Density dependence and the control of helminth parasites.

1. The transient dynamics and stability of a population are determined by the interplay between species density, its spatial distribution and the positive and negative density-dependent processes regulating population growth. 2. Using the human-helminth parasite system as an example, we propose that the life-stage upon which negative density dependence operates will influence the rate of host reinfection following anthelmintic chemotherapy, and the likely success of control programmes. 3. Simple deterministic models are developed which highlight how a parasite species whose population size is down-regulated by density-dependent establishment will reinfect a host population at a faster rate than a species with density-dependent parasite fecundity. 4. Different forms of density dependence can produce the same equilibrium behaviour but different transient dynamics. Under-representing the nature and magnitude of density-dependent mechanisms, and in particular those operating upon establishing life-stages, may cause the resilience of the parasite population to a control perturbation to be underestimated

Can field-based mosquito feeding assays be used for evaluating transmission-blocking interventions?

A recent meta-analysis of mosquito feeding assays to determine the Plasmodium falciparum transmission potential of naturally infected gametocyte carriers highlighted considerable variation in transmission efficiency between assay methodologies and between laboratories. This begs the question as to whether mosquito feeding assays should be used for the evaluation of transmission-reducing interventions in the field and whether these field-based mosquito assays are currently standardized sufficiently to enable accurate evaluations. Here, we address biological and methodological reasons for the observed variations, discuss whether these preclude the use of field-based mosquito feeding assays in field evaluations of transmission-blocking interventions, and propose how we can maximize the precision of estimates. Altogether, we underscore the significant advantages of field-based mosquito feeding assays in basic malaria research and field trials

Digital Participatory Surveillance and the Zika Crisis: Opportunities and Caveats

Managing the global threat of Zika requires innovative solutions. This article examines the potential of Digital Participatory Surveillance to support the management of global disease outbreaks by enabling citizens to report signs of infection. We discuss the status of the current evidence-base, contextual factors influencing user engagement and data quality, challenges for evaluation, and unique aspects of Zika with implications for design. We also suggest priorities for research, development and practice, to help translate the theoretical benefits of these methods into meaningful improvements in outbreak monitoring and public health.Published versio

An Analysis of Genetic Diversity and Inbreeding in Wuchereria bancrofti: Implications for the Spread and Detection of Drug Resistance

Estimates of genetic diversity in helminth infections of humans often have to rely on genotyping (immature) parasite transmission stages instead of adult worms. Here we analyse the results of one such study investigating a single polymorphic locus (a change at position 200 of the β-tubulin gene) in microfilariae of the lymphatic filarial parasite Wuchereria bancrofti. The presence of this genetic change has been implicated in benzimidazole resistance in parasitic nematodes of farmed ruminants. Microfilariae were obtained from patients of three West African villages, two of which were sampled prior to the introduction of mass drug administration. An individual-based stochastic model was developed showing that a wide range of allele frequencies in the adult worm populations could have generated the observed microfilarial genetic diversity. This suggests that appropriate theoretical null models are required in order to interpret studies that genotype transmission stages. Wright's hierarchical F-statistic was used to investigate the population structure in W. bancrofti microfilariae and showed significant deficiency of heterozygotes compared to the Hardy-Weinberg equilibrium; this may be partially caused by a high degree of parasite genetic differentiation between hosts. Studies seeking to quantify accurately the genetic diversity of helminth populations by analysing transmission stages should increase their sample size to account for the variability in allele frequency between different parasite life-stages. Helminth genetic differentiation between hosts and non-random mating will also increase the number of hosts (and the number of samples per host) that need to be genotyped, and could enhance the rate of spread of anthelmintic resistance

The influence of feeding behaviour and temperature on the capacity of mosquitoes to transmit malaria

Insecticide-treated bed nets reduce malaria transmission by limiting contact between mosquito vectors and human hosts when mosquitoes feed during the night. However, malaria vectors can also feed in the early evening and in the morning when people are not protected. Here, we explored how the timing of blood feeding interacts with environmental temperature to influence the capacity of Anopheles mosquitoes to transmit the human malaria parasite Plasmodium falciparum. In laboratory experiments, we found no effect of biting time itself on the proportion of mosquitoes that became infectious (vector competence) at constant temperature. However, when mosquitoes were maintained under more realistic fluctuating temperatures, there was a significant increase in competence for mosquitoes feeding in the evening (18:00), and a significant reduction in competence for those feeding in the morning (06:00), relative to those feeding at midnight (00:00). These effects appear to be due to thermal sensitivity of malaria parasites during the initial stages of parasite development within the mosquito, and the fact that mosquitoes feeding in the evening experience cooling temperatures during the night, whereas mosquitoes feeding in the morning quickly experience warming temperatures that are inhibitory to parasite establishment. A transmission dynamics model illustrates that such differences in competence could have important implications for malaria prevalence, the extent of transmission that persists in the presence of bed nets, and the epidemiological impact of behavioural resistance. These results indicate that the interaction of temperature and feeding behaviour could be a major ecological determinant of the vectorial capacity of malaria mosquitoes

