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Recent scientific findings based on literature reviewed after the eighth update of the ECDC Rapid Risk Assessment on Zika virus infection

28 Oct 2016

This section presents relevant scientific literature and guidance on Zika virus research published between 30 August 2016 – the release date of the eighth update of ECDC’s Zika risk assessment – and 17 October 2016. This summary outlines the main findings with regard to Zika virus research.

Pathogenesis

A number of new research findings provide insights into the pathogenesis of neurological damage caused by the Zika virus.
Zika virus strains do not form separate serotypes. In a Swiss mice model, antibodies against three wild types of Zika virus from Africa (ancestral MR766 strain), Asia and America are cross-neutralising with a 4- to 10-fold strain-dependent difference in the neutralising activity [3]. According to the authors, these results do not immediately contradict previous findings in monkeys or in mice as the titres may still be protective in vivo [4,5].

The in vitro stability of Zika virus, dengue 2 virus and West-Nile virus has been compared by measuring changes in infectivity following prolonged incubation at physiological temperatures. The stability of Zika virus is intermediate between that of dengue virus and West Nile virus, suggesting an alternative explanation for the unique clinical manifestations of the infection (the half-live of Zika virus is approximately twice as long as the half-life of dengue virus (11.8 versus 5.2 hours) but shorter than that of West Nile virus (17.7 hours) [6]. An analysis of a high-resolution cryo-electron microscopic Zika virus reconstruction supported the hypothesis that the stability of the virus may contribute to its distinctive pathobiology.

Microcephaly and congenital central nervous system malformations

In March 2016, WHO reported that there was ‘strong scientific consensus that Zika virus is a cause of GBS [Guillain–Barré syndrome], microcephaly and other neurological disorders’ [7].

A report by de Araújo et al. provides the preliminary results of a prospective case-control study conducted in eight public hospitals in Recife, Pernambuco province, Brazil, during the first half of 2016 [8]. A total of 32 cases and 62 controls were recruited prospectively between January and May 2016. A crude odds ratio of 31.7 (95% CI=4.7–∞) was estimated for the association between microcephaly and laboratory confirmation of Zika virus infection considering serum results only. This preliminary analysis indicates that neonates with microcephaly were almost 32 times more likely to have been exposed to Zika virus infection during pregnancy than neonates without microcephaly. Considering serum or cerebrospinal fluid samples for exposure classification, a crude odds ratio of 55.5 (95% CI=8.6–∞) was estimated. The estimates remain of the same order of magnitude after adjustment for maternal education or maternal age.

There is consensus that Zika virus infection during the first and second trimester of pregnancy is associated with increased risk for central nervous system malformations and microcephaly. The risk of central nervous system malformations when the infection occurs during the third trimester of pregnancy is uncertain. Soares de Souza et al. reported two cases of congenital brain injury as a result of a Zika virus infection in the third trimester. The two women became infected with Zika virus in their 36th week of pregnancy. Both babies were born at term with preserved head circumference (i.e. without microcephaly) but with lesions (subependymal cysts and lenticulostriate vasculopathy) identified by postnatal imaging in the early neonatal period [9]. In an animal model, the foetus of a pregnant macaque infected with a high viral load of an Asian lineage strain (Cambodia 2010) at a stage of pregnancy corresponding to seven months in humans developed major brain lesions [10].

Clinical features and sequelae

The full clinical spectrum of congenital Zika virus syndrome is not yet fully understood. Leal et al. report that congenital infection with Zika virus might also be associated with sensorineural hearing loss. Four of 69 (5.8%) children with microcephaly and laboratory evidence of congenital Zika virus infection were found to have sensorineural hearing loss without another potential cause [11].
Dos Santos et al. examined the temporal association between Zika virus disease and Guillain–Barré syndrome in Bahia (Brazil), Colombia, the Dominican Republic, El Salvador, Honduras, Suriname, and Venezuela [12]. Graphical and time-series analyses were applied to two independent datasets, which were collected through official international health channels and from ministry of health websites. From 1 April 2015 to 31 March 2016, a total of 164 237 confirmed and suspected cases of Zika virus disease and 1 474 cases of Guillain–Barré syndrome were reported from these locations. An analysis suggests that changes in the reported incidence of Zika virus disease during 2015 and early 2016 were closely associated with changes in the incidence of the Guillain–Barré syndrome.

