A modified vaccinia Ankara vaccine expressing spike and nucleocapsid protects rhesus macaques against SARS-CoV-2 Delta infection

• Type of Material: Article
• Authors: Nanda Kishore Routhu, Emory University; Sailaja Gangadhara, Emory University; Lilin Lai, Emory University; Meredith Elizabeth Davis-Gardner, Emory University; Katharine Floyd, Emory University; Ayalnesh Shiferaw, Emory University; Yannic C Bartsch, Massachusetts Institute of Technology; Stephanie Fischinger, Massachusetts Institute of Technology; Georges Khoury, Emory University; Sheikh Rahman, Emory University; Samuel Stampfer, Emory University; Alexandra Schäfer, The University of North Carolina at Chapel Hill; Sherrie Jean, Emory University; Chelsea Wallace, Emory University; Rachelle Stammen, Emory University; Jennifer Wood, Emory University; Joyce Cohen, Emory University; Tamas Nagy, University of Georgia; Matthew Parsons, Emory University; Lisa Gralinski, The University of North Carolina at Chapel Hill; Pamela A Kozlowski, LSU Health Sciences Center - New Orleans; Galit Alter, Massachusetts Institute of Technology; Mehul Suthar, Emory University; Rama Amara, Emory University
• Language: English
• Date: 2022-06-01
• Publisher: Emory University Libraries
• Publication Version: Final Published Version
• Copyright Statement: © 2022 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1126/sciimmunol.abo0226
• Title of Journal or Parent Work: Science Immunology
• Volume: 7
• Issue: 72
• Start Page: eabo0226
• End Page: eabo0226
• Grant/Funding Information: This work was supported in part by National Institutes of Health Grants RO1 AI148378-01S1 and Fast Grants awards #2166 and #2209 to R.R.A., the ORIP/NIH base grant P51 OD011132 to YNPRC, and NIH grants AI26683 and OD010976 to Nonhuman Primate Reagent Resource. Research reported in this publication was supported in part by Imagine, Innovate and Impact (I3) from the Emory School of Medicine, a gift from Woodruff Fund Inc., and through the Georgia CTSA NIH award (UL1-TR002378).
• Keywords: Vaccinia; Vaccinia virus; COVID-19; Immunoglobulin G; SARS-CoV-2; Mice; Antibodies, Viral; Hepatitis D; COVID-19 Vaccines; Nucleocapsid; Macaca mulatta; Animals; Viral Vaccines; Humans
• Research Categories: Biology, Microbiology; Health Sciences, Epidemiology; Health Sciences, Pathology; Health Sciences, Immunology

Abstract

SARS-CoV-2 vaccines should induce broadly cross-reactive humoral and T cell responses to protect against emerging variants of concern (VOCs). Here, we inactivated the furin cleavage site (FCS) of spike expressed by a modified vaccinia Ankara (MVA) virus vaccine (MVA/SdFCS) and found that FCS inactivation markedly increased spike binding to human ACE2. After vaccination of mice, the MVA/SdFCS vaccine induced eightfold higher neutralizing antibodies compared with MVA/S, which expressed spike without FCS inactivation, and protected against the Beta variant. We next added nucleocapsid to the MVA/SdFCS vaccine (MVA/SdFCS-N) and tested its immunogenicity and efficacy via intramuscular (IM), buccal (BU), or sublingual (SL) routes in rhesus macaques. IM vaccination induced spike-specific IgG in serum and mucosae (nose, throat, lung, and rectum) that neutralized the homologous (WA-1/2020) and heterologous VOCs, including Delta, with minimal loss (<2-fold) of activity. IM vaccination also induced both spike- and nucleocapsid-specific CD4 and CD8 T cell responses in the blood. In contrast, the SL and BU vaccinations induced less spike-specific IgG in secretions and lower levels of polyfunctional IgG in serum compared with IM vaccination. After challenge with the SARS-CoV-2 Delta variant, the IM route induced robust protection, the BU route induced moderate protection, and the SL route induced no protection. Vaccine-induced neutralizing and non-neutralizing antibody effector functions positively correlated with protection, but only the effector functions correlated with early protection. Thus, IM vaccination with MVA/SdFCS-N vaccine elicited cross-reactive antibody and T cell responses, protecting against heterologous SARS-CoV-2 VOC more effectively than other routes of vaccination.