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Recent scientific findings based on literature reviewed after the ninth update of the ECDC Rapid Risk Assessment on Zika virus infection (19 October to 27 January 2017)

ECDC comment

​This scientific advance presents relevant scientific literature and outlines the main findings from Zika virus research published between 19 October 2016 – the release date of the ninth update of ECDC’s Zika risk assessment – and 27 January 2017.

This scientific advance presents relevant scientific literature and outlines the main findings from Zika virus research published between 19 October 2016 – the release date of the ninth update of ECDC’s Zika risk assessment – and 27 January 2017.

Pathogenesis 

An in-depth retrospective assessment on Zika virus genetic evolution, based on complete genome sequences from a total of 55 Zika virus isolates, showed that the estimated substitution rate is higher in the Asian lineage compared with the African lineage. This higher genetic evolution rate has maintained a relatively higher level of diversity since 2013 and might have contributed to the higher adaptability and fitness of this strain [1].

 

Progress in stem cell-based Zika virus research since the emergence of the Zika virus in 2015 have been exhaustively reviewed by Ming and et al. [2].This review provides a synthesis focusing on the virus cycle and its structures, its molecular and cellular mechanisms, and its pathogenesis.

 

Additional research continues to investigate pathogenicity mechanisms of Zika virus on maternal and foetal cells:

  • Using an ex-vivo model mirroring the maternal-foetal interface from the first trimester of pregnancy and a Zika strain from Brazil isolated in 2016, Costa et al. present additional evidence of Zika virus’s broad cellular tropism infecting a wide range of maternal and foetal cells including decidual fibroblasts and macrophages, trophoblasts, Hofbauer cells as well as umbilical cord mesenchymal stem cells [3]. The cytopathic-induced tissue damages on first trimester foetal placenta provide evidence on how Zika virus spreads to the foetus and point toward potential mechanisms leading to associated congenital defects.
  • In vitro experiments showed that strains from both lineages (an African strain isolate from the Central African Republic in 1989 and an isolate from French Polynesia in 2013) are efficiently targeting neural stem cells and differentially affect cellular responses [4]. The African strain showed a higher rate of infection, viral production and cellular response (cell death and anti-viral response) compared to the Asian isolate. Further research on African strain neurotropism and neurovirulence are required to better understand the different molecular patterns and the consequences for congenital infection risk in areas where the African strain of Zika virus is circulating.
  • Histological investigations on tissue samples from a case series of eight fatal cases of microcephaly and 44 women suspected of being infected with Zika virus during pregnancy demonstrate localised replicative Zika virus RNA in the brains of seven infants and the placentas of nine women (including pregnancy losses during the first or second trimester) [5]. This study confirmed that the virus replicates and persists in the foetal brain and the placenta and gives further evidence of the association between Zika virus infection and congenital impairments.

New findings, based on a mouse model of infection, support that Zika virus causes testicular and epididymal damage:

  • Govero et al. reported the persistence of Zika virus in the testes, epididymis, the fluid from the epididymis, and the mature sperm of male mice at day seven and 14 days after inoculation by African or Asian Zika virus strain [6]. The Zika virus infection induced alteration of seminiferous tubules and infected spermatogonia, primary spermatocytes, and Sertoli cells in the testes. Reduced rates of pregnancy and numbers of viable foetuses were observed among female mice that mated with Zika virus-infected males compared to uninfected males.
  • In another mice model, Ma et al. observed that Zika virus can provoke inflammation of the testes and epididymitis after 60 days post-infection [7]. The prostate and seminal vesicles were spared from Zika virus infection. Studying the innate immune response of Zika virus infection on several cellular populations of the male reproductive system, the authors report that testicular peritubular-myoid cells and spermatogonia are vulnerable to Zika virus infection and hypothesise that peritubular cells and spermatogonia might be potential repositories for Zika virus.

