|Year : 2016 | Volume
| Issue : 4 | Page : 249-255
A pandemic in disguise: Zika virus vaccine development and counteractive measures analysis
Owais Fazal1, Imran A Siddiqui2
1 Certified Nurse, Frisco, Texas, USA
2 Department of Medical Education and Postgraduate Studies, Saudi Commission for Health Specialties, Saudi Arabia
|Date of Web Publication||12-Oct-2016|
7043 Mercy Road, Frisco, Texas 75035
In recent times, Zika virus has engendered concerns throughout the world, prompting the World Health Organization to promote the virus to epidemic status. This dramatic rise to prominence demands comprehensive research oriented towards effectively controlling the spread of this virulent disease. Despite the influx of information afforded by modern technology regarding the virus, there are yet to be licensed medical countermeasures (vaccines, therapies or preventive drugs) available for Zika virus infection and disease. Thus, diverting sizable funds towards prospective Zika virus vaccine candidates as well as appropriately educating the modern healthcare worker regarding the epidemiology of Zika virus is becoming increasingly imperative. Fortunately, a multitude of researchers are working towards instituting pragmatic measures directed towards limiting Zika virus's spread in an interconnected global climate.
Keywords: Clinical, prevention, research, vaccines, Zika virus
|How to cite this article:|
Fazal O, Siddiqui IA. A pandemic in disguise: Zika virus vaccine development and counteractive measures analysis. J Health Spec 2016;4:249-55
|How to cite this URL:|
Fazal O, Siddiqui IA. A pandemic in disguise: Zika virus vaccine development and counteractive measures analysis. J Health Spec [serial online] 2016 [cited 2019 Jun 20];4:249-55. Available from: http://www.thejhs.org/text.asp?2016/4/4/249/191905
| Introduction|| |
After the initial isolation of Zika virus from the serum of a febrile rhesus macaque in Uganda in 1947, evidence of human infection was uncovered at numerous sites throughout Egypt, India and Malaysia, suggesting that tropical areas with warm climates may be associated with the transmission of the virus. ,, Moreover, recent outbreaks of the virus in French Polynesia and Brazil further bolster this notion, with transmission to humans occurring primarily through the medium of endemic mosquito vectors including Aedes aegypti and Aedes albopictus. , Other reported methods of spreading Zika virus include sexual transmission from males to females during unprotected vaginal, anal or oral sex, with a recent Morbidity and Mortality Weekly Report documenting the possibility of female-to-male sexual transmission as well.  In addition, multiple confirmed cases of Zika virus transmission through blood transfusions have prompted the US-based Centers for Disease Control and Prevention (CDC) and Food and Drug Administration to recommend a 4-week deferral period before donating blood for individuals who may have recently been in contact with the virus. , Furthermore, the CDC recently released a report that outlined the various countries and territories known to harbour active sites of Zika virus transmission, and based on the findings, the virus locations are largely concentrated in Central and Southern America [Figure 1].  Several aforementioned regions have also been linked with the distribution of various similar flaviviruses such as dengue virus, yellow fever (YF), West Nile virus, Japanese encephalitis viruses and the Spondweni virus, often resulting in confusion in regards to the actual diagnosis of Zika virus, which will be addressed in more depth later in the article. 
