains, generating immunogenicity and safety data that the agency has studied.

“So, we have a sense by looking at all of those data that we know with these mRNA vaccines that you seem to be able to change the sequence and get a good immune response and have a safe vaccine,” he said. “So I think that part of the discussion that will occur at the VRBPAC [meeting] is, ‘Look, given that we’ve now seen that this can be done … can we do something that’s very analogous to what we do with influenza?’”

Though the messenger RNA vaccines — those made by Pfizer and Moderna — are the easiest to update, Marks said whatever decision is made about updating the vaccines will probably apply to all vaccines sold in the U.S. market.

“I think that it’s going to probably be most easily implemented by the mRNA vaccines, or most rapidly implemented, but I would assume our recommendations will go across the different vaccine platforms,” he said. “But again, that may be discussed at the VRBPAC meeting as well.”

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