mRNA-1273 and Ad26.COV2.S vaccines protect against the B.1.621 variant of SARS-CoV-2.

BACKGROUND: Since the emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in 2019, viral variants with greater transmissibility or immune-evasion properties have arisen, which could jeopardize recently deployed vaccine- and antibody-based countermeasures. METHODS: Here, we evaluated in mice and hamsters the efficacy of a pre-clinical version of the Moderna mRNA vaccine (mRNA-1273) and the Johnson & Johnson recombinant adenoviral-vectored vaccine (Ad26.COV2.S) against the B.1.621 (Mu) variant of SARS-CoV-2, which contains spike mutations T95I, Y144S, Y145N, R346K, E484K, N501Y, D614G, P681H, and D950N. FINDINGS: Immunization of 129S2 and K18-human ACE2 transgenic mice with the mRNA-1273 vaccine protected against weight loss, lung infection, and lung pathology after challenge with the B.1.621 or WA1/2020 N501Y/D614G SARS-CoV-2 strain. Similarly, immunization of 129S2 mice and Syrian hamsters with a high dose of Ad26.COV2.S reduced lung infection after B.1.621 virus challenge. CONCLUSIONS: Thus, immunity induced by the mRNA-1273 or Ad26.COV2.S vaccine can protect against the B.1.621 variant of SARS-CoV-2 in multiple animal models. FUNDING: This study was supported by the NIH (R01 AI157155 and U01 AI151810), NIAID Centers of Excellence for Influenza Research and Response [CEIRR] contracts 75N93021C00014 and 75N93021C00016, and the Collaborative Influenza Vaccine Innovation Centers [CIVIC] contract 75N93019C00051. It was also supported, in part, by the National Institutes of Allergy and Infectious Diseases Center for Research on Influenza Pathogenesis (HHSN272201400008C) and the Japan Program for Infectious Diseases Research and Infrastructure (JP21wm0125002) from the Japan Agency for Medical Research and Development (AMED).

Identification of three tumor antigens and immune subtypes for mRNA vaccine development in diffuse glioma.

Rationale: Diffuse glioma patients have high mortality and recurrence despite multimodal therapies. This study aims to identify the potential tumor antigens for mRNA vaccines and subtypes suitable for the immunotherapy of patients with diffuse glioma. Methods: Gene expression profiles and corresponding clinical information were obtained from the Chinese Glioma Genome Atlas (CGGA) and the Cancer Genome Atlas (TCGA) databases. Genetic alterations were extracted from cBioPortal. Differential gene analysis, survival analysis, correlation analysis, consensus clustering analysis, and immune cell infiltration analysis were conducted based on the various databases. Finally, the hub genes, the modules related to tumor antigens, and the immune subtypes were identified using WGCNA method. Results: Three over-expressed, amplified, and mutated tumor antigens, including KDR, COL1A2, and SAMD9, were associated with clinical outcomes. The expression of the three genes had a positive correlation with the abundance of antigen-presenting cells (APCs) and APC marker expression. Subsequently, three immune subtypes (Ims1, Ims2, and Ims3) were distinguished in the TCGA cohort, which exhibited distinct molecular, cellular, and clinical characteristics consistent with the CGGA cohort. Diffuse gliomas with subtype Ims1 were more malignant with immunosuppressive phenotypes and more associated with poor prognosis than the other two subtypes. The three antigens and the immune checkpoints were differentially expressed among the three immune subtypes. Finally, functional enrichment analysis of the genes related to tumor antigens and immune subtypes suggested that they are enriched in many immune-associated processes. Conclusions: KDR, COL1A2, and SAMD9 are potential antigens for developing mRNA vaccines against diffuse glioma. The results suggest that immunotherapy targeting these three antigens is more suitable for patients with subtype Ims1. This study provides insights into immunotherapy for diffuse glioma.

Lipid-nanoparticle-encapsulated mRNA vaccines induce protective memory CD8 T cells against a lethal viral infection.

It is well established that memory CD8 T cells protect susceptible strains of mice from mousepox, a lethal viral disease caused by ectromelia virus (ECTV), the murine counterpart to human variola virus. While mRNA vaccines induce protective antibody (Ab) responses, it is unknown whether they also induce protective memory CD8 T cells. We now show that immunization with different doses of unmodified or N(1)-methylpseudouridine-modified mRNA (modified mRNA) in lipid nanoparticles (LNP) encoding the ECTV gene EVM158 induced similarly strong CD8 T cell responses to the epitope TSYKFESV, albeit unmodified mRNA-LNP had adverse effects at the inoculation site. A single immunization with 10 µg modified mRNA-LNP protected most susceptible mice from mousepox, and booster vaccination increased the memory CD8 T cell pool, providing full protection. Moreover, modified mRNA-LNP encoding TSYKFESV appended to green fluorescent protein (GFP) protected against wild-type ECTV infection while lymphocytic choriomeningitis virus glycoprotein (GP) modified mRNA-LNP protected against ECTV expressing GP epitopes. Thus, modified mRNA-LNP can be used to create protective CD8 T cell-based vaccines against viral infections.