A self-amplifying mRNA SARS-CoV-2 vaccine candidate induces safe and robust protective immunity in preclinical models

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 (LNP). 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).

A dual-antigen self-amplifying RNA SARS-CoV-2 vaccine induces potent humoral and cellular immune responses and protects against SARS-CoV-2 variants through T cell-mediated immunity

“…24 This approach differs from the one used by Shattock et al in their preclinical and unsuccessful clinical trial. 25,26 Recent COVID-19 saRNA vaccine preclinical research 16,[26][27][28][29][30][31] supports the hypothesis that, because of their replicon features, saRNA vaccines are able to induce equivalent or more potent immune responses at lower doses compared to those achieved by non-replicating mRNA vaccines. 3,6 In our study, we confirm this hypothesis and find that multi-antigenic immunization of mice with only 1 mg of the ZIP1642 vaccine was able to induce 100% seroconversion toward high binding GMT values that elicited neutralizing activity against three different SARS-CoV-2 variants (Wuhan, Beta, and Delta variants) that was considerably higher than the neutralizing titers found in the sera of convalescent COVID-19 patients.…”

Universal Flu mRNA Vaccine: Promises, Prospects, and Problems

“…Several studies demonstrated the great potential of SAM vaccine usage for preventing COVID-19. Strong stimulation of either humoral or cellular immune response was revealed [ 48 , 49 ]. Notably, one SAM vaccine is undergoing Stage I clinical trials after confirmation of effectiveness against different SARS-CoV-2 strains [ 48 ].…”

“…Strong stimulation of either humoral or cellular immune response was revealed [ 48 , 49 ]. Notably, one SAM vaccine is undergoing Stage I clinical trials after confirmation of effectiveness against different SARS-CoV-2 strains [ 48 ]. Thus, it can be said that SAM vaccines have shown their immunogenic potency against multiple targets [ 46 , 47 , 48 , 49 , 50 , 51 , 52 ].…”

“…Notably, one SAM vaccine is undergoing Stage I clinical trials after confirmation of effectiveness against different SARS-CoV-2 strains [ 48 ]. Thus, it can be said that SAM vaccines have shown their immunogenic potency against multiple targets [ 46 , 47 , 48 , 49 , 50 , 51 , 52 ]. In addition, based on preclinical data, it can be concluded that SAM-mRNA vaccines could potentially induce a more durable immune response compared to non-replicating mRNA vaccines [ 53 ].…”

mRNA vaccines in the prevention and treatment of diseases

“…Data from mass vaccination efforts suggest that mRNA vaccines are safe, with adverse effects that are generally acceptable in frequency and severity. Nevertheless, rapid and robust local inflammation could be induced in mice‐administrated mRNA vaccines via intradermal, 91 intramuscular, 92 or intranasal routes 93 . This process was dependent on the ionizable lipid component of the LNP formulation 94 .…”