Epidemiology

The outbreak of Zika virus in Singapore is linked to the south-east Asian Zika virus strain, which is closely related to the Thailand strain (2014) but not to the strains circulating in the Americas [13]. The authors also observed that within the Asian lineage, the antigenic E protein surface is highly conserved. The highly similar surface E proteins of the different strains in the Asian lineage should facilitate global vaccine development, but at this point in time it cannot be determined whether the strain linked to the Singapore outbreak shows different disease characteristics from the one in French Polynesia and the Americas [13].

Transmission

 

Human-to-human transmission

A recent publication provided an explanation about how Zika virus is transmitted from human to human through intact skin or mucous membranes. The index patient had a very high viral load 2x108 copies/mL. Although uncommon, this mode of transmission has also been shown in experimental animal models and in at least one human (for dengue) [14]. 

 

Mosquito transmission

Several studies assessed the vector competence of Culex species under experimental conditions:

 

  • Amraoui et al. [15] performed a vector competence study on laboratory colonies of Culex quinquefasciatus mosquitoes (collected in the San Joaquin Valley in California, United States, in 1950) and Culex pipiens (collected in Tabarka, Tunisia, in 2010). Zika virus could not be detected in the saliva of any of the species up to 21 days after an infectious blood meal. In addition, even when bypassing the midgut barrier, through intrathoracic inoculation, Zika virus could not be detected in the saliva of any of the examined species up to 14 days post infection.
  • Boccolini et al. [16] tested the susceptibility of an Italian population of Culex pipiens to Zika virus infection. An Aedes aegypti colony was used as a positive control. No viral RNA was detected in the saliva of Culex pipiens between 3 to 24 days post infection whereas the positive control showed Zika virus saliva infection.
  • Fernandes et al. [17] orally exposed Culex quinquefasciatus from Rio de Janeiro to two Zika virus strains isolated from human cases, also from Rio de Janeiro (Rio-U1 and Rio-S1). Aedes aegypti was used as a positive control. Infection rates were minimal to completely absent in all Culex quinquefasciatus. Moreover, dissemination of the virus in the mosquito and transmission were not detected in any Culex quinquefasciatus regardless of the incubation period and the Zika virus isolate. By contrast, Aedes aegypti showed high viral dissemination and moderate to very high transmission.
  • Huang et al. [18] tested the susceptibility of recently colonised Culex species mosquitoes. Results showed a high degree of refractoriness among members of the Culex pipiens complex to Zika virus even when exposed to high-titre bloodmeals. Culex quinquefasciatus from Vero Beach, Florida, United States, was refractory to infection with Zika virus.
  • In contrast to the above studies, Guedes et al. (preprint [19]) and Guo et al. [20] concluded that Culex quinquefasciatus is a competent vector of Zika virus, based on experimental infections. Guedes et al. [19] found Zika virus in the midgut, salivary glands, and saliva of artificially fed Culex quinquefasciatus (laboratory colony CqSLab). Additionally, they found Zika virus-infected Culex quinquefasciatus. The authors did not specify whether the field-collected mosquitoes were none-fed which would have ruled out that the detected Zika virus originated from ingested infected blood. Guo et al. [20] detected the virus in the salivary glands as early as eight days post infection in Culex quinquefasciatus (Hainan, China). Further Culex quinquefasciatus could be infected orally and then transmit the virus.

Hall-Mendelin et al. [21] orally infected several Australian mosquito species (Aedes aegypti, Aedes notoscriptus, Aedes procax, Aedes vigilax, Culex annulirostris, Culex quinquefasciatus, Culex sitiens) with Zika virus. The authors concluded that Aedes aegypti is the most likely mosquito vector of Zika virus in Australia.

Richard et al. [22] evaluated the vector competence of Aedes aegypti and Aedes polynesiensis from French Polynesia. Under experimental conditions, Aedes polynesiensis showed a moderate infection rate, and the dissemination efficiency was low. No Zika virus was found in the saliva of this species. Further, the laboratory results support that the French Polynesian population of Aedes aegypti may have been a vector of Zika virus. Infectious saliva was detected from six days post infection in Aedes aegypti females in only 3% of the tested mosquitoes, increasing to 8% nine days post infection and then significantly increased to reach 36% at 14 days post infection and 73% at 21 days post infection.

