Zika can be defeated, but vaccine faces hurdles

Zika can be defeated, but vaccine faces hurdles

If and when it makes it through animal experiments, it may face a fresh set of challenges



By Priyanka Pulla (INSIGHT)

Published: Sun 21 Feb 2016, 11:00 PM

Last updated: Mon 22 Feb 2016, 7:49 AM

When Hyderabad-based firm Bharat Biotech announced earlier this month that it had developed two vaccine candidates against the Zika virus, the development was hailed by some media outlets as a breakthrough. At a press conference, the company reportedly said it would be able to complete animal testing for one of the vaccines within five months and bring it to market in two years. In the days that followed, however, the early media optimism was replaced by more conservative estimates of how long it would take Bharat Biotech (or anyone else) to launch such a vaccine. Early this week, while announcing that the bio-pharmaceutical firm did indeed have one of the two most advanced vaccine candidates against Zika, the World Health Organisation said human trials were at least 18 months away. This puts the launch of an effective vaccine at least three or four years away, if Bharat Biotech is very lucky.
Why is the road ahead for Zika vaccine developers going to be uphill?

Developing a vaccine

First, the good news: the Zika virus is a flavivirus, the family of viruses to which the eponymous yellow fever virus belongs ('flavus' is Latin for 'yellow'). Vaccines have been developed against several viruses of this family, such as chikungunya, Japanese encephalitis and the tick-borne fever. This means these viruses are vulnerable to vaccines unlike, say, the fast-changing human immunodeficiency virus (HIV).
Zika is a comparatively simpler beast to handle. It has only one serotype, putting it in the category of chikungunya and Japanese encephalitis. So, researchers can skip the tedious process of mixing and matching vaccines against all four serotypes to create a tetravalent preparation. "Flavivirus vaccines are very successful wherever you have one serotype. You take the virus, weaken it and you have a candidate that can go through regular clinical trials. Zika falls in that category. So, it shouldn't be too challenging," says Navin Khanna, a researcher working on a recombinant dengue vaccine at the International Centre for Genetic Engineering and Biotechnology, New Delhi.

Testing on animals

The bigger problem is going to be the development of an animal model to test the vaccine. Currently, next to nothing is known about the Zika virus because it wasn't thought to pose a significant threat to humans until the recent epidemic in Brazil. Very few researchers worldwide have looked for animal models for the virus - animals that are infected by the virus so that vaccine efficacy and safety can be tested in them. It is not known if Bharat Biotech has such models, although the firm has indicated that it will start animal trials in late February. Krishna Ella, chairman of Bharat Biotech, declined to comment for this story.
To understand the challenges in finding animal models, one only needs to look at dengue again. The dengue virus neither replicates, nor causes disease in mice. In monkeys, on the other hand, dengue replicates but stops short of triggering illness. So, monkeys provide only a part-model to test dengue vaccines.
Getting around this problem took decades, with vaccine researchers experimenting with several ways to make mice susceptible to the virus.
With Zika, a monkey model is possible because African monkeys are a host for the virus, says Ravi Vasanthapuram, a neurovirologist at the National Institute of Mental Health and Neurosciences (NIMHANS), Bengaluru, who has worked on a Japanese encephalitis vaccine. However, regulatory clearance for primate research is difficult in India, he cautions.
If the vaccine doesn't work well enough during animal experiments, the developer goes back to the drawing board and tinkers with the formula. There is much scope for tinkering. Like other flaviviruses, Zika has around ten proteins, out of which three are antigens that vaccine makers can work with. Which antigens will work best and whether the vaccine should be a combination of one, two or all three, can be ascertained through experimentation alone.

Testing on humans

If and when the Zika vaccine make it through animal experiments, it may face a fresh set of challenges in human trials. Just as antibodies to one serotype of the dengue virus can enhance infection from another, antibodies to one flavivirus can possibly talk to other flaviviruses, warn researchers.
It's a double edged sword. On the one hand, there is the possibility of cross-immunity, which means neutralising antibodies to dengue, Japanese encephalitis or west Nile fever in people exposed to these viruses (such as Indians and Brazilians) can protect against the Zika too. On the other, antibody-dependent enhancement, à la the dengue virus, can kick in.
Bharat Biotech has indicated that it expects its inactivated vaccine to be developed faster than its recombinant vaccine. An inactivated vaccine is a virus that has been killed off using chemicals, heat or radiation so that it cannot cause disease. However, since it still carries its antigens, its structure can trigger immunity. The polio vaccine is the most famous example of this. An inactivated Zika vaccine is believed to have a good chance at winning regulatory approval because it is likely to be safe for pregnant women, who will be the key targets for the vaccine.
Bharat Biotech's other vaccine is a recombinant one, normally developed by inserting a bit of the DNA from a Zika antigen into a cell culture such as yeast. When the yeast cells reproduce, they create large quantities of the antigen, which is then injected into humans, triggering an immune response. Designing and testing recombinant vaccines can be more complex and time-consuming.

Regulatory clearances

A final unknown in Bharat Biotech's vaccine-development programme is regulatory clearances. Some researchers have questioned how the firm was able to import the Zika virus into India, given that Zika hasn't yet affect Indians. When asked by The Wire whether his firm received an import permit from the Drug Controller General of India, Ella refused to comment.
Developing a Zika vaccine in the normal course of events would have taken around 15 years. With expedited clearances, given the emergency in South America, Bharat Biotech can avoid some regulatory lags. But the sheer R&D challenge of developing any vaccine is more difficult to bypass. Having two candidates definitely gives the firm a headstart in the Zika vaccine race, but this is just a few minutes shaved off the beginning of a marathon.
Priyanka Pulla is a freelance journalist interested in science and policy issues
The Wire


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