The ongoing and evolving Zika epidemic has captured the attention of infectious disease researchers, public health organisations and the media. Transmission of the virus is via the bite of infected female mosquitos but has now also been associated with sexual transmission in humans. Infection of pregnant women with Zika can result in fetal birth defects, namely microcephaly or “shrunken head syndrome”, as well as other serious neurological abnormalities. Additionally, infection of a small proportion of adults can result in Guillain-Barre syndrome, a debilitating disorder affecting the peripheral nervous system.
Zika virus is an RNA virus from the family Flaviviridae which is transmitted by Aedes mosquitos, a species which is widely distributed in tropical and subtropical regions worldwide. The widespread distribution of the mosquito vector capable of transmitting Zika, combined with the potential for global travel of infected people, has been a major cause for concern as it could potentially allow Zika to spread. Indeed, these concerns dominated conversations in the lead up to the Rio 2016 Olympics, with athletes from many participating countries withdrawing from the games, despite official statements from the World Health Organisation that the risk was low.
Scientists are still trying understand the precise mechanisms which lead to the development of microcephaly and to identify correlates of protection which could prevent Zika infection. It is widely believed that primary infection with Zika will confer protection from subsequent infection. However, a number of questions remain, how long after infection are women potentially at risk for microcephaly in pregnancy? how long does the virus persist in body fluids? what impact could cross-reactivity to other Flavivirus family members have? In the interim, pregnant women and couples planning pregnancy have been advised to avoid travel to Zika endemic areas and to take necessary precautions to avoid mosquito bites and sexual transmission of the virus. The uncertainties surrounding the risks associated with Zika infection emphasise the importance of developing a safe and effective vaccine as an urgent global health priority.
It has already been shown that a purified inactivated virus (PIV) from Zika strain PVRABC59 or a plasmid based vaccine containing the pre-membrane (prM) and envelope (Env) proteins of Zika can protect mice from challenge with Zika infection (Larocca et al., 2016). However, there are differences in the ability of Zika virus to replicate in mice and it is well established that responses to vaccination and/or infection vary greatly between different animal models of disease. Therefore, in order to speed up the progression of these vaccines to clinical trials in humans, a full evaluation of vaccine immunogenicity and efficacy often requires testing in other animal species, such as non-human primates.
In this study, the authors describe testing of three different vaccination approaches, an inactivated PIV vaccine, a plasmid DNA based vaccine and a simian adenoviral vectored vaccine in Rhesus monkeys (Abbink et al., 2016). Recombinant viral vectors, in particular, species of the Adenoviridae, are an attractive option for infectious disease vaccines for several reasons (Coughlan et al., 2015). These viruses can be rendered non-replicating, they are capable of delivering the vaccine antigen with high efficiency, they elicit robust cellular and humoural immune responses to the encoded antigen, they are easy to produce, scale-up and manufacture to clinical grade and have been shown to be safe and effective in humans. Evaluation of rare species or non-human, simian adenoviral vectors such as RhAd52 described in this study are attractive in order to overcome pre-existing immunity in humans to the most commonly used vector Ad5.
Following vaccination with the PIV vaccine, animals developed protective antibodies to the Zika surface protein Env whereas control, unvaccinated animals did not develop detectable anti-Zika responses. Some modest cellular immune responses to Env were also detected in vaccinated monkeys. Importantly, animals that were vaccinated were completely protected from virus challenge with Zika, and had no detectable virus in body fluids. Conversely, high levels of detectable virus were found in the body fluids of unvaccinated monkeys.
Vaccination with either naked plasmid DNA or the recombinant adenoviral vector RhAd52 expressing Zika prM-Env induced antibody responses following one vaccination. However, responses were low in the plasmid-DNA vaccinated group and required a second vaccination to reach the same levels as a single shot of RhAd52. Although both vaccination regimens provided complete protection against challenge with Zika, vaccination with a single dose of RhAd52 vector elicited a greater breadth of responses to Env epitopes and cellular immune responses which were superior to the DNA vaccine.
Transfer of high levels of Zika-specific purified antibody (IgG) from vaccinated monkeys was also able to protect recipient mice from Zika challenge. Passive transfer of high titers of Zika-specific IgG into two naïve Rhesus monkeys also resulted in complete protection in one animal and partial protection in the other. This adoptive transfer of vaccine-induced antibodies demonstrated that the mechanism of protection was largely antibody mediated, suggesting that a vaccine which elicits robust neutralising antibody responses could be sufficient to provide protection in humans. Importantly, no viral enhancement was observed at sub-therapeutic antibody concentrations, a relevant finding considering that another member of the Flaviridae family, Dengue virus, is known to cause antibody-dependent enhancement of infection, which can lead to severe disease. Anti-dengue antibodies which are cross-reactive for Zika have been isolated from humans (Dejnirattisai et al., 2016). It will be important to determine in the future how these impact on disease outcome. This will be critically important when designing an effective and safe vaccine for Zika, particularly one based on inducing high levels of neutralising antibodies.
This study assessed three different candidate vaccination approaches for immunogenicity and efficacy against Zika infection. The authors tested similar vaccination doses, routes of delivery and vaccination schedules that are normally evaluated in human clinical trials and found that each vaccine was safe and well tolerated. However, further pre-clinical studies will be required, particularly to assess vaccine success in pregnancy and to develop improved animal models which more accurately recapitulate trans-placental, fetal and neuroinvasive Zika infection (Miner et al., 2016).
The key finding from this study was that a single shot of adenoviral vector RhAd52-prM-Env was sufficient to afford protection. This is reassuring and highlights the potential for investigation of this vaccine in humans. Adenoviral vaccines are already used in numerous human clinical trials worldwide and their relatively short production times would ensure that customised vaccines could be rapidly deployed in outbreak regions to at-risk groups.
Abbink, P., Larocca, R.A., et al., (2016). Protective efficacy of multiple vaccine platforms against Zika virus challenge in rhesus monkeys. Science. 353(6304): 1129-1132.
Coughlan, L., Mullarkey, C., et al. (2015). Adenoviral vectors as novel vaccines for influenza. Journal of Pharmacy and Pharmacology. 67(3): 382-399.
Dejnirattisai, W., Supasa, P., et al. (2016). Dengue virus sero-cross-reactivity drives antibody-dependent enhancement of infection with zika virus. Nature Immunology. 17(9): 1102-1108.
Larocca, R.A., Abbink, P., et al. (2016). Vaccine protection against Zika virus from Brazil. Nature. 536(7617): 474-478.
Miner, J.J., Cao, B., et al. (2016). Zika Virus Infection during Pregnancy in Mice Causes Placental Damage and Fetal Demise. Cell. 165(5): 1081-1091.