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Causes and Features of the Zika Virus (ZV)

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The Zika Virus (ZV) is a mosquito-borne flavivirus that is transmitted by Aedes species, specifically A. aegypti, africanus, and the albopictus mosquitoes.1,2,3 ZV has recently gained global concern as recent outbreaks have occurred in the Americas. However, the virus was first isolated in 1947 from a macaque monkey in the Zika forest located in Uganda. The virus migrated to the Southeast Asian countries in 1945; the first human case was reported in Nigeria in 1952.

Multiple epidemics have been reported since its first reported case in 1952. The first large scale outbreak occurred on Yap Island, Micronesia in 2007. Between April and July 2007, there were 49 confirmed and 59 probable cases of the ZV infection.4 During this time, no deaths were reported. Of the 6,982 Yap Island residents that were at least three years of age, 5,005 (roughly 73%) were estimated to be infected with ZV during this outbreak.4

The second major outbreak occurred in the French Polynesia between October 2013 and February 2014. As of February 14, 2014, 8,510 suspected cases were reported.5 The largest and current outbreak in the Americas began in Brazil. Brazil's first reported locally transmitted case in Brazil occurred May 2015. The ZV entry into Brazil is not clear; however, it is proposed that travelers from ZV-infected areas of Chile, Asia, and Africa brought it during 2014 sporting events. This outbreak brought ZV back into the news as many athletes became weary of contracting ZV while participating in the 2016 Rio de Janeiro Olympic Games. Based on rates of asymptomatic infection, an estimated 500,000 to 1.5 million people in Brazil were affected with ZV.6

As of January 18, 2017, there are 738,783 confirmed cases, with the highest number of cases reported in Brazil, Columbia, and Venezuela.6 Mexico, Central America, the United States, and the Caribbean including the U.S. Virgin Islands and Puerto Rico reported confirmed cases of the virus. Regions outside of the Americas, specifically Singapore, Thailand, and Cape Verde reported confirmed cases of ZV.

In January 2016, a traveler returning from Latin America to Texas reported the first U.S. case of ZV infection. As of March 22, 2017, more than 5,100 cases of ZV were reported.7 Of those reported, 4,861 cases were travel-related, 1,617 cases occurred in pregnant women, and 45 cases were sexually transmitted.8,9,10 The first case of transmission within the U.S. was in Florida. Those who were traveling to the U.S. from other affected areas reported many of the subsequent ZV cases. Every state has reported laboratory-confirmed symptomatic ZV disease. Only Florida and Texas have reported local-transmission of ZV.9

ZV is a member of the virus family Flaviviridae. The Flaviviruses include arboviruses that are transmitted through mosquitoes to humans. Ranging from 40-50 nm in diameter, the Flaviviruses are positive-sense and single-stranded RNA. The ZV is an icosahedral capsid enveloped virus. Several small proteins surround the RNA genome; the capsid proteins cover the core, creating its icosahedral shape. The lipid bilayer envelope membrane contains both the membrane and the envelope proteins, which are glycosylated in many flaviviruses.11

Vectors, generally mosquitoes, are infected when they feed on viremic hosts. Humans are generally the accidental hosts. The mosquitoes will take a blood meal from an infected host and transmit it to another individual. In the U.S., these mosquito vectors are isolated to the southeastern states. Aerosols or contaminated food products can also transmit Flaviviruses; however, this only occurs under certain circumstances. Other diseases associated with Flaviviruses include Japanese encephalitis, yellow fever, dengue fever, chikungunya fever, and hemorrhagic fever.

ZV is an arthropod-borne virus (arbovirus) that infects their vectors after ingestion of a blood meal from aviremic non-human vertebrate. Some arthropods can be infected by saliva-infected transmission. The arthropod vectors develop chronic systemic infections as the virus will penetrate the gut and spread to the salivary glands. This dissemination to the salivary glands is known as extrinsic incubation, which lasts about 1-3 weeks in mosquitoes.12 The mosquito is not harmed by the infection.

