Enhanced virulence and waning vaccine-elicited antibodies account for breakthrough infections caused by SARS-CoV-2 delta and beyond

Here we interrogate the factors responsible for SARS-CoV-2 breakthrough infections in a K18-hACE2 transgenic mouse model. We show that Delta and the closely related Kappa variant cause viral pneumonia and severe lung lesions in K18-hACE2 mice. Human COVID-19 mRNA post-vaccination sera after the 2(nd) dose are significantly less efficient in neutralizing Delta/Kappa than early 614G virus in vitro and in vivo. By 5 months post-vaccination, >= 50% of donors lack detectable neutralizing antibodies against Delta and Kappa and all mice receiving 5-month post-vaccination sera die after the lethal challenges. Although a 3(rd) vaccine dose can boost antibody neutralization against Delta in vitro and in vivo, the mean log neutralization titers against the latest Omicron subvariants are 1/3-1/2 of those against the original 614D virus. Our results suggest that enhanced virulence, greater immune evasion, and waning of vaccine-elicited protection account for SARS-CoV-2 variants caused breakthrough infections.

Automated summary

In this study, we investigated the factors contributing to breakthrough infections of SARS-CoV-2 in a K18-hACE2 transgenic mouse model. We found that the Delta and closely related Kappa variants caused viral pneumonia and severe lung lesions in K18-hACE2 mice. Post-vaccination sera from humans after the 2nd dose of COVID-19 mRNA vaccines showed significantly lower neutralizing efficiency against Delta/Kappa compared to the early 614G virus both in vitro and in vivo. Five months after vaccination, more than 50% of donors lacked detectable neutralizing antibodies against Delta and Kappa, and all mice that received post-vaccination sera from 5 months post-vaccination died after lethal challenges. Although a third vaccine dose could enhance antibody neutralization against Delta in vitro and in vivo, the mean log neutralization titers against the latest Omicron subvariants were only 1/3-1/2 of those against the original 614D virus.