It is not known how far these results obtained from mice models can be extrapolated to humans. Nevertheless, these studies increase concerns about the possibility of Zika virus infection causing testicular damage and potentially impair male fertility. These new findings bolster support for further investigations, especially during the clinical and laboratory follow-up of Zika virus-infected men.

As previously described by Dejnirattisai et al. [8], additional in vitro studies showed the potential of dengue virus antibodies to enhance Zika virus infection through antibody-dependent enhancement, suggesting that pre-existing dengue virus immunity may enhance Zika virus infection in vivo [9,10]. Research projects are trying to determine if this phenomenon may lead in vivo to more severe complications, particularly for pregnant women.

Clinical features and sequelae 

 

Congenital Zika syndrome

A preliminary report on 476 cases of microcephaly identified in the Colombian national birth defects surveillance programme between January and November 2016 demonstrated a fourfold increase compared to the same period in 2015 [11]. Thirty-four percent of mothers reported symptoms consistent with Zika virus infection during pregnancy. Infants or foetuses with microcephaly had laboratory investigations including karyotyping and testing for congenital infections (Zika virus, syphilis, toxoplasmosis, rubella, cytomegalovirus, herpes simplex, and other agents). Among two-third of the individuals (n=306) who were tested for Zika virus infection, 147 (48%) had laboratory evidence of Zika virus infection (serologic evidence MAC-ELISA or RT-PCR or immunohistochemistry on any specimen). The temporal correlation with the Zika epidemic in Colombia indicates a higher risk for microcephaly during the first trimester and early in the second trimester of pregnancy.

 

An updated analysis of the Rio de Janeiro cohort of pregnant women has been published [12,13]. Brasil et al. reported a prospective investigation of pregnancy outcomes among women who had a skin rash within five days prior enrolment (n=345) [12]. Overall, 182 (53%) women had positive results for Zika virus based on PCR (blood, urine, or both). The study focused on 61 Zika virus-negative women and 125 Zika virus-positive women with expected dates of delivery near the end of July 2016. Demographic characteristics or medical history between the two groups were not significantly different, except that Zika virus-negative women were more likely to have used insect repellent. Dengue IgG antibodies were present in 88% of the women (in both groups). Zika virus-positive pregnancies resulted in 46% of adverse outcomes compared to 11.5% for Zika virus-negative pregnancies. The adverse outcomes occurred regardless of the presumed trimester of Zika virus infection (55% of pregnancies had adverse outcomes after maternal infection in the first trimester, 52% after infection in the second trimester, and 29% after infection in the third trimester). Among live infants born after Zika virus infection during pregnancy, 42% were found to have abnormal clinical or brain imaging findings or both in the first month of life (including four microcephaly cases). Neurologic examinations revealed neurological symptoms such as hypertonicity, clonus, hyperreflexia, abnormal movements, spasticity, contractures, and seizures. An imaging study using trans-fontanel ultrasonography, computed tomography (CT) and magnetic resonance imaging (MRI) revealed several CNS impairments in newborns (cerebral calcifications, cerebral atrophy, ventricular enlargement, and hypoplasia of cerebral structures) infected as late as 34 weeks of gestation.

 

Data from the US Zika Pregnancy Registry were analysed to evaluate pregnancy outcomes in 442 women with laboratory evidence of Zika infection during pregnancy (acquired abroad or sexually from a traveller) [14]. Among 395 live births, 21 infants with birth defects were identified; five additional foetuses with birth defects were identified in 47 pregnancy losses for an overall rate of 6% of primarily brain abnormalities with or without microcephaly, and eye defects. Among pregnancies with confirmed Zika infection during the first trimester, nine of 85 infants (11%) had abnormalities at birth. In contrast, infants born following maternal Zika infection during the second or third trimester did not have birth defects. Therefore, the authors stated that was a higher risk of birth defects in women in the pre-conception period or first trimester. The risk for birth defects was similar for symptomatic (10/167, 6%) and asymptomatic infections (16/271, 6%). Among the limitations of this type of studies, there might be an under-ascertainment of asymptomatic cases as only women with Zika virus testing were included and the long-term anomalies of congenital Zika syndrome were not considered [15,16].

