In the first WIMM blog post of 2017, Layal Liverpool and Antonio Gregorio Dias Jr (two DPhil students working in the MRC Human Immunology Unit) describe how our understanding of the dengue virus could hold the key to developing a vaccine for Zika. This article was originally published by Science Innovation Union.
“Deu zika!” is a popular expression in Brazil to indicate something unpleasant has happened. But Zika is of course also a virus transmitted by mosquitoes that has recently become notorious for its ability to infect pregnant women and affect foetal development. In the context of the current Zika outbreak, scientists all over the world have been studying this virus, while the search for treatments and vaccines is an ongoing progress.
Although the Zika outbreak peaked only in the last year or two, according to a recent report by the World Health Organisation (WHO), 70 countries and territories have identified cases of Zika since 2007. In approximately 20 of these countries, Zika virus infection has been associated with improper foetal brain development as well as a rare neurological disorder called Guillan-Barré syndrome in adults.
The virus is continuing to spread geographically, however its dependence on mosquitoes for transmission means it is confined to regions of the world inhabited by these insects. Currently, the four affected regions are Africa, the Americas, South-East Asia and the Western Pacific.
There had been little research on Zika virus before the current outbreak. Fortunately, however, Zika virus belongs to a group of viruses called flaviviruses, which includes “relatives” of Zika virus that have been studied for many years, such as dengue and West Nile viruses.
The viruses included in this group share a number of features amongst them, including similarity among the viral proteins they produce. Scientists have been able to use the knowledge they gained from dengue virus proteins, which have been extensively studied, to help identify methods to tackle Zika.
By searching for similarities between Zika and dengue viruses, researchers have been trying to identify overlapping mechanisms that could be targeted therapeutically. For instance, it was discovered that an antibody against a dengue virus protein can also block Zika virus infection.
Antibodies are defence molecules produced by immune cells in the body in response to an infection, the special agents of the body, aiming to destroy specific targets. In this particular case, the antibody tested specifically recognises the viral envelope protein, which is similar in both dengue and Zika viruses.
So what is a viral envelope? Whereas we store our genetic information in the form of DNA, flaviviruses like Zika and dengue actually use a sister molecule of DNA called RNA. When one of these viruses infects a human cell, its RNA is used as a template to generate new RNA molecules that will be packaged into new virus particles and translated into viral proteins with a plethora of functions.
These proteins, along with those of the host cell membrane, form the outer surface of a viral particle. Just like a postal envelope that is addressed to a specific destination, the viral envelope protects its contents from the outside world.
New infectious viral particles can then be released from the original infected cell and spread to other cells in the body. Because the envelope is on the outside of the viral particle, it has to face the immune system of the infected individual, including antibodies.
If successful, antibodies against the viral envelope protein will cover the surfaces of the infectious virus and neutralise its ability to bind and infect new cells. Consequently, viral particles covered by neutralising antibodies will be eliminated.
Zika and dengue viruses also have some of the same tricks up their sleeves when it comes to getting around our immune system. Ironically, both Zika and dengue can use a trick called antibody-dependent enhancement to actually use the antibodies produced against them as weapons to infect more cells.
Some immune cells express a protein on their surface which recognises and sticks to antibodies. When these antibodies are attached to a Zika or dengue virus particle, the virus can use this as a way to infect these immune cells, multiply inside them and spread. In line with this process, a recent study showed that some anti-dengue antibodies can actually enhance Zika virus infection.
For future antibody-based therapeutics, it is critical to distinguish antibodies which are capable of blocking virus infection from those that can be hijacked by these viruses to enhance their infectivity.
Can we turn the tricks the viruses use on their head and use them to fight infections? To this end, scientists isolated several antibodies produced against the dengue envelope protein from patients infected with the virus. Because of the similarities between Zika and dengue envelope proteins, they tested whether some of the antibodies against dengue could also bind to and neutralise Zika virus. Initial findings demonstrated that at least one antibody was able to do the job.
Generation of a protective antibody response will also be a key goal of vaccination. As such, animal models have been used to test the ability of a new Zika vaccine that would create this type of response. This vaccine contains all the information required to make specific Zika virus proteins, which can stimulate the immune cells to make anti-Zika antibodies.
Excitingly, the vaccine triggered immune responses in mice and non-human primates have been tested and has already entered Phase I of clinical trials.* It is estimated that the first results from these trials will come towards the end of 2017.
So, scientists have recognised that dengue virus possesses an envelope containing information about Zika! Indeed, learning from other better studied flaviviruses will be important in the development of therapeutic strategies. Further studies will be needed to confirm and extend these findings to tackle the current outbreak. This could ultimately contribute to improved vaccine design and novel treatments against Zika and dengue viruses.
*Phase I clinical trial is the first stage a new drug goes through after it’s confirmed to work against a specific disease in animals. In this stage the drug is tested in a small group of people to test its safety in humans.