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group_3_presentation_1_-_zika_virus [2018/02/02 11:46] duruf [Brain and Nervous System] |
group_3_presentation_1_-_zika_virus [2018/02/02 14:55] (current) duruf [Microcephaly] |
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| Zika flew under the radar after the confirmed cases in Java in 1977/8. Essentially from then on there were no publications on ZIKA until the Yap Island outbreak of 2007. The Yap outbreak of 2007 also marked the first time Zika was detected in Oceania. With a population of 10,000 people it was thought that 1 in every 5 people had manifested symptoms of Zika virus, however there were no reported fatality related to Zika (Paixao et al, 2016). Following the Yap Island outbreak of 2007, there were only 4 studies published on Zika from 2008 to 2013 and in that time frame there were only 4 cases of Zika infection. Two of those cases were reported in Cambodia and the other two were reported in Colorado, when two scientist acquired Zika from Senegal and returned home to Colorado with one of the scientist transferring it to his wife via semen. No further outbreaks were reported until the outbreak of French Polynesia (Paixao et al, 2016). During this outbreak there was an increase in the number of reported neurological and autoimmune complications such as 42 cases of Guillain Barre Syndrome (GBS). On May 7th 2015 the Pan American Health Organisation (PAHO) confirmed the first case of ZIKV infection and with the Zika outbreak of 2015 came a rise in the reported cases of microcephaly (CDC, 2018). This warranted a retrospective study on the French Polynesia outbreak, which resulted in the identification of 17 cases of malformations in the foetuses and newborns of women who were pregnant during the Zika outbreak on the Island. This discovery changed the perception of Zika as a harmless old disease. According to estimates from the Brazillian Ministry of Health, there were approximately 1.3million cases of Zika in early 2015. Unlike previous outbreaks, there were 46 confirmed deaths in Brazil linked to Zika virus (Paixao et al, 2016). | Zika flew under the radar after the confirmed cases in Java in 1977/8. Essentially from then on there were no publications on ZIKA until the Yap Island outbreak of 2007. The Yap outbreak of 2007 also marked the first time Zika was detected in Oceania. With a population of 10,000 people it was thought that 1 in every 5 people had manifested symptoms of Zika virus, however there were no reported fatality related to Zika (Paixao et al, 2016). Following the Yap Island outbreak of 2007, there were only 4 studies published on Zika from 2008 to 2013 and in that time frame there were only 4 cases of Zika infection. Two of those cases were reported in Cambodia and the other two were reported in Colorado, when two scientist acquired Zika from Senegal and returned home to Colorado with one of the scientist transferring it to his wife via semen. No further outbreaks were reported until the outbreak of French Polynesia (Paixao et al, 2016). During this outbreak there was an increase in the number of reported neurological and autoimmune complications such as 42 cases of Guillain Barre Syndrome (GBS). On May 7th 2015 the Pan American Health Organisation (PAHO) confirmed the first case of ZIKV infection and with the Zika outbreak of 2015 came a rise in the reported cases of microcephaly (CDC, 2018). This warranted a retrospective study on the French Polynesia outbreak, which resulted in the identification of 17 cases of malformations in the foetuses and newborns of women who were pregnant during the Zika outbreak on the Island. This discovery changed the perception of Zika as a harmless old disease. According to estimates from the Brazillian Ministry of Health, there were approximately 1.3million cases of Zika in early 2015. Unlike previous outbreaks, there were 46 confirmed deaths in Brazil linked to Zika virus (Paixao et al, 2016). | ||
| - | As of 2016, 27 countries in the Americas have reported Zika infections, which includes Colombia, Guatemala, Mexico, Panama, Paraguay, Venezuela, El Salvador, Honduras and Martinique, Bolivia, Guyana, Ecuador, Guadeloupe, Puerto Rico, Saint Martin and Haiti. Molecular studies later showed that the ZIKV from French Polynesia and Brazil were the same strain and clearly from the Asian lineage. It is believed that a traveller from French Polynesia was the source of the ZIKV outbreak in Brazil (Paixao et al, 2016). | + | As of 2016, 27 countries in the Americas as seen in Figure 1 have reported Zika infections, which includes Colombia, Guatemala, Mexico, Panama, Paraguay, Venezuela, El Salvador, Honduras and Martinique, Bolivia, Guyana, Ecuador, Guadeloupe, Puerto Rico, Saint Martin and Haiti. Molecular studies later showed that the ZIKV from French Polynesia and Brazil were the same strain and clearly from the Asian lineage. It is believed that a traveller from French Polynesia was the source of the ZIKV outbreak in Brazil (Paixao et al, 2016). |