|Figure 1: Countries with Active Zika Virus Transmission. Source: Centers for Disease Control and Prevention (CDC)|
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From an epidemiological standpoint, 80% of those afflicted with the initial Zika virus infection (ZVI) are asymptomatic, whereas the remaining 20% of those infected with the virus may experience mild, non-life-threatening symptoms. Acute symptoms include fever, maculopapular rash, arthralgia, conjunctivitis, myalgia, headache, retro-orbital pain and emesis, and these symptoms usually persist for up to 1 week [[Figure 2] shows the clinical symptoms diagram release by the National Epidemiological Surveillance System (SINAVE) specific to Mexican region].  Furthermore, the Brazilian Ministry of Health released a study in 2015 that suggested that instances of the ZVI during pregnancy may have teratogenic effects including a possible association between the ZVI and the development of microcephaly as well as a host of other congenital birth defects in newborn infants.  From a long-term standpoint, individuals afflicted with microcephaly can often face tremendous challenges in regards to living a normal life, with hindrances ranging from mild developmental delays to severe motor and intellectual deficits such as cerebral palsy.  In addition, ZVI has also been linked with a substantial rise in cases of the rare Guillain-Barré Syndrome (GBS), a post-infectious disorder that is characterised by rapidly progressive weakness of the extremities, the development of various respiratory insufficiencies, and possible indications of autonomic dysfunction such as the demyelination of axonal sheaths found in the peripheral nervous system. ,
|Figure 2: Clinical characterization of confirmed cases of Zika virus disease, Mexico November 25, 2015 to February 19, 2016 (Percent). Source: Public Library of Science (PLOS)|
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In regards to the detection of Zika virus, infection may be suspected based on the symptoms mentioned previously as well as the patient's recent travel history; however, resounding similarities may exist between the symptoms of ZVI as well as other flaviviruses such as dengue fever. A clinical diagnosis may be confirmed by laboratory testing for the presence of Zika virus RNA or specific Zika virus antibodies in the blood, urine or saliva.  Furthermore, in regards to serology, the timing of samples is crucial because flavivirus infections including ZVI typically cause acute infections that are often expeditiously cleared by the human immune response, thereby limiting detection of viral nucleic acid or antigens in the peripheral blood to a narrow window of 1 - 5 days following the onset of symptoms.  In regions with advanced laboratory capacities such as the US, a reverse transcriptase-polymerase chain reaction (RT-PCR) assay must be the first-line test, as patients who display the acute phase of infection with 'dengue- or chikungunya-like syndrome', or with 'fever and rash' who are found to be negative by specific dengue virus and chikungunya virus RT-PCR assays should be tested with a specific Zika virus RT-PCR assay as soon as possible.  In regards to addressing the risk factor of perinatal transmission, the CDC recommends laboratory testing for infants born to mothers who display laboratory evidence of ZVI as well as for infants who exhibit abnormal clinical findings suggestive of possible transmission. In addition, it is key to perform maternal diagnostic examination through the testing of the placenta for Zika virus PCR. However, if an infant appears clinically well, further evaluation can be deferred until maternal test results are available.  Thus, it is becoming increasingly imperative that counteractive measures are instituted in an efficacious and timely manner, especially in regions where access to a clinical laboratory capable of diagnosing the ZVI may be limited.
| Clinical perspective|| |
Countermeasures in a hospital environment
Although several viable Zika virus vaccine research and development programmes exist, Dr. Marie-Paule Kieny, assistant director-general for health systems and innovation for the World Health Organization (WHO), claims that it could be years before a universal vaccine for Zika virus is widely available for human usage.  Therefore, it is imperative that until that time, the healthcare workers who are employed in regions exposed to the ZVI adopt a defensive mechanism comparable to the 3I (Identify, Isolate, Inform) system utilised to effectively counteract the spread of the Ebola virus throughout 2014. ,
The first and perhaps a most key step in the 3I system is to correctly identify the ZVI in a patient. With an incubation period of 2 - 7 days, it is crucial to assess all patients with a suspected ZVI within 14 days of symptom onset. This objective can possibly be accomplished by taking account of the patient's recent travel history and ascertaining whether an incidence of ongoing Zika virus transmission has been reported in the areas, the patient has recently lived in or visited. Furthermore, upon admission to the emergency department, acute symptoms mentioned previously such as maculopapular rash, conjunctivitis, sudden fever and arthralgia should also be addressed immediately, as if two or more symptoms are present, it may be necessary to test for the presence of Zika virus by serologic testing.  However, in regions where other endemic flaviviruses are prevalent, utilising an enzyme-linked immunosorbent assay remains a particular challenge because of cross-reactivity with the aforementioned dengue, YF and West Nile viruses. Thus, the plaque-reduction neutralisation test for virus-specific neutralising antibodies (IgG) in serum samples is necessary to confirm a diagnosis.  Furthermore, patients should be assessed for pregnancy as well as for the various neurological indications of GBS. Generally, asymptomatic persons are not recommended to undergo serologic testing, with the exception of pregnant women 2 - 12 weeks after possible contact with a region reported to have ongoing Zika virus transmission.  Although the 'Vital Sign Zero' concept dictates that every patient should immediately be assessed for potential to transmit disease upon entrance into a healthcare facility for the safety of, not only the patients, but also the healthcare providers themselves, if the differential diagnosis only considers flaviviruses such as Zika virus, then isolation is unnecessary.  While standard patient, contact, droplet and airborne precautions must be maintained with patients who are infected with diseases such as MERS and Ebola, the precautions are not necessary for Zika virus due to its alternative method of transmission.
