Gabi I Wiggill

Background:  Oropouche virus (OROV) is an enveloped, negative-sense, single-stranded RNA virus in the Orthobunyavirus genus that causes Oropouche Fever.^1-6 It is primarily transmitted by the Culicoides paraensis midge and has caused over 30 outbreaks in South and Central America, resulting in more than 500,000 cases.² OROV infection typically presents with flu-like symptoms and neuroinvasive and vertical transmission potential.^1-6 Treatment consists of supportive treatment with antipyretics, analgesics, hydration. ^1-4 OROV’s threat as a re-emerging virus stems from its ability to undergo reassortment of its genome. ^2-4 No current vaccine exists for OROV.^1-6 Furthermore, there is significant growing concern that OROV poses a greater global threat due to anthropogenic activities that could promote rapid evolution of the virus and promote spread due to increasing temperatures from climate change.^1-7 Recent discoveries in OROV’s pathogenesis informing vaccine development have shown promise to provide preventative interventions to this virus.

Objective: The purpose of this study was to identify the structural components that prove to be research-worthy avenues for vaccine development and treatment.

Search Methods: A keyword search of the PubMed database was used to select relevant and recent papers. Key words used included “OROV”, “Oropouche virus” AND “vaccine”. The timeframe of included research was set to 2020-2026.

Results: OROV is made up of 3 genomic segments (Large, Medium, and Small). The M segment codes for two glycoproteins, Gn and Gc, which have been the most studied targets for vaccine development due to their function of attaching to the host-cell membrane. ^2-4 Multiple experimental vaccines have been in development targeting these glycoproteins. One that shows promise is an mRNA-Lipid-NanoParticle (mRNA-LNP) vaccine and was able to develop both cellular and humoral responses. ⁵ An advantage of the mRNA lineage vaccines is that they are easily reprogrammable allowing for efficient and quick changes to vaccines to respond to the reassortment events. ⁵ Virus-Like-Particle (VLP) vaccines have also proven efficacy with expression of the M polyprotein and NP that outperformed protein based VLP vaccines.⁷ The mRNA-LNP vaccine showed Th1-skewed immune response with increases observed in IL-2, IFN-γ, and TNF-α with some increase in Th2 associated cytokine levels providing evidence that mRNA vaccines are effective and mounting an appropriate immunological response. ⁵ Another potential target for therapies  and prevention may be found in the use of the low-density lipoprotein-related protein 1 (LRP1) used by OROV for cellular entry. Deletion of this protein in KO cell-lines led to markedly decreased levels of OROV detected in serology. ⁶ Furthermore, it was found that OROV competes for Lrp with Lrp1-Binding Chaperone Receptor Associated Protein (RAP). ⁶ This could also transfer into prevention of vertical transmission due to the high amount of Lrp expressed in cytotrophoblasts and extravillous trophoblasts. ⁴ Type I IFN signaling was found to be essential to control OROV infection in vertical transmission. ⁴

Conclusions: Studies have shown that the most promising vaccine targets remain the Gc and Gn glycoproteins and that mRNA vaccine technology poses an effective and efficient way to deliver this protection particularly due to its ability to quickly be edited for reassortment events. Further work is being done to explore vertical transmission preventative measures and therapeutic measures by using the Lrp1 entry method of the virus and also focusing on IFN I signaling pathways to mount a protective response.

Works Cited

1. Tilston-Lunel NL. Oropouche Virus: An Emerging Orthobunyavirus. J Gen Virol. 2024;105(9):002027. doi:10.1099/jgv.0.002027
2. Scachetti GC, Forato J, Claro IM, et al. Re-emergence of Oropouche virus between 2023 and 2024 in Brazil: an observational epidemiological study. Lancet Infect Dis. 2025;25(2):166-175. doi:10.1016/S1473-3099(24)00619-4
3. Stubbs SH, Cornejo Pontelli M, Mishra N, et al. Vesicular Stomatitis Virus Chimeras Expressing the Oropouche Virus Glycoproteins Elicit Protective Immune Responses in Mice. mBio. 2021;12(4):e0046321. doi:10.1128/mBio.00463-21
4. Muraro SP, de Souza GF, Alippe Y, et al. Type I interferon controls vertical transmission and fetoplacental infection of Oropouche virus. iScience. 2026;29(2):114647. doi:10.1016/j.isci.2026.114647
5. Yamada Y, Cha I, Kang S, et al. Lineage-matched Oropouche virus mRNA-LNP vaccines confer complete, cross-protective immunity in mice. mBio. 2026;17(2):e0365525. doi:10.1128/mbio.03655-25
6. Schwarz MM, Price DA, Ganaie SS, et al. Oropouche orthobunyavirus infection is mediated by the cellular host factor Lrp1. Proc Natl Acad Sci U S A. 2022;119(33):e2204706119. doi:10.1073/pnas.2204706119
7. Shi Y, Zhang G, Lin S, et al. A VLP-based mRNA vaccine elicits potent humoral and cellular immunity against Oropouche virus. mBio. 2026;17(2):e0365325. doi:10.1128/mbio.03653-25