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

Hyung-Joon Kwon; Martina Kosikova; Weichun Tang; Uriel Ortega-Rodriguez; Peter Radvak; Ruoxuan Xiang; Kelly E Mercer; Levan Muskhelishvili; Kelly Davis; Jerrold M Ward; Ivan Kosik; Jaroslav Holly; Insung Kang; Jonathan W Yewdell; Ewan P Plant; Wilbur H Chen; Mallory C Shriver; Robin S Barnes; Marcela F Pasetti; Bin Zhou; David E Wentworth; Hang Xie

doi:10.1016/j.isci.2022.105507

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

iScience. 2022 Dec 22;25(12):105507. doi: 10.1016/j.isci.2022.105507. Epub 2022 Nov 5.

Authors

Hyung-Joon Kwon¹, Martina Kosikova¹, Weichun Tang¹, Uriel Ortega-Rodriguez¹, Peter Radvak¹, Ruoxuan Xiang², Kelly E Mercer³, Levan Muskhelishvili⁴, Kelly Davis⁴, Jerrold M Ward⁵, Ivan Kosik⁶, Jaroslav Holly⁶, Insung Kang¹, Jonathan W Yewdell⁶, Ewan P Plant¹, Wilbur H Chen⁷, Mallory C Shriver⁷, Robin S Barnes⁷, Marcela F Pasetti⁷, Bin Zhou⁸, David E Wentworth⁸, Hang Xie¹

Affiliations

¹ Laboratory of Pediatric and Respiratory Viral Diseases, Division of Viral Products, Office of Vaccines Research and Review, Center for Biologics Evaluation and Research, United States Food and Drug Administration, Silver Spring, MD, USA.
² Division of Biostatistics, Office of Biostatistics and Epidemiology, Center for Biologics Evaluation and Research, United States Food and Drug Administration, Silver Spring, MD, USA.
³ Biomarkers and Alternative Models Branch, National Center for Toxicological Research, United States Food and Drug Administration, Jefferson, AR, USA.
⁴ Toxicologic Pathology Associates, Jefferson, AR, USA.
⁵ Global VetPathology, Montgomery Village, MD, USA.
⁶ Laboratory of Viral Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
⁷ Center for Vaccine Development and Global Health, University of Maryland School of Medicine, Baltimore, MD, USA.
⁸ CDC COVID-19 Response, Centers for Disease Control and Prevention, Atlanta, GA, USA.

Abstract

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.

Keywords: Immune response; Immunology; Virology.