Combined immunization with SARS-CoV-2 spike and SARS-CoV nucleocapsid protects K18-hACE2 mice but increases lung pathology.
Jaekwan Kim, Alla Kachko, Prabhuanand Selvaraj, David Rotstein, Charles Brandon Stauft, Naveen Rajasagi, Yangqing Zhao, Tony Wang, Marian Major
Author Information
Jaekwan Kim: Division of Viral Products, Center for Biologics Evaluation and Research, Food and Drug Administration, Silver Spring, MD, USA.
Alla Kachko: Division of Viral Products, Center for Biologics Evaluation and Research, Food and Drug Administration, Silver Spring, MD, USA. ORCID
Prabhuanand Selvaraj: Division of Viral Products, Center for Biologics Evaluation and Research, Food and Drug Administration, Silver Spring, MD, USA. ORCID
David Rotstein: Division of Food Compliance, Center for Veterinary Medicine, Food and Drug Administration, Rockville, MD, USA. ORCID
Charles Brandon Stauft: Division of Viral Products, Center for Biologics Evaluation and Research, Food and Drug Administration, Silver Spring, MD, USA. ORCID
Naveen Rajasagi: Division of Viral Products, Center for Biologics Evaluation and Research, Food and Drug Administration, Silver Spring, MD, USA.
Yangqing Zhao: Division of Viral Products, Center for Biologics Evaluation and Research, Food and Drug Administration, Silver Spring, MD, USA.
Tony Wang: Division of Viral Products, Center for Biologics Evaluation and Research, Food and Drug Administration, Silver Spring, MD, USA. ORCID
Marian Major: Division of Viral Products, Center for Biologics Evaluation and Research, Food and Drug Administration, Silver Spring, MD, USA. marian.major@fda.hhs.gov.
Vaccines against SARS-CoV-2 have targeted the spike protein and have been successful at preventing disease. However, with the emergence of variants, spike-specific vaccines become less effective. The nucleocapsid protein is relatively conserved among variants of SARS-CoV-2 and is a candidate for addition to spike in next generation vaccines for the induction of T cell protection. Previous studies on SARS-CoV have suggested that the induction of an immune response to nucleocapsid could result in enhanced disease. Using the K18-hACE2 mouse model we investigated immunization with a variant nucleocapsid, from SARS CoV (N1) alone or in combination with spike from SARS-CoV-2 and compared this to nucleocapsid from SARS-CoV-2 (N2). The spike-nucleocapsid-based vaccines conferred protection against SARS-CoV-2 in lungs and brain and decreased lung pathology compared to control mice. However, higher T and B cell immune responses were observed in N1-immunized mice prior to challenge, whether delivered alone or with spike, and immunization with N1 resulted in increased lung pathology compared to immunization with spike or N2. These findings suggest that spike-nucleocapsid-based vaccines are safe and effective, even with variant nucleocapsid sequences, but that viral control in this mouse model may be associated with higher lung pathology, compared to spike immunization alone, due to the immunogenic qualities of the nucleocapsid antigen.
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