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- Title
A modified vaccinia Ankara vaccine expressing spike and nucleocapsid protects rhesus macaques against SARS-CoV-2 Delta infection.
- Authors
Routhu, Nanda Kishore; Gangadhara, Sailaja; Lai, Lilin; Davis-Gardner, Meredith E.; Floyd, Katharine; Shiferaw, Ayalnesh; Bartsch, Yannic C.; Fischinger, Stephanie; Khoury, Georges; Rahman, Sheikh Abdul; Stampfer, Samuel David; Schäfer, Alexandra; Jean, Sherrie M.; Wallace, Chelsea; Stammen, Rachelle L.; Wood, Jennifer; Joyce, Cohen; Nagy, Tamas; Parsons, Matthew S.; Gralinski, Lisa
- 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. Vaccinia-based COVID-19 vaccine protects rhesus macaques: Despite the robust protection of the mRNA SARS-CoV-2 vaccines against COVID-19, increasing numbers of mutations in the RBD protein in variants of concern (VOCs) have begun to reduce vaccine efficacy. Thus, other strategies are needed to protect against future VOCs. Here, Routhu et al. created a modified vaccinia Ankara (MVA) virus vector containing spike with an inactivated furin cleavage site and nucleocapsid. They tested this vaccine via intramuscular and oral (buccal or sublingual) routes in rhesus macaques. This vaccine induced protection against the Delta SARS-CoV-2 VOC when given by the intramuscular and buccal routes. These effects correlated to robust multifunctional neutralizing and non-neutralizing antibody responses in the blood. Together, these researchers have created a SARS-CoV-2 vaccine vector that can protect against VOCs.
- Publication
Science Immunology, 2022, Vol 7, Issue 72, p1
- ISSN
2470-9468
- Publication type
Article
- DOI
10.1126/sciimmunol.abo0226