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Zika fever, also called Zika virus disease, is an infectious disease caused by Zika virus (ZIKV), a mosquito-borne orthoflavivirus of the family Flaviviridae. Most infections are asymptomatic. When symptoms occur, they are usually mild and brief and include low-grade fever, maculopapular rash, arthralgia, and non-purulent conjunctivitis. The disease is clinically important because of its complications. Infection during pregnancy can cause congenital Zika syndrome, a pattern of brain, eye, and musculoskeletal abnormalities that includes microcephaly, and infection in adults is associated with Guillain-Barré syndrome (GBS).

The virus is transmitted mainly by Aedes aegypti and, less efficiently, by Aedes albopictus. It can also be transmitted sexually, from mother to fetus, and by blood transfusion and organ transplantation. The virus was identified in 1947 and caused few recognized human infections for six decades. It then spread across the Pacific and into the Americas in 2013 to 2016, which led the World Health Organization (WHO) to declare a public health emergency of international concern from February to November 2016. No licensed vaccine or antiviral drug exists, and management is supportive.

Classification and genome

Zika virus belongs to the genus Orthoflavivirus (formerly Flavivirus), in the Spondweni virus serocomplex, which is a different group from the dengue virus and Japanese encephalitis virus complexes. Its genome is a single molecule of positive-sense, single-stranded RNA of about 10.8 kilobases. It has a type 1 5′ cap and no 3′ poly(A) tail, and it is flanked by structured 5′ and 3′ untranslated regions. The RNA is translated as a single open reading frame into a polyprotein, which host and viral proteases cleave into three structural proteins and seven non-structural proteins:

• Structural proteins: capsid (C), precursor membrane (prM, cleaved to M), and envelope (E).
• Non-structural proteins: NS1, NS2A, NS2B, NS3, NS4A, NS4B, and NS5.

The virion is an enveloped particle about 50 nm in diameter. In the mature virion, 180 copies each of E and M are arranged on a lipid envelope with icosahedral symmetry, and 90 E dimers lie flat against the surface in a herringbone pattern. In the immature particle, prM covers the fusion loop of E. Cleavage of prM by the host protease furin in the trans-Golgi network produces the mature, infectious virion. The E protein mediates receptor binding and pH-dependent membrane fusion and is the main target of neutralizing antibodies.

Key non-structural proteins include:

• NS3: a serine protease (with NS2B as cofactor), an RNA helicase, and an RNA triphosphatase.
• NS5: a methyltransferase that caps viral RNA and an RNA-dependent RNA polymerase that replicates the genome. NS5 of Zika virus also binds and degrades human STAT2, which blocks type I interferon signaling. This activity does not work on mouse STAT2, which is one reason that wild-type mice are poor models of infection.
• NS1: a glycoprotein found in replication complexes, on the cell surface, and as a secreted hexamer in serum, where it is used as a diagnostic marker and contributes to immune evasion and vascular effects.
• Subgenomic flavivirus RNA (sfRNA): a stable fragment of the 3′ untranslated region that resists the host exonuclease XRN1 and accumulates in infected cells. It antagonizes antiviral responses and supports transmission in mosquitoes.

Lineages

Phylogenetic analysis separates the virus into an African lineage (including the original 1947 isolate) and an Asian lineage. The epidemics in the Pacific and the Americas were caused by the Asian lineage, and viruses from these epidemics are closely related. The proposal that a single amino acid change (S139N in prM) increased infection of neural progenitor cells and the severity of microcephaly in mouse models has been influential, but the relevance of this change to human disease is still being examined. Another change (A188V in NS1) increases the infection of Aedes aegypti in experiments. Both lineages are a single serotype, and antibodies against one lineage neutralize the other.

Replication cycle

The virus enters cells by receptor-mediated endocytosis through attachment factors that bind phosphatidylserine on the virion, including AXL, TYRO3, and TIM-1. These factors are expressed on many cell types, including skin fibroblasts, dendritic cells, placental trophoblasts, and neural progenitors. After acidification of the endosome, E changes conformation and drives fusion of the viral and endosomal membranes, which releases the genome into the cytoplasm. The RNA is translated at the endoplasmic reticulum (ER), and the non-structural proteins remodel ER membranes into invaginated vesicle packets in which replication is shielded from cytosolic sensors such as RIG-I and MDA5. New virions assemble on the ER, mature during transit through the secretory pathway, and are released by exocytosis.

