Zika vaccine shows promising results in trials

Npj Vaccines published the results of pre-university trials of a Zika virus (ZIKV) vaccine candidate assembled on a virus-like particle (VLP) platform. The scientists “planted” domain III of the Zika envelope protein (EDIII) on the surface of a nanoparticle from the Qβ bacteriophage capsid — the region that produces highly specific neutralizing antibodies and is less involved in cross-reactions with other flaviviruses (and therefore a lower risk of ADE, antibody enhancement). This design turned out to be self-adjuvanted: no additional immune response enhancers were required. In two doses (with a booster after 21 days), the vaccine caused a strong Th1 response and neutralizing antibodies in mice, and in animals susceptible to Zika (a model with a defective interferon response), it prevented brain and testicular damage after infection.

Background of the study

Zika virus is a flavivirus transmitted primarily by Aedes mosquitoes, but also vertically (from mother to fetus), sexually, and through blood. Most adults have mild infection, but when infected during pregnancy, the virus can infect the placenta and developing brain tissue of the fetus, causing congenital Zika syndrome (including microcephaly and eye lesions). The virus has also been detected in semen, supporting sexual transmission and making prevention critical for reproductive health.

Despite intense countermeasure development following the 2015-2016 epidemic, there are still no licensed Zika vaccines. There are several hurdles: declining incidence has made it difficult to conduct large-scale Phase III studies, funding and industry interest have wavered, and the biology of related flaviviruses adds the risk of antibody-mediated enhancement (ADE) – where cross-reactive, weakly neutralizing antibodies (such as those seen after dengue) can enhance infection. Therefore, vaccine candidates value designs that target type-specific neutralizing epitopes and minimize cross-reactions.

One of these “narrow” targets is considered to be domain III of the envelope protein (EDIII): in people after Zika, a significant proportion of strong neutralizing antibodies are directed precisely here, and EDIII itself contains a receptor binding motif and “overlaps” less with dengue compared to other regions of the E protein. Therefore, EDIII is actively used in the designs of protein, nanoparticle and vector vaccines, hoping to obtain a highly specific neutralizing response with a lower risk of ADE.

To "boost" the immunogenicity of such point targets without unnecessary additives, virus-like particles (VLPs) are often used. They imitate the size and geometry of the virus, repeatedly and regularly repeat epitopes, drain well into the lymph nodes and effectively activate B cells. Bacteriophage-based platforms (for example, Qβ) allow chemically attaching domains like EDIII to the surface of "empty" capsids - the result is a compact, safe "hedgehog" without genetic material, which often works as a "self-adjuvant". This approach already has a long history in preclinical studies and a number of registered VLP vaccines against other infections.

Why is this important?

Zika remains a threat primarily to pregnant women: the virus infects the placenta and fetal neural precursor cells, increasing the risk of congenital Zika syndrome with microcephaly and severe developmental disabilities; in seminal fluid, the virus can persist for months, supporting sexual transmission. Despite years of work, there are still no licensed vaccines; in addition, any solution must be as safe as possible against the background of the known problem of ADE in related flaviviruses (e.g. dengue). The new candidate addresses both challenges: it targets EDIII (a more type-specific target) and does not require external adjuvants, which simplifies the formulation and potentially reduces risks.

How the vaccine works (and why the focus is on EDIII and VLPs)

The construct is a “hedgehog” nanoparticle: EDIII targets are chemically “sewn” onto the icosahedral Qβ framework (≈27 nm), and the resulting sphere grows to ≈47 nm - just right for the immune system’s “taste”. VLPs repeatedly and regularly repeat epitopes, directly activate B cells and are readily “captured” by antigen-presenting cells, which in total accelerates IgG production and the quality of the secondary response. EDIII itself was obtained in E. coli and cross-linked to VLPs using standard linkers (SMPH/SATA) - without viral RNA and without live viruses. This design is both immunogenic and safe.

