From Universal to Targeted: The Science Behind FDA’s New COVID-19 Vaccine Framework
In 2025, the U.S. FDA updated its COVID-19 vaccination policy for the 2025–2026 season, narrowing approvals for updated formulations to focus on populations at the highest risk of severe disease. The updated monovalent and bivalent vaccines were broadly authorized for adults aged ≥65 years, while access for younger individuals was restricted to those with comorbidities or immunocompromised conditions. This targeted approach aimed to maximize public health benefits by aligning vaccination deployment with populations showing the greatest absolute risk reduction.
Under the new authorizations, Moderna’s Spikevax was approved for individuals aged six months and older with at least one high-risk condition, Pfizer-BioNTech’s Comirnaty for ages five to 64 years meeting similar criteria, and Novavax’s Nuvaxovid for those aged 12 to 64 years. All three vaccines retained unrestricted approval for adults aged 65 years and above. These risk-based authorizations were guided by evidence on vaccine effectiveness, immune aging, and real-world outcomes, reinforcing a benefit–risk framework that prioritizes proportionality in regulatory decisions.
COVID-19 mRNA vaccines primarily activate B cells to generate neutralizing antibodies, while CD4⁺ and CD8⁺ T cells contribute to viral clearance and immune coordination. Robust and coordinated adaptive responses encompassing T cell and antibody activity have been linked to milder disease courses, whereas dysregulated responses correlate with severe illness.
Aging significantly affects immune competence through, characterized by reduced naïve T cell reserves and impaired immune coordination. Studies have reported that individuals aged ≥65 years displayed markedly disrupted correlations among CD4⁺, CD8⁺, and antibody responses, alongside heightened inflammatory cytokine activity. The decline in naïve CD8⁺ T lymphocytes was particularly associated with increased disease severity, underscoring how diminished adaptive capacity contributes to poorer outcomes in older adults.
Similarly, age-associated B cells (ABCs) which accumulate with age and in immunocompromised states may further impair vaccine responsiveness. Studies have observed that elevated ABC levels were linked to reduced neutralizing antibody titres and lower antigen-specific memory B cell generation following mRNA vaccination, suggesting that ABC expansion could be a key factor limiting vaccine efficacy in these populations.
Overall, age- and risk-stratified vaccination strategies remain a cornerstone of public health policy, as they enable the targeted protection of those most vulnerable to severe COVID-19 outcomes while ensuring efficient use of available vaccine resources. By directing immunization efforts toward older adults, individuals with multiple comorbidities, and those with compromised immune function, health authorities can maximize population-level benefits such as reductions in hospitalizations, mortality, and healthcare burden. Such evidence-based stratification thus reinforces the principle of equitable and efficient vaccine deployment, aligning regulatory policy with real-world epidemiological impact.