Vaccines advisory panel endorses move to trivalent formulation for U.S. flu vaccines

AgencyIQ’s quick primer on the influenza virus and how annual vaccine strains are selected

• Influenza viruses have caused untold illness and death through human history. Though most individuals who contract the respiratory illness caused by influenza experience mild to moderate illness, infants, children, the elderly and the medically frail are at risk for severe illness or death. Influenza, like many respiratory illnesses, follows a seasonal course, often peaking in late winter. This means that each hemisphere has its own influenza season.
• Each year, as part of the global campaign for influenza vaccination, the World Health Organization (WHO) and national bodies such as the U.S. Centers for Disease Control and Prevention (CDC) gather epidemiological data and conduct experiments to identify the optimal combination of strains for the annual influenza vaccine. Though vaccine “matching” is never perfect, strain selection is better some years than others. However, even an imperfect match results in greatly reduced serious illness and death on a population level when vaccine uptake is high.
• Vaccines may be cell- or egg-based, or recombinant and therefore acellular. In any case, each influenza vaccine (trivalent and quadrivalent versions are manufactured) has, at a minimum, components to protect against influenza A(H3N2), A(H1N1), and influenza B (more about these below). Quadrivalent vaccines contain influenza B/Victoria and B/Yamagata strains.
• A key part of the influenza virus’ ability to infect humans is hemagglutinin (HA), a glycoprotein found on the surface of the virus. HA’s status as a fusion protein enables it to attach and fuse to the surface of human cells. In this way, virions are able to enter the cells, where they replicate.
• Neuraminidase (NA), an enzyme on the surface of influenza viruses, is responsible for disrupting cell structures to allow replicated virus to leave the cell and not clump together, disseminating virus through the host.
• Influenza strains are named according to the HA and NA subtypes (at least 18 HA and 11 NA subtypes have been identified), as with the H1N1 influenza strain that famously wreaked havoc in 2009. That influenza A virus strain is now termed A(H1N1)pdm09, to signify the pandemic of 2009. The 1918 influenza pandemic was also caused by an H1N1 virus.
• Changes — either slow drifts across time or more abrupt mutations — can occur within lineages, clades, and sub-clades; these changes, along with changes in which viruses are responsible for more cases of influenza in a given region and season, inform WHO vaccine strain recommendations for a given influenza season.
• Virologists and epidemiologists track changes in HA particularly closely because mutations in the large molecule can make influenza vaccines less effective, causing so-called “escape” as the structure of epitopes shifts. Epitopes are the sites on a virus or other antigen that are recognized – and attacked – by the host immune system.

Regulatory context: FDA’s vaccine advisors meet twice a year to recommend strains for influenza vaccines destined for the Northern and Southern hemispheres

• The Vaccines and Related Biological Products Advisory Committee (VRBPAC) reviews recommendations made by the WHO’s vaccines group and the CDC’s WHO Collaborating Center for Surveillance, Epidemiology and Control of Influenza at the National Center for Immunization and Respiratory Diseases. At the meetings, the committee hears recommendations and supporting rationale, then votes for or against the strains. Then, the CDC’s Advisory Committee on Implementation Practices (ACIP) also hears evidence supporting the WHO and VRBPAC recommendations and weighs in with a vote for how these recommendations should be implemented for the upcoming influenza season, considering recommendations for each indicated age group, for example.
• The meetings typically take place in early March and October. FDA’s advisors also consider the composition of vaccines destined for the Southern Hemisphere because sponsors seek FDA licensure for these products manufactured in the U.S., explained JERRY WEIR, FDA’s director of the Division of Viral Products in the Office of Vaccines Research and Review in the Center for Biologics Evaluation and Research (CBER), at a VRBPAC meeting last year.
• For years, advisors have grappled with what to do about a vaccine component that protects against a strain that has not been observed in circulation since March 2020. Strains of the influenza B/Yamagata lineage have routinely been included in seasonal influenza vaccines even though the virus has not been detected in global circulation since the “bottleneck” of the early Covid-19 pandemic.
• When VRBPAC last met in October 2023 ahead of the Southern Hemisphere’s 2024 flu season, the committee considered a WHO recommendation to drop the influenza B/Yamagata strain from vaccine formulations “as soon as possible.” Advisors aligned with WHO in voting to retain the B/Yamagata strain for the upcoming Southern Hemisphere season and agreed that the strain should be removed from subsequent formulations as soon as practical.
• At that meeting, industry made the case that a transition to trivalent inactivated influenza vaccines (TIV) before the 2025-26 influenza season would be impractical for manufacturing and regulatory reasons. DAVID GREENBERG of Sanofi provided perspective based on an industry questionnaire, saying the transition will require industry to “re-activate or re-submit more than 300 TIV licenses, submit nearly 1500 variations, and update quality data in 174 countries.” Given the time for both industry and regulatory action, he made the case that the 2025-26 timeline would “minimize confusion and impact to vaccine confidence.”
• Advisory committee members were less convinced. Then-committee chair ARNOLD MONTO, emeritus of the University of Michigan, pushed back, suggesting instead that the adjustment might be possible for the 2024-25 Northern Hemisphere influenza season, at least in the United States.

