PAHO - Instituto Nacional de Salud Pública

Zika virus epidemic: Challenges and the road ahead
Regional research priorities on Zika virus infection
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
Outline
 PAHO Regional research priorities
 PAHO platform on Zika research
 Harmonization, key protocols and tools
PAHO
PAHO regional research
priorities
PAHO
PAHO regional research priorities
Relevance of
the issue
(Median)
Time of
implementation
Effectiveness of vector control measures on the transmission of ZIKV
Critical
Short-term
Effectiveness of Dengue, urban yellow fever and Chikungunya vector
control
What vectors are responsible for most human transmission (Culex,
Mansonia and Anopheles genuses)?
Very
important
Very
important
Very
important
Relevance and implementation by subtopic:
Virus vectors and reservoirs
Screening of viral strains in mosquito vectors
Short-term
Short-term
Medium-term
Epidemiology
What is the absolute risk of congenital malformation by gestational week
Critical
Short-term
Perinatal transmission and trans-placental transmission
Critical
Short-term
Characterization of clinical and subclinical ZIKV infections n pregnant
women
Critical
Short-term
Diagnostic tools: Effective methodologies and validation of new process
and platforms for serology, antigenic and molecular detection
Critical
Short-term
Sensitivity/specificity/predictive value of serum ZIKVIgM
Critical
Short-term
Biological plausibility for maternal-fetal transmission
Including incident cases, birth defects, development of an epidemic curve
Is it possible to detect ZIKVRNA in an infant or child who had the ZIKV
infection in utero if the period of viremia has passed?
Potential of individuals with previous history of infection from other
flaviviruses (especially dengue, yellow fever and West Nile) to cross-react
in tests
PAHO
Very
important
Less
important
Less
important
Short-term
Short-term
Short-term
Less
important
Short-term
Performance of ultrasound and other imaging tests to detect brain
abnormalities in prenatal and postnatal period
Less
important
Short-term
Influence of co-infections and super-infections of ZIKV and other cocirculating (CHIKV, DENV, YFV) arbovirusesas well as pre-existing immunity
/ vaccination against other Flaviviruses
Less
important
Medium-term
Use of modelling to understand the rate of infection and to understand
what is the role of natural immunity particularly in the regions with
previous ZIKV outbreaks
Less
important
Medium-term
Spatial distribution of ZIKV, dengue and Chikungunya Are there clusters?
Less
important
Medium-term
Characterization of the natural history of disease; ratio clinical to
subclinical incidence SGB and others neurological complications; rare
severe complications; mortality, dynamics of immune response
Less
important
Medium-term
PAHO regional research priorities
Disease Pathogenesis and Consequences of ZIKV infection
What types of samples are needed and how should they be collected and
transported?
Critical
ZIKV Infection teratogenic effect in function of the gestational age
Critical
Very
important
Less
important
Less
important
Shortterm
Shortterm
Shortterm
Shortterm
Effect of infection by the ZIKV (with and without microcephaly) in the
neurological, cognitive and motor development child mother with infection
Less
important
Mediumterm
What is the mechanism that makes IgM antibodies against ZIKV, dengue
viruses, and other flaviviruses have strong cross-reactivity which may
generate false positive results in serological tests? May this cross reactivity
be involved in some kind of pathogenesis mediated by immune
enhancement?
Less
important
Mediumterm
Flavivirus effects (including viral persistence and viral load) on neural tissues,
placental barrier transfer and teratogenic
Less
important
Mediumterm
Animal models of teratogenic infection
Not
important
Mediumterm
ZIKV infection pathogenesis to the fetus
Association / risk factors between ZIKV infection and autoimmune
syndromes
Sexual and body fluids transmission
PAHO
Shortterm
PAHO regional research priorities
Public health interventions and clinical management
Critical
Strategies to prevent congenital infections
Critical
Interventions for the protection from mosquito bites in endemic areas
(including the application of selective indoor residual insecticide spraying, in
houses and around them, source reduction and larviciding application, with
their corresponding evaluation)
Critical
Shortterm
Less
important
Less
important
Less
important
Shortterm
Mediumterm
Mediumterm
To implement the systematic insecticide resistance surveillance for Aedes
aegypti, for insecticides used in each country. These results must be used for
the judicious management of insecticides and decision making at local level.