 

Results of follow-ups of pregnancies with laboratory evidence of Zika infection from both the US Zika Pregnancy Registry and the cohort of Rio de Janeiro demonstrate a significant rate of adverse pregnancy outcomes and severe impairment of foetal development in Zika virus-positive pregnancies. The reasons for the large discrepancies are not clear at this stage. Nonetheless, these findings strongly support the need for long-term follow-ups, with a particular emphasis on neurological, visual and hearing development [12,14].

 

Moore et al. reviewed the characteristics of the congenital Zika syndrome for paediatric clinicians, providing practitioners with a global understanding of the current knowledge of the syndrome’s clinical presentation [17]. However, the full clinical spectrum of Zika congenital syndrome is still under scrutiny as illustrated by the recent case series about congenital Zika virus infection without microcephaly at birth [18]. This retrospective assessment focussed on 13 infants from the Brazilian states of Pernambuco and Ceará with normal head size at birth and laboratory evidence of congenital Zika virus infection. The authors recommended early neuroimaging for infants exposed to Zika virus prenatally and a subsequent follow-up because the absence of microcephaly at birth does not exclude congenital Zika virus infection, a postnatal decreases in the rate of head growth nor the presence of Zika-related brain defects and other abnormalities associated to Zika congenital syndrome.

 

Guillain–Barré syndrome

The first large case series (n=68) on the clinical and laboratory characteristics of Guillain–Barré syndrome (GBS) potentially associated with Zika virus infection in Colombia has been published  [19]. A total of 66 patients had symptoms of Zika virus infection in the four weeks preceding the onset of neurologic symptoms, which supports a temporal relationship between the Guillain–Barré syndrome and Zika virus infection. All patients fulfilled the Brighton criteria for Guillain–Barré syndrome, and 50% had a bilateral facial paralysis on examination. Nerve-conduction studies and electromyography were performed on 46 patients, 36 of whom presented an acute inflammatory demyelinating polyneuropathy. The pathophysiological mechanism of GBS after Zika virus infection, either by direct viral neuropathic mechanisms, hyperacute immune response, or post-infectious molecular mimicry, remains to be elucidated [20]. Additional case reports and case series in Colombia and Puerto Rico were published since the last scientific update, supporting the association between of Zika virus infection and GBS cases [21-23] now endorsed by the WHO Zika Causality Working Group [24].

 

Other complications

Additional case reports about atypical presentation or rare complications of Zika virus infection were reported in the literature: three cases of fatal outcomes [25], seven cases of severe thrombocytemia in Guadeloupe [26] (bringing the total number of reported case in the literature up to 16 cases), a final case report of three cases of transient hearing loss in adults [27], one case of bilateral posterior uveitis [28], a second case of encephalomyelitis in Brazil [29,30], one case of transient myocarditis [31] adding to previous report of two cases with potential acute myocardial impairment by Zonnevled [32]. As expected, several acute co-infections with dengue virus and chikungunya have been reported, raising the importance of appropriate multiplexed arboviral testing [33,34].

 

Epidemiology

Seroprevalence surveys were conducted among the French Polynesia population during/following a Zika outbreak in French Polynesia (October 2013–April 2014) [35]. The Zika virus seroprevalence rate was 49 % in the general population on the islands of the archipelago, and 66% in schoolchildren from Tahiti. The asymptomatic–symptomatic ratio was estimated at 1:1 among the general population, contrasting with the group of schoolchildren where it reached 1:2 (71% of symptomatic cases). Overall, 50% of the population of French Polynesia had detectable Zika virus IgG. This is less than estimated by modelling study [36]. Herd immunity is lower than expected, suggesting that French Polynesia remains susceptible to a new outbreak of Zika virus if the virus is reintroduced.

