Neutralizing antibody titers do not predict T cell response to live-attenuated orthoflaviviral vaccination in humans

Viral vaccine development has mostly relied on measuring neutralizing antibody responses to evaluate vaccine immunogenicity. Yet, a compelling body of evidence has now demonstrated that T cell immunity, an integral component of the adaptive immune response, also plays a critical role in controlling acute viral infection. T cell responses however, are not routinely measured in clinical trials to assess vaccine potency. If neutralizing antibody titers were indeed statistically associated with the magnitude of vaccine-induced antigen-specific T cell responses induced by a vaccine, then arguably T cell response could be inferred directly from antibody titers, without the need for independent measurement. To test this assumption, we examined, in a cohort of adult vaccinees, both neutralizing antibody titers and T cell responses induced by the live-attenuated yellow fever vaccine (YF17D). Crucially, we found no correlation between neutralizing antibody titers and the magnitude of antigen-specific T cell responses. Consistent with this observation, transcriptional profiling revealed distinct innate immune signatures that independently correlated with B and T cell immunity, suggesting that dichotomous pathways shape humoral and cellular immune responses separately. Protein-level analysis further supported this dichotomy, showing that discrete cytokine and chemokine profiles were selectively associated with neutralizing antibody production or T cell responses. Our findings suggest that neutralizing antibody titers may not always be a reliable proxy for vaccine-induced T cell response, and highlight the need for the independent measurement of T cell immunity in vaccine studies, particularly for viral infections where the protective role of T cells has been clearly demonstrated.