Impact of Schistosoma mansoni on Malaria Transmission in Sub-Saharan Africa

Background

Sub-Saharan Africa harbors the majority of the global burden of malaria and schistosomiasis infections. The co-endemicity of these two tropical diseases has prompted investigation into the mechanisms of coinfection, particularly the competing immunological responses associated with each disease. Epidemiological studies have shown that infection with Schistosoma mansoni is associated with a greater malaria incidence among school-age children.

Methodology

We developed a co-epidemic model of malaria and S. mansoni transmission dynamics which takes into account key epidemiological interaction between the two diseases in terms of elevated malaria incidence among individuals with S. mansoni high egg output. The model was parameterized for S. mansoni high-risk endemic communities, using epidemiological and clinical data of the interaction between S. mansoni and malaria among children in sub-Saharan Africa. We evaluated the potential impact of the S. mansoni–malaria interaction and mass treatment of schistosomiasis on malaria prevalence in co-endemic communities.

Principal Findings

Our results suggest that in the absence of mass drug administration of praziquantel, the interaction between S. mansoni and malaria may reduce the effectiveness of malaria treatment for curtailing malaria transmission, in S. mansoni high-risk endemic communities. However, when malaria treatment is used in combination with praziquantel, mass praziquantel administration may increase the effectiveness of malaria control intervention strategy for reducing malaria prevalence in malaria- S. mansoni co-endemic communities.

Conclusions/Significance

Schistosomiasis treatment and control programmes in regions where S. mansoni and malaria are highly prevalent may have indirect benefits on reducing malaria transmission as a result of disease interactions. In particular, mass praziquantel administration may not only have the direct benefit of reducing schistosomiasis infection, it may also reduce malaria transmission and disease burden.     

Epidemiological considerations for malaria reduction by transmission blocking vaccination

Outside of the temperate regions, malaria transmission continues throughout much of the world in a distribution which is not very different to that of one hundred years ago. However, with the notable exception of Africa sub Sahara, the morbidity and mortality due to malaria has generally been reduced to very low levels by comparison with earlier times. In a broad sense the malaria problem today falls into two distinct compartments, 1) how to deal with the remaining problem of malaria in the affected areas outside of sub Saharan Africa and 2) how to manage the, currently, much greater problem of malaria-related morbidity and mortality in Africa sub Sahara. Malaria control campaigns of the past have always placed great emphasis on reducing malaria inoculation rates in the affected populations. This may seem entirely logical, and is, indeed, an absolute requirement where eradication of malaria from an endemic area is the goal. There can, nevertheless, be dangers as well as benefits associated with reducing malaria inoculation rates in previously endemic populations. I discuss here the epidemiological issues which should be taken into account in this respect. I then examine the role that vaccination to reduce malaria inoculation rates in endemic populations--malaria transmission blocking vaccination--could play in malaria control.     

Inference and dynamic simulation of malaria using a simple climate-driven entomological model of malaria transmission

Given the crucial role of climate in malaria transmission, many mechanistic models of malaria represent vector biology and the parasite lifecycle as functions of climate variables in order to accurately capture malaria transmission dynamics. Lower dimension mechanistic models that utilize implicit vector dynamics have relied on indirect climate modulation of transmission processes, which compromises investigation of the ecological role played by climate in malaria transmission. In this study, we develop an implicit process-based malaria model with direct climate-mediated modulation of transmission pressure borne through the Entomological Inoculation Rate (EIR). The EIR, a measure of the number of infectious bites per person per unit time, includes the effects of vector dynamics, resulting from mosquito development, survivorship, feeding activity and parasite development, all of which are moderated by climate. We combine this EIR-model framework, which is driven by rainfall and temperature, with Bayesian inference methods, and evaluate the model’s ability to simulate local transmission across 42 regions in Rwanda over four years. Our findings indicate that the biologically-motivated, EIR-model framework is capable of accurately simulating seasonal malaria dynamics and capturing of some of the inter-annual variation in malaria incidence. However, the model unsurprisingly failed to reproduce large declines in malaria transmission during 2018 and 2019 due to elevated anti-malaria measures, which were not accounted for in the model structure. The climate-driven transmission model also captured regional variation in malaria incidence across Rwanda’s diverse climate, while identifying key entomological and epidemiological parameters important to seasonal malaria dynamics. In general, this new model construct advances the capabilities of implicitly-forced lower dimension dynamical malaria models by leveraging climate drivers of malaria ecology and transmission.     

