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

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.

Citation

Nanda Kishore Routhu, Sailaja Gangadhara, Lilin Lai, Meredith E Davis-Gardner, Katharine Floyd, Ayalnesh Shiferaw, Yannic C Bartsch, Stephanie Fischinger, Georges Khoury, Sheikh Abdul Rahman, Samuel David Stampfer, Alexandra Schäfer, Sherrie M Jean, Chelsea Wallace, Rachelle L Stammen, Jennifer Wood, Cohen Joyce, Tamas Nagy, Matthew S Parsons, Lisa Gralinski, Pamela A Kozlowski, Galit Alter, Mehul S Suthar, Rama Rao Amara. A modified vaccinia Ankara vaccine expressing spike and nucleocapsid protects rhesus macaques against SARS-CoV-2 Delta infection. Science immunology. 2022 Jun 24;7(72):eabo0226

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PMID: 35357886

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