Human to Mosquito Transmission of Dengue Viruses

The successful transmission of dengue virus from a human host to a mosquito vector requires a complex set of factors to align. It is becoming increasingly important to improve our understanding of the parameters that shape the human to mosquito component of the transmission cycle so that vaccines and therapeutic antivirals can be fully evaluated and epidemiological models refined. Here we describe these factors, and discuss the biological and environmental impacts and demographic changes that are influencing these dynamics. Specifically, we examine features of the human infection required for the mosquito to acquire the virus via natural blood feeding, as well as the biological and environmental factors that influence a mosquito's susceptibility to infection, up to the point that they are capable of transmitting the virus to a new host

Dengue human infection models supporting drug development.

Dengue is a arboviral infection that represents a major global health burden. There is an unmet need for effective dengue therapeutics to reduce symptoms, duration of illness and incidence of severe complications. Here, we consider the merits of a dengue human infection model (DHIM) for drug development. A DHIM could allow experimentally controlled studies of candidate therapeutics in preselected susceptible volunteers, potentially using smaller sample sizes than trials that recruited patients with dengue in an endemic country. In addition, the DHIM would assist the conduct of intensive pharmacokinetic and basic research investigations and aid in determining optimal drug dosage. Furthermore, a DHIM could help establish proof of concept that chemoprophylaxis against dengue is feasible. The key challenge in developing the DHIM for drug development is to ensure the model reliably replicates the typical clinical and laboratory features of naturally acquired, symptomatic dengue

Assessing dengue vaccination impact: Model challenges and future directions.

In response to the sharp rise in the global burden caused by dengue virus (DENV) over the last few decades, the WHO has set out three specific key objectives in its disease control strategy: (i) to estimate the true burden of dengue by 2015; (ii) a reduction in dengue mortality by at least 50% by 2020 (used as a baseline); and (iii) a reduction in dengue morbidity by at least 25% by 2020. Although various elements will all play crucial parts in achieving this goal, from diagnosis and case management to integrated surveillance and outbreak response, sustainable vector control, vaccine implementation and finally operational and implementation research, it seems clear that new tools (e.g. a safe and effective vaccine and/or effective vector control) are key to success. The first dengue vaccine was licensed in December 2015, Dengvaxia® (CYD-TDV) developed by Sanofi Pasteur. The WHO has provided guidance on the use of CYD-TDV in endemic countries, for which there are a variety of considerations beyond the risk-benefit evaluation done by regulatory authorities, including public health impact and cost-effectiveness. Population-level vaccine impact and economic and financial aspects are two issues that can potentially be considered by means of mathematical modelling, especially for new products for which empirical data are still lacking. In December 2014 a meeting was convened by the WHO in order to revisit the current status of dengue transmission models and their utility for public health decision-making. Here, we report on the main points of discussion and the conclusions of this meeting, as well as next steps for maximising the use of mathematical models for vaccine decision-making

Kinetics of Viremia and NS1 Antigenemia Are Shaped by Immune Status and Virus Serotype in Adults with Dengue

Dengue is an acute viral disease that affects tens of millions of people annually in tropical and sub-tropical countries. In some cases, this infection happens to be severe and even life threatening. Severe cases have been associated with higher levels of virus in the blood. Several hypotheses have been proposed to explain the occurrence of these cases notably by involving the patient's history of previous DEN virus infection(s). Little is known about the relationships between the evolution over time of virus levels in the blood, the clinical outcome and the previous infection(s) history—a better understanding of these features could help in anti-viral drug development. To analyze these relationships, we studied well characterized patients who participated in a clinical trial. The majority of these patients were infected by DENV-1 serotype and had higher levels of virus than those infected by DENV-2 and sometimes DENV-3 serotypes. We also found that patients with more severe symptoms had higher levels of virus in the first days of their illness. We found as well that the virus was cleared faster and earlier from the blood of patients previously infected. These findings are of major importance for further anti-viral drug testing

Evolutionarily Successful Asian 1 Dengue Virus 2 Lineages Contain One Substitution in Envelope That Increases Sensitivity to Polyclonal Antibody Neutralization.

This is the author accepted manuscript. The final version is available from Oxford University Press via http://dx.doi.org/10.1093/infdis/jiv536The 4 dengue virus serotypes (DENV-1-4) cause the most prevalent mosquito-borne viral disease of humans worldwide. DENV-2 Asian 1 (A1) genotype viruses replaced the Asian-American (AA) genotype in Vietnam and Cambodia, after which A1 viruses containing Q or M at envelope (E) residue 160 became more prevalent than those with residue 160K in both countries (2008-2011). We investigated whether these substitutions conferred a fitness advantage by measuring neutralizing antibody titer against reporter virus particles (RVPs) representing AA, A1-160K, A1-160Q, and A1-160M, using patient sera from Vietnam and a well-characterized Nicaraguan cohort. Surprisingly, we found that A1-160Q and A1-160M RVPs were better neutralized by heterologous antisera than A1-160K. Despite this, Vietnamese patients infected with A1-160Q or A1-160M viruses had higher viremia levels than those infected with A1-160K. We thus found that independent lineages in Vietnam and Cambodia acquired a substitution in E that significantly increased polyclonal neutralization but nonetheless were successful in disseminating and infecting human hosts.This work was supported by the Bill and Melinda Gates Foundation and the Instituto Carlos Slim de la Salud (FIRST Program); the Nicaraguan Pediatric Dengue Cohort Study was supported by the Pediatric Dengue Vaccine Initiative (grant VE-1 to E. H.) and the National Institutes of Health (NIH) R01 AI099631 (to Dr Angel Balmaseda); and L. C. K. was supported by a Gates Cambridge Scholarship and the NIH Oxford-Cambridge Scholars Program

Cluster-Randomized Test-Negative Design Trials: A Novel and Efficient Method to Assess the Efficacy of Community-Level Dengue Interventions.