The second step of the 3I system with respect to dealing with the unique transmissions characteristics of Zika virus is to effectively investigate the epidemiology of the disease and to ascertain how to institute preventative measures to avert further spread of the disease among a given population. For instance, after confirming that a patient has been infected with Zika virus, it is imperative to isolate that patient from mosquito vectors as well as any other possible modes of transmission to prevent the potential spread of the ZVI. Furthermore, patients present in or returning from high-risk areas must be advised to take precautionary measures such as remaining indoors, utilising a bed net if air-conditioning is not possible, wearing long-sleeved shirts and long pants, using Environmental Protection Agency-registered insect repellent products if possible and finally incorporating screen doors into their household to further deter mosquito vectors.  Furthermore, in regards to countermeasures for the sexual transmission of Zika virus, the CDC highly recommends the use of condoms during vaginal, anal or oral sex in regions known to contain Zika virus, as sexually active males or females can potentially transfer Zika virus to their sexual partners during unprotected sex. Moreover, if a man or woman is aware that her partner has recently travelled to a country known to harbour the ZVI, the best way to avoid possible infection is to temporarily abstain from sex completely, especially as semen is known to carry Zika virus longer than blood and other body fluids.  Strictly adhering to these guidelines is absolutely key to reverse the rapid and unprecedented growth undergone by the ZVI over the past few years, and meticulously investigating the modes of transmissions and possible counteractive measures encompass the second step of the 3I process.
The final step of the 3I process comprises dutifully informing the hospital infection prevention and control team as well as appropriate health authorities of all suspected cases of ZVI, as this information can be crucial in regards to determining whether or not precautionary measures must be taken by individuals travelling to and from the specific location reported to harbour the virus. Such is the case of the previously mentioned CDC and its interim travel guides on its travel website that delineate the regions where cases of the ZVI have been reported. This travel notice can not only deter women who may be pregnant from visiting specific regions known to contain the ZVI but also may be able to provide the women who inhabit any of the outlined territories with a crucial warning in regards to taking protective measures to counteract any possible infection, especially during pregnancy.  Thus, failure to report any instances of the ZVI can result in drastic consequences, as the aforementioned defects and disorders can pose significant threats to the quality of life of a sizable population.
| Preventative measures and containment strategies|| |
Progress toward a Zika virus infection vaccination
To effectively endeavour towards limiting and eventually eliminating the spread of Zika virus throughout regions such as the Eastern Mediterranean Region (EMR), which has not yet reported any confirmed instances of Zika virus, two key initiatives must be pursued. These fundamental approaches include further developing innovative vaccine and therapeutic strategies as well as instituting formalised measures that work towards vector control in the aforementioned vulnerable areas.
