Measurably recombining malaria parasites.

Genomic epidemiology has guided research and policy for various viral pathogens and there has been a parallel effort towards using genomic epidemiology to combat diseases that are caused by eukaryotic pathogens, such as the malaria parasite. However, the central concept of viral genomic epidemiology, namely that of measurably mutating pathogens, does not apply easily to sexually recombining parasites. Here we introduce the related but different concept of measurably recombining malaria parasites to promote convergence around a unifying theoretical framework for malaria genomic epidemiology. Akin to viral phylodynamics, we anticipate that an inferential framework developed around recombination will help guide practical research and thus realize the full public health potential of genomic epidemiology for malaria parasites and other sexually recombining pathogens.

Declines in prevalence alter the optimal level of sexual investment for the malaria parasite Plasmodium falciparum.

Successful infectious disease interventions can result in large reductions in parasite prevalence. Such demographic change has fitness implications for individual parasites and may shift the parasite's optimal life history strategy. Here, we explore whether declining infection rates can alter Plasmodium falciparum's investment in sexual versus asexual growth. Using a multiscale mathematical model, we demonstrate how the proportion of polyclonal infections, which decreases as parasite prevalence declines, affects the optimal sexual development strategy: Within-host competition in multiclone infections favors a greater investment in asexual growth whereas single-clone infections benefit from higher conversion to sexual forms. At the same time, drug treatment also imposes selection pressure on sexual development by shortening infection length and reducing within-host competition. We assess these models using 148 P. falciparum parasite genomes sampled in French Guiana over an 18-y period of intensive intervention (1998 to 2015). During this time frame, multiple public health measures, including the introduction of new drugs and expanded rapid diagnostic testing, were implemented, reducing P. falciparum malaria cases by an order of magnitude. Consistent with this prevalence decline, we see an increase in the relatedness among parasites, but no single clonal background grew to dominate the population. Analyzing individual allele frequency trajectories, we identify genes that likely experienced selective sweeps. Supporting our model predictions, genes showing the strongest signatures of selection include transcription factors involved in the development of P. falciparum's sexual gametocyte form. These results highlight how public health interventions impose wide-ranging selection pressures that affect basic parasite life history traits.

Leveraging mathematical models of disease dynamics and machine learning to improve development of novel malaria interventions.

BACKGROUND: Substantial research is underway to develop next-generation interventions that address current malaria control challenges. As there is limited testing in their early development, it is difficult to predefine intervention properties such as efficacy that achieve target health goals, and therefore challenging to prioritize selection of novel candidate interventions. Here, we present a quantitative approach to guide intervention development using mathematical models of malaria dynamics coupled with machine learning. Our analysis identifies requirements of efficacy, coverage, and duration of effect for five novel malaria interventions to achieve targeted reductions in malaria prevalence. METHODS: A mathematical model of malaria transmission dynamics is used to simulate deployment and predict potential impact of new malaria interventions by considering operational, health-system, population, and disease characteristics. Our method relies on consultation with product development stakeholders to define the putative space of novel intervention specifications. We couple the disease model with machine learning to search this multi-dimensional space and efficiently identify optimal intervention properties that achieve specified health goals. RESULTS: We apply our approach to five malaria interventions under development. Aiming for malaria prevalence reduction, we identify and quantify key determinants of intervention impact along with their minimal properties required to achieve the desired health goals. While coverage is generally identified as the largest driver of impact, higher efficacy, longer protection duration or multiple deployments per year are needed to increase prevalence reduction. We show that interventions on multiple parasite or vector targets, as well as combinations the new interventions with drug treatment, lead to significant burden reductions and lower efficacy or duration requirements. CONCLUSIONS: Our approach uses disease dynamic models and machine learning to support decision-making and resource investment, facilitating development of new malaria interventions. By evaluating the intervention capabilities in relation to the targeted health goal, our analysis allows prioritization of interventions and of their specifications from an early stage in development, and subsequent investments to be channeled cost-effectively towards impact maximization. This study highlights the role of mathematical models to support intervention development. Although we focus on five malaria interventions, the analysis is generalizable to other new malaria interventions.

Mechanistic within-host models of the asexual Plasmodium falciparum infection: a review and analytical assessment.