The ZV pathogen has two lineages that are based on phylogenetic analysis of viral envelope proteins:13 the African and Asian lineages. The African lineage is primarily restricted to the African countries of Central African Republic, Kenya, Nigeria, Senegal, and Uganda. The Asian lineage seems to be the strand that has been seen in recent outbreaks. This lineage has been circulating in the Southeast Asian countries since the 1950s, in French Polynesia in 2013, and the Americas in 2015.

ZV is primarily transmitted by a bite of an infected Aedes mosquito. Humans are the likely main reservoirs; however, during outbreaks, human-to-vector-to-human transmission is common. Other modes of transmission of ZV are sexual transmission and maternal-fetal transmission during pregnancy. The estimated reproduction number of ZV infection during the Columbia epidemic in 2015-2016 ranged 2.2-14.8.14 During the Yap Island and French Polynesia epidemics, the estimated reproduction number ranged 4.3-5.815, that is comparable to dengue and chikungunya fevers, which are from the same family as ZV.

Various sexual transmission has been reported: multiple cases of male to female transmission in the U.S. between January-April 201615, one case of male-to-male anal intercourse17, one case of female-to-male transmission18, and an asymptomatic case of male-to- female transmission.19 The duration of ZV RNA persistence in semen has been monitored to determine the degree of ZV infectivity. Detection of the viral RNA in semen was found up to 188 days after symptom onset in an Italian man who contracted ZV infection while traveling in Haiti.20 Additionally, it was found that ZV was found in semen up to 92 days after the illness onset.21

Various reports regarding vaginal secretions and bodily fluids have been monitored for ZV infectivity as well. Viral RNA in vaginal secretions were found up to 14 days after symptom onset.22 Viral RNA has been detected in urine and saliva in 54 days and serum up to 67 days.23 These findings were monitored in an infant whose mother displayed ZV infection symptoms during week 26 of her pregnancy and tested positive for ZV after birth. No reports of ZV in other bodily fluids of the reproductive tracts, specifically the follicular fluid, have been identified.

There are potential modes of transmission that have been explored and discussed. Blood transfusion or blood products and breast-feeding have been linked to possible transmission.2 Viral RNA has been detected in the breast milk of those women who have been infected. There was a detection of ZV and viral RNA in breast milk collected 4 days postpartum from a woman who developed ZV symptoms during prenatal period.24 Breast-feeding is not a confirmed route of transmission, as it has not yet been thoroughly evaluated. Kissing is not a confirmed route of transmission. However, one case of transmission was reported from an elderly patient with a high viral load to a family member who reported kissing and hugging an infected patient, but had no known direct contact with infected bodily fluids.25 Saliva, urine, and conjunctival fluid have been detected sources, but transmission has not been confirmed.

The incubation period of the ZV is usually 3-12 days. About 75-80% of ZV infections are asymptomatic.1 If ZV becomes symptomatic, disease is generally mild. Common symptoms include rash, fever, joint pain (known as arthralgia), and conjunctivitis. Symptoms generally resolve within a week.

Pathogenesis of the ZV is not well studied; early data indicates that ZV will infect and replicate in dermal fibroblasts, epidermal keratinocytes, and immature dendritic cells.26 Infected epidermal keratinocytes will undergo apoptotic cell death. The viral replication prompts an innate immune response. As a result, type I interferons in infected cells are produced.

The risk factors that put an individual at a greater risk for contracting ZV are those who live or travel to endemic or epidemic areas, mosquito exposure, and unprotected sexual contact with someone who has recently traveled to areas with active transmission. To determine if an individual is at risk, asking patients about travel history to ZV-infected areas, noting specific dates and location of travel, and discussing risk factors for transmission are important.

