Genetic distance predicts neutralizing antibody titers for monovalent and bivalent SARS-CoV-2 vaccines

Understanding the relationship between genetic variation and vaccine efficacy is essential for developing effective vaccines against emerging SARS-CoV-2 variants. This study evaluated monovalent (XBB.1.16.1) and bivalent (BQ.1 + XBF) mRNA vaccines in a BALB/c mouse model. Neutralizing antibody titers (pVNT50) induced by both regimens showed a strong negative correlation with genetic distance (calculated using Hamming distance). For the monovalent vaccine, the receptor-binding domain (RBD) exhibited the strongest correlation (r = -0.90). The bivalent vaccine also demonstrated robust correlations, with strength dependent on the component (XBF alone: r = -0.85; BQ.1 alone: r = -0.76). A key finding was the exceptionally strong correlation for the S2 region in the bivalent context (r = -0.86), suggesting broader cross-reactive immunity. These results establish genetic distance as a practical predictive tool and guide rational design of multivalent vaccines.