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Recently, the World Health Organization confirmed 120 new human cases of avian H7N9 influenza in China resulting in 37 deaths, highlighting the concern for a potential pandemic and the need for an effective, safe, and high-speed vaccine production platform. Production speed and scale of mRNA-based vaccines make them ideally suited to impede potential pandemic threats. Here we show that lipid nanoparticle (LNP)-formulated, modified mRNA vaccines, encoding hemagglutinin (HA) proteins of H10N8 (A/Jiangxi-Donghu/346/2013) or H7N9 (A/Anhui/1/2013), generated rapid and robust immune responses in mice, ferrets, and nonhuman primates, as measured by hemagglutination inhibition (HAI) and microneutralization (MN) assays. A single dose of H7N9 mRNA protected mice from a lethal challenge and reduced lung viral titers in ferrets. Interim results from a first-in-human, escalating-dose, phase 1 H10N8 study show very high seroconversion rates, demonstrating robust prophylactic immunity in humans. Adverse events (AEs) were mild or moderate with only a few severe and no serious events. These data show that LNP-formulated, modified mRNA vaccines can induce protective immunogenicity with acceptable tolerability profiles.

mRNA vaccines are rapidly emerging as a powerful platform for infectious diseases because they are well tolerated, immunogenic, and scalable and are built on precise but adaptable antigen design. We show that two immunizations of modified non-replicating mRNA encoding influenza H10 hemagglutinin (HA) and encapsulated in lipid nanoparticles (LNP) induce protective HA inhibition titers and H10-specific CD4+ T cell responses after intramuscular or intradermal delivery in rhesus macaques. Administration of LNP/mRNA induced rapid and local infiltration of neutrophils, monocytes, and dendritic cells (DCs) to the site of administration and the draining lymph nodes (LNs). While these cells efficiently internalized LNP, mainly monocytes and DCs translated the mRNA and upregulated key co-stimulatory receptors (CD80 and CD86). This coincided with upregulation of type I IFN-inducible genes, including MX1 and CXCL10. The innate immune activation was transient and resulted in priming of H10-specific CD4+ T cells exclusively in the vaccine-draining LNs. Collectively, this demonstrates that mRNA-based vaccines induce type-I IFN-polarized innate immunity and, when combined with antigen production by antigen-presenting cells, lead to generation of potent vaccine-specific responses.

39A SARS-CoV-2 vaccine is needed to control the global COVID-19 public health crisis. Atomic-40 level structures directed the application of prefusion-stabilizing mutations that improved 41 expression and immunogenicity of betacoronavirus spike proteins. Using this established 42 immunogen design, the release of SARS-CoV-2 sequences triggered immediate rapid 43 manufacturing of an mRNA vaccine expressing the prefusion-stabilized SARS-CoV-2 spike 44 trimer (mRNA-1273). Here, we show that mRNA-1273 induces both potent neutralizing antibody 45 and CD8 T cell responses and protects against SARS-CoV-2 infection in lungs and noses of 46 mice without evidence of immunopathology. mRNA-1273 is currently in a Phase 2 clinical trial 47 sequences (then known as "2019-nCoV") on January 10 th , the 2P mutations were substituted 98 into S positions aa986 and 987 to produce prefusion-stabilized SARS-CoV-2 S (S-2P) protein 99 for structural analysis 22 and serological assay development 23,24 in silico without additional 100 experimental validation. Within 5 days of sequence release, current Good Manufacturing 101

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