Discovery and early record

Zika virus was first isolated in April 1947 from a sentinel rhesus macaque in the Zika Forest, near Entebbe in Uganda, by investigators studying yellow fever. It was isolated from the mosquito Aedes africanus in 1948, and the first human infection was identified in the early 1950s in Uganda and Tanzania. For the next half century, only a few dozen human cases were documented, in Africa and Southeast Asia. Serological surveys suggested that infection was more common than the reports implied, and that it was often mild and mistaken for dengue or other illnesses.

Yap, French Polynesia, and the Pacific

The first large outbreak occurred in 2007 on Yap in Micronesia, where about three quarters of residents aged three years and older were estimated to have been infected. Transmission of the Asian lineage then reappeared in French Polynesia in 2013 and 2014 and spread to other Pacific islands. During the French Polynesian outbreak, clinicians noted a sharp increase in cases of Guillain-Barré syndrome, and a retrospective analysis later identified a rise in congenital brain abnormalities.

The Americas, 2015 to 2016

Zika virus was recognized in northeastern Brazil in early 2015. Phylogenetic analyses indicate that it was introduced around 2013 to 2014, and the route of introduction remains debated. In late 2015, a large increase in newborns with microcephaly was reported, first in Pernambuco state. The link between infection in pregnancy and fetal brain damage was established in 2016 on the basis of detection of virus in fetal brain tissue and amniotic fluid, and of epidemiological studies. The virus spread through South America, Central America, the Caribbean, and southern North America, and transmission was recorded in more than 80 countries and territories. The WHO declared a public health emergency of international concern on 1 February 2016 and ended it on 18 November 2016, when it recommended a transition to longer-term efforts.

After the epidemic

Reported cases fell sharply in 2017. The decline is attributed mainly to the build-up of population immunity after large epidemics, and possibly to changes in vector control and surveillance. Low-level transmission has continued in the Americas, Africa, South and Southeast Asia, and the Pacific, with periodic local outbreaks, and the virus is expected to re-emerge as new cohorts of susceptible people are born.

Vector-borne transmission

Aedes aegypti is the main vector. It is adapted to human settlements, breeds in small artificial water containers such as tires, buckets, and flower vases, bites mainly during the day, and prefers human blood. The species is found in the tropics and subtropics worldwide, and Aedes albopictus extends transmission potential into temperate regions but is generally a less efficient vector. In Africa, the virus is also maintained in a sylvatic cycle that involves forest Aedes mosquitoes (such as Aedes africanus) and non-human primates, and in Asia, evidence of sylvatic cycles is less clear.

After a mosquito takes an infected blood meal, the virus must infect the midgut, escape into the hemolymph, and infect the salivary glands before the mosquito can transmit it. The time this takes is the extrinsic incubation period (EIP), which is typically about 4 to 10 days and shortens as temperature rises. Mosquitoes remain infectious for the rest of their lives. Vertical (transovarial) transmission in mosquitoes has been reported at low frequency and is not thought to be important for maintenance of the virus.

Non-vector transmission

• Sexual transmission. Zika virus is the first arbovirus shown to be transmitted sexually between humans. Transmission from men to women is best documented, and transmission between men and from women to men has also been reported. Viral RNA persists in semen far longer than in blood, for several months in some men, although infectious virus is found for a shorter period.
• Mother to child. The virus crosses the placenta and can infect the fetus at any stage of pregnancy. Perinatal transmission has also been described. Viral RNA has been detected in breast milk, but transmission by breastfeeding has not been confirmed, and breastfeeding is encouraged.
• Blood, organs, and laboratory exposures. Transmission by transfusion and transplantation has been reported, and screening of blood donations has been used in affected areas.

