{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"submitter":["Routhu NK"],"funding":["NIDCR NIH HHS","NCATS NIH HHS","NIAID NIH HHS","NIH HHS"],"pagination":["eabo0226"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC8995033"],"repository":["biostudies-literature"],"omics_type":["Unknown"],"volume":["7(72)"],"pubmed_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."],"journal":["Science immunology"],"pubmed_title":["A modified vaccinia Ankara vaccine expressing spike and nucleocapsid protects rhesus macaques against SARS-CoV-2 Delta infection."],"pmcid":["PMC8995033"],"funding_grant_id":["UL1 TR002378","P51 OD011132","R01 DE026333","R01 AI148378","R01 AI146785","R37 AI080289","T32 AI074492","U19 AI135995"],"pubmed_authors":["Fischinger S","Khoury G","Rahman SA","Jean SM","Parsons MS","Bartsch YC","Davis-Gardner ME","Stampfer SD","Floyd K","Alter G","Suthar MS","Amara RR","Wood J","Kozlowski PA","Schafer A","Shiferaw A","Joyce C","Gangadhara S","Nagy T","Wallace C","Gralinski L","Routhu NK","Lai L","Stammen RL"],"additional_accession":[]},"is_claimable":false,"name":"A modified vaccinia Ankara vaccine expressing spike and nucleocapsid protects rhesus macaques against SARS-CoV-2 Delta infection.","description":"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.","dates":{"release":"2022-01-01T00:00:00Z","publication":"2022 Jun","modification":"2025-04-22T19:43:15.239Z","creation":"2025-04-06T02:52:17.78Z"},"accession":"S-EPMC8995033","cross_references":{"pubmed":["35357886"],"doi":["10.1126/sciimmunol.abo0226"]}}