Less
important
Mediumterm
Evaluation of the current prevention and vector control activities by the
countries, including the impact of countries current prevention strategies
Less
important
Mediumterm
Need to understand the routinely activities women do at home and at
working places, which are their priorities and how to intervene to avoid
human-vector contact
Not
important
Mediumterm
To describe clinical manifestation across a broad age of age and countries of
ZIKV infection with a common standardized protocol
Registries to understand complications of congenital birth defects
Evaluation of the impact of public health recommendations
PAHO
Shortterm
Shortterm
Prevention strategies and risk communication
PAHO regional research priorities
Health Systems and Services response
Efficient financing mechanisms for addressing outbreaks ZIKV
Critical
Shortterm
Mechanisms to ensure the provision of health services for patients with
complications from ZIKV infection
Critical
Shortterm
Effective mechanisms to ensure the availability of trained human resources in
the clinical management and complications of ZIKV
Critical
Mediumterm
Equity in risk of disease and in access to contraception, access for managing
children and adults with complications and disabilities
Less
important
Mediumterm
Research and Development of Products
PAHO
Development of serologic, blood, and urine tests
Critical
Validation and field testing of kits for the serological diagnosis of ZIKV
Critical
Construction of a panel (of samples) from arbovirus endemic areas for
validation of kits and to be used as reference in the standardization of
laboratory methodologies
Critical
Assurance of reliable, accurate, and standardized testing
Critical
Shortterm
Shortterm
Shortterm
Vaccine development
Very
important
Shortterm
Mediumterm
Development of critical reagents: ZIKV Monoclonal antibodies, usefulness of
NS1 antigen, recombinant antigen and antigenic peptides
Less
important
Shortterm
Less
important
Less
important
Mediumterm
Longterm
Safety, efficacy, and cost effectiveness of screening test for ZIKV
Using Wolbachia as mosquito population replacement strategy
Some challenges
Enhancing Coordination to Respond to ZIKV Epidemic
PAHO
Laboratory capacity (Infrastructure)
Training of researchers (Infrastructure)
Having a minimum core standardize protocol to harmonize definitions, data collection
sample collection and analysis
Harmonized guidelines available for collection and transportation of samples
Diagnostic tests in epidemiological studies
Coordination of efforts to avoid duplication
Strengthening mechanisms for implementing a collaborative international research
response
Mechanisms to identify all published and ongoing research
Need to periodically update research priorities
Open access, sharing data
Dissemination of preliminary findings
Ensuring quality of research
Development of bio-banks
Preparation for emergency response
Networks of research institutions and researchers
Country collaboration on zika Publications
2014
PAHO
The boundaries, colors, denominations, and other information shown on any map in this work do not imply any judgment on the part of PAHO concerning the legal status of
any territory or the endorsement or acceptance of such boundaries, The information was taken directly from Pubmed, using the following search (zika virus [mh] OR zika,).
Country collaboration on zika Publications
2014-15
PAHO
Country collaboration on zika Publications
2014-16
PAHO
Country collaboration on zika Publications
2014-16
PAHO
Bastian M., Heymann S., Jacomy M. (2009). Gephi: an open source software for exploring and manipulating networks.International AAAI Conference on Weblogs and Social Media.
PAHO platform on Zika research
PAHO
PAHO platform on Zika research
Virus, Vectors
and Reservoirs
(2)
- Other (1)*
-Pregnant and children
(1)
PAHO
- Brazil (1)*
- Colombia (1)
Epidemiology
(17)
Disease
Pathogenesis
and
Consequences of
Zika infection (7)
-General population (6)
- General population (1)
-Children (4)
- Pregnant and child (4)
-Pregnant and child
(10)
- Children (4)
- Pregnant and children
(3)
- GBS (2)
- GBS (2)
- GB (1)
- Reproductive age woman
(1)
-Military and their
families (1)
Causality (15)
-Brazil (12)
-Colombia (1)
-Multicenter (2)
- Brazil (14)
- France (2)
- Zambia (1)
- Brazil (6)
- France (1)
PAHO platform on Zika research
Clinical
Management
(22)
Public Health
Interventions
(4)
Health
Systems and
Services
response (1)
- General population
(4)
- Pregnant and
children (5)
- Children (9)
- General population
(4)
Research and
development
of products
(2)
General population
(2)
- GBS (1)
- GBS (3)
- Unclear (1)
- Brazil (1)
-United State (1)
PAHO
- Brazil (20)
- Brazil (2)
- Colombia (2)
- Colombia (2)
- Colombia (1)
- Diagnosis
-Therapy
PAHO platform on Zika research
Summary (72)
Causality, Strength of
association(15)
PAHO
Virus, Vectors and Reservoirs (2)
General population (17)
Epidemiology (17) [2]
Pregnant and children (24)
Disease Pathogenesis and
Consequences of Zika infection (7)
Children (17)
Clinical Management (22) [1]
Public Health Interventions (4)
Reproductive age woman
(1)
Health Systems and Services
response (1)
Military and their families
(1)
Research and development of
products (2)
N/A (2)
Unclear (1)
Ethic (1)
GBS (9)
Unclear (1)
Brazil (57)
Colombia (8)
France (3)
Zambia (1)
Multicenter Latin
America [5](1)
Multicenter Latin
America [3](1)
United State (1)
PAHO platform on Zika research
Cohort (13)
Case-control (9)
Brazil (4)
- MERG (2) (1 Children and 1 Child-pregnant)
Brazil (7)
- Faculdade de Medicina de Jundia (1 Child-pregnant)
- MERG (1 Children)
Hosp. Universitário Cassiano Antônio Moraes (1 Child-Preg)
- Secretaria de Vigilância em Saúde, Brasília (2) (1 Children
and 1 GBS)
Colombia (4, child-pregnant)
- MINSALUD (2)
- Universidad Libre de Cali (1)
- University of Cordoba (1)
- Fundacao Oswaldo Cruz, Recife (1 Children)
- Laboratorio Sabin De Analises Clinicas LTDA, Brasília (1
Child-pregnant)
- Fundação para o Desenvolvimento Científico e
Tecnológico em Saúde (1 Children)
- Instituto para o Desenvolvimento da Educação LtdaIPADE/Faculdade Christus, Fortaleza (1, Child- pregnant)
Francia (3)
- Centre Hospitalier Universitaire de Fort (1 Gen popul.)