| - | <box 72% round | >{{ :risk_areas_.png?650 |}}</box|> | + | <box 72% round | >{{ :risk_areas_.png?650 |}}</box|Figure 1 : A geographical representation of risk areas associated with the spread of Zika Virus. From this map we can see Zika is restricted to mostly countries/areas with a tropical climate (CDC, 2018)> |
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| ====== Transmission ====== | ====== Transmission ====== | ||
| - | The natural vertebrate host of Zika virus in vertebrates were primarily monkeys. The infection normally spreads in a mosquito-monkey-mosquito cycle with the occasional infection of humans. Prior to the current pandemic that began in 2007, Zika spill over to humans rarely occurred. The primary mode of ZIKV transmission in humans is through the bite of an infected Aedes aegypti mosquito, other modes of transmission includes transmission through sexual contact, blood transfusions, laboratory exposures and maternal to fetal transmission through pregnancy. The transmission of ZIKV infection is so effective that by the end of 2016 more than 50 countries have reported cases of active cases of transmission though one or more means (CDC, 2018). | + | The natural vertebrate host of Zika virus in vertebrates were primarily monkeys. The infection normally spreads in a mosquito-monkey-mosquito cycle with the occasional infection of humans. Prior to the current pandemic that began in 2007, Zika spill over to humans rarely occurred. The primary mode of ZIKV transmission in humans is through the bite of an infected Aedes aegypti mosquito as summarised in Figure 2, other modes of transmission includes transmission through sexual contact, blood transfusions, laboratory exposures and maternal to fetal transmission through pregnancy. The transmission of ZIKV infection is so effective that by the end of 2016 more than 50 countries have reported cases of active cases of transmission though one or more means (CDC, 2018). |
| - | <box 72% round | >{{ :zika-transmission.png?650 |}}</box|> | + | <box 72% round | >{{ :zika-transmission.png?650 |}}</box| Figure 2: A summary of the most reported forms of Zika Virus transmission (CDC, 2018) > |
| Although the primary mode of transmission is thought to be through the bite of the female Aedes aegypti mosquito, ZIKV has been isolated in about 6 other mosquitoes in the Aedes genus and 5 other species of mosquitoes. The truth is that the true extent of Zika vectors remains unknown (Ayres 2016)(Hayes, 2009). These posses a significant problem as one of the species of mosquitoes capable of carrying ZIKV has rapidly expanded across all continents. There have been confirmed cases of sexual transmission by both males and females in 6 countries including the USA, but there have been no confirmed cases of transmission through blood transfusions in USA although there are suspected cases in Brazil. ZIKV can also be transmitted through laboratory exposure and through mother to child during all stages of pregnancy. To date there have been only three reported case of ZIKV transmission through laboratory exposure, one in the USA and two in Italy. The recent discovery of ZIKV RNA in most bodily fluids suggest the presence of other modes of transmission (CDC 2018). | Although the primary mode of transmission is thought to be through the bite of the female Aedes aegypti mosquito, ZIKV has been isolated in about 6 other mosquitoes in the Aedes genus and 5 other species of mosquitoes. The truth is that the true extent of Zika vectors remains unknown (Ayres 2016)(Hayes, 2009). These posses a significant problem as one of the species of mosquitoes capable of carrying ZIKV has rapidly expanded across all continents. There have been confirmed cases of sexual transmission by both males and females in 6 countries including the USA, but there have been no confirmed cases of transmission through blood transfusions in USA although there are suspected cases in Brazil. ZIKV can also be transmitted through laboratory exposure and through mother to child during all stages of pregnancy. To date there have been only three reported case of ZIKV transmission through laboratory exposure, one in the USA and two in Italy. The recent discovery of ZIKV RNA in most bodily fluids suggest the presence of other modes of transmission (CDC 2018). | ||