 

In Puerto Rico an exhaustive Zika epidemiological surveillance was conducted between November 2015 and October 2016. A total of 62 500 suspected Zika virus disease cases were reported, 45% of which were confirmed and 2% were presumptive Zika virus cases [37]. The estimated incidence of confirmed and presumptive Zika virus disease was 844 cases per 100 000 residents. The reported incidence of clinically suspected Zika virus disease cases was 75% higher in non-pregnant females than in males. A difference between male and female incidence has been observed in several countries of the Americas (e.g. Bolivia, Brazil, Colombia, Dominica, the Dominican Republic, and Panama) and remains to be elucidated [38].

 

Several studies postulated a high probability of establishment of sylvatic Zika virus transmission in the Americas and raise the question about the eco-epidemiology of Zika in areas that have experienced widespread virus transmission since 2015 [39,40].New insights on virus circulation in southern Asia were published, supporting Zika virus circulation in the region, notably in Cambodia (2007 to 2009 and 2015) and in Laos (17 residents of the capital Vientiane between June 2012 to September 2013) [41-43].

 

The performance of several Zika case definitions (the US CDC and Council of State and Territorial Epidemiologists, WHO, WHO PAHO, ECDC, and the Singapore Ministry of Health) were assessed by using a cohort of 359 adults with suspected Zika virus disease during a consultation at the national referral centre for Zika virus, Tan Tock Seng Hospital, Singapore [44]. Symptoms of all patients were documented and laboratory confirmations performed through RT-PCR on blood and urine samples. The US case definition had a low specificity of 2% and a sensibility of 100%. Case definitions by ECDC, the Singapore Ministry of Health and WHO PAHO performed in a similar manner (around 60% positive predictive value and 70% negative predictive value) but fared better compared to the WHO case definition. The authors advocate that rash should be added as a symptom to the Zika case definition for epidemiological surveillance.

 

Transmission

 

Mosquito transmission

The Zika virus vector competences of Aedes albopictus (Germany and Italy), Aedes aegypti and different Culex species mosquitoes from Germany – Culex pipiens, modestus and torrentum – were assessedat two laboratory temperatures (18 °C and 27 °C) and two time points (14 and 21 days post-infection (dpi)). Transmission rate defined as the number of mosquitoes with Zika virus-positive saliva per number of Zika virus-positive mosquito bodies, were null for all Culex species. At 27 °C, the transmission rate for Aedes albopictus from Italy ranged from18% at 14 dpi to 13% at 21 dpi. Remarkably at the same temperature, Aedes albopictus from Germany showed higher transmission rate ranging from 20% at 14 dpi and 33% at 21 dpi and were almost comparable to Aedes aegypti at 21 dpi (45% at 14 dpi and 31% at 21 dpi).

This new assessment of Zika virus vector competences of Culex species mosquitoes confirms that Culex pipiens mosquitoes do not transmit Zika virus as previously reported from Italy and the USA (California and New Jersey) [45,46].With regard to entomological surveillance, a recent study showed that Zika virus can be isolated on cell culture from infected mosquito specimens stored at room temperature for up to 9 days [47]. Furthermore, viral RNA can be detected up to 30 days using molecular techniques. 

Transmission by sexual contact

Several recent publications may further contribute to the evidence-base and the understanding of sexual transmission:

 