Host-mediated regulation of superinfection in malaria

In regions of high rates of malaria transmission, mosquitoes repeatedly transmit liver-tropic Plasmodium sporozoites to individuals who already have blood-stage parasitemia. This manifests itself in semi-immune children (who have been exposed since birth to Plasmodium infection and as such show low levels of peripheral parasitemia but can still be infected) older than 5 years of age by concurrent carriage of different parasite genotypes at low asymptomatic parasitemias. Superinfection presents an increased risk of hyperparasitemia and death in less immune individuals but counterintuitively is not frequently observed in the young. Here we show in a mouse model that ongoing blood-stage infections, above a minimum threshold, impair the growth of subsequently inoculated sporozoites such that they become growth arrested in liver hepatocytes and fail to develop into blood-stage parasites. Inhibition of the liver-stage infection is mediated by the host iron regulatory hormone hepcidin, whose synthesis we found to be stimulated by blood-stage parasites in a density-dependent manner. We mathematically modeled this phenomenon and show how density-dependent protection against liver-stage malaria can shape the epidemiological patterns of age-related risk and the complexity of malaria infections seen in young children. The interaction between these two Plasmodium stages and host iron metabolism has relevance for the global efforts to reduce malaria transmission and for evaluation of iron supplementation programs in malaria-endemic regions.     

Malaria early warning in Kenya

Kenya displays large spatiotemporal diversity in its climate and ecology. It follows that malaria transmission will reflect this environmental heterogeneity in both space and time. In this article, we discuss how such heterogeneity, and its epidemiological consequences, should be considered in the development of early warning systems for malaria epidemics.     

Malaria vector analysis and control

Antivector measures in malaria control should aim for a cost-effective reduction of the transmission potential ideally to below the critical level for sustained transmission. The available measures include those that decrease vector abundance, vector-human contact and vector survival rate or that increase the length of the sporogonic cycle. These have widely different impact on malaria transmission, as shown by epidemiological modelling. Direct modification of vector receptivity to Plasmodium is also hypothetically attainable by the use of transmission-blocking vaccines or by genetic manipulation and replacement of the vector population. Vector analysis constitutes the essential prerequisite for basic malaria epidemiology as well as for the development, planning and evaluation of antivector measures. The rationale, the problems and the perspectives of vector analysis are reviewed here by Mario Coluzzi, on the basis of his experience with Afrotropical and Mediterranean malaria vectors.     

Optimal control analysis of a malaria disease transmission model that includes treatment and vaccination with waning immunity

We derive and analyse a deterministic model for the transmission of malaria disease with mass action form of infection. Firstly, we calculate the basic reproduction number, R(0), and investigate the existence and stability of equilibria. The system is found to exhibit backward bifurcation. The implication of this occurrence is that the classical epidemiological requirement for effective eradication of malaria, R(0)<1, is no longer sufficient, even though necessary. Secondly, by using optimal control theory we derive the conditions under which it is optimal to eradicate the disease and examine the impact of a possible combined vaccination and treatment strategy on the disease transmission. When eradication is impossible, we derive the necessary conditions for optimal control of the disease using Pontryagin's Maximum Principle. The results obtained from the numerical simulations of the model show that a possible vaccination combined with effective treatment regime would reduce the spread of the disease appreciably.     

The cell biology of malaria infection of mosquito: advances and opportunities

Recent reviews (Feachem et al.; Alonso et al.) have concluded that in order to have a sustainable impact on the global burden of malaria, it is essential that we knowingly reduce the global incidence of infected persons. To achieve this we must reduce the basic reproductive rate of the parasites to < 1 in diverse epidemiological settings. This can be achieved by impacting combinations of the following parameters: the number of mosquitoes relative to the number of persons, the mosquito/human biting rate, the proportion of mosquitoes carrying infectious sporozoites, the daily survival rate of the infectious mosquito and the ability of malaria‐infected persons to infect mosquito vectors. This paper focuses on our understanding of parasite biology underpinning the last of these terms: infection of the mosquito. The article attempts to highlight central issues that require further study to assist in the discovery of useful transmission‐blocking measures.     

