Building Zika preparedness in the Region of the Americas: research response

Update 23 September 2016

Building Zika preparedness in the Region of the Americas: research response Global Research Collaboration for Infectious Disease Preparedness meeting, Sao Paulo, November 30 Ludovic Reveiz MD, MSc, PhD, Knowledge Management, Bioethics and Research Pan American Health Organization Organización Panamericana de la Salud www.paho.org 111 años de salud pública

Epidemiological summary of Zika virus disease 2015-16 As of November 2016, 48 countries / territories in the Americas have reported autochthonous cases 20 countries and territories in the Americas have reported confirmed cases of congenital syndrome associated with Zika virus infection 13 countries and territories have reported increase in Guillain-Barré syndrome (GBS) with zika lab confirmation in at least one case 5 Countries in the Americas have reported sexually transmitted Zika cases: Argentina, Chile, Canada, Peru and the United States.

Timeline Spread of the Zika Virus Disease in the Americas Zika in the Americas 3

Countries and territories in the Americas with confirmed congenital syndrome associated with Zika virus infection 3 Nov 2016 Countries reporting congenital syndrome associated with Zika virus 4 Number of confirmed cases to date Brazil 2 159 Bolivia 3 Canada 1 Costa Rica 2 Colombia 58 Dominican Republic 10 El Salvador 4 French Guiana 14 Grenada 1 Guatemala 15 Haiti 1 Honduras 2 Martinique 14 Panama 5 Paraguay 2 Puerto Rico 4 Suriname 2 Trinidad and Tobago 1 United States of America 31 Total 2330

WHERE PAHO WORKED PAHO has carried out activities in 30 COUNTRIES/TERRITORIES in LAC KEY FACTS on Z I K A V Totaling approximately 1,080 days of technical work in those priority countries. Source: PAHO database of missions and contracts Information is based on official missions financed by PAHO, during 2016. Missions are considered trainings, workshops, conferences and technical support carried out by PAHO experts. This chart considers missions finished, as of 28 October 2016.. Chart not contemplating missions to PAHO HQ in Washington DC

Future of Zika virus in the region Total population in the Americas living in areas < 2000 m above sea level and within the 10 o Celsius isotherms (North & South) delimiting survival of Aedes aegypti during winter in Tropical/Temperate climates (work in progress) 520 M people

Organización Panamericana de la Salud www.paho.org 111 años de salud pública

Organización Panamericana de la Salud www.paho.org 111 años de salud pública

Who is funding zika published research? Methods: A cross sectional study of primary research Articles on primary studies investigating Zika virus published from January 2007 to October 2016 Results: 268 met the inclusion criteria 48 countries with Brazil 49/268 (18.3%) and USA 59/268 (22.0%) conducting the majority of the research The laboratory study design 80/268 (29.9%); case reports 68/268 (25.4%) and case series 54/268 (20.1%); research involving animals 22/268 (8.2%). 60% reported source of funding; 57% public funding: 146 funding bodies are represented as the primary financial source of assistance for Zika Virus research. National Institute of Health (NIH) represents 22.6%.

Objectives of ZIKV Research Portal Objectives: The PAHO Zika Research Platform houses ongoing research protocols related to the ZIKV. Available at: http://www.paho.org/zika-research/ Methods: Protocols were included following in a systematic search of databases in Latin America, Caribbean and the U.S. Researchers were contacted directly following a systematic research in PubMed, Lilacs and Embase using the term Zika Protocols were included if they included: 1.) Research on the Zika virus or 2) Ongoing research related to the outcome of Guillain-Barre syndrome, Miller Fisher Syndrome. All study designs were accepted. Data was extracted through a standardized template and checked by an additional reviewer

Key Characteristics of Selected Protocols 264 protocols available 98 research institution involved, 46 institutions from Brazil Information extracted from protocols varied Countries Year n=258 2010 1 2014 1 2015 13 2016 243

Key Characteristics of Selected Protocols Protocols included in the ZIKV Research Platform database Classification of protocols by subtopic, N=264 N (%) Clinical management 90 (34.09) Epidemiology 79 (29.92) Disease pathogenesis and consequences of infection 37 (14.02) Public health interventions 23 (8.71) Health systems and services response 8 (3.03) Research and development of products 13 (4.92) Virus Vectors and Reservoirs 11 (4.17) Ethical aspects 3 (1.14)

Key Characteristics of Selected Protocols Protocols included in the ZIKV Research Platform database Type of study, N=76 Basic research 10 (13.16) Case control 13 (17.11) Case report 4 (5.26) Case series 5 (6.58) Clinical trials 1 (1.32) Cohort 32 (42.1) Cross sectional 8 (10.53) Experimental development 2 (2.64) Review and cost estimation 1(1.32) Study participants, N=213 Children 19 (8.92) Children presenting microcephaly 61 (28.64) GBS 17 (7.98) General population 53 (24.88) Health workers 5 (2.35) Macaques 2 (0.94) Men 5 (2.35) Military and families 1 (0.47) Placenta 2 (0.94) Pregnant women 16 (7.51) Pregnant women and children 31 (14.55) Women of reproductive age 1 (0.47)

Support and harmonization of research in countries: Standardized research protocols & results 1. Case-control study to assess potential risk factors related to microcephaly including Zika virus infection during pregnancy 2. Prospective longitudinal cohort study of newborns and infants born to mothers exposed to Zika virus during pregnancy 3. Prospective longitudinal cohort study of women and newborns exposed to Zika virus during the course of pregnancy 4. Prospective longitudinal cohort study of Zika-infected patients to measure the persistence of Zika virus in body fluids 5. Case-control study to assess potential risk factors related to Guillain-Barré Syndrome including Zika virus infection 6. Cross-sectional seroprevalence study of Zika virus infection in the general population Link: http://origin.who.int/reproductivehealth/zika/zika-virus-research-agenda/en/ IPD- Meta-analysis

