Resources Background

Embarking on research in an outbreak is essential and this needs to begin as early as possible. There is an important transition that needs to be made from collecting samples to manage the clinical cases as they present and informing public health surveillance, to gathering clinical data for publication and wide dissemination. This crucial line that has to be crossed needs to happen early if this disease is to be understood and if interventions and management strategies are to be guided and informed by evidence. Therefore, this platform has been set up to encourage discussion about what the research priorities are and then support and enable the process of collecting high quality data.

The following research priorities have been identified by ISARIC investigators, international colleagues, the GloPID-R Outbreak Response Committee, and in relevant literature (as indicated in the sections below). Comments and contributions are important and welcome; please email zikainfection@tghn.org.

Basic Science 
  • Animal models (multiple species) to study infection pathogenicity, tissue tropism, viral dissemination, Guillain-Barre and intrauterine transmission
  • Modes of transmission, vertical and sexual transmission 
  • Structures of viral surface proteins compared to other flaviviruses and dynamics in cell (entry, exit and tropism)
  • How do viral surface proteins interact with cell receptors and stimulate immune response, including natural and vaccine acquired DENV antibodies (to prM protein)?
  • Replication mechanism and location
  • Maturation pathway of ZIKV compared to other flaviviruses (e.g. Dengue)
  • Viral interaction with neural tissue
  • Genetics in regards to change in virulence
Selected Literature
  1. Dick, G. Zika virus (II). Pathogenicity and physical properties. Transactions of the Royal Society of Tropical Medicine and Hygiene 46, 521–534 (1952). link.
  2. Bell, T. M., Field, E. J. & Narang, H. K. Zika virus infection of the central nervous system of mice. Arch Gesamte Virusforsch 35, 183–193 (1971). link.
  3. Baronti, C. et al. Complete Coding Sequence of Zika Virus from a French Polynesia Outbreak in 2013. Genome Announcements 2 (2014). link.
  4. Hamel, R. et al. Biology of Zika Virus Infection in Human Skin Cells. J. Virol. 89, 8880–96 (2015). link.
  5. Musso, D. et al. Potential Sexual Transmission of Zika Virus. Emerg. Infect. Dis. 21, 359–361 (2015). link.
  6. Enfissi, A., Codrington, J., Roosblad, J., Kazanji, M. & Rousset, D. Zika virus genome from the Americas. The Lancet 387, 227–228 (2016). link.
Microcephaly and other congenital abnormalities of the central nervous system
  • International consensus on a standardised case definition for microcephaly and other abnormalities to be used in diagnosis and research
  • Epidemiology of microcephaly associated with Zika virus (to be answered by the ongoing case control and cohort studies); phenotypes (any specific features that distinguish different etiologies); natural history of infection
  • Causal link between Zika virus infection in pregnancy, intra-uterine infection, and congenital abnormalities  (to be answered by the ongoing case control studies)
  • Pathogenic mechanisms
  • Diagnostic and prognostic tools for Zika related congenital disorders, with preference for methods widely accessible
  • Developmental and other impacts of microcephaly
  • Potential risk factors or co-factors, and population exposure, contributing to congenital abnormalities such as other infections; maternal exposure to toxic chemicals, heavy metals like arsenic or mercury, alcohol, radiation, smoking and severe malnutrition; and genetic abnormalities
  • Baseline rate of congenital abnormalities of the central nervous system in Brazil and other affected countries
Suggested Literature
  1. Lopez-Camelo, J. S., Orioli, I. M. & Castilla, E. Latin American Collaborative Study of Congenital Malformations (ECLAMC) Final Document: Summary and conclusions of Documents 1-5 (2015).  English and Portuguese.
  2. Soares de Araújo, J. et al. Microcephaly in northeast Brazil: a review of 16 208 births between 2012 and 2015. [Submitted]. Bull World Health Organ E-pub: 4 Feb 2016. link.
  3. Schuler-Faccini, L. et al. Possible Association Between Zika Virus Infection and Microcephaly - Brazil, 2015. MMWR. Morb. Mortal. Wkly. Rep. 65, 59–62 (2016). link.
  4. Tetro, J. A. Zika and microcephaly: causation, correlation, or coincidence? Microbes Infect. (2016). link.
  5. Oliveira Melo, A. S. et al. Zika virus intrauterine infection causes fetal brain abnormality and microcephaly: tip of the iceberg? Ultrasound Obstet. Gynecol. 47, 6–7 (2016). link.
  6. Victora, C. G. et al. Microcephaly in Brazil: how to interpret reported numbers? Lancet (2016). link.
  7. Mlakar, J. et al. Zika Virus Associated with Microcephaly. N. Engl. J. Med. (2016). link.
  8. Simmins Jr, C. Establishing base levels of microcephaly in Brazil prior to the arrival of Zika viral illnesses. [Submitted]. Bull World Health Organ E-pub: 8 Feb 2016.   link.
  9. Rocha, H. et al. Microcephaly: normality parameters and its determinants in northeastern Brazil: a multicentre prospective cohort study. [Submitted]. Bull World Health Organ E-pub: 8 Feb 2016. link.
  10. Ventura, C. V., Maia, M., Bravo-Filho, V., Góis, A. L. & Belfort, R. Zika virus in Brazil and macular atrophy in a child with microcephaly. Lancet 387, 228 (2016).  link.
