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Report

Teaser, summary, work performed and final results

Periodic Reporting for period 1 - ZIKAction (ZIKAction: Preparedness, research and action network on maternal-paediatric axis of ZIKV infection in Latin America and the Caribbean)

Teaser

Summary

The ZIKAction project was designed to address key knowledge gaps related to ZIKV epidemiology, natural history and pathogenesis with particular emphasis on maternal and child health. This research is important for society because, while sufficient evidence exists to infer a causal relationship between prenatal ZIKV infection and microcephaly and other severe brain anomalies, much remains to be elucidated regarding the natural history of ZIKV infection in pregnancy and childhood and the medium and long term sequelae of exposure to ZIKV in utero.
The first objective includes a prospective cohort studies in ZIKV-affected countries in LA and the Caribbean to assess pregnancy and fetal/infant outcomes of ZIKV in pregnancy, the risk of vertical transmission by gestational age, and the incidence of ZIKV in pregnancy and during the postnatal period in epidemic situations. This information will inform the second objective of the project to develop harmonized case definitions for congenital ZIKV infection and define its natural history through a registry of paediatric patients exposed to ZIKV in utero and/or presenting with symptoms of congenital ZIKV syndrome. The third objective is to use animal models to better understand the timing and mechanisms of ZIKV vertical transmission and to assess the causal role of ZIKV infection during pregnancy on fetal malformation and other adverse pregnancy outcomes with the use of ovine models. Human placental explants are also being used to better understand how the Zika virus interacts with placental tissues and identify factors influencing vertical transmission.
We also aim to assess laboratory diagnostics and establish clinical algorithms for rapid diagnosis of ZIKV in pregnant women, infants and children. Improved diagnostics lead to more timely and accurate information on infection, helping to avoid anxiety related to false positive test results and give more definitive results to patients and their families. A final objective of the ZIKAction project is the harmonization of activities with ZikaPLAN and ZIKAlliance.

Work performed

For epidemiologicaland operational reasons, it was decided that the cohort study should investigate vertical transmission of DENV and CHIKV as well as ZIKV, the rationale being: a) testing for these arboviruses will allow for exploration of previous arbovirus infection as a factor in determining outcomes, and will avoid missing ZIKV infections due to cross-reactivity with DENV, b) the few prior prospective VT studies on DENV and CHIKV and c) concerns that incidence of ZIKV might substantially decrease (which was shown to be the case). The study was implemented across five antenatal centres and three hospitals in Jamaica. The protocol was created along with all necessary supporting documents including ethics and regulatory approvals. By March 2018, 349 pregnant women had been enrolled and followed; there were 201 deliveries, with 204 newborns. Serological testing is underway, with ZIKV IgG positivity around 70% and 99% of samples positive for DENV IgG as well. Four newborns were diagnosed with congenital microcephaly. VT prospective cohort study materials were also adapted for Haiti and successfully submitted for competent authority approvals.
Using sample panels available in Rio, ZIKAction partners compared the performance of Euroimmune and CDC IgM assays. Output from this comparison informed the serology testing algorithm used in the prospective VT cohort study in Jamaica, where information is available from 429 sera tested with Inbios and Novatec IgM assays. For IgG, comparisons were made on the same sample panels between the Euroimmune NS1 assay and the no longer available BOB assay. Promising results have been obtained from a non-commercial assay based on the ED3 antigen developed in Hamburg, Germany. Additionally, a protocol has been developed to assess the seroepidemiology of ZIKV, DENV and CHIKV in Jamaica using samples from before and during the recent ZIKV outbreak.
A protocol has also been developed for the registry of paediatric patients exposed to ZIKV in utero and/or presenting with symptoms of congenital Zika syndrome. A protocol for a case-control study of infants identified with microcephaly was developed and has been submitted for approval in Ecuador. A specific statistical analysis plan for the VT study, as well as for the microcephaly case control study was developed.
Great strides were made during this period to facilitate the proposed work with placental explants and a sheep model of ZIKV infection. The study protocol was approved by EC and an import permit was obtained for the ZIKV strain to be used in the studies as well as a material transfer agreement. In parallel, IZSVe developed and standardized microtitration of existing ZIKV strains on 96-well plates, scaling up the traditional high throughput method and providing a high throughput model allowing the processing of large numbers of samples.
For the ovine model studies, PRNT, PFU, rtPCR and IgM capture assays have been developed. Eight sheep, (4 pregnant and 4 control), have been inoculated with ZIKV at varying doses. No ill effects were reported, and all sheeps developed anti-ZIKV IgM within about a week of infection.
Together with the ZikaPLAN and ZIKAlliance, we established a shared Scientific Advisory Board and Ethics Advisory Committee. At the joint meeting in Antwerp in October 2017 these bodies provided specific advice for ethical issues in LA countries and sample management. A joint Data Protection and Sharing Committee has also been set up to provide expert input on discussions of virtual biobanking and data sharing initiatives. The consortia also worked together to establish a shared Communications Oversight Board, to harmonize communications activities of the three consortia. ZIKAction also led collaborative efforts with the other EU funded ZIKV consortia to produce a package of SOPs outlining key ethical, regulatory and legal issues. A cross-consortium working group was also set up in this period to begin work on a Joint Statistical A

Final results

Improved knowledge of the specific risks faced by pregnant women and their infants in the context of ZIKV outbreaks is needed to identify potential interventions to prevent ZIKV. Health care professions working in ZIKV-affected regions urgently require evidence-based guidelines in order to provide the optimum clinical care to pregnant women and their children, whilst data on incidence of ZIKV in pregnancy and outcomes of this are also needed.

Despite a significant reduction in the number of cases of ZIKV, major evidence gaps related to the natural history of congenital ZIKV and the risk of transmission still remain. In terms of updating, some of the information presented has been revoked in many areas, such as Jamaica. Our preliminary seroprevalence work in Jamaica suggests that around 30% of currently pregnant women may have no evidence of prior ZIKV infection, and thus will be susceptible to infection in current or future pregnancies. We have embedded new studies such as the development of the microcephaly case-control study and the retrospective VT study in Cabo Verde. Broadly, these will address the same evidence gaps as the originally envisioned studies, but using a different approach given the epidemiological situation.