Modelling the epidemiology of residual Plasmodium vivax malaria in a heterogeneous host population: A case study in the Amazon Basin

The overall malaria burden in the Americas has decreased dramatically over the past two decades, but residual transmission pockets persist across the Amazon Basin, where Plasmodium vivax is the predominant infecting species. Current elimination efforts require a better quantitative understanding of malaria transmission dynamics for planning, monitoring, and evaluating interventions at the community level. This can be achieved with mathematical models that properly account for risk heterogeneity in communities approaching elimination, where few individuals disproportionately contribute to overall malaria prevalence, morbidity, and onwards transmission. Here we analyse demographic information combined with routinely collected malaria morbidity data from the town of Mâncio Lima, the main urban transmission hotspot of Brazil. We estimate the proportion of high-risk subjects in the host population by fitting compartmental susceptible-infected-susceptible (SIS) transmission models simultaneously to age-stratified vivax malaria incidence densities and the frequency distribution of P. vivax malaria attacks experienced by each individual over 12 months. Simulations with the best-fitting SIS model indicate that 20% of the hosts contribute 86% of the overall vivax malaria burden. Despite the low overall force of infection typically found in the Amazon, about one order of magnitude lower than that in rural Africa, high-risk individuals gradually develop clinical immunity following repeated infections and eventually constitute a substantial infectious reservoir comprised of asymptomatic parasite carriers that is overlooked by routine surveillance but likely fuels onwards malaria transmission. High-risk individuals therefore represent a priority target for more intensive and effective interventions that may not be readily delivered to the entire community.

[1]  A. Rosanas-Urgell,et al.  Differential impact of malaria control interventions on P. falciparum and P. vivax infections in young Papua New Guinean children , 2019, BMC medicine.

[2]  R. M. Corder,et al.  Statistical modeling of surveillance data to identify correlates of urban malaria risk: A population-based study in the Amazon Basin , 2019, PloS one.

[3]  R. M. Corder,et al.  Monitoring the Efficacy of Chloroquine-Primaquine Therapy for Uncomplicated Plasmodium vivax Malaria in the Main Transmission Hot Spot of Brazil , 2019, Antimicrobial Agents and Chemotherapy.

[4]  Amy Wesolowski,et al.  Mapping imported malaria in Bangladesh using parasite genetic and human mobility data , 2019, eLife.

[5]  P. Walker,et al.  Mathematical modelling of the impact of expanding levels of malaria control interventions on Plasmodium vivax , 2018, Nature Communications.

[6]  M. Gomes,et al.  Introducing risk inequality metrics in tuberculosis policy development , 2018, Nature Communications.

[7]  Su Yun Kang,et al.  Heterogeneous exposure and hotspots for malaria vectors at three study sites in Uganda , 2018, Gates open research.

[8]  Hannah C. Slater,et al.  The Relative Contribution of Symptomatic and Asymptomatic Plasmodium vivax and Plasmodium falciparum Infections to the Infectious Reservoir in a Low-Endemic Setting in Ethiopia , 2018, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[9]  R. Maude,et al.  Infectivity of Chronic Malaria Infections and Its Consequences for Control and Elimination , 2018, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[10]  Q. Bassat,et al.  Infection of Anopheles aquasalis from symptomatic and asymptomatic Plasmodium vivax infections in Manaus, western Brazilian Amazon , 2018, Parasites & Vectors.

[11]  H. Pham,et al.  The persistence and oscillations of submicroscopic Plasmodium falciparum and Plasmodium vivax infections over time in Vietnam: an open cohort study , 2018, The Lancet. Infectious diseases.

[12]  Larissa M. Sartori,et al.  Variation in Wolbachia effects on Aedes mosquitoes as a determinant of invasiveness and vectorial capacity , 2018, Nature Communications.

[13]  M. Lipsitch,et al.  Vaccine Effects on Heterogeneity in Susceptibility and Implications for Population Health Management , 2017, mBio.

[14]  Jan Hasenauer,et al.  PESTO: Parameter EStimation TOolbox , 2017, Bioinform..

[15]  Marcel Tanner,et al.  Malaria Modeling in the Era of Eradication. , 2017, Cold Spring Harbor perspectives in medicine.

[16]  D. Rex Asymptomatic Carriers of , 2017 .

[17]  E. Walker,et al.  Patterns and determinants of malaria risk in urban and peri-urban areas of Blantyre, Malawi , 2016, Malaria Journal.

[18]  A. Cowman,et al.  Malaria: Biology and Disease , 2016, Cell.

[19]  S. Herrera,et al.  Plasmodium vivax gametocyte infectivity in sub-microscopic infections , 2016, Malaria Journal.

[20]  M. Wilson,et al.  Urban Malaria: Understanding its Epidemiology, Ecology, and Transmission across Seven Diverse ICEMR Network Sites , 2015, The American journal of tropical medicine and hygiene.

[21]  Juliana K. Wambua,et al.  Multiple clinical episodes of Plasmodium falciparum malaria in a low transmission intensity setting: exposure versus immunity , 2015, BMC Medicine.

[22]  G. Killeen Characterizing, controlling and eliminating residual malaria transmission , 2014, Malaria Journal.

[23]  M. Castro,et al.  Epidemiology of Disappearing Plasmodium vivax Malaria: A Case Study in Rural Amazonia , 2014, PLoS neglected tropical diseases.

