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Zika Vaccine A Distant Dream?

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The development of the Zika virus vaccine has been hindered by its complexity and doubts over its marketability By Sachin Jagdale

The outbreak of Zika in Brazil has thrown up yet another challenge for the global healthcare fraternities, who were already bogged down with the Ebola epidemic, which mainly focused in the African region. Moreover, Zika could prove to be a bigger health threat than Ebola as it is comparatively more prevalent in various other regions of the world. According to estimates by the Centre for Disease Control and Prevention (CDC), Zika virus transmission has been noticed in and around 50 countries globally. With no specific medicines available for treatment there was an urgent need to develop vaccines for the virus.

It is a race against time as the virus has slowly but steadily spread its tentacles. Though scientists have come up with various possibilities to develop a vaccine, it is still an uphill task.

Less familiarity and increased complexity

Zika symptoms are generally mild but it can cause devastating effects such as affecting pregnant women and causing Microcephaly, a severe brain malformation in the foetus. However, its quick transmission in various parts of the world has prompted the World Health Organisation (WHO) to declare Zika as a global public health emergency. As mentioned earlier, developing a vaccine to tackle the growing incidence of the disease is of utmost importance.  However, lack of enough information about the disease is proving to be a big hurdle.

Dr Robin Mukhopadhyaya, Formerly, Prof. ACTREC, Tata Memorial Centre explains, “Zika virus is similar to the dengue virus and it belongs to the virus family Flaviviridae and the genus Flavivirus. Any laboratory having expertise in culturing and maintaining any other Flavivirus can grow this virus. Quite a few laboratories are well accomplished in that including the National Institute of Virology (NIV), Pune the nodal surveillance centre. Once a strain of virus is available, an inactivated virus format can theoretically serve as the starting material to develop a prophylactic vaccine candidate. Some flaviviruses may have different subtypes, as four subtypes (referred to as serotypes) are there for dengue and hence an effective dengue vaccine should be able to neutralise all subtypes for a given population at risk.”

However, there are certain challenges. Mukhopadhyaya highlights, “There is no peer reviewed document yet to prove whether there are different Zika serotypes or if the virus mutates. However, genome sequence of strains obtained in different countries, e.g., in Malaysia and Cambodia, have been shown to diverge, though how much of divergence have bearing on developing vaccine candidates has not been studied.”

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Dr K Anand Kumar

Dr K Anand Kumar, Managing Director, Indian Immunologicals, also expresses similar views. He further says that the first hurdle would be to identify a suitable strain of the virus, which could then be developed into a vaccine. It is imperative   that the vaccine provides cross protection against majority of prevalent strains of the virus, or else the use of such a vaccine may be restricted. It may lose its utility with the emergence of  newer strains.

He also points out that there are no suitable animal models or correlates of protection available as of now to ensure that the vaccine would have limited risk of failure in clinical trials.

“The major challenge would be to ensure the safety and efficacy of the vaccine in various age groups of the human population. Both these aspects will require large, time consuming and very well planned clinical trials in areas where the disease is prevalent considering the same regions would probably be also endemic to dengue and chikungunya,” insists Anand Kumar.

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Dr Manju Phadke

Dr Manju Phadke, Associate Prof Dept of Microbiology, SIES College of Arts, Science and Commerce, also points out, “Zika Virus has not been well studied so far in comparison to its better known cousins due to the previously low impact of the virus. Very little is known about Zika virus replicates, its pathogenesis or how the immune system protects against its infection. Structurally a complex virus, it also has a complex mechanism of protein synthesis and replication. The site of protein synthesis being the cytoplasm of the infected cell and the site of replication being the nucleus of the infected cell.”

Low commercial viability

There is a commercial angle as well to this debate. Many big pharma companies have taken a cautious approach towards Zika outbreak mainly due to doubts regarding marketability of Zika vaccine. Industry experts believe that there is a possibility that areas affected by Zika virus may develop natural immunity against the disease over the next few years. A rise in the immunity level will obviously block its spread as well. Hence, there will be a less urgent need of the vaccine due to mild impact of the virus coupled with its sluggish spread. Pharma companies are in a dilemma whether to tap this segment as there is decline in the number of cases in the virus dominated areas such as Brazil, and Colombia.

Lack of prior research has also prevented pharma companies from trying their luck on the Zika vaccine. But, companies like Sanofi has taken a keen interest to develop the vaccine, and have a valid reason to do so. This is because dengue and the Zika virus belong to the same family and Sanofi has two decades of experience in dengue vaccine development.

