Abstract
Current coronavirus disease-19 (COVID-19) vaccines are administered by the intramuscular route, but this vaccine administration failed to prevent severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus infection in the upper respiratory tract, mainly due to the absence of virus-specific mucosal immune responses. It is hypothesized that intranasal (IN) vaccination could induce both mucosal and systemic immune responses that blocked SARS-CoV-2 transmission and COVID-19 progression. Here, we evaluated in mice IN administration of three modified vaccinia virus Ankara (MVA)-based vaccine candidates expressing the SARS-CoV-2 spike (S) protein, either the full-length native S or a prefusion-stabilized [S(3P)] protein; SARS-CoV-2-specific immune responses and efficacy were determined after a single IN vaccine application. Results showed that in C57BL/6 mice, MVA-based vaccine candidates elicited S-specific IgG and IgA antibodies in serum and bronchoalveolar lavages, respectively, and neutralizing antibodies against parental and SARS-CoV-2 variants of concern (VoC), with MVA-S(3P) being the most immunogenic vaccine candidate. IN vaccine administration also induced polyfunctional S-specific Th1-skewed CD4 + and cytotoxic CD8 + T-cell immune responses locally (in lungs and bronchoalveolar lymph nodes) or systemically (in spleen). Remarkably, a single IN vaccine dose protected susceptible K18-hACE2 transgenic mice from morbidity and mortality caused by SARS-CoV-2 infection, with MVA-S(3P) being the most effective candidate. Infectious SARS-CoV-2 viruses were undetectable in lungs and nasal washes, correlating with high titers of S-specific IgGs and neutralizing antibodies against parental SARS-CoV-2 and several VoC. Moreover, low histopathological lung lesions and low levels of pro-inflammatory cytokines in lungs and nasal washes were detected in vaccinated animals. These results demonstrated that a single IN inoculation of our MVA-based vaccine candidates induced potent immune responses, either locally or systemically, and protected animal models from COVID-19. These results also identified an effective vaccine administration route to induce mucosal immunity that should prevent SARS-CoV-2 host-to-host transmission.
Keywords: MVA; S protein; SARS-CoV-2; immunogenicity; intranasal delivery; mice; protective efficacy; vaccine candidates.
【저자키워드】 SARS-CoV-2, immunogenicity, S protein, mice, protective efficacy, intranasal delivery, MVA, vaccine candidates., 【초록키워드】 COVID-19, neutralizing antibody, IgG, Efficacy, Vaccine, coronavirus, vaccination, Immunity, SARS-COV-2 infection, SARS-CoV-2 variant, lung, Transmission, animal model, CD4, CD8, vaccine dose, Protein, serum, SARS-CoV-2 transmission, Coronavirus disease-19, immune responses, vaccine candidate, morbidity and mortality, virus infection, Nasal washes, upper respiratory tract, lymph nodes, intranasal, spleen, Protective, intramuscular, T-cell immune response, K18-hACE2 transgenic mice, mucosal, administration, systemic immune response, lung lesion, COVID-19 progression, acute respiratory syndrome, immunogenic, pro-inflammatory cytokine, vaccine candidates, full-length, modified vaccinia virus, vaccine administration, Administered, C57BL/6, mucosal immune, responses, susceptible, Prevent, effective, current, bronchoalveolar, Result, blocked, caused, evaluated, absence, demonstrated, induce, histopathological, expressing, elicited, parental, nasal washe, systemically, IgA antibody, SARS-CoV-2 virus, SARS-CoV-2-specific immune response, the SARS-CoV-2, undetectable, 【제목키워드】 COVID-19, SARS-COV-2 infection, Local, vaccine candidate, single dose, administration, systemic immune response, PROTECT,