Abstract
RNA vaccines have demonstrated efficacy against SARS-CoV-2 in humans, and the technology is being leveraged for rapid emergency response. In this report, we assessed immunogenicity and, for the first time, toxicity, biodistribution, and protective efficacy in preclinical models of a two-dose self-amplifying messenger RNA (SAM) vaccine, encoding a prefusion-stabilized spike antigen of SARS-CoV-2 Wuhan-Hu-1 strain and delivered by lipid nanoparticles (LNPs). In mice, one immunization with the SAM vaccine elicited a robust spike-specific antibody response, which was further boosted by a second immunization, and effectively neutralized the matched SARS-CoV-2 Wuhan strain as well as B.1.1.7 (Alpha), B.1.351 (Beta) and B.1.617.2 (Delta) variants. High frequencies of spike-specific germinal center B, Th0/Th1 CD4, and CD8 T cell responses were observed in mice. Local tolerance, potential systemic toxicity, and biodistribution of the vaccine were characterized in rats. In hamsters, the vaccine candidate was well-tolerated, markedly reduced viral load in the upper and lower airways, and protected animals against disease in a dose-dependent manner, with no evidence of disease enhancement following SARS-CoV-2 challenge. Therefore, the SARS-CoV-2 SAM (LNP) vaccine candidate has a favorable safety profile, elicits robust protective immune responses against multiple SARS-CoV-2 variants, and has been advanced to phase 1 clinical evaluation ( NCT04758962 ).
Keywords: SARS-CoV-2 vaccine; biodistribution; efficacy; immunogenicity; self-amplifying mRNA; spike antigen; toxicity.
【저자키워드】 Efficacy, immunogenicity, SARS-CoV-2 vaccine, Spike antigen, breath, biodistribution, self-amplifying mRNA, toxicity., 【초록키워드】 SARS-CoV-2, Tolerance, Vaccine, immunogenicity, RNA vaccines, hamsters, B.1.351, Delta, B.1.617.2, Toxicity, CD4, immunization, variants, SARS-CoV-2 vaccine, LNP, Lipid nanoparticles, Antigen, RNA, T cell, Viral, SARS-CoV-2 variants, Viral load, clinical evaluation, B.1.1.7, mice, animals, humans, immune responses, response, vaccine candidate, Alpha, Germinal center, Beta, disease, safety profile, Protective, biodistribution, Lipid nanoparticle, Evidence, Frequency, CD8 T cell, evidence of, no evidence of, Phase 1, (Beta, (Alpha), emergency response, Messenger RNA, dose-dependent manner, protective immune response, RATs, upper and lower airways, lower airways, spike-specific antibody response, CD8 T cell responses, Wuhan-Hu-1, SARS-CoV-2 Wuhan strain, neutralized, robust, reduced, characterized, demonstrated, elicit, the vaccine, elicited, SAM, the SARS-CoV-2, 【제목키워드】 protective immunity, mRNA, Safe, robust, induce,