According to Mukhopadhyaya, some biopharma companies in the US and/or Europe should have already taken initiatives to develop the vaccine as tropical countries are infested with the Aedes mosquitoes, which are again large markets for them. Even, Pasteur Institute in France has long studied this virus.

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Dr Sunit K Singh

Highlighting a few more key global developments, Dr Sunit K Singh, Associate Professor (Molecular Immunology) and Head-Molecular Biology Unit, Institute of Medical Sciences, Banaras Hindu University says, “Efforts are on to design and test a vaccine against Zika but it is a long process which needs years to complete. Scientists believe that it will take at least three to four years to come out with something concrete. National Institute of Allergy and Infectious Diseases (NIAID) in Bethesda, Maryland, plans to begin phase-I trial of a DNA vaccine against Zika Virus by September 2016. Inovio Pharmaceuticals and GeneOne Life Science have
received approvals to initiate phase I clinical trials to evaluate Zika DNA vaccine (GLS-5700). In pre-clinical testing, these companies have reported that the vaccine induced robust antibody and T cell responses in small and large animal models.”

Singh adds, “Recently, Grant et al published a manuscript in Cell Host and Microbe May 2016 issue, where it has been demonstrated that viral protein known as NS5 is a promising target for vaccines against Zika. They reported that NS5 protein of the Zika virus prevents Zika virus-infected human cells from signalling immune system cells to make interferon, a powerful antiviral protein. Scientists believe that it may be possible to design a vaccine against Zika virus by using a live, weakened form of the virus made by altering the NS5 protein.”

Coincidentally, though India hasn’t reported any case of Zika virus yet, the country is one of the key contributors in the global arena to help develop a vaccine for the zika virus. As mentioned in Wikipedia, Hyderabad-based Bharat Biotech had reported in early February 2016 that it was working on vaccines for the Zika virus using two approaches: ‘recombinant’, involving genetic engineering, and ‘inactivated’, where the virus is incapable of reproducing itself but can still trigger an immune response with animal trials of the inactivated version.

Susceptibility in Indian population

India, being a tropical country, is a breeding ground for the Aedes aegypti mosquitoes. A vector for dengue and chikungunya, it is a vector for the Zika virus too. Hence, the chances of Zika virus affecting the Indian population is high.

“With modern day intercontinental travel ease, emergence of Zika virus in India is fairly possible, though the time of emergence cannot be predicted. Detection is a standard procedure. NIV, ICMR regional virology centres as well as other few research institute labs with research expertise in dengue virus/ JE virus can be geared for quick detection. Usually, the viral genome (RNA) in the blood (serum) samples of suspected individuals is detected by RT-PCR method, which is a common technique these days. However, appearance of early antibody/ immunoglobulin (IgM) in serum or presence of viral genome in urine have also been tried,” says Mukhopadhyaya.

Seeing that India not immune to the Zika virus, Government of India took immediate steps and deployed remedial measures as soon as WHO declared it as a public health emergency. This included travel advisory, screening, laboratory diagnosis at certified ICMR laboratories etc. However, Anand Kumar also rings the warning bell and says, “Considering the diversity and socio politico –economic structure of our country, I believe it will be a Herculean task to contain the disease if it spreads across the country.”

He adds, “I feel that as Indian vaccine manufacturers have a lot of expertise to develop such vaccines, it will be vital for the Ministry of Science & Technology and Ministry of Health and Family Welfare, Government of India, to engage with major players and provide suitable vaccine strain of Zika in coordination with the WHO as well as offer support for clinical development of the vaccine. This will also facilitate the generation of a suitable vaccine with broader cross protection.”

Long road ahead

As discussed earlier, lack of prior research and its commercial viability are the two major roadblocks. Lack of prior research and documentation will only further delay the process. The lack of market potential will prevent pharma companies from investing in the development of this vaccine. So, the chance of a vaccine for the Zika virus hitting the shelves in the near future is rare.

From an India perspective, the good thing is that though we are still unaffected by the Zika virus, we have already started taking preventive measures against it. As Anand Kumar mentions, “It is high time that the scientific fraternity from both academia and industry come together and start planning for future exigencies based on the current outbreak rather than focusing on just immediate needs. We need to have more discussions on similar vector borne or other zoonotic diseases, which can have major repercussions in the future due to climate change and trans-boundary migration of humans and animals. It will ensure vaccine preparedness in case of emergence of new diseases.”

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