Background
Standard advice regarding vector control is to prefer interventions that reduce the lifespan of adult mosquitoes. The basis for this advice is a decades-old sensitivity analysis of ...‘vectorial capacity’, a concept relevant for most malaria transmission models and based solely on adult mosquito population dynamics. Recent advances in micro-simulation models offer an opportunity to expand the theory of vectorial capacity to include both adult and juvenile mosquito stages in the model.
Methods
In this study we revisit arguments about transmission and its sensitivity to mosquito bionomic parameters using an elasticity analysis of developed formulations of vectorial capacity.
Results
We show that reducing adult survival has effects on both adult and juvenile population size, which are significant for transmission and not accounted for in traditional formulations of vectorial capacity. The elasticity of these effects is dependent on various mosquito population parameters, which we explore. Overall, control is most sensitive to methods that affect adult mosquito mortality rates, followed by blood feeding frequency, human blood feeding habit, and lastly, to adult mosquito population density.
Conclusions
These results emphasise more strongly than ever the sensitivity of transmission to adult mosquito mortality, but also suggest the high potential of combinations of interventions including larval source management. This must be done with caution, however, as policy requires a more careful consideration of costs, operational difficulties and policy goals in relation to baseline transmission.
Anti-malaria vaccines and drugs could be greatly improved if we knew which phases of Plasmodium falciparum development in red blood cells are major inducers and which are major targets of natural ...immune responses. This information should focus attention on relevant immunogens and prove useful in developing immune-based therapies. Here we explore the hypothesis that innate immune responses mediate synchronization between the replication cycles of parasites in different red blood cells which is reflected in periodic fevers. Based on a recently developed, rather general mathematical model, we find that periodicity is highly sensitive to the position of both the inducing phase interval and the target phase interval in the parasite replication cycle. In addition, the degree of variability in the length of the replication cycle also strongly affects periodicity. To produce synchronization, the inducing and the target phase intervals must be developmentally distant from each other. We developed a computer program which prompts for information based on measurements of the numbers of erythrocytes in two replication cycle intervals chosen by the researcher, tests our model, and predicts the two phase intervals most critical to the synchronizing immune response. The program can be obtained from the authors.
The within-host and between-host dynamics of malaria are linked in myriad ways, but most obviously by gametocytes, the parasite blood forms transmissible from human to mosquito. Gametocyte dynamics ...depend on those of non-transmissible blood forms, which stimulate immune responses, impeding transmission as well as within-host parasite densities. These dynamics can, in turn, influence antigenic diversity and recombination between genetically distinct parasites. Here, we embed a differential-equation model of parasite–immune system interactions within each of the individual humans represented in a discrete-event model of
Plasmodium falciparum transmission, and examine the effects of human population turnover, parasite antigenic diversity, recombination, and gametocyte production on the dynamics of malaria. Our results indicate that the local persistence of
P. falciparum increases with turnover in the human population and antigenic diversity in the parasite, particularly in combination, and that antigenic diversity arising from meiotic recombination in the parasite has complex differential effects on the persistence of founder and progeny genotypes. We also find that reductions in the duration of individual human infectivity to mosquitoes, even if universal, produce population-level effects only if near-absolute, and that, in competition, the persistence and prevalence of parasite genotypes with gametocyte production concordant with data exceed those of genotypes with higher gametocyte production. This new, integrated approach provides a framework for investigating relationships between pathogen dynamics within an individual host and pathogen dynamics within interacting host and vector populations.
Smallpox models as policy tools McKenzie, F Ellis
Emerging infectious diseases,
11/2004, Letnik:
10, Številka:
11
Journal Article
Recenzirano
Odprti dostop
Mathematical models can help prepare for and respond to bioterrorism attacks, provided that their strengths and weaknesses are clearly understood. A series of initiatives within the Department of ...Health and Human Services brought modelers together with biologists and epidemiologists who specialize in smallpox and experts in bioterrorism response and health policy and has led to the parallel development of models with different technical approaches but standardized scenarios, parameter ranges, and outcome measures. Cross-disciplinary interactions throughout the process supported the development of models focused on systematically comparing alternate intervention strategies, determining the most important issues in decision-making, and identifying gaps in current knowledge.
Accurate identification and quantification of malaria parasites are critical for measuring clinical trial outcomes. Positive and negative diagnosis is usually sufficient for the assessment of ...therapeutic outcome, but vaccine or prophylactic drug trials require measuring density of infection as a primary endpoint. Microscopy is the most established and widely-used technique for quantifying parasite densities in the blood.
Results obtained by 24-27 expert malaria microscopists, who had independently read 895 slides from 35 donors, were analysed to understand how reader technique contributes to discrepancy in measurements of parasite density over a wide range of densities.
