iScience (Dec 2022)
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
- Journal volume & issue
-
Vol. 25,
no. 12
p. 105507
Abstract
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.
