SARS-CoV-2 Variant Replacement Constrains Vaccine-Specific Viral Diversification

Abstract Background COVID-19 vaccine breakthrough infections have been important for all circulating SARS-CoV-2 variant periods, but the contribution of vaccine specific SARS-CoV-2 viral diversification to vaccine failure remains unclear. Methods This study analysed 595 SARS-CoV-2 sequences collected from Military Health System beneficiaries between December 2020 and April 2022 to investigate the impact of vaccination on viral diversity. Results By comparing sequences based on the vaccination status of the participant, we found limited evidence indicating that vaccination was associated with increased viral diversity in the SARS-CoV-2 spike, and we show little to no evidence of a substantial sieve effect within major variants; rather we show that rapid variant replacement constrained intra-genotype COVID-19 vaccine strain immune escape. Conclusions These data suggest that, during past and perhaps future periods of rapid SARS-CoV-2 variant replacement, vaccine-mediated effects were subsumed with other drivers of viral diversity due to the massive scale of infections and vaccinations that occurred in a short time frame. However, our results also highlight some limitations of using sieve analysis methods outside of placebo-controlled clinical trials.