Fortunately, in regards to pursuing insightful Zika virus vaccine research, the committed efforts of organisations such as the WHO, which recently declared the outbreak of the ZVI in Brazil and the subsequent link to microcephaly and other congenital defects as a Public Health Emergency of International Concern, are playing a monumental role in stimulating cutting-edge research solely focussed on developing a viable vaccination for the dangerous virus.  One specific research initiative is that of the National Institute of Allergy and Infectious Diseases, which has been actively pursuing a multitude of potential vaccine candidates, including a DNA-based vaccine that is comparable to the investigative flavivirus West Nile vaccine that has been successfully tested in a Phase 1 trial, a live-attenuated investigative vaccine, an investigative vaccine that utilises the genetically engineered vesicular stomatitis virus, and a whole-particle inactivated vaccine based on the work of the Walter Reed Army Institute of Research (WRAIR) with Japanese encephalitis and dengue virus. 
Furthermore, the National Institutes of Health has funded two prospective vaccine development projects, each of which has been successfully proven to effectively shield mice challenged with the ZVI for 4 - 8 weeks following the initial inoculations. The first vaccine, referred to as a DNA vaccine, essentially influences powerful immune responses through the use of genetic snippets from a Zika virus strain recently acquired from Brazil. The project to synthesise the vaccine was led by Dr. Dan H. Barouch, M.D., Ph.D. of the Beth Israel Deaconess Medical Center (BIDMC) and Harvard Medical School and also was participated in by the Ragon Institute of MGH, MIT and Harvard. The second vaccine, referred to as an inactivated virus vaccine, was synthesised from a purified, inactivated Zika virus that was obtained from Puerto Rico and was intended to elicit a response similar to the DNA vaccine. Moreover, the vaccine was developed by Stephen J. Thomas et al., at the WRAIR in Maryland.  In regards to the procedure followed throughout the experiment, during the first set of trials with the mice, the BIDMC investigators were able to confirm that Zika virus-specific antibodies were induced by the DNA vaccine. Subsequently, a second trial comprised injecting either of the two vaccines into different groups of mice, and then waiting 4 weeks before exposing both groups of mice to the Brazilian strain of Zika virus that had been known to cause congenital defects. Following the exposure, neither of the vaccinated groups of mice displayed any signs of virus replication. A similar procedure was conducted with both groups after 8 weeks, and the same result was yielded for both vaccinations. Moreover, the Zika-specific antibody levels of both groups of mice seemingly corresponded with infection protection. The profound results of these projects, coupled with the fact that multiple DNA and inactivated virus vaccinations have already been synthesised for the West Nile virus, dengue virus and tick-borne encephalitis virus, suggest that in the near future it may be quite possible for a similar Zika virus vaccine to be developed for human usage. 
Another major immunotherapeutic organisation that has made valuable progress in regards to developing a Zika vaccine is Inovio Pharmaceuticals, Inc., one of the foremost corporations in the field of biotechnology throughout the United States. Using the previous vaccinations, they had designed for related flaviviruses such as the dengue and West Nile virus as a baseline, the research teams employed by the organisation are well equipped in regards to attacking Zika virus from an immunotherapeutic standpoint. In a preclinical study conducted with mice, Inovio's SynCon vaccine technology was utilised to synthetically generate DNA vaccine constructs targeting multiple Zika virus antigens. After the initial administration of the vaccination, a process known as seroconversion, or the development of specific Zika antibodies in the blood, was observed in a multitude of the specimen. Furthermore, researchers claimed that the vaccination helped trigger powerful and broad T-cell responses, emphasising the key role played by T cells in regards to counteracting the Zika infection by means of eliminating the cells that harbour the virus itself. The initial success experienced by the research teams prompted Dr. J. Joseph Kim, Inovio's President and CEO, to release a statement claiming that 'With robust antibody and killer T cell responses generated by our vaccine in mice, we will next test the vaccine in non-human primates and initiate clinical product manufacturing. We plan to initiate phase I human testing of our Zika vaccine before the end of 2016'.  In addition, the fact that the SynCon vaccine technology utilised by Inovio is synthesised to be able to have the same therapeutic effects for multiple strains of Zika virus further bolsters its potential to be a truly groundbreaking counteractive measure in the fight against the ZVI. 