BACKGROUND: Malaria blood-stage infection length and intensity are important drivers of disease and transmission; however, the underlying mechanisms of parasite growth and the host's immune response during infection remain largely unknown. Over the last 30 years, several mechanistic mathematical models of malaria parasite within-host dynamics have been published and used in malaria transmission models. METHODS: Mechanistic within-host models of parasite dynamics were identified through a review of published literature. For a subset of these, model code was reproduced and descriptive statistics compared between the models using fitted data. Through simulation and model analysis, key features of the models were compared, including assumptions on growth, immune response components, variant switching mechanisms, and inter-individual variability. RESULTS: The assessed within-host malaria models generally replicate infection dynamics in malaria-naïve individuals. However, there are substantial differences between the model dynamics after disease onset, and models do not always reproduce late infection parasitaemia data used for calibration of the within host infections. Models have attempted to capture the considerable variability in parasite dynamics between individuals by including stochastic parasite multiplication rates; variant switching dynamics leading to immune escape; variable effects of the host immune responses; or via probabilistic events. For models that capture realistic length of infections, model representations of innate immunity explain early peaks in infection density that cause clinical symptoms, and model representations of antibody immune responses control the length of infection. Models differed in their assumptions concerning variant switching dynamics, reflecting uncertainty in the underlying mechanisms of variant switching revealed by recent clinical data during early infection. Overall, given the scarce availability of the biological evidence there is limited support for complex models. CONCLUSIONS: This study suggests that much of the inter-individual variability observed in clinical malaria infections has traditionally been attributed in models to random variability, rather than mechanistic disease dynamics. Thus, it is proposed that newly developed models should assume simple immune dynamics that minimally capture mechanistic understandings and avoid over-parameterization and large stochasticity which inaccurately represent unknown disease mechanisms.

Proteome-wide analysis of a malaria vaccine study reveals personalized humoral immune profiles in Tanzanian adults.

Tanzanian adult male volunteers were immunized by direct venous inoculation with radiation-attenuated, aseptic, purified, cryopreserved Plasmodium falciparum (Pf) sporozoites (PfSPZ Vaccine) and protective efficacy assessed by homologous controlled human malaria infection (CHMI). Serum immunoglobulin G (IgG) responses were analyzed longitudinally using a Pf protein microarray covering 91% of the proteome, providing first insights into naturally acquired and PfSPZ Vaccine-induced whole parasite antibody profiles in malaria pre-exposed Africans. Immunoreactivity was identified against 2239 functionally diverse Pf proteins, showing a wide breadth of humoral response. Antibody-based immune 'fingerprints' in these individuals indicated a strong person-specific immune response at baseline, with little changes in the overall humoral immunoreactivity pattern measured after immunization. The moderate increase in immunogenicity following immunization and the extensive and variable breadth of humoral immune response observed in the volunteers at baseline suggest that pre-exposure reduces vaccine-induced antigen reactivity in unanticipated ways.

Future use-cases of vaccines in malaria control and elimination.

Malaria burden has significantly changed or decreased over the last 20 years, however, it remains an important health problem requiring the rigorous application of existing tools and approaches, as well as the development and use of new interventions. A malaria vaccine has long been considered a possible new intervention to aid malaria burden reduction. However, after decades of development, only one vaccine to protect children has completed phase 3 studies. Before being widely recommended for use, it must further demonstrate safety, impact and feasibility in ongoing pilot implementation studies. Now is an appropriate time to consider the use-cases and health targets of future malaria vaccines. These must be considered in the context of likely innovations in other malaria tools such as vector control, as well as the significant knowledge gaps on the appropriate target antigens, and the immunology of vaccine-induced protection. Here we discuss the history of malaria vaccines and suggest some future use-cases for future malaria vaccines that will support achieving malaria health goals in different settings.

Mass campaigns combining antimalarial drugs and anti-infective vaccines as seasonal interventions for malaria control, elimination and prevention of resurgence: a modelling study.

BACKGROUND: The only licensed malaria vaccine, RTS,S/AS01, has been developed for morbidity-control in young children. The potential impact on transmission of deploying such anti-infective vaccines to wider age ranges, possibly with co-administration of antimalarial treatment, is unknown. Combinations of existing malaria interventions is becoming increasingly important as evidence mounts that progress on reducing malaria incidence is stalling and threatened by resistance. METHODS: Malaria transmission and intervention dynamics were simulated using OpenMalaria, an individual-based simulation model of malaria transmission, by considering a seasonal transmission setting and by varying epidemiological and setting parameters such as transmission intensity, case management, intervention types and intervention coverages. Chemopreventive drugs and anti-infective vaccine efficacy profiles were based on previous studies in which model parameters were fitted to clinical trial data. These intervention properties were used to evaluate the potential of seasonal mass applications of preventative anti-infective malaria vaccines, alone or in combination with chemoprevention, to reduce malaria transmission, prevent resurgence, and/or reach transmission interruption. RESULTS: Deploying a vaccine to all ages on its own is a less effective intervention strategy compared to chemoprevention alone. However, vaccines combined with drugs are likely to achieve dramatic prevalence reductions and in few settings, transmission interruption. The combined mass intervention will result in lower prevalence following the intervention compared to chemoprevention alone and will increase chances of interruption of transmission resulting from a synergistic effect between both interventions. The combination of vaccine and drug increases the time before transmission resurges after mass interventions cease compared to mass treatment alone. Deploying vaccines and drugs together requires fewer rounds of mass intervention and fewer years of intervention to achieve the same public health impact as chemoprevention alone. CONCLUSIONS: Through simulations we identified a previously unidentified value of deploying vaccines with drugs, namely the greatest benefit will be in preventing and delaying transmission resurgence for longer periods than with other human targeted interventions. This is suggesting a potential role for deploying vaccines alongside drugs in transmission foci as part of surveillance-response strategies.