Transmission dynamics

For a vector-borne pathogen, the basic reproduction number R₀ in the classical Ross-Macdonald model is:

where m is the number of female mosquitoes per human, a is the biting rate per mosquito per day, b is the probability that an infectious bite infects a human, c is the probability that a mosquito becomes infected when it bites an infectious human, μ is the daily mosquito mortality rate, n is the EIP in days, and r is the human recovery rate. The term e^−_μn_ is the probability that a mosquito survives the EIP. If, for example, μ = 0.1 per day and n = 7 days, then this probability is e^−0.7 ≈ 0.50, and when the EIP lengthens to 14 days, it falls to e^−1.4 ≈ 0.25. The vector-specific part of the expression is called the vectorial capacity:

The herd immunity threshold, the fraction of the population that must be immune to stop sustained transmission, is:

Estimates of R₀ in the 2013 to 2016 outbreaks varied widely, from just above 1 to about 6, because they depended on the location, the mosquito density, and the method used. An R₀ of 3 corresponds to a threshold of about 67 percent. Sexual transmission adds a modest contribution to R₀ in models, but it is not thought to be able to sustain epidemics by itself.

Temperature and climate

Mosquito and viral traits respond nonlinearly to temperature, so transmission is a unimodal function of temperature. Trait-based models for Aedes aegypti and Zika virus estimate that transmission is possible between roughly 23 °C and 35 °C and peaks at about 29 °C, which is warmer than the optimum for West Nile virus transmission by Culex mosquitoes. The EIP shortens with warming, while adult survival falls above the optimum. The distribution of suitable conditions is changing with climate and urbanization, and models project that the populations at risk of _Aedes_-borne viruses will grow in some regions, such as at higher elevations and latitudes, while declining in the hottest regions. Rainfall, water storage practices, and El Niño years also influence vector abundance.

Population burden

Attack rates in naive populations were high in island outbreaks (about 70 percent on Yap, and a large majority on some Pacific islands), and in the Americas, seroprevalence in affected cities was high after the epidemic. Because most infections are asymptomatic or mild, reported cases are a small fraction of infections. The principal burden of disease is from congenital infection and neurological complications, rather than from the acute illness.

Some estimate of the number of affected births in an epidemic can be made from:

where N_f is the number of women of reproductive age in the population, A is the attack rate, π is the fraction of those women who are pregnant, and ρ is the risk of congenital Zika syndrome following infection in pregnancy. Estimates of ρ are uncertain and depend on the time of infection and the definition of outcome.

Acute illness

About 80 percent of infections are thought to be asymptomatic. The incubation period is typically 3 to 14 days. Symptomatic illness is mild and self-limited, and lasts about 2 to 7 days. Common features include:

• Low-grade fever, often absent or mild.
• An itchy maculopapular rash, often starting on the face and trunk.
• Arthralgia and mild arthritis, especially of the small joints of the hands and feet.
• Non-purulent conjunctivitis.
• Myalgia, headache, retro-orbital pain, and malaise.

Hospitalization and death are uncommon. Zika fever resembles dengue and chikungunya, but fever is usually lower and rash and conjunctivitis are more frequent, and severe hemorrhage and shock are rare.

Neurological complications

Guillain-Barré syndrome is an acute immune-mediated polyneuropathy that was associated with Zika virus in French Polynesia, Brazil, Colombia, and elsewhere. It typically begins a few days to about two weeks after infection, which is a shorter delay than that after many other infections, and the neurological picture is often an acute motor axonal or demyelinating form. The estimated risk in French Polynesia was on the order of a few cases per 10,000 infections. Other neurological conditions associated with infection include meningoencephalitis, acute myelitis, and, less often, uveitis and thrombocytopenia.

Congenital Zika syndrome

Congenital Zika syndrome describes a recognizable pattern of abnormalities in infants infected before birth. Features include:

• Brain: Severe microcephaly (head circumference more than 2 standard deviations below the mean for sex and gestational age, and a more severe form below 3), a collapsed skull with overlapping sutures, ventriculomegaly, calcifications at the junction of cortical and subcortical white matter, cortical malformations and thin cortex, and hypoplasia of the corpus callosum, cerebellum, and brainstem. This is an example of a fetal brain disruption sequence, in which a brain that began developing normally is destroyed.
• Eyes: Macular pigment mottling and chorioretinal atrophy, optic nerve hypoplasia and cupping, and other abnormalities. Vision may be impaired.
• Musculoskeletal system: Congenital contractures such as clubfoot, and hypertonia and spasticity.
• Other: Hearing loss, seizures, irritability, swallowing problems, and developmental delay.