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| Those infected with Zika Virus may not experience symptoms or might have mild symptoms associated with the infection. The typical symptoms include a fever, rash (flat and red covered by small bumps), headaches, joint pain, conjunctivitis, muscle pain, weakness and an overall lack of energy. The incubation period, from the time of exposure to the presentation of symptoms, is unclear but is usually around three to seven days. The symptoms are mild and can last from several days to a week. Individuals are not usually sick enough to go to the hospital and thus might not even realize they have been infected. Only one in four people are believed to develop symptoms and the symptoms are similar to other viruses spread by mosquitos such as Dengue and Chikungunya virus. | Those infected with Zika Virus may not experience symptoms or might have mild symptoms associated with the infection. The typical symptoms include a fever, rash (flat and red covered by small bumps), headaches, joint pain, conjunctivitis, muscle pain, weakness and an overall lack of energy. The incubation period, from the time of exposure to the presentation of symptoms, is unclear but is usually around three to seven days. The symptoms are mild and can last from several days to a week. Individuals are not usually sick enough to go to the hospital and thus might not even realize they have been infected. Only one in four people are believed to develop symptoms and the symptoms are similar to other viruses spread by mosquitos such as Dengue and Chikungunya virus. | ||
| - | <box 49% round| > {{ :zika-virus-symptoms.jpg?300 |}} </box| Figure 1 : Illustration of the primary symptoms of Zika Virus which includes a fever, headache, red eyes, skin rash, fatigue and muscle/joint pain (UWSWA, 2016)> | + | <box 49% round| > {{ :zika-virus-symptoms.jpg?300 |}} </box| Figure 3 : Illustration of the primary symptoms of Zika Virus which includes a fever, headache, red eyes, skin rash, fatigue and muscle/joint pain (UWSWA, 2016)> |
| ====== Testing ====== | ====== Testing ====== | ||
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| ==== Zika Virus Preclinical Studies ==== | ==== Zika Virus Preclinical Studies ==== | ||
| - | Several studies, such as a study conducted by Abbink et al. (2016), have shown promising results in the preclinical phase of vaccine development. Abbink et al. (2016) immunized eight rhesus monkeys with a Zika Purified Inactivated Virus (PIV) and eight with aluminum potassium sulfate as a control at both zero and four weeks. Upon analysis, it was determined that all eight Rhesus monkeys who received the Zika PIV developed Zika specific binding antibodies according to enzyme-linked immunosorbent assays and microneutralization assays (MN50) whereas the other eight Rhesus monkeys did not develop the antibodies. The researchers then infected both groups with viral particles of Zika-BR or Zika-PR with an n=4 per treatment. After measuring the viral load with RT-PCR, researchers determined that the control monkeys showed ZIKV-specific MN50 tigers increase after the Zika Virus challenge. Control monkeys also showed six to seven day viremia with peak loads on days three to five. The virus was detected in the urine, CSF as well as colorectal secretions as seen in Figure 2. In contrast, PIV vaccinated monkeys showed complete protection against ZIKV challenge as no virus was present in any of the detection methods. | + | Several studies, such as a study conducted by Abbink et al. (2016), have shown promising results in the preclinical phase of vaccine development. Abbink et al. (2016) immunized eight rhesus monkeys with a Zika Purified Inactivated Virus (PIV) and eight with aluminum potassium sulfate as a control at both zero and four weeks. Upon analysis, it was determined that all eight Rhesus monkeys who received the Zika PIV developed Zika specific binding antibodies according to enzyme-linked immunosorbent assays and microneutralization assays (MN50) whereas the other eight Rhesus monkeys did not develop the antibodies. The researchers then infected both groups with viral particles of Zika-BR or Zika-PR with an n=4 per treatment. After measuring the viral load with RT-PCR, researchers determined that the control monkeys showed ZIKV-specific MN50 tigers increase after the Zika Virus challenge. Control monkeys also showed six to seven day viremia with peak loads on days three to five. The virus was detected in the urine, CSF as well as colorectal secretions as seen in Figure 4. In contrast, PIV vaccinated monkeys showed complete protection against ZIKV challenge as no virus was present in any of the detection methods. |
