FDA’s vaccines advisory committee to consider annual strain selection for Covid-19 vaccines

Background

• On June 15, 2023, the FDA’s Vaccines and Related Biologic Products Advisory Committee (VRBPAC) will meet to discuss which strain, or strains, should be included in Covid-19 vaccines for what the FDA is describing as a “2023-2024 vaccination campaign.”
• The meeting was presaged when VRBPAC met in January 2023; at that session, the committee voted to streamline the administration schedule for Covid-19 vaccines to the format currently laid out by the FDA, with bivalent vaccines to be used for all doses and a streamlined dosing schedule.
• Many issues were touched on at that wide-ranging meeting, including how (or if) the U.S. should coordinate with the rest of the world in vaccine administrations, how closely to model Covid-19 vaccination on influenza campaigns, and the need for different – and more durable – Covid-19 vaccine choices. Low vaccine uptake and increasing vaccine hesitancy are other prominent public health themes weighing on regulators and sponsors.
• Below, AgencyIQ provides a recap of some of the issues likely to be at play as the committee looks ahead to the upcoming fall and winter, highlighting public health issues, regulatory challenges in the areas of international harmonization, and licensing and labeling issues for protein-based vaccines, which are likely to be an increasingly prominent part of the Covid-19 vaccine landscape.

Can better data combat low vaccine uptake?

• As AgencyIQ has previously discussed, recently issued contract notices indicate that FDA is planning new investments in its biologics post-market surveillance system through the Biologics Effectiveness and Safety (BEST) arm of the Sentinel Initiative. BEST has primarily focused on vaccine surveillance in recent years, as shown by the program’s curation of recent publications and presentations. This accumulation of real-world data should help sort out vaccine effectiveness over time, and perhaps assuage flagging public confidence in public health – and vaccine campaigns.
• Regarding low uptake of updated vaccine boosters, Peter Marks, the Director of the FDA’s Center for Biologics Evaluation and Research (CBER), last month explained his position that the “crisis in vaccine confidence has to be addressed head-on by FDA doing their job.” Certain contributors to the issue, like perception of privacy intrusions, could be addressed through technical safeguards like encryption or blockchain.
• Marks thinks these developments can position the U.S. and FDA to be leaders for what comes after COVID-19. “We’ve got to look at the next generation of vaccines coming along,” said Marks at the event.

Moving forward, more choices beyond mRNA will be needed for Covid-19 vaccines

• These recent remarks echo those made by Marks and coauthors in a December 2022 JAMA Viewpoint, where they argued that a new approach is necessary to achieve “the depth and breadth of protection needed to interrupt viral transmission during a prolonged period.” Some approaches they say are not likely to work in the long run are “updating the existing vaccine constructs with new variant sequences,” or even producing multivalent vaccines to cover multiple variants.
• Crucially, Marks also said immunobridging – the same practice it had relied upon recently for the authorization of vaccine boosters – was unlikely to be effective unless stronger correlates of protection were identified. “Therefore, unless correlates of protection that are strongly associated with duration of protection against COVID-19 can be identified, it is likely that rather than relying on immunobridging to infer vaccine effectiveness, large randomized clinical trials similar to the initial trials of the currently authorized or licensed vaccines for COVID-19 will be required to ascertain the effectiveness of these new vaccines.” That, in turn, could make an annual update process slower and more onerous.
• Completely new vaccine platforms are going to need large clinical trials like the ones currently authorized/approved vaccines were based on, rather than just immunobridging trials, observed Marks and his coauthors: “Although experience with the mRNA vaccine platforms has enabled authorization of updated versions of vaccines without large clinical trials, when more significant modifications are made to a vaccine, the clinical effects are often unexpected. Biological properties that may plausibly have beneficial effects often have unanticipated consequences.”
• The authors pointed to other COVID-19 vaccine strategies currently in development. Some of the vaccine strategies being explored include targeting S protein viral sequences, looking to target other vulnerable portions of the SARS-CoV-2 virus, and other strategies, including addressing T-cell immunity. Looking forward, “success” for these future vaccines would mean they provide protection that applies “across a wide range of potential variants that might emerge,” asserted Marks and his coauthors. At a minimum, we should expect the same level of protection that will be expected for a future universal flu vaccine, which should be suitable for all age groups, have a duration of protection of at least one year, and achieve 75% effectiveness in preventing influenza-like illness. “Aiming even further, the vaccines would ideally not only protect against hospitalization, death, and symptomatic disease leading to increased health care use but would also reduce viral transmission. Even using the criterion for success of a moderate 40% to 60% reduction in transmission is predicted to have a notable positive impact on outbreak control,” wrote the editorialists.