[24]  R. Hickson,et al.  How population heterogeneity in susceptibility and infectivity influences epidemic dynamics. , 2014, Journal of theoretical biology.

[25]  S. Meshnick,et al.  The role of submicroscopic parasitemia in malaria transmission: what is the evidence? , 2014, Trends in parasitology.

[26]  S. P. Kachur,et al.  The silent threat: asymptomatic parasitemia and malaria transmission , 2013, Expert review of anti-infective therapy.

[27]  N. F. Lima,et al.  Plasmodium vivax: reverse transcriptase real-time PCR for gametocyte detection and quantitation in clinical samples. , 2012, Experimental parasitology.

[28]  David L. Smith,et al.  Quantifying the Impact of Human Mobility on Malaria , 2012, Science.

[29]  G. Katriel The size of epidemics in populations with heterogeneous susceptibility , 2012, Journal of mathematical biology.

[30]  J. Conn,et al.  Amazonian malaria: asymptomatic human reservoirs, diagnostic challenges, environmentally driven changes in mosquito vector populations, and the mandate for sustainable control strategies. , 2012, Acta tropica.

[31]  A. Dicko,et al.  Intermittent Preventive Treatment of Malaria Provides Substantial Protection against Malaria in Children Already Protected by an Insecticide-Treated Bednet in Mali: A Randomised, Double-Blind, Placebo-Controlled Trial , 2011, PLoS medicine.

[32]  É. Braga,et al.  Epidemiology and control of frontier malaria in Brazil: lessons from community-based studies in rural Amazonia. , 2010, Transactions of the Royal Society of Tropical Medicine and Hygiene.

[33]  Chris J Drakeley,et al.  Heterogeneity in malaria exposure and vaccine response: implications for the interpretation of vaccine efficacy trials , 2010, Malaria Journal.

[34]  A. Allison Genetic control of resistance to human malaria. , 2009, Current opinion in immunology.

[35]  J. Coura,et al.  Age-dependent acquisition of protective immunity to malaria in riverine populations of the Amazon Basin of Brazil. , 2009, The American journal of tropical medicine and hygiene.

[36]  E. Seto,et al.  Factors determining the heterogeneity of malaria incidence in children in Kampala, Uganda. , 2008, The Journal of infectious diseases.

[37]  R. Snow,et al.  Evidence for Over-Dispersion in the Distribution of Clinical Malaria Episodes in Children , 2008, PloS one.

[38]  M. Gabriela M. Gomes,et al.  Prospects for Malaria Eradication in Sub-Saharan Africa , 2008, PloS one.

[39]  Thomas A. Smith Estimation of heterogeneity in malaria transmission by stochastic modelling of apparent deviations from mass action kinetics , 2008, Malaria Journal.

[40]  J. Dushoff,et al.  The entomological inoculation rate and Plasmodium falciparum infection in African children , 2005, Nature.

[41]  M. T. Marrelli,et al.  Asymptomatic Carriers of Plasmodium spp. as Infection Source for Malaria Vector Mosquitoes in the Brazilian Amazon , 2005, Journal of medical entomology.

[42]  M Tanner,et al.  Relationships between the outcome of Plasmodium falciparum infection and the intensity of transmission in Africa. , 2004, The American journal of tropical medicine and hygiene.

[43]  E. P. Camargo,et al.  High prevalence of asymptomatic Plasmodium vivax and Plasmodium falciparum infections in native Amazonian populations. , 2002, The American journal of tropical medicine and hygiene.

[44]  M. Alpers,et al.  Age- and species-specific duration of infection in asymptomatic malaria infections in Papua New Guinea , 2000, Parasitology.

[45]  Eduardo Massad,et al.  Modelling heterogeneities in individual frailties in epidemic models , 1999 .

[46]  J. Elkinton,et al.  Host Heterogeneity in Susceptibility and Disease Dynamics: Tests of a Mathematical Model , 1997, The American Naturalist.

[47]  C. Dye,et al.  Heterogeneities in the transmission of infectious agents: implications for the design of control programs. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[48]  T. Klein,et al.  Infection of Anopheles darlingi fed on patients infected with Plasmodium vivax before and during treatment with chloroquine plus primaquine in Costa Marques, Rondönia, Brazil. , 1992, Memórias do Instituto Oswaldo Cruz.

[49]  T. Klein,et al.  Infection of Anopheles darlingi fed on patients infected with Plasmodium vivax before and during treatment with chloroquine in Costa Marques, Rondonia, Brazil. , 1991, American Journal of Tropical Medicine and Hygiene.

[50]  P. Boreham,et al.  The relationship of host size to feeding by mosquitoes of the Anopheles gambiae Giles complex (Diptera: Culicidae) , 1980 .

[51]  M. Castro,et al.  Malaria Situation in Latin America and the Caribbean: Residual and Resurgent Transmission and Challenges for Control and Elimination. , 2019, Methods in molecular biology.

[52]  Mark P. J. van der Loo,et al.  The stringdist Package for Approximate String Matching , 2014, R J..

[53]  N. White,et al.  Chapter Two - Relapse , 2012 .

[54]  William E. Winkler,et al.  String Comparator Metrics and Enhanced Decision Rules in the Fellegi-Sunter Model of Record Linkage. , 1990 .

[55]  J. Trape,et al.  Malaria and urbanization in central Africa: the example of Brazzaville. Part II: Results of entomological surveys and epidemiological analysis. , 1987, Transactions of the Royal Society of Tropical Medicine and Hygiene.