Zika: the origin and spread of a mosquito-borne virus

Abstract Objective To describe the temporal and geographical distribution of Zika virus infection and associated neurological disorders, from 1947 to 1 February 2016, when Zika became a Public Health Emergency of International Concern (PHEIC). Methods We did a literature search using the terms “Zika” and “ZIKV” in PubMed, cross-checked the findings for completeness against other published reviews and added formal notifications to WHO submitted under the International Health Regulations. Findings From the discovery of Zika virus in Uganda in 1947 to the declaration of a PHEIC by the World Health Organization (WHO) on 1 February 2016, a total of 74 countries and territories had reported human Zika virus infections. The timeline in this paper charts the discovery of the virus (1947), its isolation from mosquitos (1948), the first human infection (1952), the initial spread of infection from Asia to a Pacific island (2007), the first known instance of sexual transmission (2008), reports of Guillain-Barré syndrome (2014) and microcephaly (2015) linked to Zika infections and the first appearance of Zika in the Americas (from 2015). Conclusion Zika virus infection in humans appears to have changed in character as its geographical range has expanded from equatorial Africa and Asia. The change is from an endemic, mosquito-borne infection causing mild illness to one that can cause large outbreaks linked with neurological sequelae and congenital abnormalities.


Introduction
Zika, a flavivirus transmitted mainly by mosquitos in the genus Aedes, was discovered in 1947 in Uganda. 1 From the 1960s to 1980s, human infections were found across Africa and Asia, typically accompanied by mild illness. The first large outbreak of disease caused by Zika infection was reported from the island of Yap (Federated States of Micronesia) in 2007, as the virus moved from south-east Asia across the Pacific. During an outbreak in French Polynesia in 2013-2014, Guillain-Barré syndrome was linked to Zika infection and cases of microcephaly in newborn children were also retrospectively linked to this outbreak. The World Health Organization (WHO) received the first reports of locally-transmitted infection from Brazil in May 2015. In July 2015, health ministry officials from Brazil reported an association between Zika virus infection and Guillain-Barré syndrome in adults. In October 2015, WHO received reports from Brazil of microcephaly in babies whose mothers had been exposed to Zika during pregnancy. At this time, there was no proof of a causal link between Zika infection and these neurological complications.
In February 2016, as infection moved rapidly through the range occupied by Aedes mosquitos in the Americas, WHO declared that Zika infection associated with microcephaly and other neurological disorders constituted a Public Health Emergency of International Concern (PHEIC). By the start of February 2016, local transmission of Zika infection had been reported from more than 20 countries and territories in the Americas and an outbreak numbering thousands of cases was under way in Cabo Verde in western Africa. Beyond the range of its mosquito vectors, Zika virus infections are expected to be carried worldwide by people as they travel and be transmitted by travellers to sexual partners who have not been to places where the virus is endemic.

Methods
To illustrate the spread of Zika virus and associated neurological complications, we did a literature search in PubMed using "Zika" and "ZIKV" as the search terms and cross-checked our findings for completeness against other published reviews. 2,3 In addition, we drew on formal notifications to WHO under the International Health Regulations (IHR), 4 which are archived in the WHO Event Information Site (EIS). EIS contains information about public health events of potential international concern notified to WHO as required by the IHR. EIS notifications sometimes contain confidential patient information and therefore are not publicly available. Other details of specific events can be provided by the authors on request.

Results
The first reported case of Zika virus dates to 1947 when the virus was isolated in samples taken from a captive sentinel rhesus monkey by scientists conducting routine surveillance for yellow fever in the Zika forest of Uganda. 1 The virus was recovered from Aedes (Stegomyia) africanus, caught on a tree platform in the forest. 1 Laboratory infection experiments showed the virus to be neurotropic in mice. 5 The timeline presented in this paper includes numerous serological surveys that purportedly detected antibodies to Zika virus in the 1950s and 1960s in Africa and Asia. Because serological (antibody detection) tests for Zika cross-react with antibodies stimulated by other viral infections, the presence of Zika virus is ideally confirmed by the detection of viral nucleic acids by polymerase chain reaction (PCR) testing or by virus isolation. A chronological map of the presence of Zika in those countries for which there is evidence of autochthonous transmission by mosquitos is presented in Fig. 1

