FDA calls for Omicron BA.4/5 inclusion in bivalent Covid boosters for the fall

Just two days after an FDA advisory committee voted to recommend that boosters target newer COVID-19 strains, the agency has released specific recommendations for manufacturers, advising them to shift testing and plan for regulatory submissions that focus on the omicron BA.4/5 subvariants that will soon be the predominant source of U.S. Covid-19 infectious.

Peter Marks announced CBER’s decision just two days after the FDA’s vaccines advisory committee meeting.

• Noting that the currently authorized and approved vaccines have helped reduce Covid-19 hospitalization and death, CBER Director Peter Marks also observed in a statement Thursday that “results from post-authorization observational studies have shown that effectiveness of primary vaccination wanes over time against certain variants, including omicron.”
• The boosters offered as a follow-up to the initial series have been effective at restoring protection against severe disease, said Marks, but he also pointed out that “while initial booster doses have helped restore protection against severe disease and hospitalization associated with omicron, studies have also indicated waning effectiveness of first booster doses over time.”
• On June 28, an FDA advisory committee recommended including an omicron-targeted component in upcoming Covid-19 vaccines, with a realistic timeline of making the adjustment this fall. Though the exact variant that would be best was not a voting question for the Vaccines and Related Biologics Advisory Committee (VRBPAC), it was a topic of discussion at the meeting. Most committee members supported BA.4/5 as the strain to add to the ancestral strain for a bivalent booster. [Read our analysis of the day-long meeting here.]
• Marks himself seemed to lean this way as well, citing the relatively poor performance of both ancestral-strain and Omicron BA.1 vaccines against BA.4/5 in terms of neutralizing antibody response in clinical data presented by mRNA vaccine sponsors.
• Today, Marks followed through and announced that the FDA has “advised manufacturers seeking to update their COVID-19 vaccines that they should develop modified vaccines that add an omicron BA.4/5 spike protein component to the current vaccine composition to create a two component (bivalent) booster vaccine, so that the modified vaccines can potentially be used starting in early to mid-fall 2022.” Sponsors should also conduct clinical trials with vaccines that have the BA.4/5 component.
• To date, most of the trials looking into bivalent boosters have been conducted using the omicron BA.1 strain that predominated in early 2022. However, the BA.4/5 sub-lineage is now accounting for about half of the new U.S. Covid-19 cases, with expected transition to near-complete BA.4/5 dominance in the coming weeks to months.
• Marks asked sponsors directly about their variant vaccine capacity for the fall. During the June 28 VRBPAC meeting, Marks took the unusual step of breaking into the committee’s discussion time to ask each sponsor attending the virtual meeting – Moderna, Pfizer, and Novavax – to come online and report on their status and capacity for variant-targeted vaccines. “I actually think it would be very helpful to ask each of the manufacturers when they will have vaccines available of these various sorts,” said Marks.
• Moderna’s BA.4/5 capacity could ramp up in mid-fall, said Moderna’s president Stephen Hoge, noting that the firm will have “hundreds of millions of doses” of Omicron BA.1 bivalent vaccine available in July and August that the firm has been manufacturing at risk. Regarding the question of the strain update to BA.4/5, Hoge said: “If we were to switch over to a BA.4-BA.5-containing vaccine, it takes about three months to switch the manufacturing processes over and to prepare the submissions for the FDA. Again, assuming no clinical data requirements at all. And if we did that, we would have that, assuming a rapid review cycle, sometime in late October or early November at large scale, and again be able to produce large amounts of that vaccine.”
• Kathrin Jansen, head of vaccine research and development at Pfizer, also indicated readiness. “Regardless of if we want to look at a BA.1-containing or a BA.4’5-containing vaccine, we are prepared… to satisfy all of our contractual obligations – those that are currently existing and future ones – in the United States,” she said. Jansen noted they also have produced large volumes of BA.1-modified vaccine, “and we are in the process of producing large numbers of a BA.4/5-modified omicron vaccine that is available for rollout, pending, of course, that there is an agreement on a regulatory pathway, and there’s an agreement on which vaccine is recommended in the United States in the first week of October.”
• Novavax “has begun work at risk in this,” as have the other manufacturers, according to CEO Gregory Glenn. “And that’s included both BA.1 and BA.5.” Novavax’s EUA request for a primary 2-dose series of its adjuvanted protein subunit vaccine is pending before the FDA. As the firm sets up its manufacturing, Glenn noted that “we have been waiting for the results” of the VRBPAC meeting and an FDA decision on vaccine strain composition. Depending on whether clinical data are required, the timing may vary, “but BA.1 or BA.5 – we could supply those in the fourth quarter” of 2022, Glenn said. “We would also like to make the case that the prototype, with our technology, seems to give very broad antibodies,” and might be well suited for use as a booster to previously vaccinated or infected individuals.
• As noted in AgencyIQ’s analysis of the VRBPAC meeting, the FDA and WHO appear to be taking different paths on the booster strain selection question. WHO’s Kanta Subarrao told VRBPAC on Tuesday that the Technical Advisory Group has selected BA.1 as the recommended strain for inclusion in boosters, since it’s most antigenically distant from the ancestral strain in WHO’s view — so a BA.1-containing booster might produce more breadth of response. FDA’s Peter Marks had already signaled on Tuesday that he “would perhaps take issue” with that characterization. Marks cited the relatively poor performance of both ancestral-strain and Omicron BA.1 vaccines against BA.4/5 in terms of neutralizing antibody response.
• For now, manufacturers should not plan to adjust their formulations for the primary vaccine series. Marks called the coming year “a transitional period” during which a modified booster might be rolled out.
• What’s next? Marks also questioned Novavax directly about when they might be able to release doses at scale for their primary vaccine series “were an emergency use authorization to be granted,” receiving the response that doses could roll out in July. A non-mRNA vaccine option suitable for all adults may soon be forthcoming if the FDA issues that EUA.
• Though manufacturers will have capacity, in theory, for large-scale BA.4/5 bivalent booster rollouts by fall, the big wild card is whether, and how much, clinical data the FDA will require. Both Moderna and Pfizer made the case for relying primarily on safety data from already-tested vaccine versions together with limited new safety data and immunobridging, in the seasonal influenza vaccine model. The FDA’s decision on this matter will affect timing and availability of boosters that might pack more of a punch against circulating COVID-19 variants.

To contact the author of this item, please email Kari Oakes.
To contact the editor of this item, please email Laura DiAngelo.

Key Documents and Dates

• Coronavirus (COVID-19) Update: FDA Recommends Inclusion of Omicron BA.4/5 Component for COVID-19 Vaccine Booster Doses