| What is the mechanism of the intervention? |
Different vaccine platforms elicit different specificities of Ab responses; these could be to the whole virus, nonstructural proteins, envelope or envelope subdomains only. An intervention on the environment would have no direct effect on ZIKV immunity at the individual level. Vaccines, drugs, immunotherapeutics may have various effects at the level of the host-pathogen interaction and include protective (potentially sterilizing) immunity or attenuate viral infection and/or symptoms. Interventions that target the vector will reduce total infection and a corresponding proportion of disease because symptomatic infection is by definition a subset of total infection.
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| What is the ultimate goal of the intervention? |
The goal may be to reduce disease manifestations, prevent apparent cases, or reduce transmission in the population. The goal may be to prevent infection from ever occurring or to reduce symptoms and risk of complication in a subject after Zika has already been diagnosed.
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| Who are the key stakeholders and what is their priority? |
Stakeholders may include the local community, scientific community, health ministry, trial sponsor, or product developer. Some may prefer to see study results that reflect high confidence and specific diagnosis of each infection. Others may prefer relaxed specificity and greater sensitivity to assess a “bigger picture” of all Aedes-borne virus transmission. Disease endpoints as assessed by a physician or a nurse may carry much more validity in the perspective of some stakeholders, whereas others would accept or prefer total infection endpoints that are determined entirely by laboratory testing or even data augmentation or mathematical modeling.
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| Who is the study population? |
A highly mobile population may not work well in a cluster design. A transient population would not be amenable to frequent longitudinal sampling. A pediatric population may have increased retention and sampling compliance if using noninvasive techniques rather than phlebotomy. A study population with high rates of flavivirus vaccination (such as yellow fever or Japanese encephalitis virus) may have increased rates of cross-reactive Ab.
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| What is the epidemiology at the trial site? |
Knowledge of historic flavivirus transmission and likelihood of adequate event rates facilitate planning for optimal serologic testing and design of testing algorithms. If DENV is endemic in the region, assays readily compromised by cross-reactivity, such as those using whole ZIKV antigen, will not be useful. In low seroprevalence settings, ZIKV seroconversion on simple serologic assays can be a robust outcome measure. An area with a high event rate can achieve adequate power with fewer subjects and a shorter trial duration. Additionally, the statistical analysis plan may better account for potential confounding effects of imperfect sensitivity and specificity of serologic assays in this setting.
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| What resources are available? |
Lab capacity for multiplex, high throughput testing and high volume of assays could increase the quality of serologic data generated. However, it may also be reasonable to use less frequent sampling and less expensive assays (such as in-house ELISA and neutralization tests) to preserve funding for other essential trial activities such as clinical evaluations, stakeholder engagement, entomologic monitoring, etc. If specimen transport and cold chain is an issue, DBS is an attractive method to sample large populations.
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