The FDA has continued to express interest in “next-generation” vaccines

• An April 27 virtual workshop addressing recombinant protein-based COVID-19 vaccines was co-hosted by the FDA and the Biomedical Advanced Research and Development authority (BARDA). Officials from several Federal agencies as well as the international vaccines alliance CEPI gave presentations and participated in a panel discussion; a half dozen industry representatives also gave brief overviews of their recombinant protein vaccine development programs. Notably, the Dutch firm Intravacc, a government spinoff, shared early data on a nasal mucosal vaccine, while Novavax data demonstrated high, durable immunogenicity for its monovalent protein subunit vaccine compared with the bivalent formulation.
• At the workshop, John Beigel, associate director for clinical research at the National Institute of Allergy and Infectious Diseases (NIAID), reviewed work the agency and its collaborators have been doing to characterize antibody response produced by Covid vaccines against various strains. Noting that current vaccines still protect well against severe disease and death from Covid-19, Beigel cautioned that “cross-reactive antibody titers to new variants emerging within a year” of vaccine administration are “marginal.” He explained that antibodies produced by current vaccines are not sufficient “to cover newly emerging strains with high titers.”
• Pointing to “next generation” vaccines, and echoing Marks’ concepts in the December 2022 piece, Beigel said that these vaccines should be relatively “variant-proof,” with enhanced breadth of protection. They also should have improved durability and enhanced ability to block infection and transmission, over and above preventing severe disease and death.
• New antigens or constructs, including looking at conserved elements across strains, may point to a path forward for these next-generation products, said Beigel. Targeting mucosal immunity also holds promise to block infection and transmission; intranasal or oral administration could achieve this, as could a parenteral delivery method that would produce higher mucosal immunity.
• Another key point raised by Beigel that has been a subtext through Covid-19 vaccine development is that “neutralizing antibody does not explain all of vaccine efficacy.” Beyond antibody titers, T-cell immunity, additional mucosal antibodies not captured in serum titers, and other cellular responses may all factor into protection conferred by a vaccine. However, measuring the strength of these other defenses is challenging, and not a routine part of vaccine development work.