The risk to the fetus varies with the stage of pregnancy. Infection in the first trimester carries the highest risk, but abnormalities can result from infection later in pregnancy. In prospective registries and cohorts, birth defects were identified in roughly 5 to 14 percent of pregnancies with laboratory evidence of Zika infection, with a higher fraction in studies that included neuroimaging and neurodevelopmental assessment. Some children born with a normal head size at birth develop later neurodevelopmental problems, including delayed milestones, motor problems, and postnatal microcephaly, so follow-up is recommended. Whether a woman's infection was symptomatic is not a reliable predictor of fetal outcome.

Comparative Clinical, Virological, and Diagnostic Profile of Zika Virus Syndromes

After a mosquito bite, the virus replicates in skin cells, including fibroblasts, keratinocytes, and dendritic cells, and then spreads through blood and lymph. Viremia peaks within the first week and is cleared in most people within about 2 weeks, although RNA can be detected for longer in urine, semen, and (in pregnancy) blood.

The virus infects neural progenitor cells (including radial glia) in the developing brain. Infection slows or arrests the cell cycle, causes abnormalities of the centrosomes and mitotic spindle, activates innate immune signaling, and triggers apoptosis and premature differentiation, so that the pool of progenitors is depleted and the cortex is thinned. In the placenta, the virus infects trophoblasts, Hofbauer cells, and endothelial cells, and inflammation and placental dysfunction may add to the damage. In human infection, the NS5 protein degrades STAT2, which suppresses the interferon response, and this is one reason that the virus replicates efficiently in human cells.

Because Zika virus is antigenically related to dengue virus, pre-existing immunity to dengue could change the outcome, and the proposal that antibody-dependent enhancement affects Zika infection has been investigated. Epidemiological studies of the effect of prior dengue immunity on Zika severity and on congenital outcomes have given inconsistent results, and the question is not settled. Cross-reactivity between flaviviruses also complicates diagnosis.

Clinical diagnosis is difficult because the illness resembles other infections, including dengue, chikungunya, measles, rubella, parvovirus B19 infection, leptospirosis, and malaria, and because these infections often occur in the same places at the same time. Laboratory methods include:

• Nucleic acid amplification: RT-PCR on serum or whole blood in the first week of illness, and on urine for a longer period (about 2 weeks or more). A positive result confirms infection, and a negative result does not exclude it later in the illness.
• Serology: IgM antibody capture enzyme-linked immunosorbent assays (MAC-ELISA) become positive from about the end of the first week, but they cross-react with other flaviviruses and can remain positive for months. Confirmation by a plaque reduction neutralization test (PRNT), which measures neutralizing antibodies, is more specific but can still be difficult to interpret in people who have had dengue or flavivirus vaccination.
• Prenatal and neonatal evaluation: Serial ultrasound of the fetus, with magnetic resonance imaging where needed, is used to monitor fetal brain development in exposed pregnancies. Amniocentesis may be used to detect viral RNA. In newborns, testing of serum, urine, and cord blood, neuroimaging, and eye and hearing examinations are recommended.

Guidance on testing depends on the clinical and epidemiological situation and changes over time, so national and WHO recommendations should be consulted.

No specific antiviral treatment is approved. Acute infection is managed with rest, fluids, and paracetamol (acetaminophen) for fever and pain. Where dengue has not been excluded, aspirin and other nonsteroidal anti-inflammatory drugs are avoided because of the risk of bleeding. Guillain-Barré syndrome is managed with supportive care, which may require ventilation, and with intravenous immunoglobulin or plasmapheresis. Infants with congenital Zika syndrome need multidisciplinary care, including neurological, ophthalmological, audiological, developmental, and orthopedic follow-up and early intervention. Counseling about contraception and the timing of pregnancy has been used to reduce the risk of congenital infection.

