Andrew Meador

Background:  Many became aware of the Zika virus (ZIKV) during the 2016 outbreak in Latin America.¹ Today, in 2025, Zika virus is still prevalent as a threat with its ability to cross the fetal-maternal interface and cause congenital infection. This ability is due to ZIKVs ability to bind to placental TIM1 and TAM (Tyro3, AXL, MER) receptors and undergo endocytosis.² Once ZIKV has crossed the fetal-maternal interface, it can infect neural progenitor cells and cause apoptosis.³ This leads to congenital Zika syndrome, which is characterized by microcephaly.^1,3 Currently, treatment is supportive.¹ ZIKV can reemerge in many ways, such as the increase in global temperatures, which expands the range of the Aedes mosquito, or mutations that can increase pathogenicity. No vaccines are currently available, and there is no antiviral treatment. ZIKV vaccines need to be able to modify or mask conserved epitopes on the ZIKV E protein or risk antibody dependent enhancement of the dengue virus.^4,8

Objective:  This literature review explores the future of congenital Zika virus, including potential mutations, interferons as a potential treatment method, and RNA vaccinations.

Search Methods:  An online search in the PubMed database was conducted from 2017 to 2025 using keywords such as “Zika Virus,” “Zika Virus Treatment,” “antiviral maternal-fetal interface,” “Zika virus mutation,” “Zika Virus Vaccine,” “Zika Virus circular RNA Vaccine,” and “Interferon Lambda Zika.”

Results:  In a study, scientists mimicked ZIKVs’ natural evolution in a lab using alternative passaging of mosquito cells and mice.⁵ They found that NS2B-I39V, a single point mutation, increased ZIKV’s viral replication and disease severity.⁵ More significantly, the mutation increased transplacental infections and fetal mortality.⁵ Another study investigated Trophoblast and decidual organoids (TO&DO) to simulate the maternal fetal interface against viruses.⁶ Basally, TOs secreted more Interferon-λ2(IFN-λ2) , whereas DOs secreted immune factors.⁶ Using a synthetic ligand, scientists modeled how the organoids would respond to a viral infection, in response TO’s secreted more Type I Interferons than the DO’s.⁶ The organoids were tested against human cytomegalovirus (HCMV), where the TOs defended well against HCMV.⁶ However, when using a JAK-STAT inhibitor, the TOs struggled to defend.⁶ Scientists have evaluated the effectiveness of IFN-B and IFN-λ in protecting the female reproductive tract against ZIKV.⁷ It was determined that both type I and type III interferons protected the female reproduction system against ZIKV.⁷ The researchers also found that ZIKV protection during the estradiol high, estrous phase was IFN independent.⁷ IFN-λ protection of the vagina is hormone-stage dependent when estradiol and progesterone are high.⁷ Recent ZIKV vaccination research has revolved around RNA vaccinations, including circular RNA and mRNA vaccines. The most effective circular RNA vaccine contained EDIII-Fc and ZIKV NS1 combined with E glycoprotein, incorporating the circular RNA in separate lipid nanoparticles.⁸ The circular RNA vaccine that was tested did not cause ADE of the dengue virus (DENV) and protected ZIKV in mice.⁸ There was a review of two human mRNA vaccine trials, mRNA-1325 and mRNA-1893.⁹ The mRNA-1893 had a response to Zika specific nAb for up to 13 months.⁹

Conclusions:  Preventing ZIKV is becoming increasingly important as ZIKV ranges expand with mutations and rising temperatures. Understanding how the body defends itself against ZIKV is pivotal to optimizing treatment. Preventative vaccines using RNA technology are in the initial stages, but optimistic toward a viable ZIKV vaccine that also provides protection against antibody dependent enhancement of DENV.

Work Cited

1. Song BH, Yun SI, Woolley M, Lee YM. Zika virus: History, epidemiology, transmission, and clinical presentation. J Neuroimmunol. 2017;308:50-64. doi:10.1016/j.jneuroim.2017.03.001
2. Nobrega GM, Samogim AP, Parise PL, et al. TAM and TIM receptors mRNA expression in Zika virus infected placentas. Placenta. 2020;101:204-207. doi:10.1016/j.placenta.2020.09.062
3. Giraldo MI, Gonzalez-Orozco M, Rajsbaum R. Pathogenesis of Zika Virus Infection. Annu Rev Pathol. 2023;18:181-203. doi:10.1146/annurev-pathmechdis-031521-034739
4. Brown JA, Singh G, Acklin JA, et al. Dengue Virus Immunity Increases Zika Virus-Induced Damage during Pregnancy. Immunity. 2019;50(3):751-762.e5. doi:10.1016/j.immuni.2019.01.005
5. Regla-Nava JA, Wang YT, Fontes-Garfias CR, et al. A Zika virus mutation enhances transmission potential and confers escape from protective dengue virus immunity. Cell Rep. 2022;39(2):110655. doi:10.1016/j.celrep.2022.110655

6. Yang L, Semmes EC, Ovies C, et al. Innate immune signaling in trophoblast and decidua organoids defines differential antiviral defenses at the maternal-fetal interface. Carette JE, Sawyer SL, Karvas R, eds. eLife. 2022;11:e79794. doi:10.7554/eLife.79794
7. Caine EA, Scheaffer SM, Arora N, et al. Interferon lambda protects the female reproductive tract against Zika virus infection. Nat Commun. 2019;10(1):280. doi:10.1038/s41467-018-07993-2
8. Liu X, Li Z, Li X, et al. A single-dose circular RNA vaccine prevents Zika virus infection without enhancing dengue severity in mice. Nat Commun. 2024;15(1):8932. doi:10.1038/s41467-024-53242-0
9. Essink B, Chu L, Seger W, et al. The safety and immunogenicity of two Zika virus mRNA vaccine candidates in healthy flavivirus baseline seropositive and seronegative adults: the results of two randomised, placebo-controlled, dose-ranging, phase 1 clinical trials. The Lancet Infectious Diseases. 2023;23(5):621-633. doi:10.1016/S1473-3099(22)00764-2