Limitations of neutralizing antibody titers in COVID-19 vaccine efficacy trials and a call for additional correlates of protection.

The coronavirus disease (COVID-19) pandemic accelerated development of various vaccine platforms. Among them, mRNA vaccines played a crucial role in controlling the pandemic due to their swift development and efficacy against virus variants. Despite the success of these vaccines, recent studies highlight challenges in evaluating vaccine efficacy, especially in individuals with prior COVID-19 infection. Weakened neutralizing antibody responses after additional doses are observed in these populations, raising concerns about using neutralizing antibody titers as the sole immune correlate of protection. While neutralizing antibodies remain the primary endpoint in immunogenicity trials, they may not fully capture the immune response in populations with widespread prior infection or vaccination. This review explores reduced neutralizing antibody responses in previously infected individuals, and their impact on vaccine efficacy evaluation. It also offers recommendations for improving efficacy assessment, stressing incorporation of additional immune markers such as cell-mediated immunity to enable more comprehensive understanding of vaccine-induced immunity.