Vector control

Control is difficult because Aedes aegypti breeds in small containers around homes and bites during the day. Measures include:

• Source reduction: removal or covering of water containers, and community engagement.
• Larviciding and adulticiding: biological larvicides such as Bacillus thuringiensis israelensis (Bti), insect growth regulators, and space spraying or residual spraying in outbreaks. Insecticide resistance to pyrethroids is widespread in Aedes aegypti and limits the effectiveness of some measures.
• Biological and genetic approaches: Releases of Aedes aegypti carrying the endosymbiotic bacterium Wolbachia reduce the capacity of the mosquito to transmit dengue virus and some other viruses, and have been associated with large reductions in dengue incidence in several trials and field programs. Their effect on Zika transmission has been shown mostly in laboratory studies, and field evidence is limited because Zika transmission fell after 2016. Other methods, such as the sterile insect technique, the incompatible insect technique, and genetically modified male mosquitoes, are being used and evaluated.

Personal protection

Individual measures include repellents with DEET, icaridin (picaridin), IR3535, or oil of lemon eucalyptus, long-sleeved clothing, window screens, and air conditioning. Because the main vector bites during the day, bed nets are less useful than they are for malaria, although they help people who sleep in the day, such as infants.

Sexual and travel-related precautions

Because of the risk of sexual transmission, public health agencies advise condom use or abstinence for periods after travel to or residence in an affected area, and these periods are longer after symptomatic infection and for couples who are planning a pregnancy. Pregnant women are advised to avoid travel to areas with active transmission where possible. Specific recommendations change, so current guidance from the WHO and national agencies should be followed.

Vaccines and drugs under development

No Zika vaccine is licensed. Candidates include purified inactivated virus vaccines, DNA vaccines (such as VRC5283), messenger RNA vaccines, live attenuated vaccines, and viral-vectored vaccines. Several have shown safety and the induction of neutralizing antibodies in phase 1 and 2 trials. Large efficacy trials have been hard to run because the decline in cases after 2016 left too little transmission for testing, and one regulatory route proposes the use of antibody titers as a surrogate of protection. Candidate antiviral drugs and neutralizing monoclonal antibodies have shown activity in laboratory and animal studies, but none is approved for use in humans. Developing treatments for pregnancy is especially difficult because of safety requirements.

Surveillance of Zika has been affected by overlap with dengue and chikungunya, the high proportion of asymptomatic infections, and cross-reactive serology. Integrated surveillance of arboviruses, combined with entomological monitoring, sequencing, and monitoring of birth outcomes and Guillain-Barré syndrome, is used to detect transmission. Major research questions include the long-term neurodevelopmental outcome of children exposed in the womb, the role of prior flavivirus immunity, the persistence of virus in semen and other sites, the possibility of a sylvatic cycle outside Africa, and the future dynamics of immunity and re-emergence in the Americas as the generation exposed in 2015 to 2016 ages.

• Dengue fever
• Chikungunya
• Yellow fever
• West Nile fever
• Arbovirus
• Zika virus outbreak in the Americas

Why does Zika virus persist in semen and urine much longer than in serum?

Zika virus exhibits enhanced virion thermal and structural stability compared to dengue virus, allowing intact particles to survive in non-blood compartments. In the male reproductive tract, Zika virus infects AXL-expressing Sertoli cells, Leydig cells, and epididymal epithelium; because the blood-testis barrier restricts cytotoxic T-cell infiltration to protect developing germ cells, viral replication persists in this immune-privileged reservoir for weeks to months after peripheral serum viremia clears.

How is congenital Zika syndrome distinguished radiologically from congenital cytomegalovirus infection?

Congenital Zika syndrome produces a fetal brain disruption sequence characterized by punctate calcifications concentrated specifically at the gray–white matter junction between the thinned cerebral cortex and subcortical white matter, accompanied by severe ventriculomegaly, cortical malformations (lissencephaly or polymicrogyria), and skull collapse with overlapping sutures. By contrast, congenital cytomegalovirus (CMV) infection characteristically produces periventricular calcifications lining the lateral ventricles rather than subcortical junctional deposits.

Why are urine and whole blood preferred over serum for Zika virus RT-PCR testing?

In acute human Zika virus infection, free plasma and serum viremia is low-titer and transient, frequently dropping below the limit of detection within 5 to 7 days of symptom onset. However, Zika virions are shed at higher concentrations into urine for 14 to 21 days and remain physically bound to erythrocytes in EDTA whole blood for up to 2 to 3 months, substantially extending the molecular diagnostic window.