The Centers for Disease Control and Prevention (CDC) concluded that ZV is a cause of microcephaly and other severe fatal neural defects, such as Guillain-Barré Syndrome. This is a complication associated with pregnancy. The CDC has determined this based on epidemiologic evidence showing an increase number of infants born with microcephaly during the French Polynesian and Brazilian outbreaks.3 Through cohort and case series studies, the CDC has found a cause and effect between the ZV and various brain defects, such as microcephaly, "cerebral malformation, intracranial calcifications, neurologic dysfunction, and ophthalmologic abnormalities."3 Various studies have detected ZV in brain tissue of affected fetuses. Brain tissue was collected from infants with microcephaly who later died and in the placenta of mothers who suffered a miscarriage. As of result of these findings, the CDC has established two surveillance systems to monitor pregnancies and congenital outcomes in women with ZV infection: The U.S. Zika Pregnancy Registry and Zika Active Pregnancy Surveillance System (ZAPSS) for women in Puerto Rico. Due to the CDC findings regarding malformations of embryos, ZV is considered teratogenic.

Microcephaly is a common defect of infants that have contracted ZV from their mothers. Microcephaly is a condition where a baby is born with a smaller than normal head or the head stops growing after birth.27 Because there is a delay in the growth of a head, there are neural developmental abnormalities. Babies born with microcephaly typically have physical and learning disabilities as they continue to grow and age.

During ZV outbreaks, there was an increased incidence of microcephaly reported. During the 2013 French Polynesia outbreak, 8,750 suspected ZV cases were reported.28 Estimated risk of microcephaly reported 95 cases per 10,000 women who contracted ZV in the first trimester, while the baseline microcephaly prevalence for that area was two per 10,000 neonates.28 In 2015, an annual rate of microcephaly in Brazil "increased from 5.7 cases per 100,000 live birth in 2014 to 99.7 cases per 100,000 in 2015."29

For diagnosing ZV, polymerase chain reaction, specifically quantitative or qualitative real-time reverse transcription polymerase chain reaction (RT-PCR) is considered the gold standard. RT-PCR distinguishes ZV from other flaviviruses such as dengue and chikungunya fevers. This test can be performed on serum, urine, or blood; however, serum and urine are commonly used.

Sensitivity of RT-PCR can vary within 14 days of symptom onset. If symptoms are less than 14 days from onset, it is recommended that RT-PCR of urine or serum samples be performed. Cohort studies have found that RT-PCR of plasma samples appear more sensitive than RT-PCR of urine samples within the first 5 days of symptomatic ZV infection.30

In addition to performing RT-PCR, a physical examination must be done to diagnosis ZV. During physical examination, a clinician should examine a patient for fever, maculopapular rash, arthralgia, and conjunctivitis. Most symptomatic patients will present with rash and conjunctivitis.1,2 Clinicians should access the patient's risk of exposure, such as travel history to an area of active transmission and unprotected sexual contact with someone who recently traveled to an affected area.

Bloodwork should be completed. Generally bloodwork results are normal, but mild leukopenia (low white blood cell count), thrombocytopenia (low platelet count) and hepatic transaminitis (elevated liver enzymes) have been reported with ZV infection.31 Patients with suspected ZV should be evaluated for dengue and chikungunya virus infections as they all cause symptoms that overlap. The same mosquito vector transmits ZV, dengue fever, and chikungunya fever. Other illnesses to differentiate are malaria, influenza, infectious mononucleosis, and acute HIV infection.

Other ZV testing options include serum virus-specific immunoglobulin M (IgM) and culture. IgM testing has a greater sensitivity at the end of the first week of illness. IgM has the potential to cross-react with other flaviviruses.2 The FDA approved the CDC IgM Antibody Capture Enzyme-Linked Immunosorbent Assay (Zika MAC-ELISA) as the first antibody test for emergency evaluation in selected laboratories.32 In addition to the Zika MAC-ELISA, Trioplex Real-Time RT-PCR assay can be used for ZV diagnosis. Culture is generally not used as a tool, but rather an aid to determine if any additional infections are present. If a patient is symptomatic or thought to have contracted the infection due to recent ZV exposure, these diagnostic tools are used to diagnose ZV.

Coinfection with other viral illnesses transmitted by the same infected Aedes mosquito can occur. Dengue and chikungunya fever are the common illnesses that are associated with ZV. These coinfections were found in Nicaragua. Between September 2015 and April 2016, 356 patients in Nicaragua with suspected arboviral illnesses provided serum samples for ZV, dengue, and chikungunya fevers.33 A real-time RT-PCR confirmed the presence of a virus. Of those that provided serum samples, 263 had at least one of these viruses, 71 of these cases had a coinfection with 2-3 viruses.