  • In longitudinal follow-up studies using PCR for the detection of viral RNA in symptomatic men, viral RNA was detected in sperm six months and more after the onset of the disease [48,49], with the longest duration of at least twelve months (intermittent detection of low viral load [Luisa Barzon, personal communication]. The immune-privileged nature of the male testes may explain the persistence of Zika virus in these tissues, potentially acting as a reservoir for the virus [7].
  • The detection of Zika virus RNA until day 77 after onset of symptoms in the ejaculate of a vasectomised patient [50] is in line with previous observations [51], suggesting that Zika virus infection also involves distal portions of the male genital organs (i.e. prostate, seminal vesicles, proximal or distal bulbourethral glands), pre-ejaculate secretions and in this study presumably inflammatory cells, and is not restricted to spermatozoa. The isolation of Zika virus through cell culture was possible up to 21 days post symptom onset [50]. This observation is in line with other studies on the timeframe of sexual transmission events, which have been reported mostly within three weeks of onset of symptoms; it indicates the need for vasectomised men to follow sexual transmission prevention recommendations.
  • Data on virus clearance from the female genital tract are still limited. A recent study reported positive viral culture from a vaginal swab on day three after symptom onset in a woman with well-controlled HIV infection returning from the French Caribbean [52]. A second swab on day 10 was negative, supporting a short duration of infectivity of women with acute Zika virus infection through genital secretions [52]. The longest reported duration of virus RNA in vaginal swabs was 14 days after onset [53].
  • In a mice model, Tang et al. demonstrated that intravaginal deposition of Zika virus can cause transgenital transmission and that hormonal changes in the female reproductive tract influence transmission; Zika virus replication persisted in the female mouse genital tract for 10 days after infection [54]. The finding that transgenital transmission is progesterone-dependent lead the authors to infer that progesterone-based contraceptive strategies in women may alter the infectivity of Zika virus. Hormonal stage of the female mouse oestrous cycle might influence susceptibility to vaginal infection, transgenital transmission, and persistence of viral replication in the female genital tract.

Limited data are available on the presence of viable virus, viral load or kinetics in saliva and other oral secretions. A study on non-human primates reported extended Zika virus shedding in saliva – up to day 28 after infection, compared with up to day seven in blood – suggesting that the oral mucosa can sustain viral replication over extended periods and may facilitate viral transmission beyond the symptomatic period [55]. In humans, Zika virus RNA has been detected in saliva up to 29 and 49 days after onset; it could also be detected from Zika virus isolated in cell culture from samples taken six days after symptom onset [50,56]. The role and risk that saliva poses with regard to Zika transmission remains to be defined.

The risk that Zika virus infection turns into a sexually transmitted epidemic in settings where vector-borne transmission is absent has been estimated as low [57]. Modelling estimates for the contribution of sexual transmission to Zika epidemics are limited. Towers et al. estimated that sexual transmission accounted for 23% (95% CI 1–47%) of cases when the reproductive number for sexual transmission was assumed to be below 1 in a model calibrated on data from an area experiencing the early exponential growth phase of a vector-borne Zika virus outbreak (Barranquilla, Colombia, until November 2015) [58]. Gao et al. estimated that sexual transmission contributed 3% of cases (95% CI: 0.1–46%) in a model calibrated to epidemic data from Brazil, Colombia and El Salvador [59]. According to Towers et al., adjusting the methodology used by Gao et al. to their methodology leads to an approximate estimate of around 9% of cases being sexually transmitted. Both studies report very wide confidence intervals, and more research is needed to determine better estimates of the contribution of sexual transmission to Zika epidemics. The lack of comprehensive surveillance and the likelihood of under-ascertainment of asymptomatic cases increases the need for further modelling studies to provide better estimates of the burden and risk of sexual transmission.

To further strengthen the evidence around prevention of sexual transmission, comprehensive research needs to address, in symptomatic and asymptomatic individuals, the kinetics and location of Zika virus persistence in the male genital tract and its potential timeframe of infectivity through sexual transmission. 

Diagnosis 

Whole blood appears to be a relevant sample for late detection of viral RNA detection in comparison with plasma or serum. One subject tested positive (by RT PCR), with detection up to 101 days post-infection [50], confirming previous observations from Lustig et al. [60] and Murray [53].

Additional case reports provided supplementary information about the prolonged detection of Zika virus by RT-PCR in the blood of a pregnant woman infected by Zika virus. Maternal viraemia was reported for up to 107 days (15 weeks) in a pregnant woman who developed rash at nine weeks of pregnancy [61]. At that date, the foetal infection was unnoticed; there were no apparent abnormalities during a scan in weeks 12 and 15. The viral RNA load in maternal blood was lower than in the foetus amniotic fluid tested in week 19 of the pregnancy. This case report is in line with previous observations suggesting that long-term Zika virus viraemia in infected pregnant woman might point towards a possible foetal infection [62,63].