The conflicting results for Culex quinquefasciatus might be due to different experimental setups, i.e. the use of different Zika virus strains for infection or the fact that different mosquito populations were tested by different research groups. Before incriminating a new mosquito species as a vector for Zika virus, further evidence is needed on its vector competence and vector capacity. 

Transmission by sexual contact

Since the rapid risk assessment of 30 August 2016, additional evidence became available:

 

  • Zika virus RNA persistence in the semen of symptomatic men increased from six months, as communicated previously [23,24], to more than eight months [Barzon, personal communication].
  • Prolonged detection of Zika virus RNA in semen 69 days after symptom onset (based on culture result) [25]; previously reported prolonged detection of infectious Zika virus in semen was 24 days [26].
  • Identification of Zika virus antigens inside of spermatozoa, with 3.5% of the cells infected. This was demonstrated in a symptomatic man at day 56 after onset [27].
  • Zika virus RNA clearance in the genital tract of women: a follow-up study of five Zika-infected women showed the virus RNA disappearing from the genital tract three weeks after symptom onset (last detection at 12 days – weekly testing for the first month, then monthly) with no reappearance over a three-month period of genital sampling [28]. Longest detection of viral RNA in female genital secretions is at day 13 and 14 after onset [29,30].

A summary of evidence for sexual transmission is outlined below.

As of 17 October 2016, events of sexual transmission of Zika virus were reported from symptomatic men to female partners [26,31-36], from asymptomatic men to female partners [37,38], from a symptomatic man to his male partner [39] and from a symptomatic woman to her male partner [40]. The secondary female cases were infected after condomless vaginal intercourse and/or fellatio with ejaculation. The secondary male case had unprotected receptive anal intercourse with his infected partner.
Events of sexual transmission with less detailed information on sexual exposure (from symptomatic men to female partners) were reported through the WHO-IHR platform (Argentina, Chile, Peru), EWRS (Netherlands) and media (Canada). There was one WHO situation report and a media report on transmission from an asymptomatic man to his female partner (Portugal).

Five European countries reported sexual transmission events, all from male partners to females: France (3 from published literature, 11 from TESSY), Italy (1 published literature, 2 TESSy), Netherlands (1 EWRS and TESSy), Portugal (1 WHO report and TESSy) and Spain (1 literature, 1 TESSy). Exposure of the primary cases (when reported) took place in: Brazil (2), Guatemala (1), Maldives (2), Martinique (1), Puerto Rico (1) and Thailand (1). Non-European countries reporting sexual transmission include: Argentina (1), Canada (1), Chile (1), New Zealand (1), Peru (1) and the US (7).

With one exception, all events of sexual transmission were reported in couples with males as primary cases and were linked to sexual contact a few days before (≤7 days) or after (≤10 days) the onset of symptoms in the male case. The median time between first reported sexual contact with a primary case and symptoms onset in the secondary case was 9.5 days (IQR 7.5,12.25 days) [41]; the longest period between sexual contact with a symptomatic man and onset of symptoms in the secondary case was estimated at between 32 and 41 days [35].

Among the reported cases of sexual transmission with information on Zika virus testing in semen, the longest duration of viral RNA detection after onset of symptoms was 96 days [25]. Two studies presented the results of longitudinal follow-ups of virus persistence in semen from symptomatic men. Both studies demonstrated that virus RNA could be detected at as long as six months after symptom onset [23,24]. The duration reported previously by Barzon et al. appears to be longer and could reach up to eight months [Barzon, personal communication]. A study on a sample of five symptomatic men that were followed-up for virus RNA presence in semen showed RNA present for 69 days and 115 days after onset, respectively, in two of the five patients; in the other three, no RNA was detected at day 20, leading the authors to suggest that the length of virus excretion varies and may depend on viral and host characteristics. They concluded that long-lasting excretion might occur more frequently among symptomatic cases [27]. The results from a prospective follow-up study of ten male patients with Zika infection support the evidence for a wide range in the duration of virus RNA shedding: semen samples from all ten were negative for viral RNA between 128 and 146 days after onset [42].

