Flavivirus mRNA Vaccines

Flaviviruses belong to a diverse family of positive-sense, RNA viruses. During translation, the polyprotein is cleaved into ten individual proteins. Among them, pre-membrane (prM), envelope (ENV), and capsid (CAP) belong to structural proteins, and NS1, NS2A, NS2B, NS3, NS4A, NS4B, and NS5 are nonstructural proteins (NS). Flaviviruses are spread predominantly by arthropod vectors and have pandemic potential. Thus, there is an urgent need for the preparation of these potential flaviviral outbreaks through developing effective vaccination strategies. mRNA vaccine as an ideal vaccine can lead to pan-flaviviral immunity by targeting conserved epitopes, such as conserved ENV dimer epitope. Here, we focus on the mRNA vaccines that have been developed against diverse flaviviruses, including vaccines against Zika virus (ZIKV), Dengue virus (DENV), and Powassan virus (POWV).

The different mRNA vaccination strategies. (Wollner, C. J., et al, 2021)

Zika mRNA vaccines

Zika virus (ZIKV) is a neurotropic virus and is predominantly transmitted by the Aedes aegypti mosquito. It has emerged as a global health problem since its arrival in the Western Hemisphere in 2013. ZIKV can lead to varying degrees of disease (from a mild, febrile illness to severe neurological disorders) in adults and cause congenital malformations and microcephaly in newborns. To face the ongoing pandemic, mRNA vaccines are one of the vaccine strategies tested and developed to fight against ZIKV. Targeting two surface glycoproteins of ZIK, prM and ENV (prM-E), mRNA vaccines have shown protective efficacy in mice and nonhuman primates. Notably, a similar vaccine, a modified prM-E mRNA-LNP vaccine with mutated fusion loop epitope in the E protein was found to elicit protective antibodies against dengue virus (DENV) infection through antibody-dependent enhancement (ADE). Since DENV and ZIKV often overlap in the subtropical and tropical areas, a safe and effective Zika vaccine with the potential to enhance DENV disease is highly desirable. Besides, a nucleoside modified prM-E mRNA-LNP vaccine has been demonstrated to elicit protective immune responses against ZIKV-induced congenital disease in mice.

In addition, the self-replicating mRNA vaccines are effective against ZIKV infection. A recent study has demonstrated that intradermal electroporation of naked self-amplifying Zika mRNA vaccine encoding prM-E into BALB/c mice with two doses can elicit antibody responses and T cell response (including antigen-specific splenic CD4+ and CD8+ T cell). It was interesting to find that a lower dose with more potent immune responses.

Other flavivirus mRNA vaccines

Given the development of nucleoside-modified mRNA-LNP vaccines has been proved to be effective against ZIKV infection, researchers are developing other flavivirus vaccines using the same vaccine platform, including vaccines against POWV. POWV is an emerging tick-borne flavivirus that has the potential to cause life-threatening encephalitis. Intramuscular administration of mRNA-LNP vaccines encoding POWV prM-E led to protection from POWV infection in mice. It is worth mentioning that this vaccine could elicit cross-neutralizing antibodies against other tick-transmitted flaviviruses, such as Langat virus (LGTV), tick-borne encephalitis virus and Gadgets Gully virus.

DENV is the most common vector-borne viral infection and its endemic region is steadily expanding. Similar to ZIKV, the spread of DENV is predominantly caused by the Aedes aegypti mosquito. A recent study developed a nucleoside-modified mRNA-LNP vaccine targeting conserved T cell epitopes from the DENV-1 non-structural (NS) proteins. It was reported that this vaccine elicited a robust antiviral CD8+ T cell response and some level of protection from DENV in mouse models. Another recent study developed DENV serotype 2 mRNA vaccines, involving multiple antigens. Among them, mRNA vaccine encoding the soluble portion of DENV-2 ENV (E80) induced humoral and cell-mediated immune responses in mice, which protected against a homologous serotype of DENV2 infection. A more recent study developed a nucleotide-modified mRNA -LNP vaccine encoding the structural proteins (prM and ENV) from DENV serotype 1 (prM/E mRNA-LNP). The vaccine elicited robust antiviral immune responses with high levels of neutralizing antibody titers as well as antiviral CD4⁺ and CD8⁺ T cells.

Creative Biogene provides a range of customized and inventive solutions, involving the development of influenza mRNA vaccines, anti-parasite mRNA vaccines, mRNA vaccines against HIV as well as the global SARS-CoV-2 pandemic. We are committed to exerting the potential of synthetic mRNA as an important vaccine candidate for infectious diseases, hoping to meet our customers' specific requirements for projects at the preclinical stages. If you are interested in this area, please feel free to contact us. We look forward to providing services for your next project.

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