An update on Zika virus infection

doi:10.1016/S0140-6736(17)31450-2

The Lancet

Volume 390, Issue 10107, 4–10 November 2017, Pages 2099-2109

https://doi.org/10.1016/S0140-6736(17)31450-2 Get rights and content

Summary

The epidemic history of Zika virus began in 2007, with its emergence in Yap Island in the western Pacific, followed in 2013–14 by a larger epidemic in French Polynesia, south Pacific, where the first severe complications and non-vector-borne transmission of the virus were reported. Zika virus emerged in Brazil in 2015 and was declared a national public health emergency after local researchers and physicians reported an increase in microcephaly cases. In 2016, WHO declared the recent cluster of microcephaly cases and other neurological disorders reported in Brazil a global public health emergency. Similar clusters of microcephaly cases were also observed retrospectively in French Polynesia in 2014. In 2015–16, Zika virus continued its spread to cause outbreaks in the Americas and the Pacific, and the first outbreaks were reported in continental USA, Africa, and southeast Asia. Non-vector-borne transmission was confirmed and Zika virus was established as a cause of severe neurological complications in fetuses, neonates, and adults. This Review focuses on important updates and gaps in the knowledge of Zika virus as of early 2017.

Introduction

Zika virus, a member of the family Flaviviridae and genus flavivirus, was first isolated in 1947 from a sentinel monkey in the Zika forest in Uganda, east Africa. Subsequent epidemiological studies suggested that Zika virus had a broad geographical distribution in sub-Saharan Africa and southeast Asia. The first human infection was reported in 1954 in Nigeria, but the identification of this virus was subsequently questioned and thought to be Spondweni. The first confirmed human infection was reported in Uganda in 1962–63.¹ Although known to infect people, Zika virus infection was rarely investigated and could have been misdiagnosed as dengue virus infection based on clinical presentation and serological cross-reactivity with closely related viruses. Thus, silent transmission in the absence of severe disease and large outbreaks allowed Zika virus infection to go undetected while spreading throughout Africa and Asia, with fewer than 20 human infections confirmed in 60 years.² The 2007 Yap Island outbreak marked the beginning of a new chapter in the history of Zika virus (figure 1).

Section snippets

Geographical distribution of Zika virus infections

In 2007, the first known Zika virus outbreak occurred on the isolated island of Yap, in the western Pacific.³ 6 years later, a larger epidemic occurred in French Polynesia, in the south Pacific, followed by smaller outbreaks on other Pacific islands.⁴ The virus was introduced into Brazil between 2013 and 2015, most probably from the Pacific, and caused a large epidemic that peaked in November, 2015, subsequently spreading rapidly throughout Brazil and the Americas, while continuing to circulate

Favourable factors for Zika virus emergence

As Zika virus has circulated for several decades with sporadic or silent transmission to human beings and no reported epidemics, it was surprising when it suddenly emerged as a major public health problem. Although the epidemic potential of the virus has changed, allowing epidemic transmission, it is unclear whether the virulence has changed. Because of the close genetic and epidemiological relationship between dengue virus and Zika virus, the same demographic, societal, and technological

In-vitro and in-vivo models

Zika virus infects human embryonic cortical neural progenitor cells, inducing cell death and providing evidence that human neurons are susceptible to the virus.¹⁶ The virus seems to mainly target neuronal progenitors in the developing brain and, in rare instances, some areas of the adult brain.17, 18 Early infection is associated with proliferation arrest and an increase in neuronal progenitor death. Similar results were observed in cortical neurospheres.¹⁹

Mouse and rhesus macaque models

Vector-borne

Zika virus is part of the mosquito-borne group of flaviviruses that are mainly transmitted in the urban environment by aedes (subgenus stegomyia) mosquitoes, which also transmit dengue virus, chikungunya, and yellow fever virus.²

Nearly all tropical and subtropical areas of the world, containing a total population of approximately 3·6 billion people, are infested with Aedes aegypti, Aedes albopictus, and a variety of other aedes mosquitoes, and are at risk for Zika virus, dengue virus,