The relevance of the prolonged presence of Zika virus RNA in semen with regard to the risk of sexual transmission remains unclear as only a few studies paired reporting of viral RNA with the presence of replicative/infectious virus particles. The longest reported detection of virus particles by culture in semen was at 69 days after onset in a man whose semen was tested on days 47, 69 and 96 (RT-PCR) [25]. The man, who had been vasectomised several years earlier, potentially infected his female partner after having sex seven days after his onset of symptoms. Detection of the virus in semen from a vasectomised man and of viral RNA in semen plasma from a man with azoospermia [37] suggest that Zika virus infection also involves the male genital organs (i.e. prostate, seminal vesicles, proximal or distal bulbourethral glands) and pre-ejaculate secretions, and are not restricted to spermatozoa. This also indicates that recommendations for the prevention of sexual transmission should include men with these conditions.

Detection of Zika virus antigens in the spermatozoa of a symptomatic man 56 days after Zika infection onset may indicate virus tropism for male sexual cells and may explain the prolonged viral persistence in semen [27].

Limited data exist on virus clearance from the female genital tract. A recent follow-up study of five Zika-infected women showed that virus RNA disappeared from the genital tract three weeks after symptom onset (last detection at 12 days – weekly testing for the first month, then monthly), with no reappearance over a three-month period of genital sampling [43]. Two recent case reports detected Zika virus RNA in vaginal swabs up to day 13 and 14 after onset [29,30]; previously, viral RNA was detected in genital secretions 11 days after onset [43].  

Limited data about the presence of viable virus, viral load or kinetics in saliva and other oral secretions are available through case reports. A study on non-human primates reported extended Zika virus shedding in the saliva – as opposed to viral shedding in the blood – suggesting that the oral mucosa can sustain viral replication over extended periods and may facilitate viral transmission beyond the symptomatic period [44]. However, the effective role and the risk that saliva poses with regard to Zika transmission still remain to be defined.

The risk that Zika virus infection turns into a sexually transmitted epidemic was estimated as low in a modelling exercise which used a simple model previously used for HIV transmission dynamics. Zika virus would need to be twice as infectious as HIV, and an individual would need to remain infectious for more than one year for the basic reproductive number R0 to approach a value of 1 [41].

The evidence for formulating recommendations for the prevention of sexual transmission is limited. Several main gaps that warrant further research are:

  • Studies describing the duration of Zika virus persistence in the male genital tract and in semen, viral load dynamics, significance of prolonged shedding of viral RNA for sexual transmission/infectivity
  • Factors driving viral kinetics/clearance in semen (e.g. haematospermia, symptomatic versus asymptomatic infection)
  • Studies on virus clearance in asymptomatic men and duration of infectiousness
  • Testing algorithms and methods for assessing infectiousness of semen or other bodily fluids potentially involved in sexual transmission
  • Better estimates of the burden and risk of sexual transmission through modelling or other studies; such estimates can build on the evidence from case reports described in the literature. The lack of comprehensive surveillance and the likelihood of missing/under-ascertaining asymptomatic cases increases the need for such studies.

Diagnosis

No major developments in this area were reported since the last scientific development update, which was published on 29 August.

Prevention and vaccine development

The primary goal of vaccination will be to prevent infection and protect against serious sequelae, particularly congenital anomalies following in utero infection. Challenges for vaccine development include several important questions, some of which are currently being explored such as the characteristics of a vaccine-elicited immune response capable of preventing vertical transmission [45].

Vector control

In the context of the Zika virus outbreak in Miami-Dade County (Florida, Unites States), the initial control efforts to reduce the number of Aedes aegypti mosquitoes included the reduction of mosquito-breeding sites and larviciding and ground-based mosquito control with pyrethroid insecticides [46]. Aerial sprayings with an organophosphate insecticide were alternated with aerial larviciding with Bacillus thuringiensis (subsp) israeliensis because of the persistence of high numbers of Aedes aegypti mosquitoes. The implementation of the aerial spraying resulted in a drop of the vector density in the treated area and most likely contributed to a decrease in Zika virus transmission. The density threshold of Aedes aegypti below which transmission is interrupted is unknown, and although the application significantly reduced the Aedes aegypti populations, its precise impact on the decrease in Zika virus transmission cannot be definitively established [46].

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