Suspected cases should be reported to local health departments in the U.S. for coordination of testing, care, and spread prevention. The CDC and selected state health departments perform more testing to confirm the diagnosis of ZV. The CDC provides instruction for sending ZV samples for testing.

There are specific considerations for pregnant women. In 2016, the CDC provided guidelines for evaluation and management for pregnant women and infants with suspected ZV infections (Appendices 1 and 2). Possible Zika virus exposure should be discussed with all pregnant women during each prenatal visit. Testing symptomatic pregnant women should be based on the time of potential exposure. Additional testing is needed to rule out other illnesses, such as dengue, chikungunya, and yellow fever. Other illnesses to consider include malaria, rubella, measles, parvovirus B19 infection, influenza, rickettsial illnesses, enterovirus illnesses, acute HIV infection, and group A streptococcal infection.34 If asymptomatic pregnant women have an ongoing risk for exposure, routine ZV IgM testing should be performed at visits during the first and second trimesters.

Offering RT-PCR testing for asymptomatic women with possible infection is recommended for those who have had exposure within the past two weeks of their prenatal visits. Positive results from RT-PCR testing confirm infection. However, a negative result does not exclude infection; IgM testing should be performed for further analysis.

In addition to testing, if ZV is suspected or confirmed, serial ultrasounds are necessary every 3-4 weeks to monitor fetal growth and anatomy. Decisions on amniocentesis should be discussed as it is considered a high-risk procedure. Amniocentesis is a medical procedure where a small sample from the amniotic sac surrounding a fetus is sampled and examined for genetic abnormalities. The optimal time to perform this procedure to accurately diagnose ZV is unknown. Amniocentesis is generally performed after 15 weeks of gestation. Because of the uncertainty surrounding the accuracy of this test, amniocentesis should be discussed on an individualized basis.

Currently there is no specific antiviral treatment available for ZV. The recommended treatment is supportive with a focus primarily on rest, hydration, and fever and pain control. Acetaminophen is preferred to address fever and pain. Until dengue fever can be excluded, aspirin and other nonsteroidal anti-inflammatory (NSAIDS), such ibuprofen and naproxen, should be avoided to reduce the risk of hemorrhage.

Most infected individuals recover within a week. Hospitalization or severe disease is not common. Those individuals infected with ZV are encouraged to avoid mosquito exposure during the first week of symptom onset to reduce the risk of continued transmission.2,3 While infected, individuals should isolate themselves, refrain from sexual contact, and avoid mosquito exposure.

Mosquito avoidance is the main option for prevention and further spread of ZV. This is the key to preventing illness while traveling to endemic or epidemic affected regions. Eliminating mosquito habitat is also recommended. Mosquitoes can breed in small amounts of water. Individuals traveling in affected locations should wear light-colored clothing that completely cover the body, use mosquito repellents with DEET, and utilize mosquito nets.

There are additional precautions for pregnant women and women trying to become pregnant. Women should avoid traveling to areas of active transmission. Consulting healthcare providers before traveling is recommended. The CDC instructs pregnant women to avoid traveling to elevations less than <2,000 meters in regions of active transmission.35 Because of evidence of sexual transmission of ZV, men who live in areas of active transmission should abstain from sexual activity or effectively use condoms during all sexual contact, especially with pregnant partners.

No vaccine or preventive medications are available; however, research efforts are currently being done to develop a ZV vaccine. In order to develop antiviral treatments to combat ZV, more research needs to be done to learn about ZV and its effects. Being one of the prominent organizations to explore infectious diseases, The National Institute of Allergy and Infectious Diseases (NIAID) has committed to provide funding to research ZV. Through their efforts and research, NIAID hopes to expand current diagnostic testing, further understand the pathogenesis of ZV, and develop and utilize vaccines to prevent future infections and transmission.

