|Year : 2017 | Volume
| Issue : 1 | Page : 10-15
Zika virus: Vaccine initiatives and obstacles
Reema Mukherjee1, Anurag Khera2
1 Department of Community Medicine, Army College of Medical Sciences, New Delhi, India
2 Department of Community Medicine, Armed Forces Medical College, Pune, Maharashtra, India
|Date of Web Publication||9-Jan-2017|
Dr. Anurag Khera
Department of Community Medicine, Armed Forces Medical College, Pune, Maharashtra
Source of Support: None, Conflict of Interest: None
Over 130,000 humans in Brazil are infected with Zika virus (ZIKV) since March 2015, and presently 29 countries in Americas have reported local autochthonous ZIKV transmission. Besides the associated clinical features, Brazil has also reported a temporal and spatial association of ZIKV with Guillain-Barre syndrome (GBS) and Zika fetal syndrome. ZIKV vaccine approaches include purified inactivated virus, nucleic acid-based vaccines (DNA, RNA), live vector vaccines, subunit vaccines, virus-like particle technologies, and live recombinant vaccines similar to the technologies used against other human flaviviruses. At present, 15 commercial entities are involved in the development of ZIKV vaccine. Vaccines developed through different approaches would have their own inherent advantages and disadvantages. The presentation of disease in different populations and lack of clarity on the pathogenesis and complications is the most important obstacle. Second, Zika belongs to a genus that is notorious for the antibody-mediated enhancement of infection, which proved to be a stumbling block during the development of the dengue vaccine. Identifying large naive and yet uninfected at-risk populations may be an obstacle to demonstrating efficacy. Next, the association of Zika with GBS is being researched since the vaccine may have the potential to provoke similar neuropathophysiologic mechanisms. Zika's association with adverse fetal outcomes necessitates that pregnant women and women of childbearing age are considered for evaluating vaccines, which form a vulnerable group for vaccine trials.
Keywords: Zika, Zika vaccine, Zika virology, Zika virus
|How to cite this article:|
Mukherjee R, Khera A. Zika virus: Vaccine initiatives and obstacles. Med J DY Patil Univ 2017;10:10-5
| Introduction|| |
Zika virus (ZIKV) since its discovery in 1947 in Uganda was for the better part of several decades detected primarily in forests, circulating between primates and mosquitoes., It occurred sporadically among humans, in both Asia and Africa and was known to cause mild, self-limiting infection. According to information available till date, the virus is known to exist in two genetic lineages: African and Asian. From the 1960s to 1980s, the African lineage of the virus caused sporadic infections in the countries of equatorial Africa. Toward the end of the 80s, the virus spread to equatorial Asia. However, the manifestations continued to be mild infection in few human cases. There was no outbreak ever reported though the reason, as researchers now claim, could be due to the clinical similarity of Zika infection with both dengue and chikungunya fever, which is prevalent in these areas. However, seroprevalence studies indicated widespread exposure in countries such as Pakistan, Malaysia, and Indonesia.,,, For the first time in 2007, which later genetic studies proved to be the Asian lineage of the virus, caused an outbreak on the Yap Island, Micronesia. The ZIKV then spread to French Polynesia and other regions of the South Pacific and caused epidemics in 2013–2014.,, On March 02, 2015, Brazil reported an increase in the incidence of cases of fever and rash from its North Eastern states, cases continued to occur infecting around 7000 people in a short period. In May of the same year, Brazil's National Reference Laboratory confirmed that the cases were ZIKV infections, which marked the entry of Zika into the Americas. As of early this year, more than 1.5 million individuals in Brazil have been infected and 29 countries in Americas have reported local autochthonous ZIKV transmission.,
| Disease|| |
More than 70%–80% humans infected with ZIKV continue to remain asymptomatic. In the remaining 30%–40% cases, symptoms persist from days to 1 week and include fever, maculopapular rash, arthralgia, conjunctivitis, myalgia, headache, retro-orbital pain, and emesis. Immunocompromised individuals may develop more severe disease. Most of these symptoms are similar to dengue and chikungunya fever. Both viruses also circulate in similar geographical areas, and thus establishing diagnosis may be difficult at times.