| Researchers did other studies using adoptive transfer of vaccine elicited antibodies (IgG) and at high doses they protected from Zika virus. Researchers also tested DNA plasmid based vaccines on Rhesus monkeys which also showed protection against Zika Virus. They determined that there were no adverse side effects and that there were also similar results with the PIV vaccine seen in mice. The only side note the researchers mentioned was that studies needed to be performed to evaluate cross-reactivity with antibodies to dengue viruses and other similar viruses. | Researchers did other studies using adoptive transfer of vaccine elicited antibodies (IgG) and at high doses they protected from Zika virus. Researchers also tested DNA plasmid based vaccines on Rhesus monkeys which also showed protection against Zika Virus. They determined that there were no adverse side effects and that there were also similar results with the PIV vaccine seen in mice. The only side note the researchers mentioned was that studies needed to be performed to evaluate cross-reactivity with antibodies to dengue viruses and other similar viruses. | ||
| - | <box 44% round | > {{ {{ :f2.large.jpg?300 |}} |}} </box| Figure 2 : Observed levels of Zika Virus in Rhesus monkeys with and without the Purified Inactivated Virus (PIV), challenged with Zika-BR and Zika-PR. No difference was seen between the two strains of Zika Virus used to challenge the Rhesus monkeys (Abbink et al., 2016).> | + | <box 44% round | > {{ {{ :f2.large.jpg?300 |}} |}} </box| Figure 4 : Observed levels of Zika Virus in Rhesus monkeys with and without the Purified Inactivated Virus (PIV), challenged with Zika-BR and Zika-PR. No difference was seen between the two strains of Zika Virus used to challenge the Rhesus monkeys (Abbink et al., 2016).> |
| ==== Zika Virus Clinical Studies ==== | ==== Zika Virus Clinical Studies ==== | ||
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| Guillain-Barre Syndrome (GBS) is a rare autoimmune disease that affects neurons. Specifically, the myelin coating around axons is damaged and the conduction of signals between nerve cells is compromised. | Guillain-Barre Syndrome (GBS) is a rare autoimmune disease that affects neurons. Specifically, the myelin coating around axons is damaged and the conduction of signals between nerve cells is compromised. | ||
| - | A recent study by Cao-Lormeau et al. (2016) published in //The Lancet// presented considerable evidence linking GBS with previous Zika virus infection. The researchers presented a case study involving 42 individuals with confirmed GBS during a massive Zika virus outbreak in French Polynesia between 2013 and 2014. Blood samples were taken from patients with confirmed GBS (n=42) and patients without GBS (control; n=98). The researchers used various techniques to detect antibodies against Zika virus (IgM/IgG) in both groups of patients. Evidence of previous Zika virus infection, demonstrated by the presence of Zika antibodies, was shown for 41 (98%) patients in the GBS group compared to 35 (36%) of patients in the control group (Figure 3; p<0.0001). In addition, a neutralizing response against Zika virus was seen in 42 (100%) of the GBS patients and 54 (56%) of the control group patients (Figure 3; p<0.0001). This data presented by Cao-Lormeau et al. (2016) exhibits a significant association between previous Zika virus infection and GBS. | + | A recent study by Cao-Lormeau et al. (2016) published in //The Lancet// presented considerable evidence linking GBS with previous Zika virus infection. The researchers presented a case study involving 42 individuals with confirmed GBS during a massive Zika virus outbreak in French Polynesia between 2013 and 2014. Blood samples were taken from patients with confirmed GBS (n=42) and patients without GBS (control; n=98). The researchers used various techniques to detect antibodies against Zika virus (IgM/IgG) in both groups of patients. Evidence of previous Zika virus infection, demonstrated by the presence of Zika antibodies, was shown for 41 (98%) patients in the GBS group compared to 35 (36%) of patients in the control group (Figure 5; p<0.0001). In addition, a neutralizing response against Zika virus was seen in 42 (100%) of the GBS patients and 54 (56%) of the control group patients (Figure 5; p<0.0001). This data presented by Cao-Lormeau et al. (2016) exhibits a significant association between previous Zika virus infection and GBS. |
| - | <box 57% round | > {{:gbs_cao.png?625|}} </box| Figure 3 : Presence of Zika virus antibodies and positive neutralizing response in GBS affected and control patients. OR= Odds Ratio. (Modified from Cao-Lormeau et al., 2016)> | + | <box 57% round | > {{:gbs_cao.png?625|}} </box| Figure 5 : Presence of Zika virus antibodies and positive neutralizing response in GBS affected and control patients. OR= Odds Ratio. (Modified from Cao-Lormeau et al., 2016)> |
