Establishing Immune Correlates of Protection Against Respiratory Syncytial Virus Infection to Accelerate Vaccine Development: A Model‐Based Meta‐Analysis

The objectives of this study were to quantify the relationship between vaccine-induced immunogenicity responses and the protection against respiratory syncytial virus (RSV) infection-related clinical outcomes, and to evaluate immunogenicity as a surrogate marker for vaccine efficacy (VE) to accelerate RSV vaccine development. Serum neutralizing activity (SNA) and cell-mediated immunity (CMI) may serve as surrogate markers for the protection against RSV infection and are evaluated as immunogenicity endpoints in clinical trials of RSV vaccine candidates. Two meta-analytical approaches were applied to data from seven randomized placebo-controlled clinical trials that investigated RSV vaccines in older adults. The primary analysis examined the relationship between SNA and VE across three different clinical severity levels: (1) acute respiratory infection, (2) RSV lower respiratory tract disease (LRTD) with ≥ 2 clinical symptoms, and (3) RSV LRTD with ≥ 3 clinical symptoms (LRTD 3+). Furthermore, the additional contribution of CMI to VE, after accounting for the effect of SNA, was explored in a secondary analysis. The results demonstrated a positive correlation between SNA and VE across three clinical severity levels. Higher CMI was associated with higher VE specifically for RSV LRTD 3+, the most severe clinical level, suggesting that CMI may be correlated with additional clinical benefits in mitigating the severity of RSV infection. These findings provided preliminary evidence for immune correlates of protection against RSV infection and may aid in accelerating the development of new RSV vaccines.