Using evolutionary costs to enhance the efficacy of malaria control via genetically manipulated mosquitoes

An earlier mathematical model exploring the use of genetically manipulated mosquitoes for malaria control suggested that the prevalence of malaria is reduced significantly only if almost all mosquitoes become completely resistant to malaria. Central to the model was the 'cost of resistance': the reduction of a resistant mosquito's evolutionary fitness in comparison with a sensitive one's. Here, we consider the possibility of obtaining more optimistic outcomes by taking into account the epidemiological (in addition to the evolutionary) consequences of a cost of resistance that decreases the life-span of adult mosquitoes (the most relevant parameter for the parasite's epidemiology). There are two main results. First, if despite its cost, resistance is fixed in the population, increasing the cost of resistance decreases the intensity of transmission. However, this epidemiological effect is weak if resistance is effective enough to be considered relevant for control. Second, if the cost of resistance prevents its fixation, increasing it intensifies transmission. Thus, the epidemiological effect of the cost of resistance cannot compensate for the lower frequency of resistant mosquitoes in the population. Overall, our conclusion remains pessimistic: so that genetic manipulation can become a promising method of malaria control, we need techniques that enable almost all mosquitoes to be almost completely resistant to infection.     

Seasonally Dependent Relationships between Indicators of Malaria Transmission and Disease Provided by Mathematical Model Simulations

Evaluating the effectiveness of malaria control interventions on the basis of their impact on transmission as well as impact on morbidity and mortality is becoming increasingly important as countries consider pre-elimination and elimination as well as disease control. Data on prevalence and transmission are traditionally obtained through resource-intensive epidemiological and entomological surveys that become difficult as transmission decreases. This work employs mathematical modeling to examine the relationships between malaria indicators allowing more easily measured data, such as routine health systems data on case incidence, to be translated into measures of transmission and other malaria indicators. Simulations of scenarios with different levels of malaria transmission, patterns of seasonality and access to treatment were run with an ensemble of models of malaria epidemiology and within-host dynamics, as part of the OpenMalaria modeling platform. For a given seasonality profile, regression analysis mapped simulation results of malaria indicators, such as annual average entomological inoculation rate, prevalence, incidence of uncomplicated and severe episodes, and mortality, to an expected range of values of any of the other indicators. Results were validated by comparing simulated relationships between indicators with previously published data on these same indicators as observed in malaria endemic areas. These results allow for direct comparisons of malaria transmission intensity estimates made using data collected with different methods on different indicators. They also address key concerns with traditional methods of quantifying transmission in areas of differing transmission intensity and sparse data. Although seasonality of transmission is often ignored in data compilations, the models suggest it can be critically important in determining the relationship between transmission and disease. Application of these models could help public health officials detect changes of disease dynamics in a population and plan and assess the impact of malaria control interventions.     

Elucidating relationships between P.falciparum prevalence and measures of genetic diversity with a combined genetic-epidemiological model of malaria

There is an abundance of malaria genetic data being collected from the field, yet using these data to understand the drivers of regional epidemiology remains a challenge. A key issue is the lack of models that relate parasite genetic diversity to epidemiological parameters. Classical models in population genetics characterize changes in genetic diversity in relation to demographic parameters, but fail to account for the unique features of the malaria life cycle. In contrast, epidemiological models, such as the Ross-Macdonald model, capture malaria transmission dynamics but do not consider genetics. Here, we have developed an integrated model encompassing both parasite evolution and regional epidemiology. We achieve this by combining the Ross-Macdonald model with an intra-host continuous-time Moran model, thus explicitly representing the evolution of individual parasite genomes in a traditional epidemiological framework. Implemented as a stochastic simulation, we use the model to explore relationships between measures of parasite genetic diversity and parasite prevalence, a widely-used metric of transmission intensity. First, we explore how varying parasite prevalence influences genetic diversity at equilibrium. We find that multiple genetic diversity statistics are correlated with prevalence, but the strength of the relationships depends on whether variation in prevalence is driven by host- or vector-related factors. Next, we assess the responsiveness of a variety of statistics to malaria control interventions, finding that those related to mixed infections respond quickly (∼months) whereas other statistics, such as nucleotide diversity, may take decades to respond. These findings provide insights into the opportunities and challenges associated with using genetic data to monitor malaria epidemiology.     

