Update 23 September 2016

Organización Panamericana de la Salud – www.paho.org

111 años de salud pública

Ludovic Reveiz MD, MSc, PhD, Knowledge Management, Bioethics and Research Pan American Health Organization

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

Global Research Collaboration for

Infectious Disease Preparedness meeting,

Sao Paulo, November 30

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

3Zika in the Americas

4

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

Number of confirmed cases

to dateBrazil 2 159Bolivia 3Canada 1

Costa Rica 2Colombia 58

Dominican Republic 10El Salvador 4

French Guiana 14Grenada 1

Guatemala 15Haiti 1

Honduras 2Martinique 14

Panama 5Paraguay 2

Puerto Rico 4Suriname 2

Trinidad and Tobago 1United States of America 31

Total 2330

PAHO has carried out activities in

30 COUNTRIES/TERRITORIES

in LAC

Totaling approximately

1,080 days of technical workin those priority countries.

WHERE PAHO WORKEDKEY FACTS on

Z I K A V

Source: PAHO database of missions and contractsInformation 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 10o 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

Year n=258

2010 1

2014 1

2015 13

2016 243

Countries

Key Characteristics of Selected Protocols

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)

Protocols included in the ZIKV Research Platform database

Key Characteristics of Selected Protocols Type of study, N=76Basic 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)

Protocols included in the ZIKV Research Platform database

Study participants, N=213Children 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

15

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

16

Methods Presentation of potential bias in current and

future studies

Primary Risk to

Study

Tools & guides

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.

3. Underuse of multicenter studies.

4. Variations in matching criteria

5. Variations in ratio case to control in case

control studies

Power

Feasibility

Costs

Consider the sample size according to

the hypothesis and to design of study.

Power 80%.

Confidence level 95%.

In case control study the ratio case:

control: 1:1 until 1:4

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

Minimizing bias in observational studies

17

Methods Presentation of potential bias in current and

future studies

Primary Risk to

Study

Tools & guides

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.

Information bias

External

comparability

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.

Minimizing bias in observational studies

18

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).

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 (PRNT90 for Zika virus with titre

≥20 and Zika virus PRNT90 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

19

Methods Presentation of potential bias in current and

future studies

Primary Risk to

Study

Tools & guides

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 non-

exposed 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.

Information bias

External

comparability

WHO definition of:

- Microcephaly

-Congenital syndrome associated with

Zika virus infection.

-Zika-virus-associated abortion or

stillbirth

-GBS

- Vertical transmission without

congenital syndrome

Minimizing bias in observational studies

20

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)