| ==== Microcephaly ==== | ==== Microcephaly ==== | ||
| - | Microcephaly is a birth defect associated with Congenital Zika Syndrome. Babies with microcephaly have a smaller head circumference than age and sex-matched patients. The decreased head circumference is due to improper or lack of brain development during pregnancy (CDC, 2018). Severe microcephaly (Figure 4) is an extreme form of the condition where the baby's head circumference is much smaller (~1st percentile) than babies of the same age and sex (~3rd percentile) (CDC, 2018). | + | Microcephaly is a birth defect associated with Congenital Zika Syndrome. Babies with microcephaly have a smaller head circumference than age and sex-matched patients. The decreased head circumference is due to improper or lack of brain development during pregnancy (CDC, 2018). Severe microcephaly (Figure 6) is an extreme form of the condition where the baby's head circumference is much smaller (~1st percentile) than babies of the same age and sex (~3rd percentile) (CDC, 2018). |
| - | <box 58% round| > {{::microcephaly_screen_shot_2018-01-24_at_11.19.55_am.png?625|}} </box| Figure 4: Baby with normal head circumference, microcephaly, and severe microcephaly, respectively (Modified from CDC, 2018)> | + | <box 58% round| > {{::microcephaly_screen_shot_2018-01-24_at_11.19.55_am.png?625|}} </box| Figure 6: Baby with normal head circumference, microcephaly, and severe microcephaly, respectively (Modified from CDC, 2018)> |
| - | A case study published by Mlakar et al. (2016) in //The New England Journal of Medicine// described the morphology of a baby with confirmed severe microcephaly. The mother, who had been infected with Zika virus, requested termination of the pregnancy at 32 weeks. At the time of termination the fetus' head circumference was 26cm (1st percentile). An autopsy performed on the fetal brain showed clear degeneration, calcifications, malformation and incomplete development of important structures (Figure 5), resulting in the small head circumference characteristic of microcephaly. | + | A case study published by Mlakar et al. (2016) in //The New England Journal of Medicine// described the morphology of a baby with confirmed severe microcephaly. The mother, who had been infected with Zika virus, requested termination of the pregnancy at 32 weeks. At the time of termination the fetus' head circumference was 26cm (1st percentile). An autopsy performed on the fetal brain showed clear degeneration, calcifications, malformation and incomplete development of important structures (Figure 7), resulting in the small head circumference characteristic of microcephaly. |
| - | <box 58% round| > {{:fetal_autopsy_brain.png?625|}} </box| Figure 5: Autopsy of fetal brain. Panel C shows white calcifications and loss of gyration in cortex (Black arrows), open sylvian fissures (Black arrowheads), and poorly delineated basal ganglia (Black asterisks). Panel D shows dilated lateral ventricles and collapsed left ventricle (White arrowheads), thalami are well developed (Black asterisks) along with the hippocampus (White asterisks), however contralateral structure failed to develop. (Modified from Mlakar et al., 2016)> | + | <box 58% round| > {{:fetal_autopsy_brain.png?625|}} </box| Figure 7: Autopsy of fetal brain. Panel C shows white calcifications and loss of gyration in cortex (Black arrows), open sylvian fissures (Black arrowheads), and poorly delineated basal ganglia (Black asterisks). Panel D shows dilated lateral ventricles and collapsed left ventricle (White arrowheads), thalami are well developed (Black asterisks) along with the hippocampus (White asterisks), however contralateral structure failed to develop. (Modified from Mlakar et al., 2016)> |
| - | In addition, Mlakar et al. (2016) used electron microscopy to image ultra-thin sections of the fetal brain and staining of viral particles in order to visualize the presence of Zika virus in the fetal brain tissue. Imaging showed dense clusters of viral particles among the damaged brain tissue, as well as the presence of active viral replication (Figure 6). | + | In addition, Mlakar et al. (2016) used electron microscopy to image ultra-thin sections of the fetal brain and staining of viral particles in order to visualize the presence of Zika virus in the fetal brain tissue. Imaging showed dense clusters of viral particles among the damaged brain tissue, as well as the presence of active viral replication (Figure 8). |
