A Modified mRNA Vaccine Targeting Immunodominant NS Epitopes Protects Against Dengue Virus Infection in HLA Class I Transgenic Mice

Abstract

Dengue virus (DENV) induces strong T and B cell responses upon infection. Hence, it is difficult to determine the contribution of cell-mediated immunity alone in the long lasting protection against DENV infection and disease. Numerous CD4+ and CD8+ T cell epitopes have been identified, mainly in the non-structural proteins of DENV. Taking into account the immunogenicity and peptide sequence conservation among the different DENV serotypes, a minimal DENV antigen, called DENV1-NS, has been designed. This antigen is enriched in conserved and highly antigenic epitopes located in the NS3, NS4B, and NS5 regions of DENV1. To evaluate the ability of the DENV1-NS poly-epitope to express the antigenic peptides in the context of different HLA class I molecules, we established its in vivo immunogenicity by measuring, after DNA immunization and electroporation, the activation of DENV-specific CD8 T cells in transgenic mice expressing the human HLA-A * 0201, -A * 2402, -B * 0702, and -B * 3502 class I alleles. We then engineered a lipid nanoparticle (LNP) encapsulated modified mRNA vaccine encoding DENV1-NS and tested immunogenicity and protection in these human HLA class I transgenic mice, after transient blockade of the interferon (IFN) type I receptor. Significant protection was observed, after two injections of the mRNA vaccine. Collectively, these data strongly support the development of T cell-based vaccines targeting immunodominant T cell epitopes that generate potent virus-specific T cell responses conferring immunity against DENV infection.

Modified mRNA-LNP Vaccines Confer Protection against Experimental DENV-2 Infection in Mice

“…This is consistent with a previous report that mRNA vaccine with selected NS peptides provided partial protection in transgenic mice against experimental DENV infection. 54 …”

Cross-Reactive Immunity Among Flaviviruses

“…Interestingly, for human T cells, prior exposure to DENV skewed the immunodominance of ZIKV-specific T cells toward non-structural proteins (35), yet these cross-activated T cells retained their ex vivo functionality (37). This cross-reactivity may be beneficial for clearing a secondary infection since it has been shown that a vaccine utilizing non-structural epitopes of DENV can protect against DENV infection in mice (38). Still, the broad question of whether flavivirus cross-reactive CD8 T cells are protective or pathological in nature remains to be resolved.…”

A Single Immunization with Nucleoside-Modified mRNA Vaccines Elicits Strong Cellular and Humoral Immune Responses against SARS-CoV-2 in Mice

“…One of the most widely studied of these vaccine platforms uses antigen-encoding nucleoside-modified mRNA encapsulated into lipid nanoparticles (mRNA-LNP) ( Pardi et al., 2015 ). Nucleoside-modified mRNA-LNP vaccines have induced protective immune responses against various pathogens in preclinical studies ( Awasthi et al., 2019 ; Espeseth et al., 2020 ; Freyn et al., 2020 ; Meyer et al., 2018 ; Pardi et al., 2017 , 2018a , 2018c ; Richner et al., 2017 ; Roth et al., 2019 ), in many cases, after administration of a single dose ( Freyn et al., 2020 ; Pardi et al., 2017 , 2018a , 2018c ). This vaccine type has been shown to elicit particularly strong CD4 + T cell, germinal center B cell and long-lived plasma cell responses associated with durable, protective neutralizing antibody responses ( Lindgren et al., 2017 ; Pardi et al., 2018a ).…”