Many studies currently being conducted focus on gathering more information about Zika and its effects. Collaborating with National Institute of Health (NIH) and various investigators globally, NIAID began its Zika in Infants and Pregnancy (ZIP) trial, enrolling as many 10,000 pregnant women in Brazil, Colombia, Guatemala, Nicaragua, and Puerto Rico.36 This study will enroll women in their first trimester of pregnancy and will follow them until at least one year after birth. Researchers will observe any effects, if any, in the event that a woman contracts ZV while enrolled in this trial. Primary outcomes include incidence of congenital malformation, adverse fetal outcomes of ZV symptomatic and infected patients. Researchers will also collect maternal samples of urine, blood, genital secretions, saliva, breast milk and amniotic fluid and tissue (if available).36 Researchers will only collect urine, blood, and saliva from infants.

Understanding the effects of ZV on infants is critical. Collaboration among the University of North Carolina at Chapel Hill, Michigan State University, and Universidad Industrial de Santander in Columbia has created a prospective cohort study exploring the fetal effects of ZV, specifically examining the neurodevelopment effects. Beginning May 2016, researchers aimed to enroll 440 pregnant women suspected of having ZV. Researchers will confirm the exposure of ZV by maternal symptoms, blood and urine RT-PCR, and serologic testing specific to ZV.37 Neurodevelopment outcomes and fetal CNS impairment will be monitored throughout the two-year study. There is a similar study being conducted in France where researchers are monitoring the ZV effects of over 2,000 infants and toddlers up to the age of two that are affected by the infection.38

Because blood transfusions have been linked to possible ZV transmission, research concerning blood donors and transfusions are being conducted. The NIH Clinical Center is currently studying the risk of viruses from the Flaviviridae family on the U.S. blood supply. The viruses being evaluated are ZV, dengue virus, and chikungunya virus. Because donated blood generally is not tested for these viruses, researchers want to study how these viruses infect people with time. Individuals who deferred donating blood because of potential sexual or travel exposure to ZV are eligible for this study. An anticipated 200 subjects will be asked about travel in more detail and tested for any virus.39 If virus results test positive, researchers will closely follow subjects for 6 months with weekly visits where physical exams will be conducted in addition to collection of blood and urine samples. Optional semen samples from men will be collected. Weekly clinic visits will become monthly visits once test results return negative for two weeks straight.

Late 2016, Cereus Corporation and the Biomedical Advanced Research and Development Authority (BARDA) announced it received additional funding to further its research in a program designed to reduce the risk of virus-transmission via blood transfusions. Cereus and BARDA developed a Phase III clinical trial, known as "RedeS," to evaluate the efficacy and safety of INTERCEPT RBCs compared to the standard RBCs in areas greatly impacted by the ZV, including Puerto Rico and Florida.40 The INTERCEPT Blood System is a technology designed to reduce the transfusion-transmitted infections. This technology becomes effective by inactivating various pathogens, such as viruses, bacteria, parasites, and leukocytes that may been in donated blood. Cereus and BARDA hope the INTERCEPT blood system will be utilized during blood borne pathogen endemics and epidemics. Clinicians can continue routine care with the use of the INTERCEPT.

Many researchers have conducted research to gather more information about ZV. This knowledge has led the way to develop potential vaccines. NIAID has done vast research regarding ZV vaccines. NIAID's VRC developed a DNA-based vaccine that will create an immune response to ZV. The idea for developing this vaccine is similar to VRC's investigational vaccine for the West Nile virus, which was found to be safe in a Phase I clinical trial. The investigational vaccine for ZV completed recruitment and follow-up is ongoing.41 NIAID plans to continue research with this vaccine by conducting a Phase II clinical trial aiming to enroll over 5,000 participants. The objective of this trial will be to evaluate the effectiveness of the vaccine to prevent ZV.

Developed by the Walker Reed Army Institute of Research (WRAIR), the Zika Purified Inactivated Virus (ZPIV) was created using a similar model the WRAIR used to develop vaccines for Japanese encephalitis and dengue virus. The ZPIV vaccine has ZV particles that cannot replicate and cause disease in humans. The protein shell of the inactivated virus remains intact so that the immune system can recognize it and cause an immune response.Sponsored by the NIAID, there are five planned Phase I clinical trials using ZPIV vaccine.