Cluster-randomized controlled trials are the gold standard for assessing efficacy of community-level interventions, such as vector-control strategies against dengue. We describe a novel cluster-randomized trial methodology with a test-negative design (CR-TND), which offers advantages over traditional approaches. This method uses outcome-based sampling of patients presenting with a syndrome consistent with the disease of interest, who are subsequently classified as test-positive cases or test-negative controls on the basis of diagnostic testing. We used simulations of a cluster trial to demonstrate validity of efficacy estimates under the test-negative approach. We demonstrated that, provided study arms are balanced for both test-negative and test-positive illness at baseline and that other test-negative design assumptions are met, the efficacy estimates closely match true efficacy. Analytical considerations for an odds ratio-based effect estimate arising from clustered data and potential approaches to analysis are also discussed briefly. We concluded that application of the test-negative design to certain cluster-randomized trials could increase their efficiency and ease of implementation

Changes in wave climate over the northwest European shelf seas during the last 12,000 years

Because of the depth attenuation of wave orbital velocity, wave-induced bed shear stress is much more sensitive to changes in total water depth than tidal-induced bed shear stress. The ratio between wave- and tidal-induced bed shear stress in many shelf sea regions has varied considerably over the recent geological past because of combined eustatic changes in sea level and isostatic adjustment. In order to capture the high-frequency nature of wind events, a two-dimensional spectral wave model is here applied at high temporal resolution to time slices from 12 ka BP to present using paleobathymetries of the NW European shelf seas. By contrasting paleowave climates and bed shear stress distributions with present-day conditions, the model results demonstrate that, in regions of the shelf seas that remained wet continuously over the last 12,000 years, annual root-mean-square (rms) and peak wave heights increased from 12 ka BP to present. This increase in wave height was accompanied by a large reduction in the annual rms wave- induced bed shear stress, primarily caused by a reduction in the magnitude of wave orbital velocity penetrating to the bed for increasing relative sea level. In regions of the shelf seas which remained wet over the last 12,000 years, the annual mean ratio of wave- to (M-2) tidal-induced bed shear stress decreased from 1 (at 12 ka BP) to its present-day value of 0.5. Therefore compared to present- day conditions, waves had a more important contribution to large-scale sediment transport processes in the Celtic Sea and the northwestern North Sea at 12 ka BP

Good Genes and Sexual Selection in Dung Beetles (Onthophagus taurus): Genetic Variance in Egg-to-Adult and Adult Viability

Whether species exhibit significant heritable variation in fitness is central for sexual selection. According to good genes models there must be genetic variation in males leading to variation in offspring fitness if females are to obtain genetic benefits from exercising mate preferences, or by mating multiply. However, sexual selection based on genetic benefits is controversial, and there is limited unambiguous support for the notion that choosy or polyandrous females can increase the chances of producing offspring with high viability. Here we examine the levels of additive genetic variance in two fitness components in the dung beetle Onthophagus taurus. We found significant sire effects on egg-to-adult viability and on son, but not daughter, survival to sexual maturity, as well as moderate coefficients of additive variance in these traits. Moreover, we do not find evidence for sexual antagonism influencing genetic variation for fitness. Our results are consistent with good genes sexual selection, and suggest that both pre- and postcopulatory mate choice, and male competition could provide indirect benefits to females

Zika vaccines and therapeutics: landscape analysis and challenges ahead.

BACKGROUND: Various Zika virus (ZIKV) vaccine candidates are currently in development. Nevertheless, unique challenges in clinical development and regulatory pathways may hinder the licensure of high-quality, safe, and effective ZIKV vaccines. DISCUSSION: Implementing phase 3 efficacy trials will be difficult given the challenges of the spatio-temporal heterogeneity of ZIKV transmission, the unpredictability of ZIKV epidemics, the broad spectrum of clinical manifestations making a single definite endpoint difficult, a lack of sensitive and specific diagnostic assays, and the need for inclusion of vulnerable target populations. In addition to a vaccine, drugs for primary prophylaxis, post-exposure prophylaxis, or treatment should also be developed to prevent or mitigate the severity of congenital Zika syndrome. CONCLUSION: Establishing the feasibility of immune correlates and/or surrogates are a priority. Given the challenges in conducting phase 3 trials at a time of waning incidence, human challenge trials should be considered to evaluate efficacy. Continued financial support and engagement of industry partners will be essential to the successful development, licensure, and accessibility of Zika vaccines or therapeutics