- Centre d’Investigation Clinique (1 Child-pregnant)
PAHO
- ZIFAG Clinical Study (1 Military)
Colombia (1 Gen. Population)
- MINSALUD
Multicenter (2) (1 Child-pregnant)
- International Research Consortium on Dengue Risk
Assessment, Management and Surveillance
- TBD countries (Brazil, Colombia, Guatemala, Nicaragua,
Puerto Rico)
Zambia (1 Women in reproductive period)
- University of Zambia School of Veterinary Medicine
Harmonization, protocols and tools
Methods
Recommendation
Objective
1. Clear definitions: Descriptive or analytic study. Prevalence or Incidence.
Associated or causal factors. Effective of treatments
Population
Risk/ advantage
Feasibility
2. Design: According to the objectives.
Internal validity
1. Clear definition: Definition of type of population, geographical location and
risk characteristics (Use the international definitions or the most technical
appropriate definition).
Selection bias
Pregnant woman and newborn, Newborn, Children, General population,
Symptomatic infections, Asymptomatic infections
External
comparability
2. Population-based vs. Hospital-based, Primary care based
Describe
setting and
locations
PAHO
1. Exposed and non-exposed cohorts or case / control will be recruited from
the same population.
Selection bias
2. Describe details population risk groups in ecological study.
1. Sample size calculation to evaluate the main hypothesis.
Power
Sample size 2. Estimation of recruitment time, considering that the epidemic peak possibly
Feasibility
was over and the epidemiology pattern of ZIKV infection is unknown.
Costs
3. Considering multicenter studies.
Harmonization, protocols and tools
PREGNANT WOMEN
1 Trimester
2 Trimester
Asymptomatic
3 Trimester
Symptomatic
BIRTH
OUTCOMES
Lab ZIKV +
PAHO
Lab ZIKV -
Suspected
Probable
Confirmed
case
case
case
Rash
Suspected
+
+
2 or more other
syntoms
Zika IgM
antibodies
Suspected
+
Lab confirmation
Relative risk of
malformations
Harmonization, protocols and tools
Methods
Recommendation
Recruitment
and Follow up
Simultaneously recruitment and follow-up in exposed and non-exposed
cohort or case and control.
Selection bias
Confusion bias
1. Similar follow-up time in exposed and non-exposed cohort.
Information bias
Follow up
Risk/ advantage
2. Enough time to evaluate psychomotor development in children.
3. Appropriate instruments to collect the information.
External
comparability
1. Clear definition: Standardized definition.
2. Collection of the same samples in exposed and non-exposed cohort or
case and control (Blood, urine, CRL, saliva samples and others).
3. Using the same test to confirm/discard ZIKV infection in exposed and
non-exposed cohort or case and control.
Exposition
PAHO
Information bias
4. ZIKV infection confirmed by laboratory vs. clinical diagnosis (suspected,
probable and Confirmed) .
5. Diagnosis tests of ZIKV infection depending of the phase (acute or
convalescence phase): RT-PCR, serology diagnosis, culture, and others.
6. Diagnosis tests of ZIKV infection in asymptomatic infections (paired
serum samples?).
7. Differential diagnosis with other locally circulating flaviviruses.
External
comparability
Harmonization, protocols and tools
Methods
Recommendation
Risk/ advantage
1. Clear 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.
Outcomes
Information bias
3. Same measures in exposed and non-exposed cohort or case and control.
4. Standard: scales, images (USG-TF, MR, CT), physical examination, samples
and other measures.
External
comparability
5. Same schedule of measures in exposed and non-exposed cohort or case
and control.
Other
variables
PAHO
1. Other possible confusion factors should be evaluated.
 Other infections: STORCHS diagnosis.
 Gestational age.
 Other exposition factors (environmental factors or individual factors).
Confusion bias
Information bias
2. Using the same schedule and instruments to do the measure in exposed
and non-exposed cohort or case and control.
Health Care 1. Counseling and psychological support to affected mothers.
2. Definition of management algorithms.
3. Absence of evidence about the impact of ZIKV infection on psychomotor
development of children with microcephaly and other complications
Autonomy and
beneficence
Harmonization, key protocols and tools
Methods
Recommendation
1. Shared information with the surveillance local system.
Information
management
Risk/ advantage
Update and
consolidate
2. Data sharing.
Ethics and
Legislation
PAHO
1. Local legislation about interruption of pregnancy.
2. Gestational age for interruption of pregnancy considering that intrauterine lesions are detected late.
3. Use of CT in children
4. Pregnant women treatment and vaccines
Feasibility