ancer immunotherapies have shown promise in harnessing the immune system to target and destroy cancers, leading to clinical benefit enriched in patients with a high mutational burden [1][2][3][4][5] . Multiple studies indicate that cytotoxic CD8 T cells targeting tumor neoantigens are critical to tumor control and clearance in response to immunotherapies targeting CTLA-4 or PD-1 [6][7][8][9][10] . Clinical responses to CPI therapy rely mostly on reinvigorating preexisting tumor-specific T cell responses 11 , and active vaccination to expand preexisting and prime de novo tumor-specific T cells is anticipated to overcome this limitation.The limited success of cancer vaccines in the past can be attributed to a number of factors, including selection of poorly immunogenic self-antigens 12 , insufficiently immunogenic vaccine platforms and immunosuppressive milieus in patients with advanced cancers 4 . Accordingly, peptide-based neoantigen vaccine platforms have to date failed to consistently induce robust neoantigen-specific CD8 T cell responses in the majority of patients [13][14][15] . Although more immunogenic, a homologous prime boost messenger RNA (mRNA)-based vaccination approach elicited predominantly CD4 T cell responses [16][17][18] . Cumulatively, previous findings suggest that a successful cancer vaccine should (1) target tumor-specific neoantigens, (2) use highly immunogenic vaccine platform(s), (3) expand and prime T cells, (4) be combined with CPI therapy 19 and (5) generate long-term memory responses to ensure continuous tumor control for durable clinical benefit.Viral vector-based vaccine platforms, such as recombinant adenovirus, are able to prime robust T cell responses [20][21][22][23][24] . Although high seroprevalence of anti-adenoviral antibodies in human populations

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. 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 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. Spike-specific T cell responses were observed with all tested vaccine regimens. 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. 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.

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. 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 potent cellular and humoral immune responses at low doses in mice and rhesus macaques. The homologous prime-boost vaccination regimen of SAM at 3, 10 and 30 μg induced potent neutralizing antibody 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. Spike-specific T cell responses were observed at all dose levels. 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. Protection was most effective with a SAM prime-boost vaccination regimen at 10 and 30 μg and with a ChAd/SAM heterologous prime-boost regimen. 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.