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.
【초록키워드】 neutralizing antibody, SARS-CoV-2, IgG, Efficacy, Vaccine, vaccination, Neutralizing antibodies, furin, spike, VoC, variant, variants of concern, Delta, lung, SARS-CoV-2 vaccines, delta variant, virus, CD4, human ACE2, serum, T cell, mice, nucleocapsid, inactivation, furin cleavage site, response, T cell responses, VOCs, Beta, Neutralizing, Beta variant, homologous, moderate, T cell response, function, Blood, Heterologous, inactivated, intramuscular, binding, rhesus macaques, CD8 T cell, humoral, cross-reactive, cross-reactive antibody, nose, secretion, rectum, spike-specific IgG, neutralized, robust, PROTECT, tested, added, less, expressed, correlated, induce, elicited, FCS, non-neutralizing antibody, positively correlated, the SARS-CoV-2, 【제목키워드】 SARS-CoV-2, Vaccine, Infection, Delta, rhesus macaque, PROTECT, expressing,