Incidence and admission rates for severe malaria and their impact on mortality in Africa.

BACKGROUND: Appropriate treatment of life-threatening Plasmodium falciparum malaria requires in-patient care. Although the proportion of severe cases accessing in-patient care in endemic settings strongly affects overall case fatality rates and thus disease burden, this proportion is generally unknown. At present, estimates of malaria mortality are driven by prevalence or overall clinical incidence data, ignoring differences in case fatality resulting from variations in access. Consequently, the overall impact of preventive interventions on disease burden have not been validly compared with those of improvements in access to case management or its quality. METHODS: Using a simulation-based approach, severe malaria admission rates and the subsequent severe malaria disease and mortality rates for 41 malaria endemic countries of sub-Saharan Africa were estimated. Country differences in transmission and health care settings were captured by use of high spatial resolution data on demographics and falciparum malaria prevalence, as well as national level estimates of effective coverage of treatment for uncomplicated malaria. Reported and modelled estimates of cases, admissions and malaria deaths from the World Malaria Report, along with predicted burden from simulations, were combined to provide revised estimates of access to in-patient care and case fatality rates. RESULTS: There is substantial variation between countries' in-patient admission rates and estimated levels of case fatality rates. It was found that for many African countries, most patients admitted for in-patient treatment would not meet strict criteria for severe disease and that for some countries only a small proportion of the total severe cases are admitted. Estimates are highly sensitive to the assumed community case fatality rates. Re-estimation of national level malaria mortality rates suggests that there is substantial burden attributable to inefficient in-patient access and treatment of severe disease. CONCLUSIONS: The model-based methods proposed here offer a standardized approach to estimate the numbers of severe malaria cases and deaths based on national level reporting, allowing for coverage of both curative and preventive interventions. This makes possible direct comparisons of the potential benefits of scaling-up either category of interventions. The profound uncertainties around these estimates highlight the need for better data.

Country specific predictions of the cost-effectiveness of malaria vaccine RTS,S/AS01 in endemic Africa.

BACKGROUND: RTS,S/AS01 is a safe and moderately efficacious vaccine considered for implementation in endemic Africa. Model predictions of impact and cost-effectiveness of this new intervention could aid in country adoption decisions. METHODS: The impact of RTS,S was assessed in 43 countries using an ensemble of models of Plasmodium falciparum epidemiology. Informed by the 32months follow-up data from the phase 3 trial, vaccine effectiveness was evaluated at country levels of malaria parasite prevalence, coverage of control interventions and immunization. Benefits and costs of the program incremental to routine malaria control were evaluated for a four dose schedule: first dose administered at six months, second and third - before 9months, and fourth dose at 27months of age. Sensitivity analyses around vaccine properties, transmission, and economic inputs were conducted. RESULTS: If implemented in all 43 countries the vaccine has the potential to avert 123 (117;129) million malaria episodes over the first 10years. Burden averted averages 18,413 (range of country median estimates 156-40,054) DALYs per 100,000 fully vaccinated children with much variation across settings primarily driven by differences in transmission intensity. At a price of $5 per dose program costs average $39.8 per fully vaccinated child with a median cost-effectiveness ratio of $188 (range $78-$22,448) per DALY averted; the ratio is lower by one third - $136 (range $116-$220) - in settings where parasite prevalence in children aged 2-10years is at or above 10%. CONCLUSION: RTS,S/AS01has the potential to substantially reduce malaria burden in children across Africa. Conditional on assumptions on price, coverage, and vaccine properties, adding RTS,S to routine malaria control interventions would be highly cost-effective. Implementation decisions will need to further consider feasibility of scaling up existing control programs, and operational constraints in reaching children at risk with the schedule.