What the experiments showed: immunogenicity and protection - step by step

In a series of six independent experiments, the authors tested both the immune response (wild-type C57BL/6 strain) and real protection during infection (sensitive G129 model deficient in the type I interferon receptor). The regimen was prime + booster after 21 days; doses of 20 or 50 μg EDIII-QβVLPs.

• Humoral response. After two vaccinations, neutralizing antibody titers suppressed the cytopathic effect of ZIKV in most mice at a dilution of ≈1:80; protein EDIII alone without “landing” on VLPs did not produce such antibodies. The IgG2b/IgG1 ratio shifted toward Th1, which is characteristic of the antiviral profile.
• Cellular response. In the spleens of vaccinated animals, the secretion of IFN-γ and TNF-α increased, the proportion of effector T cells (CD38^high, CD62L^low) expanded, and the population of CD4+ TNF-α+ / IL-2+ increased in the absence of “allergenic” IL-4.
• Protection of organs during infection. Two weeks after the booster, G129 mice were infected with 10^5 PFU of the Brazilian ZIKV strain. The control group showed weight loss, high viral titers in the liver, kidneys, ovaries and especially in the brain; histology showed necrosis and microhemorrhages in the cortex and midbrain. Vaccinated animals maintained their weight, viral levels in the organs were barely detectable, and the brain looked like that of healthy animals. In males, the vaccine prevented testicular atrophy, preserving the size, weight and normal architecture of the seminiferous tubules.

What makes this approach different from previous ones?

• Narrow targeting rather than “whole envelope” EDIII is chosen to capture neutralizing and type-specific antibodies and reduce the involvement of “cross-over” epitopes that could theoretically contribute to ADE.
• Self-adjuvanted platform. Qβ-VLPs themselves work "as an adjuvant", eliminating the need for additional additives - plus simple biotech-manufacturing (EDIII from E. coli, chemical conjugation).
• Organ protection as an endpoint. The authors looked not only at titers, but also at functional outcomes - brain and testicular histology, which is important specifically for Zika pathogenesis.

Where is caution?

This is a preclinical study in mice. The G129 model is hypersensitive to the virus and is not identical to humans; the doses and vaccination intervals are experimental. The neutralization titer ( CPE-VNT ~1:80 ) is a good guideline for mice, but it cannot be directly transferred to predict protection in humans. Although the choice of EDIII is intended to reduce the risks of ADE, only multi-level preclinical testing (including non-human primates) and clinical phases will ultimately decide the issue.

What is the next logical thing for authors and regulators to do?

• Expand preclinical: test safety/efficacy in pregnancy models and primates; refine dosing and schedule; test strain breadth and duration of protection.
• Compare platforms: naked EDIII, EDIII-VLPs, mRNA-EDIII, head-to-head vector solutions for neutralization, T-cell response and organ pathology.
• Monitor surveillance: in the context of sporadic outbreaks (India, Brazil), the priority is phase I preparedness in adults, followed by careful expansion into vulnerable groups.

A Quick Guide: What Are VLP Vaccines and Why Are They Loved?

• No genome - no risk of replication. VLPs mimic the shape of the virus but are empty inside.
• Multiple "showcase" of epitopes. Signal repetition enhances B-cell triggering.
• The size is "appropriate" for the lymphatic system. Particles of ≈20-100 nm effectively enter the lymph nodes and meet with T-follicular cells.
• Flexible chemistry. Different antigens can be hung on the same "framework" - convenient for platform development.

Context: Why the Race for a Zika Vaccine Isn't Over

Even outside of major epidemics, Zika has not gone away: the number of people in risk zones is in the billions, Aedes carriers are expanding their range, transmission is possible not only through mosquitoes, but also vertically/sexually/through blood. Infection during pregnancy can result in severe developmental defects - from microcephaly to cognitive impairment - which makes the vaccine a reproductive health issue.

Research source: Côrtes N. et al. A VLPs-based vaccine protects against Zika virus infection and prevents cerebral and testicular damage. npj Vaccines, May 27, 2025 (volume 10, article 107). DOI: https://doi.org/10.1038/s41541-025-01163-4