Minimizing bias in observational studies Methods Presentation of potential bias in current studies Primary Risk to Study Tools & guides Study objective 1. Objectives are often unclear 2. Objectives are often inappropriate in relation to study design Feasibility Internal validity 1. Clearly defined objectives 2. Consideration of outcomes relevant to the study design Population 1. Unstandardized case definitions 2. Population-based vs. Hospital-based 3. Inclusion criteria 4. Exclusion criteria Selection bias External comparability Use & implement. of standardized Congenital Microcephaly Case Definitions Newborn: with microcephaly vs. all newborn exposed to congenital infection Children: with microcephaly vs. all children exposed to congenital infection Use of WHO interim case definitions for ZIKV Standardized definition of symptomatic/asymptomatic infection 15

Minimizing bias in observational studies Methods Presentation of potential bias in current and future studies Sample size 1. Difficulties in the recruitment of cases 2. Unknowns in recruitment time, considering that the epidemic peak and the unknown epidemiology pattern of ZIKV infection is unknown. Primary Risk to Study Power Feasibility Costs Tools & guides Consider the sample size according to the hypothesis and to design of study. Power 80%. Confidence level 95%. 3. Underuse of multicenter studies. 4. Variations in matching criteria In case control study the ratio case: control: 1:1 until 1:4 5. Variations in ratio case to control in case control studies Recruitment 1. Simultaneously recruitment and follow-up in exposed and non-exposed cohort or case and control. Selection bias Confusion bias Controls should provide an accurate representation of the exposure status of the source population 16

Minimizing bias in observational studies Methods Presentation of potential bias in current and future studies Follow up 1. Ensuring a consistent follow-up time in exposed and non-exposed cohort. 2. Allowing enough time to evaluate the psychomotor development in children. 3. Appropriate instruments to collect the information. Primary Risk to Study Information bias External comparability Tools & guides Standardized the need for ultrasounds to be carried out in a standardized frequency. Follow-up to monitor adverse events in pregnancy Consider follow up weekly by telephone and monthly face-to-face. Follow CDC recommendation of follow up for newborn and children for at least 30 months Consider hearing and ophthalmologic evaluations along with examinations of the retina. 17

Minimizing bias in observational studies Methods Presentation of potential bias in current and future studies Primary Risk to Study Tools & guides Exposure 1. Collection of samples consistent in exposed and non-exposed (Blood, urine, CSF, saliva samples and others). 18 2. Using the same test to confirm/discard ZIKV infection in exposed and non-exposed cohort or case and control. 3. ZIKV infection confirmed by laboratory vs clinical diagnosis (suspected, probable and confirmed). 4. Diagnosis tests of ZIKV infection depending of the phase (acute or convalescence phase): RT-PCR, serology diagnosis, culture, and others. Clearly diagnostic algorithm 5. Diagnosis tests of ZIKV infection in asymptomatic infections (Serology IgM, IgG). 6. Differential diagnosis with other locally circulating flaviviruses or other exanthematous diseases. 7. Storage of biological samples for future complementary studies Information bias External comparability Sample in Asymptomatic : Serum sample for serology (PRNT 90 for Zika virus with titre 20 and Zika virus PRNT 90 titre ratio 4 compared to other flaviviruses). ELISA IgM positive with neutralizing antibody titers against Zika virus, at levels 4-fold higher than those against dengue virus Sample in Symptomatic: RT-PCR: Blood or saliva until 8 days after symptoms onset or urine sample until 14-20 days after symptoms onset. GB: RT-PCR urine samples until 15-20 after onset of neurological symptoms. Newborn with microcephaly: ELISA IgM on blood sample and IgM in CSF until 1-40 days. Stillbirth: RT-PCR of brain, cerebroespinal and amniotic fluids, placenta, umbilical cord. Immunohistochemistry of brain or chorionic villi from miscarriages

Minimizing bias in observational studies Methods Presentation of potential bias in current and future studies Outcomes 1. Clearly definition: Standardized definition (primary, secondary and tertiary outcomes). 2. Demonstration that outcome of interest was not present at start of study in exposed and non-exposed cohort. 3. Same measures in exposed and nonexposed cohort or case and control. 4. Standard: questionnaires, scales, images (USG-TF, MR, CT), physical examination, samples and other measures. 5. Same schedule of measures in exposed and non-exposed cohort or case and control. Primary Risk to Study Information bias External comparability WHO definition of: - Microcephaly Tools & guides -Congenital syndrome associated with Zika virus infection. -Zika-virus-associated abortion or stillbirth -GBS - Vertical transmission without congenital syndrome 19

Regional Response Challenges Transition from 15 years Dengue surveillance to integrated arbovirus surveillance (DENV + CHIKV + ZIKV + YFV + MAYV + OROV + SLV.) Complex transition and numerous bottle necks for ZIKV PCR (SinglePlex to MultiPlex) and Zika serology, needs for follow-up Health Services and staff challenged by GBS characterization and management, needs for deployment of experts, IV Ig stock Change of paradigm for Vector Control: from house to house inspection to protection of pregnant women, from house index to virus surveillance in vectors, from insecticide use to new methodologies (GMM, Wolbachia) 20