Determination of the processes driving the acquisition of immunity to malaria using a mathematical transmission model

Acquisition of partially protective immunity is a dominant feature of the epidemiology of malaria among exposed individuals. The processes that determine the acquisition of immunity to clinical disease and to asymptomatic carriage of malaria parasites are poorly understood, in part because of a lack of validated immunological markers of protection. Using mathematical models, we seek to better understand the processes that determine observed epidemiological patterns. We have developed an age-structured mathematical model of malaria transmission in which acquired immunity can act in three ways (“immunity functions”): reducing the probability of clinical disease, speeding the clearance of parasites, and increasing tolerance to subpatent infections. Each immunity function was allowed to vary in efficacy depending on both age and malaria transmission intensity. The results were compared to age patterns of parasite prevalence and clinical disease in endemic settings in northeastern Tanzania and The Gambia. Two types of immune function were required to reproduce the epidemiological age-prevalence curves seen in the empirical data; a form of clinical immunity that reduces susceptibility to clinical disease and develops with age and exposure (with half-life of the order of five years or more) and a form of anti-parasite immunity which results in more rapid clearance of parasitaemia, is acquired later in life and is longer lasting (half-life of >20 y). The development of anti-parasite immunity better reproduced observed epidemiological patterns if it was dominated by age-dependent physiological processes rather than by the magnitude of exposure (provided some exposure occurs). Tolerance to subpatent infections was not required to explain the empirical data. The model comprising immunity to clinical disease which develops early in life and is exposure-dependent, and anti-parasite immunity which develops later in life and is not dependent on the magnitude of exposure, appears to best reproduce the pattern of parasite prevalence and clinical disease by age in different malaria transmission settings. Understanding the effector mechanisms underlying these two immune functions will assist in the design of transmission-reducing interventions against malaria.     

Blockade of TNF receptor 1 reduces disease severity but increases parasite transmission during Plasmodium chabaudi chabaudi infection

Reducing host carriage of transmission-stage malaria parasites (gametocytes) is expected to decrease the population-wide burden of malaria. Some malaria disease severity is attributed to the induction of the pro-inflammatory cytokines TNF-alpha and lymphotoxin-alpha (LT-alpha), and we are interested in whether anti-malaria interventions which ameliorate the symptoms induced by those cytokines may have the capacity to alter malaria transmission. As many functions of TNF-alpha and LT-alpha are exerted through TNF receptor 1 (TNFR1), we investigated the effect TNFR1 blockade exerted on parasite transmission using the rodent malaria Plasmodium chabaudi chabaudi. We found that blocking TNFR1 simultaneously increased gametocyte density and infectivity to mosquitoes, whilst reducing disease severity (weight loss). These transmission-enhancing and severity-reducing effects of TNFR1 blockade were independent of asexual parasite load and were observed for several P. c. chabaudi genotypes. These results suggest that the effects of candidate malaria interventions on infectivity should be examined alongside effects on disease severity so that the epidemiological consequences of such interventions can be evaluated.     

A strain theory of malaria transmission

Does the fact that the risk o f getting malaria is high in most endemic areas mean that it will be impossible to control through vaccination? Not if malaria is composed of several mildly transmissible strains, and what we are measuring as the high risk is the probability of being infected by any one of the several strains circulating independently within the same area. In this article, Sunetra Gupta and Karen Day discuss a strain theory of malaria transmission that fits both recent serological and molecular observations and more conventional epidemiological data on age distributions of infection and disease. Their analyses suggest that the transmissibility of malaria has been grossly overestimated, and that the control of malaria through vaccination may be far easier than previously assumed.     