The first trial to use ZPIV vaccine is enrolling about 75 individuals with no previous Flavivirus infection in Silver Spring, Maryland. Subjects will be randomly allocated into three groups: the first group will receive two intramuscular (IM) injections of the ZPIV vaccine or a placebo 28 days apart. The other two groups will either receive a two-dose regimen of Japanese encephalitis vaccine or one dose of the yellow fever before starting the two-dose ZPIV vaccine regimen.42 Researchers designed the study in this fashion because those tasked to assist with the ZV outbreak are often vaccinated before arriving to outbreak area. This study plans to complete by fall 2018.

The second trial will be evaluating the safety of the ZPIV vaccine in Flavivirus-naïve healthy males and non-pregnant female adult subjects at the Saint Louis University School of Medicine. Beginning in October 2016, NIAID began to enroll 90 subjects in one of three groups, either receiving a low, moderate, or high dose of the experimental or placebo vaccine.43 Subjects would receive their vaccine on Day 1 and 29. During the 14-month duration of the study, researchers will examine the safety and immune response of ZPIV vaccine. Currently there are no results of this study, as it is still in the data collection phase of research.

In Puerto Rico, the third trial will evaluate ZPIV vaccine's safety and immunogenicity of those who have previously been exposed to dengue virus. With a planned February 2017 start, 90 healthy males and non-pregnant women will randomly be assigned to receive either a high dose, moderate dose, or a placebo.44 Each dose will be 28 days apart. Follow-up for subjects will be 40 months.

The fourth clinical trial to use ZPIV vaccine will explore the vaccine as a boost vaccination to the DNA Zika vaccine. Beginning July 2016, the NIH Clinical Center, the Center for Vaccine Development at the University of Maryland School of Medicine's Institute for Global Health, and Emory University recruited 120 subjects.45 Half of the subjects will receive the NIAID ZV DNA vaccine followed by a ZPIV boost four or twelve weeks later. The subjects will only receive two doses of ZPIV vaccine either four or twelve weeks apart. In Boston, the fifth trial is enrolling 48 adults to compare different dosing regimens of ZPIV vaccine.46 Beginning October 2016, subjects were randomly assigned to either receive a single dose of ZPIV vaccine or two doses of ZPIV vaccine and placed into one of 4 experimental dosing intervals.

Collaborating with the NIH and the VRC, NIAID developed a ZV DNA investigational vaccine called, VRC-ZKADNA090-00-VP. These institutions are currently conducting a Phase I randomized trial evaluating the safety and immunogenicity of a 3-dose vaccination regimen using this investigational product (IP). Forty-five subjects will be randomized into one of three experimental groups. Subject will either receive a full dose in one injection of IP IM injection using needle and syringe, a split dose via IM using needle and syringe, or an intramuscular injection with needle-free injection device, PharmaJet.47 Researchers hypothesized that the IP will be safely tolerated at three different time points during the two-year study. Researchers also want to examine the immunogenicity of the vaccine and the vaccine regimens.

Research regarding ZV vaccination is extremely important for reducing risk of transmission. Perceptions about the potential vaccination are just as imperative. The University of Colorado at Denver conducted an online questionnaire distributed to mothers to gain information regarding their knowledge of Colorado vaccination legislation, their opinions on childhood vaccination, and their views on a potential Zika vaccine.48 This study was completed November 2016. Unfortunately, results have not been published for public view.

Currently there are only 20 open research studies regarding ZV. With the exception of the research being conducted by NIAID, all research being done is to gain more knowledge about the different associations between ZV and various risk factors. In late 2016, the World Health Organization declared that ZV is no longer a global threat. However, it is important to continue exploring potential risk factors and mode of transmission. From gaining valuable knowledge, a vaccine is being developed for global use. Due to developing research, a safe and effective ZV vaccine will not be available for several years. Ongoing surveillance and awareness of ZV are needed to prevent future outbreaks.


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