Estimating the effects of temperature on transmission of the human malaria parasite, Plasmodium falciparum

Despite concern that climate change could increase the human risk to malaria in certain areas, the temperature dependency of malaria transmission is poorly characterized. Here, we use a mechanistic model fitted to experimental data to describe how Plasmodium falciparum infection of the African malaria vector, Anopheles gambiae, is modulated by temperature, including its influences on parasite establishment, conversion efficiency through parasite developmental stages, parasite development rate, and overall vector competence. We use these data, together with estimates of the survival of infected blood-fed mosquitoes, to explore the theoretical influence of temperature on transmission in four locations in Kenya, considering recent conditions and future climate change. Results provide insights into factors limiting transmission in cooler environments and indicate that increases in malaria transmission due to climate warming in areas like the Kenyan Highlands, might be less than previously predicted

Reducing Plasmodium falciparum malaria transmission in Africa: a model-based evaluation of intervention strategies.

BACKGROUND: Over the past decade malaria intervention coverage has been scaled up across Africa. However, it remains unclear what overall reduction in transmission is achievable using currently available tools. METHODS AND FINDINGS: We developed an individual-based simulation model for Plasmodium falciparum transmission in an African context incorporating the three major vector species (Anopheles gambiae s.s., An. arabiensis, and An. funestus) with parameters obtained by fitting to parasite prevalence data from 34 transmission settings across Africa. We incorporated the effect of the switch to artemisinin-combination therapy (ACT) and increasing coverage of long-lasting insecticide treated nets (LLINs) from the year 2000 onwards. We then explored the impact on transmission of continued roll-out of LLINs, additional rounds of indoor residual spraying (IRS), mass screening and treatment (MSAT), and a future RTS,S/AS01 vaccine in six representative settings with varying transmission intensity (as summarized by the annual entomological inoculation rate, EIR: 1 setting with low, 3 with moderate, and 2 with high EIRs), vector-species combinations, and patterns of seasonality. In all settings we considered a realistic target of 80% coverage of interventions. In the low-transmission setting (EIR approximately 3 ibppy [infectious bites per person per year]), LLINs have the potential to reduce malaria transmission to low levels (90%) or novel tools and/or substantial social improvements will be required, although considerable reductions in prevalence can be achieved with existing tools and realistic coverage levels. CONCLUSIONS: Interventions using current tools can result in major reductions in P. falciparum malaria transmission and the associated disease burden in Africa. Reduction to the 1% parasite prevalence threshold is possible in low- to moderate-transmission settings when vectors are primarily endophilic (indoor-resting), provided a comprehensive and sustained intervention program is achieved through roll-out of interventions. In high-transmission settings and those in which vectors are mainly exophilic (outdoor-resting), additional new tools that target exophagic (outdoor-biting), exophilic, and partly zoophagic mosquitoes will be required

The therapeutic efficacy and macrofilaricidal activity of doxycycline for the treatment of river blindness

Background. Onchocerca volvulus and lymphatic filariae, causing river blindness and elephantiasis, depend on endosymbiotic Wolbachia bacteria for growth, development, fertility, and survival. Clinical trials have shown that doxycycline treatment eliminates Wolbachia, causing long-term sterilization of adult female filariae and effecting potent macrofilaricidal activity. The continual reinfection by drug-naive worms that occurs in these trial settings dilutes observable anti-Wolbachia and antifilarial effects, making it difficult to estimate therapeutic efficacy and compare different doxycycline regimens, evaluated at different times after treatment. Methods. A meta-analytical modeling framework is developed to link all usable data collected from clinical trials measuring the Wolbachia status and viability of individual female adult worms collected at various times after treatment with 4, 5, or 6 weeks of daily 100 or 200 mg oral doxycycline. The framework is used to estimate efficacy parameters that are not directly measurable as trial outcomes. Results. The estimated efficacy of doxycycline (the maximum proportional reduction in the percentage of adult female O. volvulus positive for Wolbachia) is 91%–94% on average, irrespective of the treatment regimen. Efficacy is >95% in the majority of trial participants. The life span of Wolbachia-depleted worms is reduced by 70%–80%, from approximately 10 years to 2–3 years. Conclusions. The efficacy parameters are pertinent to the prospects of using doxycycline on a “test and treat” basis for onchocerciasis control and confirm doxycycline as a potent macrofilaricidal therapy. The modeling approach is more generally relevant to the design and evaluation of clinical trials for antifilarial drugs conducted in endemic settings