Climate Drivers on Malaria Transmission in Arunachal Pradesh,India

The present study was conducted during the years 2006 to 2012 and provides information on prevalence of malaria and its regulation with effect to various climatic factors in East Siang district of Arunachal Pradesh, India. Correlation analysis, Principal Component Analysis and Hotelling’s T² statistics models are adopted to understand the effect of weather variables on malaria transmission. The epidemiological study shows that the prevalence of malaria is mostly caused by the parasite Plasmodium vivax followed by Plasmodium falciparum. It is noted that, the intensity of malaria cases declined gradually from the year 2006 to 2012. The transmission of malaria observed was more during the rainy season, as compared to summer and winter seasons. Further, the data analysis study with Principal Component Analysis and Hotelling’s T² statistic has revealed that the climatic variables such as temperature and rainfall are the most influencing factors for the high rate of malaria transmission in East Siang district of Arunachal Pradesh.     

Malaria and social health determinants: a new heuristic framework from the perspective of Latin American social medicine

Traditionally, malaria research and study have followed the positivist scientific paradigm and its biomedical conception of disease. From this perspective, diverse control actions and strategies have been designed. However, despite a century of scientific experience and the depth and thoroughness achieved in the knowledge of malaria, this has not been translated into a constant and progressive decrease of its epidemiological burden. This essay argues for the need for a change in malaria conception, reconfiguring it as a process of biological and social character, where the geno-phenotypical possibilities of the host-parasite relationship and of the diseases clinical expression are articulated with the historic and social dynamics of the spaces in which they occur. In addition, it proposes rethinking the epidemiological research of this entity on the basis of the visualization of the dynamic, heterogeneous, dialectic and complex character of biosocial organizations that constitute the reality of malaria (from the social structure to the genetic and phenotypic level of parasite individuals, vectors and humans). To achieve this, it is suggested that: 1) the Latin American perspective on the social determinants of health be adopted; 2) new analytical categories (for instance, malaria social territory) and new investigation tools (matrices of critical processes of social determination) be incorporated, and 3) the conventional epidemiological categories of infectious diseases such as the transmission and infectiousness be reinterpreted.     

mtDNA inheritance in the mosquitoes of Anopheles stephensi

The inheritance of mtDNA was tested in malaria vector mosquitoes of Anopheles stephensi strains using PCR-RFLP analysis for its utility in addressing epidemiological questions related to the transmission and spread of malaria. Reciprocal crosses were made between two haplotypes with distinct mtDNA restriction fragment length polymorphism (RFLP) profiles through 20 consecutive generations. All of the progenies produced by these crosses had the mtDNA haplotype of the female parent suggesting that, if it occurs, paternal inheritance of mtDNA in An. stephensi is rare.     

A model for the coevolution of immunity and immune evasion in vector-borne diseases with implications for the epidemiology of malaria

We describe a model of host-parasite coevolution, where the interaction depends on the investments by the host in its immune response and by the parasite in its ability to suppress (or evade) its host's immune response. We base our model on the interaction between malaria parasites and their mosquito hosts and thus describe the epidemiological dynamics with the Macdonald-Ross equation of malaria epidemiology. The qualitative predictions of the model are most sensitive to the cost of the immune response and to the intensity of transmission. If transmission is weak or the cost of immunity is low, the system evolves to a coevolutionarily stable equilibrium at intermediate levels of investment (and, generally, at a low frequency of resistance). At a higher cost of immunity and as transmission intensifies, the system is not evolutionarily stable but rather cycles around intermediate levels of investment. At more intense transmission, neither host nor parasite invests any resources in dominating its partner so that no resistance is observed in the population. These results may help to explain the lack of encapsulated malaria parasites generally observed in natural populations of mosquito vectors, despite strong selection pressure for resistance in areas of very intense transmission.     

A Locally Acquired Falciparum Malaria via Nosocomial Transmission in Korea

A 57-year old man who was admitted to an emergency room of a tertiary hospital with hemoptysis developed malarial fever 19 days later and then died from severe falciparum malaria 2 days later. He had not traveled outside of Korea for over 30 years. Through intensive interviews and epidemiological surveys, we found that a foreign patient with a recent history of travel to Africa was transferred to the same hospital with severe falciparum malaria. We confirmed through molecular genotyping of the MSP-1 gene that Plasmodium falciparum genotypes of the 2 patients were identical. It is suggested that a breach of standard infection control precautions resulted in this P. falciparum transmission between 2 patients in a hospital environment. This is the first report of a nosocomial transmission of falciparum malaria in Korea.