During the 2015 outbreak, Brazil reported an increased incidence of Guillain-Barre syndrome (GBS) in patients infected with ZIKV. Researchers working on the epidemiology of the outbreak in Brazil also noted an approximate 20-fold increase in incidence of Zika fetal syndrome (primary microcephaly, retinopathy, and other neurologic birth defects) which spatially and temporally coincided with the arrival of ZIKV infection into Brazil and also countries like Columbia.,, Retrospective studies, of the French Polynesian outbreak, also indicate a possible association between ZIKV infection and congenital malformations and severe neurological and autoimmune complications. The case fatality rate of Zika is low. Although definitive causal relationship remains to be strengthened through robust studies, reports of unusually high rates of GBS and primary microcephaly, associated with the ZIKV outbreak in Brazil, have raised alarms that genetically modified virus variant, different from the one circulating in equatorial Africa and probably Asia with neuropathic and teratogenic outcomes, is probably circulating in the region of Brazil and surrounding countries.
| Virology and Pathogenesis|| |
ZIKV is a positive-sense single-stranded RNA virus in the family Flaviviridae, which includes several other mosquito-borne viruses of clinical importance such as the dengue virus, West Nile virus and yellow fever virus, Japanese encephalitis virus, and tick-borne encephalitis virus. Its closest relative is Spondweni virus, the only other member of its clade,, and it is also closely related to the dengue virus. The ZIKV genome contains 10,794 nt encoding 3419 aa. ZIKV, like the other flaviviruses, comprised 2 noncoding regions (5′ and 3′) that flank an open reading frame, which encodes a polyprotein cleaved into the capsid, precursor of membrane, envelope, and 7 nonstructural (NS) proteins with are NS1, NS2A, NS2B, NS3, NS4A, NS4B, and NS5. After the mosquito inoculates the virus into a human host cellular response, it is hypothesized, likely resembles that of other flaviviruses, in which the virus enters skin cells through cellular receptors, enabling migration to the lymph nodes and bloodstream. As of date, only a few studies have investigated the pathogenesis of ZIKV infection, and it has been shown that human skin fibroblasts, keratinocytes, and immature dendritic cells allow entry of ZIKV. After the cellular entry, the known flaviviruses, such as the dengue and yellow fever virus, were known to replicate within endoplasmic reticulum-derived vesicles. However, ZIKV antigens were found only in the nuclei of infected cells, this finding is significant as it seems to suggest that the preferred location for replication of the ZIKV is different from the other flaviviruses, and this finding may be of significance, as research now focuses on countermeasures for ZIKV.
Phylogenetic analysis shows that ZIKV can be classified into distinct African and Asian lineages; both emerged from East Africa during the late 1800s or early 1900s. Although various preventive measures such as control of the vector and use of condoms to prevent sexual transmission are being practiced in the Americas, the vaccine against the ZIKV holds the potential to have a long-term control and later offer possible avenues for elimination or even eradication.
| Zika Virus Vaccine|| |
Researchers working in the field of vaccine development are hopeful that a ZIKV vaccine could be developed taking forward the technologies that have been used to develop human flavivirus vaccines such as yellow fever, Tick-borne encephalitis, Japanese encephalitis, and the recently introduced dengue fever vaccine. Currently, there are licensed vaccines for four flavivirus diseases: Yellow fever vaccine (live attenuated), tick-borne encephalitis vaccine (inactivated), Japanese encephalitis vaccine (both inactivated and live attenuated), and dengue virus (recombinant chimeric live attenuated). The vaccine approaches for ZIKV vaccine include purified inactivated virus, nucleic acid-based vaccines (DNA, RNA), live vector vaccines, subunit vaccines, virus-like particle technologies, and live recombinant approach.