Laboratory diagnosis of Zika virus infection

In the absence of an antigenic detection test, acute phase diagnosis relies on molecular detection of Zika virus RNA. Blood and urine are the samples of choice. The virus can be detected only briefly in plasma or serum during acute illness. Compared with serum, urine was reported to increase the detection rate of viral RNA within the first week after symptom onset and expand the window of detection, as Zika virus RNA was detectable up to 39 days after exposure.70, 71 However, discrepant results

Clinical features and complications of Zika virus infections

The clinical presentation of uncomplicated Zika virus infection has been extensively described.² Because of its non-specific nature, infection is often not detected, or is misdiagnosed. The percentage of asymptomatic infections has been reported to be around 80%; however, a retrospective serosurvey in French Polynesia showed that, among patients who were seropositive for the virus, the percentage of asymptomatic infections was about 30% in infants and 50% in adults.⁸³ These results underscore

Vaccines and drugs against Zika virus

Vaccine development has been well supported by international funding agencies. A DNA vaccine has entered phase 1 clinical trials and there are more than 40 vaccine candidates in the pipeline, some of which are being fast tracked for licensure.¹⁰⁰ Nevertheless, a vaccine will probably not be available for at least 2 years. It is also not known if Zika virus infections lead to lifelong immunity.¹⁰¹

Using large screening strategies, several compounds have been found to have in-vitro activity

Knowledge gaps

Although important advances have been made since Zika virus emerged in the Pacific, gaps remain in the knowledge of the epidemiology, virology, and biology of infections (table 2). For example, in July, 2016, WHO told The Lancet that “we don't know what the full spectrum of the Zika-caused congenital defects will be. Will apparently unaffected children whose mothers had Zika in pregnancy develop normally? Will they be able to walk and talk normally? Will they be mentally impaired or have other

Applicability and effectiveness of recommendations

The effectiveness and applicability of strict recommendations are debatable. Recommendations are based on an extreme interpretation of the precautionary principle, which is awaiting data that will be generated by ongoing studies to further inform guidelines. Is the response always proportionate to the risk? For example, guidelines recommending that all blood donations be tested for Zika virus RNA in the USA, even in states without competent vectors, were issued without consultation with the US

Conclusion

WHO declared Zika virus a public health emergency of international concern in February, 2016, subsequently declaring the virus an ongoing challenge requiring intense action, but no longer a public health emergency of international concern, in November, 2016.¹⁰⁷ As of May, 2017, more than 200 000 infections and 3000 congenital syndromes associated with Zika virus infections have been confirmed in the Americas in a susceptible population of 1 billion inhabitants.⁵ The number of cases in other

Search strategy and selection criteria

References for this Review were identified through searches of PubMed, Scopus, Web of Science, and Google Scholar, for articles published before April, 2017 by use of the terms “Zika virus”, “ZIKV”, “microcephaly”, “Guillain-Barré syndromes”, and “emerging viruses”. Articles in English and French resulting from these searches and relevant references cited in those articles were reviewed.