  11. Martines, R. B. et al. Notes from the Field : Evidence of Zika Virus Infection in Brain and Placental Tissues from Two Congenitally Infected Newborns and Two Fetal Losses — Brazil, 2015. MMWR. Morb. Mortal. Wkly. Rep. 65, 1–2 (2016).  link.
Epidemiology
  • Zika transmission dynamics (attack rates) and population dynamics among vectors, humans and other hosts
  • Risk factors for Zika infection among different populations
  • Burden of infection and pathogenicity of disease
  • Proportion of infections going on to develop neurological complications or congenital abnormalities of the central nervous system, and risk factors
  • Pathogen genetic diversity and evolution in relation to virulence and transmissibility
Suggested Literature
  1. Duffy, M. R. et al. Zika virus outbreak on Yap Island, Federated States of Micronesia. N. Engl. J. Med. 360, 2536–2543 (2009). link.
  2. Haddow, A. D. et al. Genetic Characterization of Zika Virus Strains: Geographic Expansion of the Asian Lineage. PLoS Negl Trop Dis 6, e1477 (2012). link.
  3. Roth, A. et al. Concurrent outbreaks of dengue, chikungunya and zika virus infections: An unprecedented epidemic wave of mosquito-borne viruses in the Pacific 2012-2014. Eurosurveillance 19 (2014). link.
  4. Ioos, S. et al. Current Zika virus epidemiology and recent epidemics (2014). Link.
  5. Faye, O. et al. Molecular Evolution of Zika Virus during Its Emergence in the 20th Century. PLoS Negl Trop Dis 8, e2636 (2014). link.
  6. Bogoch, I. I. et al. Anticipating the international spread of Zika virus from Brazil. Lancet 387, 335–336 (2016).  link.
  7. Majumder, M., Cohn, E., Fish, D. & Brownstein, J. Estimating a feasible serial interval range for Zika fever. Bull World Heal. Organ (2016). link.
  8. Cao-Lormeau, V., Roche, C., Teissier, A., Nilles, E. & Musso, D. Epidemiological and molecular features of dengue, Zika and Chikungunya concurrent outbreaks in the pacific, 2014. Am. J. Trop. Med. Hyg. 91, 588 (2014).  link.
  9. Kindhauser, M., Allen, T., Frank, V., Santhana, R. & Dye, C. Zika: the origin and spread of a mosquito-borne virus. Bull World Heal. Organ (2016).  link.
Diagnostic test development and validation
Priorities recommended in Charrel et al (2016): 
  • Rapid and extensive field validation of available molecular and serology tests in background of both affected areas and areas unaffected but welcoming returning travellers. Special focus should be given to the patient population of pregnant women.
  • Monitoring of genomic diversity of circulating ZIKV strains to allow verification against operational molecular tests to ensure continuous sensitivity.
  • Development of External Quality Assessments (EQA) for both molecular and serology testing for multiple sample types.
  • Insight in infection kinetics should be obtained through prospective studies, including pregnant women, to determine ideal sampling type or combinations thereof and sampling time. This should focus on plasma/serum, urine and saliva combinations
  • The availability of reagents for diagnostic development should be facilitated.
Suggested Literature
  1. Lanciotti, R. S. et al. Genetic and serologic properties of Zika virus associated with an epidemic, Yap State, Micronesia, 2007. Emerg. Infect. Dis. 14, 1232–1239 (2008). link.
  2. Faye, O. et al. One-step RT-PCR for detection of Zika virus. J. Clin. Virol. 43, 96–101 (2008). link.
  3. Balm, M. N. D. et al. A diagnostic polymerase chain reaction assay for Zika virus. J. Med. Virol. 84, 1501–1505 (2012). link.
  4. Maeda, A. & Maeda, J. Review of diagnostic plaque reduction neutralization tests for flavivirus infection. Vet. J. 195, 33–40 (2013).   link.
  5. Faye, O. et al. Quantitative real-time PCR detection of Zika virus and evaluation with field-caught mosquitoes. Virol. J. 10, 311 (2013). link.
  6. Gourinat, A. C., O'Connor, O., Calvez, E., Goarant, C. & Dupont-Rouzeyrol, M. Detection of zika virus in urine. Emerg. Infect. Dis. 21, 84–86 (2015). link.
  7. Musso, D. et al. Detection of Zika virus in saliva. J. Clin. Virol. 68, 53–5 (2015). link.
  8. Charrel, R. et al. State of knowledge on Zika virus for an adequate laboratory response. [Submitted]. Bull World Health Organ E-pub: 10 Feb 2016. link.
Vaccines and therapeutics
  • Target Product Profiles of vaccines and therapeutics
  • Identification and validation of vaccines
  • Identification and validation of candidate therapeutic targets for antiviral therapies
  • Screening of compounds/molecules for anti-Zika activity in-vitro
  • Identification and validation of mono or poly-clonal antibodies 
Suggested Literature 
  1. Owen Dyer. Zika vaccine could be in production by year’s end, says maker. BMJ 352, i630 (2016). Link.
Vector Control and Biology
  • Vector competence
  • Basic biology of viral replication and dynamic in vector species
  • Evidence-based vector control efforts, with efficacy in decreasing vector populations and minimising the development of resistance in Aedes.
Suggested Literature
  1. Ayres, C. F. J. Identification of Zika virus vectors and implications for control. Lancet Infect. Dis. (2016). link.
  2. Yakob, L. & Walker, T. Zika virus outbreak in the Americas: the need for novel mosquito control methods. Lancet Glob. Heal. (2016). link.
Data Collection Tools
Research Training and Support
Guidelines 
Laboratory Support
Current and Planned Research
Research Priorities
Funding Initiatives