With respect to vector control in the EMR, A. aegypti and A. Albopictus, the primarily suspected vector species of Zika virus in regards to human transmission, have been located in a number of countries within or in the vicinity of EMR including Djibouti, Egypt, Lebanon, Oman, Pakistan, Kingdom of Saudi Arabia (KSA), Somalia, Sudan and Yemen. Moreover, sporadic cases of dengue fever, either locally transmitted or imported, have been reported from Djibouti, Egypt and Oman, indicating the very real possibility of future Zika virus outbreaks in the same regions. The previously mentioned virus outbreaks have largely been caused by the high density of Aedes mosquitoes throughout those specific regions, with infection usually peaking during the warm, humid summer months. It has also been documented that temperature plays a key role in adult vector survival, viral replication and infective period.  Therefore, the climatic conditions of the EMR will heavily favour the geographic expansion of the Aedes vector distribution and the risk of spread of Zika virus and other arboviral infections such as dengue, chikungunya and YF in the endemic belt. Thus, a comprehensive entomological surveillance system is imperative to obtain data regarding the distribution of vector species, the extent and types of breeding habitats, and the intensity and seasonal fluctuations of the breeding of vector species. Furthermore, the entomological sampling methods successfully utilised by various Southeast Asian countries to assess Aedes population density and evaluate control interventions must be adapted and optimised in the aforementioned countries through appropriate standardised protocols. The acceleration of this process is especially necessary in countries such as KSA, which receives millions of foreign visitors each year including a significant portion from areas known to harbour Zika virus [[Figure 3] shows details in tourists for different countries in GCC region]. If the vector species responsible for spreading Zika virus are not monitored closely, then it is quite likely that we may see Zika virus outbreaks in countries such as KSA. 
|Figure 3: Number of yearly tourist arrivals in the GCC in year 2014. Source: World Bank|
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| Prospective areas for further research|| |
Although the world is diligently working towards containing the transmission of Zika virus by calling for awareness of the flavivirus's possibly detrimental effects, the alarming ability of the virus to spread across territories and nations throughout the Americas, Oceania, the Pacific Islands and Africa indicate that there is still much to be accomplished in the fight against this pandemic. 
One key area for Zika virus research is clarifying the risk factors in regards to sexual transmission of the virus, as researchers have yet to ascertain how long the virus remains in semen and vaginal fluids. The acquisition of such knowledge could definitely aid in determining how long couples may decide to postpone unprotected sex to prevent ZVI during pregnancy.
Another possible research gap exists in regards to whether or not acquiring Zika virus from sexual intercourse has any different impact on congenital defects in the foetuses of pregnant women than obtaining the virus from a mosquito vector.
In addition, another possible avenue for Zika virus research includes the reported association of Zika virus with potential neuropathophysiologic mechanisms. Therefore, researching any possible neurological repercussions of acquiring Zika virus is crucial to address the rare incidences of neuropathological disorders including GBS.  Moreover, another crucial area for research comprises discovering more cost-effective means of screening blood donors for Zika virus to avert any possible transfusion transmissions of Zika virus. Although donor screening by nucleic acid testing has been seriously considered, exorbitant costs and regulatory considerations render this option inefficacious for the time being.  Synthesising the necessary products to counteract these inefficiencies may take significant periods of time, and yet the need for such products grows everyday.
| Conclusion|| |
Thus, as the ZVI continues to manifest itself across the world, we as a human collective must not lose sight of our seemingly distant goals, but rather channel our ambitions to conquering the next obstacle, one step at a time. The creation of several viable vaccine development programmes as well as the determination of what specific factors contribute to the virulence of Zika virus has allowed the human race to make tremendous progress in regards to controlling the spread of the virus, and we sincerely hope that our recent advancements serve as indications of what is to come in the fight against Zika virus.
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Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3]