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Zika virus infection is a threat to at-risk populations, causing major birth defects and serious neurological complications. Development of a safe and efficacious Zika virus vaccine is, therefore, a global health priority. Assessment of heterologous flavivirus vaccination is important given co-circulation of Japanese encephalitis virus and yellow fever virus with Zika virus. We investigated the effect of priming flavivirus naive participants with a licensed flavivirus vaccine on the safety and immunogenicity of a purified inactivated Zika vaccine (ZPIV).
This phase 1, placebo-controlled, double-blind trial was done at the Walter Reed Army Institute of Research Clinical Trials Center in Silver Spring, MD, USA. Eligible participants were healthy adults aged 18–49 years, with no detectable evidence of previous flavivirus exposure (by infection or vaccination), as measured by a microneutralisation assay. Individuals with serological evidence of HIV, hepatitis B, or hepatitis C infection were excluded, as were pregnant or breastfeeding women. Participants were recruited sequentially into one of three groups (1:1:1) to receive no primer, two doses of intramuscular Japanese encephalitis virus vaccine (IXIARO), or a single dose of subcutaneous yellow fever virus vaccine (YF-VAX). Within each group, participants were randomly assigned (4:1) to receive intramuscular ZPIV or placebo. Priming vaccinations were given 72–96 days before ZPIV. ZPIV was administered either two or three times, at days 0, 28, and 196–234. The primary outcome was occurrence of solicited systemic and local adverse events along with serious adverse events and adverse events of special interest. These data were analysed in all participants receiving at least one dose of ZPIV or placebo. Secondary outcomes included measurement of neutralizing antibody responses following ZPIV vaccination in all volunteers with available post-vaccination data. This trial is registered at ClinicalTrials.gov, NCT02963909.
Between Nov 7, 2016, and Oct 30, 2018, 134 participants were assessed for eligibility. 21 did not meet inclusion criteria, 29 met exclusion criteria, and ten declined to participate. 75 participants were recruited and randomly assigned. 35 (47%) of 75 participants were male and 40 (53%) were female. 25 (33%) of 75 participants identified as Black or African American and 42 (56%) identified as White. These proportions and other baseline characteristics were similar between groups. There were no statistically significant differences in age, gender, race, or BMI between those who did and did not opt into the third dose. All participants received the planned priming IXIARO and YF-VAX vaccinations, but one participant who received YF-VAX dropped out before receipt of the first dose of ZPIV. 50 participants received a third dose of ZPIV or placebo, including 14 flavivirus-naive people, 17 people primed with Japanese encephalitis virus vaccine, and 19 participants primed with yellow fever vaccine. Vaccinations were well tolerated across groups. Pain at the injection site was the only adverse event reported more frequently in participants who received ZPIV than in those who received placebo (39 [65%] of 60 participants, 95% CI 51·6–76·9 who received ZPIV vs three [21·4%] of 14 who received placebo; 4·7–50·8; p=0·006). No patients had an adverse event of special interest or serious adverse event related to study treatment. At day 57, the flavivirus-naive volunteers had an 88% (63·6–98·5, 15 of 17) seroconversion rate (neutralising antibody titre ≥1:10) and geometric mean neutralising antibody titre (GMT) against Zika virus of 100·8 (39·7–255·7). In the Japanese encephalitis vaccine-primed group, the day 57 seroconversion rate was 31·6% (95% CI 12·6–56·6, six of 19) and GMT was 11·8 (6·1–22·8). Participants primed with YF-VAX had a seroconversion rate of 25% (95% CI 8·7–49·1, five of 20) and GMT of 6·6 (5·2–8·4). Humoral immune responses rose substantially following a third dose of ZPIV, with seroconversion rates of 100% (69·2–100; ten of ten), 92·9% (66·1–99·8; 13 of 14), and 60% (32·2–83·7, nine of 15) and GMTs of 511·5 (177·6–1473·6), 174·2 (51·6–587·6), and 79 (19·0–326·8) in the flavivirus naive, Japanese encephalitis vaccine-primed, and yellow fever vaccine-primed groups, respectively.
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ReviewAn update on Zika virus infection

Summary

Introduction

Section snippets

Geographical distribution of Zika virus infections

Favourable factors for Zika virus emergence

In-vitro and in-vivo models

Vector-borne

Laboratory diagnosis of Zika virus infection

Clinical features and complications of Zika virus infections

Vaccines and drugs against Zika virus

Knowledge gaps

Applicability and effectiveness of recommendations

Conclusion

Search strategy and selection criteria

Lancet Infect Dis

Clin Microbiol Infect

Lancet Infect Dis

J Clin Virol

Lancet Infect Dis

Cell Stem Cell

Cell Stem Cell

Cell Stem Cell

Cell

Cell Rep

Cell Host Microbe

Lancet

Lancet Infect Dis

Lancet

Lancet Infect Dis

Lancet

Lancet Infect Dis

Lancet Infect Dis

Lancet

Lancet Infect Dis

Lancet

Am J Obstet Gynecol

Lancet

Zika virus

Clin Microbiol Rev

Zika virus outbreak on Yap Island, Federated States of Micronesia

N Engl J Med

Situation report. Zika virus microcephaly Guillain-Barré syndrome. March 10, 2017. Data as of 9 March 2017

One year after the Zika virus outbreak in Brazil: from hypotheses to evidence

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Four in Florida are infected with Zika from local mosquitoes

BMJ

Congenital cerebral malformations and dysfunction in fetuses and newborns following the 2013 to 2014 Zika virus epidemic in French Polynesia

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Dengue, urbanization and globalization: the unholy trinity of the 21(st) century

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Review
An update on Zika virus infection