Officials Review Seasonal Immunization Strategy for 2025–2026

Introduction

In late May 2025, the FDA’s Vaccines and Related Biological Products Advisory Committee (VRBPAC) convened for its annual review to recommend the optimal strain composition for the upcoming fall COVID-19 vaccines. This meeting, typically a technical formality, was colored by sweeping policy changes introduced by the FDA’s new leadership under Health Secretary Robert F. Kennedy Jr. These reforms threaten to restrict booster availability to adults over 65 and high-risk groups, while imposing full randomized, placebo-controlled trials for broader licensure—stirring intense debate among advisors.

Regulatory Overhaul and Its Implications

In early May, the FDA announced a new framework that would:

• Limit booster shots to individuals aged 65+ and those with comorbidities.
• Require large-scale, randomized controlled trials (RCTs) for healthy adults and children, potentially delaying approval timelines.
• Reframe the use of real-world evidence versus traditional Phase III endpoints.

These changes conflict with international immunobridging approaches and World Health Organization (WHO) guidance, which permit strain updates based on non-inferiority immunogenicity data. The FDA’s pivot has sparked concerns over vaccine rollout delays just as new variants emerge and global preparedness hinges on rapid immunization campaigns.

Key Questions Raised by Advisors

Thirty minutes into the seven-hour meeting, VRBPAC members pressed the agency on operational details that remain undefined:

1. Will switching to a new strain necessitate full safety and efficacy trials? Capt. Sarah Meyer (CDC) asked whether selecting a different variant would trigger additional RCT requirements, potentially sidelining the entire 2025–2026 shot.
2. How will age‐specific licensure be handled? Henry Bernstein (Zucker School of Medicine) probed whether selecting a new lineage would alter authorizations for younger age groups, currently cleared down to six months of age.
3. Are placebo‐controlled RCTs ethical or feasible? Harvard’s Eric Rubin questioned the equipoise of RCTs when extensive observational data demonstrate clear booster efficacy, suggesting immunobridging as an ethical imperative.

“A randomized controlled trial has no equipoise right now, and you cannot do one,” said Eric Rubin. “We have robust real-world data showing clear benefit.”

FDA officials, including viral products director Jerry Weir and CBER deputy director David Kaslow, deferred detailed answers, indicating ongoing discussions with manufacturers about trial design and licensure pathways.

Strain Selection Process

The committee unanimously endorsed continuing with vaccines targeting the Omicron JN.1 lineage, mirroring WHO’s recommendation. Within JN.1, two formulations were considered:

• JN.1/KP.2: The primary variant used in the 2024–2025 vaccines, characterized by the spike mutations K147E and A845S.
• JN.1/LP.8.1: A newly predominant sublineage featuring the R346T and F486S substitutions, which antigenic cartography suggests may confer modest immune escape.

VRBPAC ultimately voted to advise manufacturers to produce monovalent JN.1-based vaccines for fall 2025, preferably incorporating LP.8.1 where feasible. The FDA’s follow-up statement confirmed this flexible recommendation, leaving final strain choice to biopharma partners.

Additional Analysis

Antigenic Drift and Strain Evolution

Since late 2023, SARS-CoV-2 has undergone a drift rate of ~1.2×10^-3 substitutions/site/year in the spike gene. Lab studies using pseudovirus neutralization assays report a 3–5-fold reduction in serum neutralizing titers against LP.8.1 compared to earlier JN.1 strains. Continuous genomic surveillance by GISAID and the CDC’s Nextstrain pipeline remains critical to detect emergent mutations in the receptor-binding domain (RBD) and N-terminal domain (NTD) that could undermine vaccine‐induced immunity.

Regulatory Pathways and Clinical Trial Designs

Globally, regulators have embraced immunobridging trials that measure non‐inferior geometric mean titers (GMTs) against a reference strain, bypassing large efficacy RCTs when the disease incidence is low. The FDA’s insistence on RCTs diverges from this trend, potentially delaying vaccine licensure by 9–12 months. Experts advocate alternative endpoints:

• Neutralizing antibody GMTs by live‐virus PRNT₅₀ assays.
• ACE2‐spike competitive binding inhibition assays.
• Memory B‐cell ELISpot results as a correlate of long‐term protection.

Implementing these immunobridging designs could reduce study sizes to 300–500 participants with focused age stratification, compared to >10,000 per arm in traditional RCTs.

Manufacturing and Distribution Considerations

mRNA vaccine production relies on scaled lipid nanoparticle (LNP) formulation and stringent GMP controls. Upstream in vitro transcription of mRNA is followed by downstream LNP encapsulation using microfluidic mixers to achieve particle sizes of 80–100 nm. Fill-finish operations are bottlenecked by ultra-low temperature (-80 °C) storage and cold-chain logistics. Proactive strain selection by June allows for a 12‐week production cycle, global release via World Federation of Diagnostics and Medicines networks, and distribution through federal channels ahead of the fall vaccination campaign.

Conclusion

Amid regulatory uncertainty, VRBPAC’s unanimous support for targeting the Omicron JN.1 lineage provides a data‐driven path forward. Yet, critical questions about trial design, ethical considerations, and licensure pathways linger. As manufacturers finalize vaccine compositions, ongoing dialogue between the FDA, industry, and international bodies will be essential to ensure timely, effective protection for all eligible populations.