Over the last two years Zika virus has emerged as one of the major global health threats. Even though the virus has been known since 1947, when it was first isolated from a rhesus monkey in Zika forest in Uganda, only recently has it become a major research interest. Generally, Zika virus infections in healthy individuals are quite mild, with a few non-specific symptoms, which is why for the most part the interest in Zika was more a scientific curiosity than a treatment necessity. However, when the first reports from Brazil in 2015 noted the links between neurological abnormalities and Zika virus infections, scientists have rushed to study and better understand this once-ignored virus. We now know that, if the Zika virus crosses the placenta in a pregnant mother, it can cause microcephaly in newborns. In addition, in some rare instances, adults infected with Zika can acquire the Guillain–Barré syndrome, a condition where a person’s immune system starts attacking its own nerve cells.
In the light of the recent Zika outbreak and spread, a lot of attention has been focused on developing a vaccine against the virus. While there’s still no vaccine available, the process for its development is somewhat speedier, due to the knowledge that we have about the related viruses. Zika belongs to the flavivirus genus, the same group also includes Dengue, Yellow fever, West Nile and Japanese encephalitis viruses. Vaccines for several flaviviruses have already been approved for human use and similar platforms are now being used to develop vaccines against Zika as well.
A recent study published in the journal Nature presents a Zika vaccine that is based on an mRNA molecule. mRNAs, or messenger RNAs, are molecules in cells that carry the messages telling what kind of proteins a cell should be making. An mRNA is recognised by the ribosomes in the cells, which read the mRNA nucleotide sequence and produce the encoded protein. Zika virus, like all other viruses, relies on cellular machinery to make its proteins. The genome of Zika virus is essentially one big mRNA, which the virus packages into the newly made particles. The mRNA that the scientists used to make the vaccine, however, is not an exact copy of Zika’s genome. Instead, the mRNA codes for only two viral proteins- the premembrane protein and an envelope protein. Expressing these two proteins inside a cell from the mRNA is sufficient to make structures that look almost identical to the virus particle itself. Just like the virus, the virus-like particles are released from a cell and can be detected by the immune system. Once the particles are recognised the immune system mounts a response, which should ultimately lead to a development of a long-term immune memory that would protect the individual from an infection with a real virus later on. The study published in Nature showed that mice vaccinated with the mRNA vaccine were protected from Zika infection even 20 weeks after the vaccination. The mice produced high levels of antibodies in their blood, which were able to neutralise the virus and just a single vaccination with mRNA vaccine was sufficient to provide the protection.
While mouse models are important for initial studies, they do not always reflect the disease progression in humans. For example, number of immune-competent mouse strains infected with Zika quickly clear the virus and do not develop the pathologies seen in humans. The Nature study, therefore, also tested the mRNA vaccine in non-human primates- rhesus macaques. Like in mice the vaccine was able to protect the macaques from the virus challenge at least 5 weeks post vaccination. Only one vaccinated animal showed some signs of viral infection, but all mice in the non-vaccinated control group developed a viraemia.
The mRNA vaccine is just one of many vaccine candidates being developed for the Zika virus. A similar vaccine encoding the premembrane and the envelope proteins but based on a DNA molecule rather than RNA has also recently been made. While the DNA vaccine is already in a phase 1 clinical trial, in primate studies it required higher doses vaccination than the mRNA-based approach. In addition, after just one immunisation the mRNA vaccine led to greater neutralising antibody titres in primates than two immunisations with the DNA vaccine. Other vaccines that use adenovirus vectors and inactivated Zika virus particles, are also progressing through clinical trials.
There are still many challenges left until Zika vaccine is available for use to the people living in endemic areas As Zika infection is often asymptomatic or the symptoms are common to many other health problems, it is not trivial to diagnose Zika infection. Also, many flaviviruses can be found in the same areas as Zika. As the flaviviruses tend to have quite similar proteins many lab tests used to diagnose infection cross-react between the flaviviruses, making it difficult to distinguish which virus is responsible for the infection. Another pressing issue is perhaps the ability of antibodies against one flavivirus to enhance the infection of another virus. The so-called antibody dependent enhancement has been extensively described for Dengue virus, but some studies have also observed that antibodies against Dengue can enhance Zika virus infection. These observations still require a better evaluation, but it is important to understand these possible cross-reactive interactions when considering a wide-range vaccination campaign for the people living in the areas where other flaviviruses are endemic.
Pardi N et al. (2017). Zika virus protection by a single low-dose nucleoside-modified mRNA vaccination. Nature PMID: 28151488
Dowd, Kimberly A., et al. “Rapid development of a DNA vaccine for Zika virus.” Science (2016).
Barouch, Dan H., et al. “Prospects for a Zika Virus Vaccine”. Immunity, (2017).