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
Affiliations
Hyung-Joon Kwon
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
Martina Kosikova
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
Weichun Tang
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
Uriel Ortega-Rodriguez
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
Peter Radvak
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
Ruoxuan Xiang
Division of Biostatistics, Office of Biostatistics and Epidemiology, Center for Biologics Evaluation and Research, United States Food and Drug Administration, Silver Spring, MD, USA
Kelly E. Mercer
Biomarkers and Alternative Models Branch, National Center for Toxicological Research, United States Food and Drug Administration, Jefferson, AR, USA
Levan Muskhelishvili
Toxicologic Pathology Associates, Jefferson, AR, USA
Kelly Davis
Toxicologic Pathology Associates, Jefferson, AR, USA
Jerrold M. Ward
Global VetPathology, Montgomery Village, MD, USA
Ivan Kosik
Laboratory of Viral Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA
Jaroslav Holly
Laboratory of Viral Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA
Insung Kang
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
Jonathan W. Yewdell
Laboratory of Viral Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA
Ewan P. Plant
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
Wilbur H. Chen
Center for Vaccine Development and Global Health, University of Maryland School of Medicine, Baltimore, MD, USA
Mallory C. Shriver
Center for Vaccine Development and Global Health, University of Maryland School of Medicine, Baltimore, MD, USA
Robin S. Barnes
Center for Vaccine Development and Global Health, University of Maryland School of Medicine, Baltimore, MD, USA
Marcela F. Pasetti
Center for Vaccine Development and Global Health, University of Maryland School of Medicine, Baltimore, MD, USA
Bin Zhou
CDC COVID-19 Response, Centers for Disease Control and Prevention, Atlanta, GA, USA
David E. Wentworth
CDC COVID-19 Response, Centers for Disease Control and Prevention, Atlanta, GA, USA
Hang Xie
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; Corresponding author
Summary: 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 2nd 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 3rd 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.
