Abstract
With the onset of the COVID-19 pandemic 4 years ago, viral sequencing continues to document numerous individual mutations in the viral spike protein across many variants. To determine the ability of vaccine-mediated humoral immunity to combat continued SARS-CoV-2 evolution, we construct a comprehensive panel of pseudoviruses harboring each individual mutation spanning 4 years of the pandemic to understand the fitness cost and resistance benefits of each. These efforts identify numerous mutations that escape from vaccine-induced humoral immunity. Across 50 variants and 131 mutants we construct, we observe progressive loss of neutralization across variants, irrespective of vaccine doses, as well as increasing infectivity and ACE2 binding. Importantly, the recent XBB.1.5 booster significantly increases titers against most variants but not JN.1, KP.2, or KP.3. These findings demonstrate that variants continue to evade updated mRNA vaccines, highlighting the need for different approaches to control SARS-CoV-2 transmission.