Author: Antonio Gregorio Dias Jr Edited by: Layal Liverpool and Inês Barreiros
Looking at the burden of Zika virus in the Americas during its most recent outbreak, a vaccine is urgently needed. Above all, it must protect pregnant women and the developing foetus from the teratogenic effects that Zika virus infection can cause. To tackle this issue, scientists all over the world have been working on the development of vaccine candidates. More recently, advances in a live-attenuated vaccine have generated promising results in mice and tests in non-human primates are now well underway.
A live-attenuated Zika virus vaccine
As the name suggests, a live-attenuated vaccine means the generation and use of a “live” Zika virus particle with a lowered ability to infect and replicate within its host. This might sound strange and scary… has this been successful before? Yes! The Yellow Fever virus vaccine is a good example. It is a live-attenuated vaccine that protects nearly all vaccinated individuals in a life-long single dose. Another example is a dengue virus vaccine candidate that is currently in phase 3 clinical trials and may become commercially available in the future. Could a similar approach also work with Zika virus? Again, according to a group of scientists from the University of Texas (USA) and Instituto Evandro Chagas (Brazillian Ministry of Health) in a recent high profile scientific report, the answer is yes. To understand how they generated this elegant vaccine, we need to think about genes.
Engineering a live-attenuated Zika virus vaccine
The human genome is made of 3 billion base pairs of DNA. Simply, this means 3 billion of the four letters A, T, G and C in many combinations (but not really at random!). A strand of DNA can generate a strand of a sister molecule called “RNA”, which will contain one different letter, “U” instead of “T” (for example, AUGC).
The Zika virus genome is composed of RNA rather than DNA. Additionally, it is much shorter containing about 10,000 instead of billions of base pairs. Nevertheless, the scientists deleted only ten bases from a strategic location on the virus genome and rendered an attenuated Zika virus.
This mutant virus can infect mice but replicates very poorly. Yet, it triggers a protective immune response similar to the original virus. By protective immune response, we mean that once the mice are vaccinated with the mutant virus, they become resistant to future infections with the original highly pathogenic virus. Therefore, it demonstrates that this vaccine generates robust protection against Zika virus in mice. Importantly, the mutant virus is also unable to infect mosquitoes and thus decreases the risks of an uncontrolled transmission of a laboratory engineered virus. Although the results sound very exciting, is this everything we need to define it as a safe candidate?
A not-so-protective immune response
When we are exposed to a virus like Zika, our body mounts an immune response in an attempt to eliminate it. This sometimes leads to disease symptoms depending on how difficult the fight is and how well adapted the virus is to fight back. When the battle is over with our victory, the virus has been eliminated. But how can we be prepared for possible future encounters? Our body generates defence molecules called ‘antibodies’ which will be able to recognise a future infection with the same enemy. In this case, we will be prepared and waiting, and the battle should be over much easier. This is one of the fundamental goals of vaccination: to generate defence molecules against a pathogen to prevent its successful replication in a future encounter.
As discussed above, the Zika virus vaccine candidate (mutant virus) once injected led to the mice generating antibodies against Zika. Weeks later, these mice were infected with a high infectious Zika virus strain. These mice (pre-immunised) did not develop disease or major symptoms because they were now protected. This is a protective immune response that is likely life-long - one of the benefits of live-attenuated vaccines.
However, dengue virus (a close relative to Zika virus) has learned how to fight back antibodies produced against them. There are four types of dengue: dengue 1, dengue 2, dengue 3, and dengue 4. For a simpler understanding, imagine one individual who becomes infected with dengue 1 and survives. This means this individual eliminated dengue 1 and produced antibodies against it. These will be life-long and will prevent dengue 1 from causing disease again in the future. These antibodies are, however, protective against dengue 1, but not against other types of dengue. Instead, the antibodies against dengue 1 can rather facilitate the infection of the other types of dengue. This means if this individual gets exposed to dengue 2 in the future, the disease severity may be even higher than that from the first exposure. This is why a vaccine for dengue virus is taking so long to be produced and considered safe.
We are now worried Zika virus may have learned similar tricks. Scientists from Icahn School of Medicine at Mount Sinai (USA) have demonstrated that antibodies against dengue can also facilitate infection against Zika virus. It is thus feasible to believe that the other way around may also be possible, i.e. antibodies against Zika facilitating dengue virus infection. This poses a potential barrier to developing a Zika vaccine.
Therefore, it remains to be addressed whether the Zika virus live-attenuated vaccine candidate described above will not enhance dengue virus infection. Also, what is the safety of injecting this Zika vaccine in individuals that were previously exposed to dengue virus? Finally, and importantly, this vaccine is yet to be tested in pregnant mice and/or other animal models of mother-to-foetus virus transmission.
Fortunately, scientists are aware of these gaps and are now addressing these issues before they can call their vaccines “safe”. We now cross our fingers and hope for the immediate success of this great work.
Shan et al. 2017. A live-attenuated Zika virus vaccine candidate induces sterilizing immunity in mouse models. Nature Medicine, 2017.
Bardina et al. Enhancement of Zika virus pathogenesis by preexisting antiflavivirus immunity. Science 356 (6334): 175-180, 2017.