There are as of reports available with WHO, 18 different experimental and research programs, which include 15 commercial entities who are involved in the development of ZIKV vaccine following different vaccine approaches. Some of these organizations, prominent among them Bharat biotech, based in India, are following two or more parallel approaches to vaccine development. Although most programs are in the early preclinical stages, some are expected to start stage 1 clinical studies, as soon as end of this year. Given the fact that the ZIKV infection has been declared a public health emergency, there is a need to work on all of the above approaches simultaneously, so that an effective vaccine can be developed in the shortest time possible and also because vaccines developed through different approaches would have their own inherent advantages over the others. For instance, a subunit vaccine could be safer and could require a shorter development time prior to clinical testing when compared to a live-attenuated virus vaccine; however, the subunit vaccine will likely require multiple doses to induce protective immunity. In contrast, a live-attenuated virus vaccine may require only one dose and elicit a more rapid and robust immune response, leading to better, long-lived protection. [Table 1] enumerates technologies used in some of the reported candidate vaccines which are being developed by various agencies.
| Obstacles to Vaccine Development|| |
The first and most important obstacle to vaccine development is unclear knowledge of several aspects of Zika infection in humans, differing presentations in different populations and lack of clarity on the pathogeneses of infection and complications in human beings.
The development of a general use prophylactic vaccine for ZIKV-induced disease will require considerable time and careful evaluation of safety, effectiveness, and risk/benefit ratio for the population at large. The dengue vaccine, introduced after 20 years of rigorous research, is a pointer toward the efforts required to develop a flavivirus vaccine. Similarly, despite the West Nile vaccine being available for equines, there is still no vaccine till date for humans., Zika vaccine development will pose similar challenges, especially since the virus belongs to a genus that is known for the antibody-mediated enhancement of infection, which proved to be a stumbling block during the development of the dengue vaccine. ZIKV with its association with neurological autoimmune disease and teratogenic effects will prove to be a challenge for vaccine development. However, as technologies and processes that were used to develop the dengue vaccine are already present, it is hoped that the process of Zika vaccine development will not take as long. Time taken to develop and test the vaccine will also become important considering the speed which with the virus is crossing borders. During the outbreak in Polynesia, more than 70% of the population were infected in a span of merely 4 months. This assumes importance because the virus may spread so efficiently that by the time a vaccine becomes available for human clinical trials, identifying large naive and yet uninfected at-risk populations may be an obstacle and, thus, an obstacle to demonstrating efficacy.
Research into countermeasures (drugs/vaccines/antibodies/interferon) against Zika has been hampered as there are no approved animal models in which to test them. Testing is normally done first in cell lines, and then in mice and finally in monkeys before human testing can ethically begin. Normal laboratory mice when tested appear to be immune to the ZIKV infection. However, recently, virologists at the University of Texas Medical Branch in Galveston have announced that they had found a type of immune-deficient mice that lost weight, became lethargic, and died when infected.
Multiple aspects of ZIKV disease pathogenesis remain unclear. The association of the infection with neurologic complications, namely, GBS, is being actively researched. Hence, any vaccine, which is developed, which carries either an attenuated or a dead form of the virus, may have the potential to provoke similar neuropathophysiologic mechanisms. To understand the risks involved in possible vaccine-mediated GBS in any future Zika vaccine that may be developed, we need to study why and how GBS appears to be associated with Zika infection in the first place. Researchers have presented two theories as to how ZIKV infection results in GBS. First, Zika infection activates the body's autoimmune system causing an immune-mediated syndrome similar to what occurs in dengue, which then results in GBS. The other theory being that the neuroinvasive virus itself directly attacks neural cells and destabilizes the myelin sheath around them or damages axons to cause GBS. However, when viewed from the aspect of the development of a safe and effective vaccine, the first theory would spell increased difficulties for vaccine researchers as predicting what triggers off the cascade of immune system would be difficult. Unfortunately, initial research into this aspect is suggestive of the former mechanism; though much work still needs to be done to confirm the findings, preliminary data suggest that this feared immune response is exactly what is happening. However, analysis of GBS suggests the incidence of increases by 20% with each decade of increase in age. Hence, while testing the vaccine, this would necessitate attention, thus possibly making it safer to test on those in their early twenties of life than those in the fourth decade.