What to expect at the meeting

• A Covid-19 vaccine regimen that incorporates an annual booster or seasonally adjusted vaccination will align well with the current fall influenza vaccine, with many logistic and public health benefits. Each year, as part of the global campaign for influenza vaccination, the World Health Organization (WHO) and national bodies such as 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. Harmonizing Covid-19 vaccines to an annual cadence that meshes with the influenza campaign could do much to boost uptake. [ Read AgencyIQ’s analysis of the October 2022 VRBPAC influenza strain selection meeting here.]
• As AgencyIQ has previously observed, the FDA’s existing approach to influenza can’t be transferred wholesale over to Covid-19. At a January 2023 VRBPAC meeting, Marks noted that “We totally agree with everyone that this isn’t flu.” However he said, “We are very much of the mind that we would like to work with our global partners,” adding that ultimately, a global approach is the goal. The U.S. is in the process of being added to the World Health Organization team that monitors variants, which should speed a more coordinated global approach to variant selection. This strategy would be an obvious boon to manufacturers, as well.
• For these reasons and others, the FDA is not going to wait to coordinate its strain selection efforts with WHO, according to the agency’s briefing documents for its January 2023 VRBPAC meeting. “However, unlike influenza, a well-established, highly coordinated infrastructure and governance of global semi-annual vaccine composition evaluation and recommendations do not currently exist for SARS-CoV-2,” wrote the agency. Other factors, including the wide array of manufacturers and global supply issues, contribute to the fact that this approach isn’t practical, at least for the time being.
• At a high level, the process of updating vaccine composition FDA proposed will be an iterative three-step process that continuously loops back. First, the FDA will review available data in an integrated way to see whether an updated vaccine composition is needed. If so, this decision would trigger a VRBPAC meeting where a recommendation would be made for a string change.
• The second step in the process would be for manufacturers to make recommended updates to their vaccines, gather their data package, and submit information to the FDA for review. The outcome of this step would be a decision regarding emergency use authorization or approval, as appropriate.
• The third step in the process is gathering real world evidence on the effectiveness of the updated vaccines. With the completed cycle, the FDA and other health authorities would then continue ongoing surveillance to determine when the next three step cycle to consider a strain change should begin. The FDA is currently seeing this as a process that will happen at least annually, with the caveats that there’s only limited experience thus far with COVID-19, and it has not shown the same seasonality that influenza has.
• But with this week’s announcement of the June VRBPAC meeting, the FDA is signaling that it’s moving to an annual reassessment of Covid-19 vaccines – a transition that does not preclude the need for more frequent adjustments, depending on the global situation.
• Practically speaking, a large tranche of predictable seasonal vaccine orders, based on a predictable schedule of vaccine updates, would be an economically stabilizing approach for vaccine manufacturers. But if “a more pathogenic escape variant” should emerge, the FDA still wants to be able to bring VRBPAC together to assess an interim plan for strain selections to address a SARS-CoV-2 variant that has the potential to evade the current vaccines, wrote the FDA in its January 2023 briefing document.
• Some issues that may emerge from VRBPAC, and from the ensuing transition to an annual cadence for strain selection for Covid-19 vaccines, include the longer lead time required for protein vaccine production – approximately six months, according to Novavax’s Filip Dubovsky, speaking at the April protein vaccines workshop. For the 2023-24 season, this gives the clear edge to mRNA vaccines, which can be adjusted relatively nimbly, so manufacturers will not have to produce a large stock of vaccine at risk.
• Dubovsky, Novavax EVP and chief medical officer, also noted that licensing issues currently cap the per-strain dose in the bivalent formulation – a likely reason that the Novavax monovalent formulation performed better against newer variants than did an “updated” bivalent formulation, he said. Although this issue has not been seen with mRNA vaccines, the question of per-strain dose reduction for bivalent vaccines has previously been raised by Paul Offit of the Children’s Hospital of Philadelphia – a member of both VRBPAC and the vaccines advisory committee of the Centers for Disease Control and Prevention (CDC).
• In a potential workaround for the lead time issue for protein-based vaccines, industry also asked at the workshop that the FDA consider including “like-strain” language in labeling for protein subunit vaccines. For these vaccines, a sufficiently similar strain will likely confer good protection against whatever SARS-CoV-2 strain is in circulation at the time of vaccine administration. In this case, manufacturers would still have to make a correct judgment about where along the SARS-CoV-2 phylogenetic tree the next dominant strain will likely emerge, but global patterns and trends to date mean this is not completely a guessing game.
• Comments submitted by June 7, 2023 will be forwarded to the committee. AgencyIQ will attend the meeting and provide an analysis.

Featuring previous research by Amanda Conti.
To contact the author of this piece, please email Kari Oakes ( [email protected])
To contact the editor of this piece, please email Alec Gaffney ( [email protected])

Key documents and dates

• Meetings: Vaccines and Related Biological Products Advisory Committee
• Docket No. FDA-2023-N-1553