Among these 35 donations, standard deviations ranged from 30% to 250% of the mean parasite density and the percent discrepancy was inversely correlated with the mean parasite density. The number of white blood cells indexed and whether parasites were counted in the thick film or thin film were shown to significantly contribute to discrepancy amongst microscopists.
Errors in microscopy measurements are not widely appreciated or addressed but have serious consequences for efficacy trials, including possibly abandoning promising vaccine candidates.
Giemsa-stained blood smears from each of 2,190 patients from Thai government-operated clinics on the Thailand-Myanmar border were independently examined by the on-duty microscopists at the clinics ...and by 2-3 research microscopists, each blinded to the clinics' and each other's reports. Using a strictly defined protocol, a consensus reference-standard blood smear interpretation for each sample was produced by the research microscopists. This result was compared with the clinic's diagnostic interpretation for the corresponding sample with respect to detection of parasitemia and diagnosis of infecting species. Reference-standard results reported parasitemia in 13.2% of the samples reported negative by the clinic. Reference-standard results were negative in 24.3% of the samples reported parasite-positive by the clinic. For samples in which both the reference-standard result and the clinic result reported parasitemia, species identification differed for 13.7% of the samples. The likelihood of parasite detection and correct diagnosis at the clinic varied in accordance with the reference-standard estimates of parasite density.
WHO estimates that 80% of mortality due to malaria occurs among infants and young children. Though it has long been established that malaria disproportionately affects children under age five, our ...understanding of the underlying biological mechanisms for this distribution remains incomplete. Many studies use age as an indicator of exposure, but age may affect malaria burden independently of previous exposure. Not only does the severity of malaria infection change with age, but the clinical manifestation of disease does as well: younger children are more likely to suffer severe anaemia, while older children are more likely to develop cerebral malaria. Intensity of transmission and acquired immunity are important determinants of this age variation, but age differences remain consistent over varying transmission levels. Thus, age differences in clinical presentation may involve inherent age-related factors as well as still-undiscovered facets of acquired immunity, perhaps including the rates at which relevant aspects of immunity are acquired. The concept of "allometry" - the relative growth of a part in relation to that of an entire organism or to a standard - has not previously been applied in the context of malaria infection. However, because malaria affects a number of organs and cells, including the liver, red blood cells, white blood cells, and spleen, which may intrinsically develop at rates partly independent of each other and of a child's overall size, developmental allometry may influence the course and consequences of malaria infection. Here, scattered items of evidence have been collected from a variety of disciplines, aiming to suggest possible research paths for investigating exposure-independent age differences affecting clinical outcomes of malaria infection.
Mathematical models have long provided basic insights for malaria control. The recent success of the Onchocerciasis Control Program in west Africa shows that models can make great pragmatic ...contributions to intervention programs if the modeling is integrated into the overall program, and if the participants are clear about what models can and cannot do. This lesson can be applied to evidence-based malaria control.
We assess the consequences of competition for red blood cells (RBCs) in co-infections with the two major agents of human malaria, Plasmodium vivax and Plasmodium falciparum, using differential ...equations to model the population dynamics of RBCs and parasites. P. vivax parasitizes only the youngest RBCs, but this can reduce the broader RBC population susceptible to P. falciparum. We found that competition for RBCs typically causes one species to suppress the other, depending on their relative reproduction rates and timing of inoculation. However, if the species' reproduction rates are nearly equal, transient increases in RBC production stimulated by the presence of P. falciparum may boost P. vivax parasitemia above its single-species infection level. Conversely, P. falciparum parasitemia is rarely enhanced above its single-species level. Furthermore, transients in RBC production can induce coupled oscillations in the parasitemia of both species. These results are remarkably robust to changes in model parameters.
Malaria parasites that concurrently infect a host compete on the basis of their intrinsic growth rates and by stimulating cross-reactive immune responses that inhibit each others' growth. If the ...phenotypes also show different drug sensitivities ('sensitive' vs. 'resistant' strains), drug treatment can change their joint dynamics and the long-term outcome of the infection: most obviously, persistent drug pressure can permit the more resistant, but otherwise competitively-inferior, strains to dominate.
Here a mathematical model is developed to analyse how these and more subtle effects of antimalarial drug use are modulated by immune response, repeated re-inoculation of parasites, drug pharmacokinetic parameters, dose and treatment frequency.
The model quantifies possible effects of single and multiple (periodic) treatment on the outcome of parasite competition. In the absence of further inoculation, the dosage and/or treatment frequency required for complete clearance can be estimated. With persistent superinfection, time-average parasite densities can be derived in terms of the basic immune-regulating parameters, the drug efficacy and treatment regimen.
The functional relations in the model are applicable to a wide range of conditions and transmission environments, allowing predictions to be made on both the individual and the community levels, and, in particular, transitions from drug-sensitive to drug-resistant parasite dominance to be projected on both levels.
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