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Improving the evidence base for COVID-19 vaccines

Nature Medicine volume 31, pages 3595–3596 (2025)Cite this article

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The beginning of the COVID-19 pandemic marked an unprecedented time when safe and effective vaccines were developed, authorized, and approved for use within months of the initial identification of the novel coronavirus1. These authorizations and approvals were based on large, placebo-controlled trials powered to characterize safety and efficacy against clinically significant infection — appropriate designs given the use of vaccine platforms, such as mRNA technology, and antigens, including the prefusion spike protein, that had not previously been studied at large scale in humans. These early studies were among the largest clinical trials in recent history, enrolling tens of thousands of participants and providing definitive evidence of the safety and efficacy of the SARS-CoV-2 vaccines.

Since then, the evolution of SARS-CoV-2 has prompted annual updates to COVID-19 vaccine composition to match the predominant circulating strain. Multiple national surveillance platforms provide data on the effectiveness of current vaccines to inform the need for updates5. As with other seasonal vaccines (for example, influenza), these updates are based on immunobridging studies that compare neutralizing antibody titers induced by vaccines with new variant inserts to those induced by approved vaccines6. Licensure by a regulatory body typically requires non-inferiority of the investigational vaccine versus the approved vaccine, meaning that the investigational vaccine is not clinically significantly worse than the approved vaccine (Fig. 1b). For seasonal vaccines, this is appropriate for several reasons. Annual vaccine updates require considerable lead time for production. For influenza, strain selection decisions are typically made 4–6 months in advance at a semiannual meeting convened by the World Health Organization, followed by a meeting of the US Food and Drug Administration’s Vaccine and Related Biologics Advisory Committee, which recommends strains to domestic vaccine manufacturers. To match the vaccine to circulating strains while also giving manufacturers sufficient time to produce the necessary doses for distribution, strain selection recommendations are made using immunobridging studies that show neutralization of new circulating variants. The timeline for COVID-19 vaccine updates might differ based on the evolution of the virus as well as use of mRNA technology, though it still requires lead time for production and distribution. Immunobridging is a well-established approach for seasonal vaccine strain selection and is standard practice in many countries.

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Fig. 1: Correlates of protection used to infer vaccine efficacy.

References

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Authors and Affiliations

  1. Department of Medicine, University of Washington School of Medicine, Seattle, WA, USA

    Helen Y. Chu

  2. Department of Epidemiology, University of Washington School of Public Health, Seattle, WA, USA

    Helen Y. Chu

  3. Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Center, Seattle, WA, USA

    Holly Janes & Peter B. Gilbert

  4. Department of Biostatistics, University of Washington, Seattle, WA, USA

    Marco Carone & Peter B. Gilbert

  5. Public Health Sciences Division, Fred Hutchinson Cancer Center, Seattle, WA, USA

    Peter B. Gilbert

  6. Department of Pediatrics, University of Pennsylvania, Philadelphia, PA, USA

    Stanley Plotkin

  7. Vaxconsult, Doylestown, PA, USA

    Stanley Plotkin

Authors
  1. Helen Y. Chu
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  2. Holly Janes
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  3. Marco Carone
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  4. Peter B. Gilbert
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  5. Stanley Plotkin
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Corresponding author

Correspondence to Helen Y. Chu.

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Competing interests

H.Y.C. has served on advisory boards for Roche, Vir, Merck and Abbvie, outside of the submitted work. M.C., P.B.G., H.J. and S.P. declare no competing interests.

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Chu, H.Y., Janes, H., Carone, M. et al. Improving the evidence base for COVID-19 vaccines. Nat Med 31, 3595–3596 (2025). https://doi.org/10.1038/s41591-025-03908-z

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