Zika's association with microcephaly and adverse fetal outcomes necessitates that pregnant women and women of childbearing age are considered the priority group while developing and evaluating vaccines. There are several current scientific barriers to developing vaccines for pregnant women. These include the ability to prepare and respond to epidemics and public health emergencies that have pregnant women and their unborn fetuses as the primary affected population.
The most critical issue in the vaccine development is lack of comprehensive data from randomized controlled trials from the first and early second trimester. Since the Zika's teratogenic effects may occur in the earlier phase of pregnancy, the forthcoming Zika vaccine schedule should target women in reproductive age or during the early parts of pregnancy.
Human ZIKV infection, as initial research suggests, has undergone a genotypic and phenotypic changes during its spread from Africa into Asia and now Americas. The change has been from an endemic, arboviral infection causing self-limiting illness in humans in equatorial Africa and Asia, to an infection causing, from 2007 onward, large outbreaks, and from 2013 onward, outbreaks linked with neurological disorders such as GBS and microcephaly in newborns, across the Pacific region and the Americas. Though, there still remains a possibility that the African and Asian countries, due to a poor surveillance and reporting system, and also due to the co-endemicity of dengue and chikungunya, may have missed reporting the supposed complications of ZIKV infection. Another postulate that researchers are working on is that the populations of equatorial Africa and Asia, being exposed to the virus early in life, develop an immunity which protects them against the complications, which are now being observed in the Americas, where the virus infected a naive populations. Understanding the age of infection in endemic areas and whether childhood exposure provides protection could help clarify the paradox of low microcephaly rate in endemic regions, and would guide immunization strategy when a vaccine becomes available.
All these aspects of immunity and genetic modification will need to be studied and will also in turn influence vaccine development research and later on aspects of vaccine efficacy in different groups and different populations.
| The Way Ahead|| |
Despite ZIKV being declared a public health emergency just a few months back, considerable progress has already been made in the field of vaccine development, mainly because various agencies were already involved in the development of vaccines for dengue and chikungunya. Responding to the seriousness of the situation, the President of United States of America urged the Congress to dedicated 1.8 billion USD toward vaccine development. The National Institutes of Allergy and Infectious Diseases has initiated work on a DNA-based vaccine. The DNA-based vaccine is similar to an investigational flavivirus vaccine for West Nile virus infection and found to be safe and induced an immune response when tested in a Phase 1 clinical trial. The National Institutes of Health is also working on a live attenuated vaccine in addition to recombinant vaccine candidate, which uses a genetically engineered version of vesicular stomatitis virus, which is an animal virus that primarily affects cattle. Early stage human trials are expected in 2016.
Closer home, Bharat Biotech, the Hyderabad-based company, has submitted two vaccine candidates one inactivated and one recombinant to the Indian Government. Bharat Biotech filed patents for both vaccine candidates in July 2015. As per the reports from the company, the inactivated vaccine has reached the stage of preclinical testing in animals.
The impact of the current ZIKV epidemic goes beyond public health. ZIKV is affecting global security and the global economy. A coordinated effort is required by government, academia, industry, and funding agencies to efficiently study the virus, develop counter measurements, and halt the spread of this potentially devastating virus. Till a highly efficacious vaccine covering the most vulnerable population is developed, accepted for the use after undergoing large trials, the focus of the prevention and control strategies for ZIKV are anti-larval and anti-adult measures against Aedes mosquito and personnel protective measures.
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Conflicts of interest
There are no conflicts of interest.
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