to 1959
As shown in Table 1, Zika virus was first isolated from rhesus monkeys. The first human cases were detected in Uganda and the United Republic of Tanzania in 1952 in a study demonstrating the presence of neutralizing antibodies to Zika virus in sera. 74 During the same year, there was confirmation of the presence of the virus in humans in India. 8

to 1999
Between 1960 and 1999, Zika virus was being detected in mosquitos and sentinel rhesus monkeys used for field research in a narrow band of countries that stretch across equatorial Africa (Table 1). Altogether, the virus was isolated from more than 20 mosquito species, mainly in the genus Aedes. Sporadic human cases were identified, mostly by serological methods, but such cases were rare and the disease was regarded as benign. No deaths or hospitalizations were reported and seroprevalence studies consistently indicated widespread human exposure to the virus. 68,69,[75][76][77][78][79][80] Molecular studies of viruses later mapped the disease as it moved from Uganda to West Africa and Asia in the second half of the 20th century. 35,81 Between 1969 and 1983, the known geographical distribution of Zika expanded to equatorial Asia, including India, Indonesia, Malaysia and Pakistan, where the virus was detected in mosquitos. As in Africa, sporadic human cases occurred but no outbreaks were detected and infections in humans continued to be regarded as rare, with mild symptoms. Seroprevalence studies in Indonesia, Malaysia and Pakistan indicated widespread population exposure. [34][35][36][37] Researchers later suggested that the clinical similarity of Zika infection with dengue and chikungunya may be one reason why the disease was so rarely reported in Asia. 75

to 2009
In 2007, Zika virus spread from Africa and Asia to the Pacific island of Yap, in the Federated States of Micronesia, and caused the first large outbreak in humans. Before this event, only 16 cases of human Zika virus disease (including one experimental infection) had been documented worldwide (Table 3). 46 House-to-house surveys done among the island's population of 7391 people identified 185 cases of suspected Zika virus infections. The sample for the survey was 200 of 1276 total households. Of the 185 suspected cases, 49 (26%) were confirmed by PCR, or a specific neutralizing antibody response to Zika virus in the serum and 59 (32%) were classified as probable (patients with immunoglobulin M (IgM) antibody against Zika virus who had a potentially cross-reactive neutralizing antibody response). An estimated 73% (95% confidence interval: 68-77) of Yap residents older than three years were infected with Zika virus. No deaths, hospitalizations or haemorrhagic complications were reported. [82][83][84] Although wind-blown mosquitoes can travel distances of several hundred kilometres over the open ocean, introduction of the virus by travel or trade involving an infected person or an inadvertently imported mosquito is considered the most likely source of this outbreak, especially as no monkeys were present on the island. 75,82 The outbreak on Yap Island showed that Zika virus could rapidly cause more than a hundred confirmed and probable cases. In the absence of any evidence that viral mutations were the reason for this change in epidemic behaviour, other explanations should be considered. The first is a lack of population immunity. Regular exposure to infection in Africa and Asia may have prevented the large outbreaks eventually seen in Pacific Islands and in the Americas. The second possible explanation is that cases of Zika virus infection were historically misattributed -due to clinical similarities -to other pathogens, including malaria, dengue and chikungunya, and the frequent cocirculation of many infectious agents in these settings. The third possibility is underreporting, due to lack of surveillance systems, the often mild nature of the disease in adults and the many other causes of rare, but serious, neurological complications in adults and in utero.

