2025 - COVID-19 Vaccine Variant Target: Who Should Choose?
As of Aug 30, 2024, the US FDA has granted approval for Comirnaty (Pfizer) and Spikevax (Moderna) and emergency use authorization for Novavax for use in fall 2024 COVID-19 vaccine programs.1,2 Moderna and Pfizer have manufactured mRNA vaccines targeting the KP.2 SARS-CoV-2 variant, a descendent of the JN.1 strain, whereas the Novavax recombinant protein platform targets the JN.1 variant. This marks the first instance where the FDA has given a recommendation for COVID-19 vaccines targeting two different variants for the same season. The regulatory history of the fall 2024 COVID-19 vaccine campaign provides insight into vaccine policy and has implications for the future of annual vaccine programs.
In contrast to influenza, in which vaccine strains are selected by a collaborative process led by the World Health Organization (WHO), the COVID-19 strain selection approach is fragmented and lacks global alignment. The WHO Technical Advisory Group on COVID-19 Vaccine Composition (TAG-CO-VAC) periodically reviews the evidence and analyzes emerging variants of concern to determine the impact on performance of currently used COVID-19 vaccines. On April 26th 2024, TAG-CO-VAC advised the use of monovalent JN.1 lineage as the antigen in future formulations of the COVID-19 vaccine.3
In the United States, COVID-19 vaccine antigen selection is led by an FDA COVID-19 workgroup that invites industry manufacturers who develop candidate vaccines and present data at the Vaccines and Related Biological Products Advisory Committee (VRBPAC) meeting.4 This season, the VRBPAC meeting was scheduled for May 16, 2024, however, it was subsequently postponed until June 5, 2024 to allow additional time to obtain surveillance data. At the June 5th meeting, voting members of the advisory committee recommended 16 to 0 to support a monovalent JN.1-lineage vaccine composition, citing the importance of providing the choice of a protein-based vaccine alternative for the United States. A JN.1 antigen target was in line with recommendations from the WHO and the European Medicines Agency.5
Although the consensus of VRBPAC was to target a JN.1 variant, the head of the committee asked the group if they felt the US should target KP.2, in analogy compared to purchasing milk at the store. “When I go to the milk case to buy milk… I always tend to buy the most recent dating rather than an older dating.” After further discussion the VRBPAC voting group still supported a JN.1 target. In the closing remarks, the head of the committee stated, “We wanted to make sure that we gave people the option to potentially make a choice of a KP.2 vaccine. We hear loud and clear from all of the members that they don't feel like that is necessary at this time, that a JN.1 vaccine for all is acceptable.”4
Yet, after the discussion at VRBPAC, on June 15, 2024, FDA issued guidance to industry stating that they recommend that the preferred JN.1 lineage for the COVID-19 vaccines (2024-2025 formula) is the KP.2 strain, if feasible. Given this guidance, manufacturers in the US have responded with mRNA vaccines targeting KP.2, whereas Novavax targets the JN.1 variant. Conversely, at the time of this decision, Europe and Asia decided that all vaccine platforms target the JN.1 variant, in alignment with recommendations from the WHO.
The prevalence of different SARS-CoV-2 subvariants has changed since the June 2024 VRBPAC meeting. KP.2 has declined from 12.8% to 0% (as of January 7, 2025), and KP3.1.1. has grown from 1% to 24% during the same time frame. The JN.1 variant has also declined from 10.4% to 0%.6 The XEC variant, which was not circulating then, now makes up 45% of the variant proportions.
The decision to target either the JN.1 or KP.2 variant highlights several questions with regards to neutralization assays and evolution of variants. At the June 5, 2024 VRBPAC meeting, each manufacturer selected their data and neutralization assays, limiting direct comparison of data between the vaccine manufacturers. Pfizer’s data on 10 mice (who had received 4 prior COVID-19 vaccines) suggested that the KP.2 targeted vaccine provides enhanced protection against the KP.2 and KP.3 variants based on small differences in neutralization titers.7 The Moderna data on 8 mice primed with an ancestral series and then boosted with JN.1 or KP.2 suggested that, in contrast, the JN.1 vaccine provided slightly higher neutralization titers against the KP.3 variant in comparison to a KP.2 targeted vaccine.4
Data presented at VRBPAC are presented by each manufacturer in small groups of mice who are disease naive (in contrast with the American public) and have received different primary series and booster doses. Furthermore, with COVID-19, we have no threshold correlate of protection,8 and immunologic titers in animals are poorly predictive of clinical response.9 This raises important questions: Is there any clinical significance of these small differences in neutralization titers with regards to protection against infection or severe disease? And what is the magnitude of the clinical benefit of these products in different age/ risk groups? Additionally, as new variants emerged by the time of the fall COVID-19 vaccine campaign, with JN.1 and KP.2 barely still circulating, are these small differences in variant targets clinically relevant?
The presence of 2 different COVID-19 vaccine antigen targets leads to uncertainty for US consumers and healthcare providers, as experts provide contradictory messaging on which variant strain to choose. It is possible that a vaccine effectiveness study of the 2024-2025 season will show a difference between JN.1 and KP.2 targeted strains, but such retrospective observational data will be confounded by vaccine type and patient populations. All of this raises the question of how the process should be optimized in the future.
Should a global process, analogous to flu strain selection be implemented for COVID-19 strain selection? Or alternatively, is there a virtue to offering 2 or more different products, with post marketing randomized studies conducted to determine the winner? A perennial criticism of randomized trials of annual respiratory vaccines is that any information learned will become obsolete the moment the trial concludes (after the season has passed). Yet, proposals exist for expediting such trials, and testing that goes beyond individual products, assessing different strategies for choosing targets, with randomized trials asking which strategy results in better target choices across seasons.10 Such trials may help regulators decide which vaccine formulations or strategies are more likely to improve public health and provide more accurate targets year-over-year. In the absence of direct clinical evidence, the development of validated surrogate assays would be of value. These can be standardized across the industry, permitting comparisons of future products and allow for global harmonization of the COVID-19 vaccine strain selection process. Fragmented strain selection processes that differ between the United States and the rest of the world provokes further confusion and lack of confidence in the process. Ultimately, the core question remains: Who decides which COVID-19 vaccine antigen is targeted each season?
References
8. Gilbert PB, Donis RO, Koup RA, Fong Y, Plotkin SA, Follmann D. A Covid-19 Milestone Attained - A Correlate of Protection for Vaccines. N Engl J Med. 2022;387(24):2203-2206. doi:10.1056/NEJMp2211314
9. Clever S, Volz A. Mouse models in COVID-19 research: analyzing the adaptive immune response. Med Microbiol Immunol. 2023;212(2):165-183. doi:10.1007/s00430-022-00735-8
10. Barosa M, Ioannidis JPA, Prasad V. Evidence base for yearly respiratory virus vaccines: Current status and proposed improved strategies. Eur J Clin Invest. July 30, 2024:e14286. doi:10.1111/eci.14286
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Personally I feel more comfortable with the Pfizer shot because they splurged and tested on 10 mice. That’s 25% more mice than Moderna used.
I'm confused. People are still taking the Covid vaccine?