On March 5, VRBAC met to weigh in on vaccine strains for the 2024 to 2025 influenza season

• The WHO recommendations for the 2024-2025 Northern hemisphere vaccines align with the recommendation for the 2024 Southern hemisphere season. For trivalent egg-based vaccines, WHO recommends an A/Victoria/4897/2022 (H1N1)pdm09-like virus antigen; an A/Thailand/8/2022 (H3N2)-like virus antigen; and a B/Austria/1359417/2021 (B/Victoria lineage)-like virus. For trivalent cell- or recombinant-based vaccines, WHO recommends an A/Wisconsin/67/2022 (H1N1)pdm09-like virus antigen; an A/Massachusetts/18/2022 (H3N2)-like virus antigen; and a B/Austria/1359417/2021 (B/Victoria lineage)-like virus antigen. For quadrivalent vaccines, WHO recommends following the recommendations for trivalent composition and adding a B/Phuket/3073/2013 (B/Yamagata lineage)-like antigen.
• Part of the meeting followed the classic VRBPAC flu vaccine strain selection format, covering epidemiological surveillance and vaccine effectiveness (VE) data. REBECCA KONDOR from the CDC WHO Collaborating Center walked through the selection process. The recommendations were informed by a variety of data sources indicating that the A(H1N1) viruses targeted by the previous Northern hemisphere vaccines remain in circulation. In addition, data supported shifting the A(H3N2) strain to align with the Southern hemisphere vaccine. In addition, B/Victoria lineage viruses have continued to co-circulate with the influenza A viruses in all geographic regions. Both post-infection ferret antisera and post-vaccination human sera studies indicated that the antigens in the vaccine elicit an immune response.
• In a familiar plotline, Kondor confirmed that there have still been zero confirmed detections of circulating B/Yamagata/16/88 lineage viruses after March 2020.
• Representing the Department of Defense, ANTHONY FRIES supplemented the epidemiological data with mid-season VE data in a population of U.S. service members and dependents. In general, the data indicated that the vaccines were “moderately protective” and significant among dependents (35%) and adults (52%).
• Unlike previous meetings, both FDA Director of the Division of Viral Products JERRY WEIR and industry guest speaker Greenberg confirmed to the panel that industry is ready to shift flu vaccines to a trivalent composition for the 2024-2025 season in the United States. Per Greenberg’s presentation, “industry has or will have the necessary CBER approval for TIV distribution in the US for the NH 2024-2025 season with agreed timing.” This is a full year ahead of the timeline proposed by industry at the previous VRBPAC meeting.
• The transition will occur according to timelines set by national/regional authorities. Many countries other than the United States will not transition make the transition prior to the 2024-2025 season and will distribute quadrivalent vaccines. For vaccines manufactured in the United States for foreign markets, CBER release is still required. As a result, the committee was also asked to weigh in on a quadrivalent composition for those cases.
• Greenberg flagged a more existential issue for flu vaccines: divergent supply and demand. According to his presentation, the US market has seen consistent oversupply amid decreased demand. Last year, the US demand for flu vaccines decreased by 37 million doses compared to the 2020-2021 season.

The committee discussion and vote

• VRBPAC voted unanimously in favor of all three of the WHO recommendations for 2024-2025 flu season vaccine compositions. In general, the committee members felt that the data supporting the selected strains was straightforward and compelling.
• The interim inclusion of B/Yamagata in quadrivalent vaccines pending the ongoing transition to trivalent formulations was acceptable to the committee. As explained by CDC’s SARAH MEYER, “…it was really reassuring to hear that this surveillance for Yamagata would continue so that we could pick it up in the future.”
• While many committee members expressed concern regarding data on flu vaccine uptake, they recognized the multifaceted nature of the issue. VRBPAC Chair and Baylor Professor HANA EL SAHLY explained, “We all know it’s post pandemic, but we don’t know why it’s happening. It’s probably the interplay of other respiratory viruses, the messaging around vaccination against those other viruses and flu,” she added.

Analysis and what’s next

• This meeting was a surprisingly straightforward watershed moment in the years-long discussion on vaccine composition and B/Yamagata. While FDA allotted additional time for this meeting, with the event scheduled for an hour and a half longer duration than the most recent strain selection meeting, the absence of clarifying questions led to adjournment ahead of schedule.
• While advisors have previously discussed adjusting quadrivalent vaccines to protect against more influenza A strains, this strategy did not receive much air time. This formulation change strategy could offer increased public health benefits. However, it would require a heavy lift for industry and regulators compared to the chosen path of dropping the B/Yamagata strain and shifting to trivalent formulations. Quadrivalent licenses are set up specifically to include single strains within the established lineages, and changing the composition to include multiple strains of the same lineage would involve a license change for each of the manufacturers—a change that needs data supporting it. Rather than the immunobridging studies that can support yearly strain updates, industry would need to conduct clinical trials to generate data that demonstrates that vaccines with two influenza A H3N2 (or H1N1) strains do not cause unfavorable interference. That said, the move to trivalent vaccines does not preclude companies from conducting R&D to develop novel quadrivalent vaccines.
• What’s next? In July 2024, a workshop will discuss lessons learned from the B/Yamagata experience. According to Greenberg’s presentation, the WHO Coordinating Center will gather industry and other stakeholders to gather input for “a formulation change framework.” AgencyIQ will monitor for additional details on this meeting.

Featuring previous research by Kari Oakes.

To contact the author of this item, please email Amanda Conti ( [email protected]).
To contact the editor of this item, please email Kari Oakes ( [email protected]).

Key Documents and Dates

• Vaccines and Related Biological Products Advisory Committee March 5, 2024
• Docket No. FDA-2024-N-0014