| - | <box 45% round| > {{:electron_microscopy.png?475|}} </box| Figure 6: Electron microscopy of ultra-thin sections of the fetal brain and staining of viral particles. Panel A shows dense clusters of virions amongst damaged brain cells. Panel B is a magnified image of Panel A, clearly showing the virion clusters. Panel C shows viral particles with bright interiors indicative of viral replication. Panel D is a negative staining of a virion showing morphological characteristics consistent with Zika virus (Modified from Mlakar et al., 2016)> | + | <box 45% round| > {{:electron_microscopy.png?475|}} </box| Figure 8: Electron microscopy of ultra-thin sections of the fetal brain and staining of viral particles. Panel A shows dense clusters of virions amongst damaged brain cells. Panel B is a magnified image of Panel A, clearly showing the virion clusters. Panel C shows viral particles with bright interiors indicative of viral replication. Panel D is a negative staining of a virion showing morphological characteristics consistent with Zika virus (Modified from Mlakar et al., 2016)> |
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| ======References====== | ======References====== | ||
| Abbink, P., Larocca, R. A., De La Barrera, R. A., Bricault, C. A., Moseley, E. T., Boyd, M.,… Barouch, D. H. (2016). Protective efficacy of multiple vaccine platforms against Zika virus challenge in rhesus monkeys. Science, 353(6304), 1129-32. doi:10.1126/science.aah6157 | Abbink, P., Larocca, R. A., De La Barrera, R. A., Bricault, C. A., Moseley, E. T., Boyd, M.,… Barouch, D. H. (2016). Protective efficacy of multiple vaccine platforms against Zika virus challenge in rhesus monkeys. Science, 353(6304), 1129-32. doi:10.1126/science.aah6157 | ||
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| + | Ayres, C. (2016). Identification of Zika virus vectors and implications for control. The Lancet Infectious Diseases, 16(3), 278-279. http://dx.doi.org/10.1016/s1473-3099(16)00073-6 | ||
| Baud, D., Gubler, D. J., Schaub, B., Lanteri, M. C., & Musso, D. (2017). An update on Zika virus infection. The Lancet, 390(10107), 2099-2109. | Baud, D., Gubler, D. J., Schaub, B., Lanteri, M. C., & Musso, D. (2017). An update on Zika virus infection. The Lancet, 390(10107), 2099-2109. | ||
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| Government of Canada. (2017, March 8). Prevention of Zika Virus. Retrieved from https://www.canada.ca/en/public-health/services/diseases/zika-virus/prevention-zika-virus.html | Government of Canada. (2017, March 8). Prevention of Zika Virus. Retrieved from https://www.canada.ca/en/public-health/services/diseases/zika-virus/prevention-zika-virus.html | ||
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| + | Hayes, E. (2009). Zika Virus Outside Africa. Emerging Infectious Diseases, 15(9), 1347-1350. http://dx.doi.org/10.3201/eid1509.090442 | ||
| Mlakar, J., Korva, M., Tul, N., Popovic, M., Poljsak-Prijatelj, M., Mraz, J, Kolenc M.,... Zupanc, T.A. (2016). Zika virus associated with microcephaly. New England Journal of Medicine, 374(10), 951-958.10.1056/NEJMoa1600651 | Mlakar, J., Korva, M., Tul, N., Popovic, M., Poljsak-Prijatelj, M., Mraz, J, Kolenc M.,... Zupanc, T.A. (2016). Zika virus associated with microcephaly. New England Journal of Medicine, 374(10), 951-958.10.1056/NEJMoa1600651 | ||
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| National Institute of Allergy and Infectious Diseases. (2017, March 3). Phase 2 Zika Vaccine Trial Begins in U.S., Central and South America | NIH: National Institute of Allergy and Infectious Diseases. Retrieved from https://www.niaid.nih.gov/news-events/phase-2-zika-vaccine-trial-begins-us-central-and-south-america | National Institute of Allergy and Infectious Diseases. (2017, March 3). Phase 2 Zika Vaccine Trial Begins in U.S., Central and South America | NIH: National Institute of Allergy and Infectious Diseases. Retrieved from https://www.niaid.nih.gov/news-events/phase-2-zika-vaccine-trial-begins-us-central-and-south-america | ||
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| + | Paixão, E., Barreto, F., da Glória Teixeira, M., da Conceição N. Costa, M., & Rodrigues, L. (2016). History, Epidemiology, and Clinical Manifestations of Zika: A Systematic Review. American Journal Of Public Health, 106(4), 606-612. http://dx.doi.org/10.2105/ajph.2016.303112 | ||
| Public Health Agency of Canada. (2017, December 15). Zika virus. Retrieved from https://www.canada.ca/en/public-health/services/diseases/zika-virus.html | Public Health Agency of Canada. (2017, December 15). Zika virus. Retrieved from https://www.canada.ca/en/public-health/services/diseases/zika-virus.html | ||
| World Health Organization. (2016, September 6). Zika virus. Retrieved from http://www.who.int/mediacentre/factsheets/zika/en/ | World Health Organization. (2016, September 6). Zika virus. Retrieved from http://www.who.int/mediacentre/factsheets/zika/en/ | ||
