Due to the different kinetics of the humoral and cellular immune response, a separate cohort of mice was immunized and splenocytes collected at 2-weeks post-immunization to assess T-cell response by IFNγ ELISpot. Serum was collected at various timepoints post a single immunization and assessed for total anti-S1 IgG and pseudovirus neutralizing antibodies (nAb). SAM and ChAd vaccines encoding full-length SARS-CoV-2 spike were evaluated for immunogenicity in mice. We demonstrate that SAM in both homologous and heterologous regimens can provide protection against SARS-CoV-2 replication post infection in NHP, comparable to currently authorized conventional mRNA vaccines and achieved at lower doses. In this study, we evaluated a SAM-SARS-CoV-2 vaccine either as a homologous prime/boost vaccine regimen (SAM/SAM), or as a boost vaccine following a ChAd-SARS-CoV-2 prime (ChAd/SAM) in both mice and non-human primates (NHP). We have developed and tested SAM based vaccines, initially in immuno-oncology applications, and have demonstrated their safety and potency in boosting neoantigen-specific T-cell responses primed by a chimpanzee adenovirus (ChAd68) vaccine in clinical trials (manuscript in press).
SAM vaccines offer the potential benefit of driving potent immune responses at low doses, as the mRNA replicates intracellularly, leading to high and durable antigen expression 8. Non-viral delivery systems, such as lipid nanoparticles (LNPs), allow repeated RNA administrations without inducing anti-vector immunity. Production of mRNA vaccines by a cell-free transcription reaction enables simple downstream purification and rapid vaccine release, providing for a cost-effective manufacturing process. The authorized mRNA COVID vaccine doses are either 30 μg for the BNT162b2 vaccine or 100 μg for mRNA-1273, and both provide clinical protection in the range of 88–93% 5. Both have demonstrated potency in preclinical and clinical testing 1, 4, 6, 7, with a standard vaccination regimen of two doses given 3–4-weeks apart. mRNA-based vaccines are relatively new to the clinic, with the BNT162b2 and mRNA-1273 COVID vaccines being the first to receive emergency use authorization. Adenovirus (Ad) based vaccine vectors have previously been shown to be potent inducers of both humoral and cellular immunity, and the authorized adenovirus COVID vaccines demonstrate effectiveness in the range of 64.3–71% 2, 5. Two main vaccine platforms have come to the fore in this pandemic, mRNA (mRNA-1273, Moderna BNT162b2, Pfizer/BioNTech) and adenovirus based vaccines (ChAdOx1/AZD1222, AstraZeneca, Janssen), both of which have demonstrated protection from hospitalization and death 1, 2, 3, 4. Novel vaccine platforms, such as self-amplifying mRNA (SAM), which could potentially be dose sparing due to the platform’s ability to replicate post vaccination, should be explored to address the ongoing or future pandemics. The current severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has spurred the rapid development and approval of multiple vaccines however, the virus continues to spread globally with devasting humanitarian and economic tolls. The SAM vaccine is currently being evaluated in clinical trials as both a homologous prime-boost regimen at low doses and as a boost following heterologous prime. SAM vaccination provided protective efficacy against SARS-CoV-2 challenge as both a homologous prime-boost and as a single boost following ChAd prime, demonstrating reduction of viral replication in both the upper and lower airways. Spike-specific T cell responses were observed with all tested vaccine regimens. The homologous prime-boost vaccination regimen of SAM at 3, 10 and 30 μg induced potent neutralizing antibody (nAb) titers in rhesus macaques following two SAM vaccinations at all dose levels, with the 10 μg dose generating geometric mean titers (GMT) 48-fold greater than the GMT of a panel of SARS-CoV-2 convalescent human sera. We report the preclinical development of a self-amplifying mRNA (SAM) vaccine encoding a prefusion stabilized severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike glycoprotein and demonstrate strong cellular and humoral immune responses at low doses in mice and rhesus macaques. The coronavirus disease 2019 (COVID-19) pandemic continues to spread globally, highlighting the urgent need for safe and effective vaccines that could be rapidly mobilized to immunize large populations.
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