Immunization with a Prefusion SARS-CoV-2 Spike Protein Vaccine (RBMRNA-176) Protects against Viral Challenge in Mice and Nonhuman Primates

Abstract

There is an urgent need for a broad-spectrum and protective vaccine due to the emergence and rapid spreading of more contagious SARS-CoV-2 strains. We report the development of RBMRNA-176, a pseudouridine (Ψ) nucleoside-modified mRNA-LNP vaccine encoding pre-fusion stabilized trimeric SARS-CoV-2 spike protein ectodomain, and evaluate its immunogenicity and protection against virus challenge in mice and nonhuman primates. A prime-boost immunization with RBMRNA-176 at intervals of 21 days resulted in high IgG titers (over 1:819,000 endpoint dilution) and a CD4+ Th1-biased immune response in mice. RBMRNA-176 vaccination induced pseudovirus-neutralizing antibodies with IC50 ranging from 1:1020 to 1:2894 against SARS-CoV-2 spike pseudotyped wild-type and variant viruses, including Alpha, Beta, Gamma, and Kappa. Moreover, significant control of viral replication and histopathology in lungs was observed in vaccinated mice. In nonhuman primates, a boost given by RBMRNA-176 on day 21 after the prime induced a persistent and sustained IgG response. RBMRNA-176 vaccination also protected macaques against upper and lower respiratory tract infection, as well as lung injury. Altogether, these findings support RBMRNA-176 as a vaccine candidate for prevention of COVID-19.

A 10-valent composite mRNA vaccine against both influenza and COVID-19

“…The results showed that the FLUCOV-10 elicited significantly higher HA- and spike-specific interferon γ (IFN-γ) and interleukin-2 (IL-2) producing splenocytes, compared to those of placebo (Figure 3A and B), while the FLUCOV-10 did not elicit higher IL-4 and IL-5 producing splenocytes (Figure 3C and D). These results indicate that the FLUCOV-10 vaccination activates Th1-biased immune responses, aligning with the observation in our previously developed mRNA vaccine platform (11, 12).…”

“…We dissected the protein expression and immune response induction for each component of FLUCOV-10. Similar to previous findings (11, 12), each component in FLUCOV-10 resulted in abundant expression of HA or spike proteins in cell lysates (Figure 1 D and E), leading to robust component-specific humoral responses (Figure 2) and Th1-favored cellular responses (Figure 3) following a two-dose regimen. In response to the constantly evolving and antigenically diverse strains of influenza and SARS-CoV-2, we also evaluated the cross-reactive immunity conferred by FLUCOV-10.…”

“…The vaccine strains for seasonal influenza in FLUCOV-10 were selected to represent the currently circulating strains (Figure 1B), while the vaccine strains for avian influenza viruses were chosen based on the WHO’s recommendations for vaccine candidates (26). In FLUCOV-10, the inclusion of the ancestral SARS-CoV-2 strain is designed to offer cross-protection against several variants of concern, such as alpha, beta, gamma, delta and so on (11). Additionally, the incorporation of three Omicron subvariants in FLUCOV-10 was deliberately designed to address the newly emerged circulating SARS-CoV-2 variants, which possess escape properties to neutralization (27, 28) (Figure 1C).…”

Host Genetic Variation Impacts SARS-CoV-2 Vaccination Response in the Diversity Outbred Mouse Population

“…However, early preclinical studies with these vaccines using inbred mouse strains generally showed uniform immunogenicity and protection against SARS-CoV-2 infection [ 18 , 44 , 51 , 52 , 53 ]. Although variation is observed in lower vaccine doses (<1 µg), mouse studies analyzing neutralizing response in inbred strains with protein vaccination and similar adjuvants have little variation in neutralizing antibody titers [ 54 , 55 , 56 ].Therefore, one of our goals was to determine whether the DO mice would more accurately reflect the variation in vaccine immunogenicity and efficacy seen in human populations. This was borne out in our studies, where the DO mice showed over 100-fold variation in the magnitude of vaccine-induced neutralizing antibody responses.…”

Lipid Nanoparticle (LNP) Delivery Carrier-Assisted Targeted Controlled Release mRNA Vaccines in Tumor Immunity

“…Therefore, balancing and regulating the response of the immune system, in order to ensure that the vaccine does not trigger inappropriate inflammation or autoimmune damage when inducing immunity, are key issues in the application of mRNA vaccines. In addition, the versatility of mRNA vaccines across different tumor types and individuals is also a challenge [ 92 , 93 , 94 , 95 ]. Due to tumor heterogeneity and individual patient differences, it is difficult for a single mRNA vaccine to cover all tumor types.…”