to 2015
Between 2010 and 2015 sporadic cases of Zika virus infection were reported from several countries in south-east Asia. [49][50][51][52][53][54][55][56]85 These cases included an Australian traveller returning from Indonesia in 2012, a Canadian traveller returning from Thailand in 2013, two German travellers; one returning from Thailand in 2013, and one from Malaysian Borneo in 2014, and a Finnish traveller returning from the Maldives in 2015. We may infer that mosquito-borne transmission of Zika virus was ongoing in the places that these travellers had visited. The presence of infection was also reaffirmed in Africa (Cameroon).
In 2012, researchers published genetic sequences of Zika virus strains collected in Cambodia, Malaysia, Nigeria, Senegal, Thailand and Uganda, and constructed phylogenetic trees to assess the relationships between them. 75 Two geographically-distinct lineages of the virus, African and Asian, were identified, as well as multiple strains within each lineage. Analysis of viral samples from Yap Island strengthened previous epidemiological evidence that the outbreak on Yap Island originated in southeast Asia. 54,75,82,84 Between 2013 and 2014, the virus caused outbreaks in four other groups of Pacific islands: French Polynesia; Isla de Pascua (Chile); the Cook Islands; and New Caledonia. [57][58][59][60] The outbreak in French Polynesia generated thousands of suspected infections and was intensely investigated. The results of retrospective investigations were reported to WHO on 24 November 2015 and 27 January 2016. These reports indicated a possible association between Zika virus infection and congenital malformations and severe neurological and autoimmune complications. 61 In particular, an increase in the incidence of Zika infection towards the end of 2013 was followed by a rise in the incidence of Guillain-Barré syndrome. 47,86 This finding challenged previous assumptions that Zika infection causes only mild illness in humans. 74,83,87 During the 2013-14 outbreak of Zika virus in French Polynesia, two mothers and their newborn babies had Zika virus infection confirmed by PCR done on serum samples collected within four days of birth. Because they were able to show evidence of infection in the first week of life, the researchers concluded that Zika virus had been Hemagglutination inhibition test Simpson 25 1964 Uganda (Zika forest) First report and confirmation that Zika virus causes human disease.
The first report from a research worker who became ill in the Zika Forest. He proved -by isolating the virus from his own blood, by infecting mice and reisolating the virus from their blood -that Zika virus is a causative agent of human disease. The report was published with a description of the clinical features he experienced, including skin rash. Given the mild nature of his illness, the author concludes that "it is not surprising under normal circumstances the virus is not isolated frequently from man. " Brès 14 1965 Niger Antibodies to Zika virus found in human blood samples.

Discussion
Results of previous studies in which Zika virus was confirmed by serological surveys need to be interpreted with some caution, as they used different serological methods with varying degrees of specificity. These methods include hemagglutination inhibition, complement fixation and enzyme-linked immunosorbent assays, in addition to more specific sero-neutralization tests. The fact that Zika virus cross-reacts immunologically with dengue, other flaviviruses and chikungunya, which frequently co-circulate with Zika and have the same vectors, complicates the interpretation of serological results. Nonetheless, the results of serological surveys, supported by the isolation of Zika virus from mosquitoes and vertebrate hosts, suggest that the virus is endemic in several African and Asian countries. 64 Travellers who returned with Zika infections from Malaysia, the Maldives, Senegal and Thailand in 2012, were sentinels for virus circulation that may otherwise have gone undetected. Reasons why the virus may not always be detected include widespread immunological protection in the local population, the asymptomatic or mild and self-limiting nature of most Zika infections, clinical symptoms that overlap with dengue and chikungunya, the weakness of surveillance systems and the lack of specific diagnostic tests in many settings.
Therefore, additional research is needed to understand whether population immunity in endemic countries will confer protection against the epidemic strains of Zika currently circulating in Latin America and the Caribbean.

Conclusion
Zika virus infection in humans appears to have changed in character while expanding in geographical range. The change is from an endemic arbovirus causing mild illness across equatorial Africa and Asia. From 2007 onwards, Zika virus caused large outbreaks in Table 3.

Sixteen Zika virus infections reported in humans before the first outbreak on a Pacific island in 2007 Reference
Case number

Year Location Description
MacNamara 11 1 1954 Nigeria 10-year-old African female with fever and headache. Bearcroft 70 2 a 1956 Nigeria Experimentally induced in a 34-year-old European male, residing in Nigeria for 4.5 months before inoculation; symptoms included headache and fever. Simpson 25 3 1964 b Uganda 28-year-old European male, residing in Uganda for 2.5 months before illness; with headache, rash and fever. Moore et al. 68 4-6 1968 Nigeria Virus isolated from three febrile children, aged: 10 months, 2.5 years and 3 years; no clinical details available. Fagbami 69 7,8 1979 c Nigeria 2.5-year-old boy with fever; 10-year-old boy with fever, headache and body pains. 40% persons tested had neutralizing antibodies to Zika virus, demonstrating high prevalence of immunity in Nigeria. Unreported cases likely misdiagnosed as malaria. Filipe et al. 46 9 a 1973 Portugal Male arbovirus laboratory worker who had been vaccinated against yellow fever 2 months before infection; presented with chills, fever, sweating, retro-orbital and joint pain and cervicalgia. Olson et al. 35 10