The testing of neonates for Zika virus infection may require specific investigations, including detection of IgM antibodies which do not normally cross either the placenta or the blood-brain barrier. A Brazilian study showed the importance of IgM antibodies in neonate serum to confirm congenital Zika virus infection; equally important is the detection of IgM antibodies in the cerebrospinal fluid of neonates with microcephaly for confirming a neurologic infection [64].

Improving serological assay performance for Zika virus is a priority. A multi-cohort study conducted by European laboratories using an NS1-based antigen showed high specificity for the detection of Zika virus IgM and IgG antibodies and a low cross reactivity with dengue antibodies [65]. The study provided promising results and also reported the importance of combining the detection of IgM and IgG antibodies for Zika virus infection investigation. In the absence of a panel of well-identified Zika viruses from human samples, it is not possible to conduct comparative studies with other serological assays, including the gold standard neutralisation test.  

Prevention, treatment and vaccine development

Wang et al. tested specific human monoclonal antibodies neutralisation capacity from a single patient infected with Zika virus [66]. Two antibodies (namely Z23 and Z3L1) revealed potent Zika virus-specific neutralisation in vitro without binding or neutralising activity against strains 1 to 4 of dengue virus. The antibodies bound to tertiary epitopes in envelope protein domain. Additional investigations on potential antibody-dependent cellular and complement-dependent cytotoxicity should be conducted. These results support the potential of antibody-based therapeutics and provide a rationale for the design of future Zika virus-specific vaccines.

 

Several antimalarial compounds such as amodiaquine and derivatives were shown to have potent anti-dengue viral activity against dengue virus in cellular model. Three additional compounds, quinacrine, mefloquine, and GSK369796 have shown significant anti-DENV and anti-Zika virus activity in laboratory conditions [67]. In addition, chloroquine antiviral activity against Zika virus (Asian and African strain) was observed on Vero cells, human brain microvascular endothelial cells, human neural stem cells, and mouse neurospheres.

 

Choloroquine induced a reduction of Zika virus-infected cells in vitro and inhibited virus production at non-cytotoxic concentrations. Interestingly, treatment of Zika virus-infected mouse neurospheres showed a partial reversion of morphological changes induced by Zika virus infection [68]. Interestingly, chloroquine is able to reach the foetal plasma at half maximal effective concentration as indicated by Delvecchio et al. [68]. Chloroquine is an FDA-approved molecule for malaria treatment and prophylaxis for pregnant women.

 

Azithromycin, belonging to the macrolide antibiotics group, is generally considered safe during pregnancy and has been shown to reduce Zika virus viral proliferation and cytopathic effects in glial cell lines and human astrocytes [69].

 

Sofosbuvir, an FDA-approved nucleotide polymerase inhibitor for the treatment of hepatitis C infection, reduces replication of multiple Zika virus isolates in the human liver, placental cells and neuronal stem cells. The drug also protects infected mice against Zika virus-induced death [70].

 

The therapeutic potential against Zika infection of the above three components – alone or in association with other molecules with anti-flavivirus activity – warrants further investigation on the reduction of Zika virus infection.

 

A few Zika candidate vaccines are presently under phase I trials, including a DNA-based vaccine (GLS-5700) [71] and a vaccine using the mRNA technology [72]. 

 

Vector control

A meta-review of 13 systematic reviews assessing the effectiveness of any Aedes control measures using the GRADE criteria showed that educational campaigns help to reduce breeding habitats and that biological controls might attain a better reduction of entomological indices than chemical controls [73,74]. However, the authors recommend better designed studies and observational methodologies as quality of evidence was low to poor. Appropriate quality studies to assess the impact of vector control interventions on the incidence of Aedes-borne human infections are required to produce evidence-based recommendations.  

 

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