Advances in Zika virus vaccination: from testes to brain

Written by: Antonio Gregorio Dias Junior, PhD. @GregorioDias1 (Twitter)
Edited by: Layal Liverpool. @Layallivs (Twitter)


Zika virus goes both ways. It can infect testes (1). It can infect the vagina (2). These observations are supported by epidemiological evidence in humans and research using experimental animal models (3–5). Importantly, these animal models are currently being further explored for the development and testing of vaccine candidates.

The risk of sexual transmission and potential brain damage
Zika virus is mainly transmitted by mosquitoes in tropical and sub-tropical countries. Increasing evidence also suggests the virus can spread from human-to-human through a new potential route: sexual transmission. This is because the virus has the ability to replicate in the reproductive organs of men and women.
In the laboratory, scientists have discovered that Zika virus infection can lead to infertility in young male mice. These animals presented with smaller testes and reduced sperm production. Because the virus can replicate in the testes, it has the potential to be sexually transmitted. In humans, these events pose a risk to pregnant women or raise concerns for those planning pregnancy.
In pregnant women, Zika virus can cross the placental barrier and make a new home in the foetal brain, where more damage can be caused. One example is that newborn babies might present with microcephaly (smaller than average head size) that will most likely have a deleterious impact on their life expectancy. Due to these effects of the virus, known as teratogenic effects, a vaccine is urgently needed.

Current progress of Zika virus vaccine candidates
In my previous post, I talked about a promising candidate for a Zika virus vaccine (6). However, whether the candidate vaccine was safe and could protect the foetus in pregnant mice had not yet been evaluated. Fortunately, the scientists continued investigating this and recently published a new set of exciting results (7).
The new study demonstrated that at least two candidate vaccine models can induce protection against Zika virus infection. This time, female mice received the vaccine before mating and the foetus became protected from virus infection at early stages post-pregnancy (Figure 1). In future studies, it would also be interesting to investigate the foetal susceptibility when pregnant mice are directly vaccinated.

Figure 1 – Zika virus vaccine candidate protects the foetuses of pregnant female mice. The foetuses from unvaccinated mice can become highly infected by Zika virus (Top scheme). In contrast, a recent study has demonstrated that female mice vaccinated pre-pregnancy were protected against Zika virus infection. The foetuses of these vaccinated female mice were also protected when exposed to the virus during pregnancy (Bottom scheme).


The vaccine was also tested in male mice. Zika virus-mediated damage in the testes was much reduced or prevented in vaccinated young males (Figure 2). This finding is of particular interest for preventing male infertility and, perhaps, potential male-to-male and male-to-female sexual transmissions.
Altogether, these results encourage further tests in non-human primates and humans. These vaccines would potentially have the benefit of protecting women before pregnancy and protecting the male reproductive system from Zika virus.

What’s next
In addition to these promising results, two other important aspects that deserve attention are: a) whether Zika virus vaccine and infection could have side effects in humans naturally exposed to dengue virus (as previously discussed); b) whether it should be safe, ethical and encouraged to test these vaccine candidates in pregnant women.
Finally, it is very reassuring that additional vaccine models are currently being developed and tested in parallel by various groups of scientists. Indeed, different vaccine designs could be applied to target different susceptible groups, such as pregnant women, healthy and immunodeficient individuals.

Figure 2 – Zika virus vaccine candidate protects the testes of male mice from infertility. Unvaccinated young male mice can become infertile after Zika virus-mediated damage in the testes. This is associated with a reduction in testis size and sperm production (Top scheme). Importantly, these damaging effects were avoided in vaccinated male mice (Bottom scheme).

Thanks to:
a) Members of Rehwinkel Group (MRC human immunology unit, Oxford University) for expert review and help with the illustrations;
b) Johanna Hopp for non-expert review.


Main References
1. Govero, J. et al. Zika virus infection damages the testes in mice. Nature 540, 438–442 (2016).
2. Yockey, L. J. et al. Vaginal Exposure to Zika Virus during Pregnancy Leads to Fetal Brain Infection. Cell 166, 1247–1256.e4 (2016).
3. Li, C. et al. Correction: Zika Virus Disrupts Neural Progenitor Development and Leads to Microcephaly in Mice (Cell Stem Cell (2016) 19(5) (672) (S1934590916300844) (10.1016/j.stem.2016.04.017)). Cell Stem Cell 19, 672 (2016).
4. Cugola, F. R. et al. The Brazilian Zika virus strain causes birth defects in experimental models. Nature 534, 267–271 (2016).
5. Miner, J. J. et al. Zika Virus Infection during Pregnancy in Mice Causes Placental Damage and Fetal Demise. Cell 165, 1081–1091 (2016).
6. Shan, C. et al. A live-attenuated Zika virus vaccine candidate induces sterilizing immunity in mouse models. Nat. Med. 23, 763–767 (2017).
7. Shan, C. et al. A single-dose live-attenuated vaccine prevents Zika virus pregnancy transmission and testis damage. Nat. Commun. 8, 676 (2017).