ABSTRACT
BACKGROUND: Natural immunity to Plasmodium falciparum has been widely studied, but its effects on parasite dynamics are poorly understood. Acquisition and clearance rates of untreated infections are key elements of the dynamics of malaria, but estimating these parameters is challenging because of frequent super-infection and imperfect detectability of parasites. Consequently, information on effects of host immune status or age on infection dynamics is fragmentary. METHODS: An age-stratified cohort of 347 individuals from Northern Ghana was sampled six times at 2 month intervals. High-throughput capillary electrophoresis was used to genotype the msp-2 locus of all P. falciparum infections detected by PCR. Force of infection (FOI) and duration were estimated for each age group using an immigration-death model that allows for imperfect detection of circulating parasites. RESULTS: Allowing for imperfect detection substantially increased estimates of FOI and duration. Effects of naturally acquired immunity on the FOI and duration would be reflected in age dependence in these indices, but in our cohort data FOI tended to increase with age in children. Persistence of individual parasite clones was characteristic of all age-groups. Duration peaked in 5-9 year old children (average duration 319 days, 95% confidence interval 318;320). CONCLUSIONS: The main age-dependence is on parasite densities, with only small age-variations in the FOI and persistence of infections. This supports the hypothesis that acquired immunity controls transmission mainly by limiting blood-stage parasite densities rather than changing rates of acquisition or clearance of infections.
Subject(s)
Malaria, Falciparum/parasitology , Plasmodium falciparum/genetics , Adolescent , Adult , Age Factors , Aged , Antigens, Protozoan/genetics , Child , Child, Preschool , Cohort Studies , Female , Genotype , Ghana , Humans , Infant , Infant, Newborn , Malaria, Falciparum/immunology , Male , Middle Aged , Models, Biological , Plasmodium falciparum/immunology , Protozoan Proteins/genetics , Young AdultABSTRACT
Parameters describing the infection dynamics of Plasmodium falciparum are important determinants of the potential impact of interventions and are potential outcome measurements for malaria intervention trials. Low parasite densities, periodic sequestration of parasites, and the presence of multiple concurrent infections make it essential to use molecular techniques to estimate the force of infection and duration of infections in endemic areas. We now compare two approaches for tracking individual genotypes of the highly polymorphic merozoite surface protein 2: 1) fluorescence-labeled polymerase chain reaction (PCR) and GeneScan-sizing and 2) restriction fragment length polymorphism (RFLP). We analyze samples from a longitudinal field study in Ghana and use statistical approaches that allow for imperfect detectability. The two methods gave broadly similar estimates of parasite dynamics, but GeneScan is more precise and can achieve a higher throughput. The analysis of parasite dynamics indicated an average duration of infection of 210 days by GeneScan versus 152 days by PCR-RFLP in the study population in Kassena-Nankana, Northern Ghana. This reflects the good performance of GeneScan-based genotyping for studies of parasite infection dynamics.
Subject(s)
Malaria, Falciparum/epidemiology , Malaria, Falciparum/parasitology , Molecular Diagnostic Techniques/standards , Plasmodium falciparum/genetics , Polymerase Chain Reaction/methods , Adolescent , Adult , Age Factors , Animals , Antigens, Protozoan/genetics , Child , Child, Preschool , DNA, Protozoan/chemistry , DNA, Protozoan/isolation & purification , Gene Frequency/genetics , Genotype , Ghana/epidemiology , Humans , Infant , Longitudinal Studies , Middle Aged , Molecular Diagnostic Techniques/methods , Plasmodium falciparum/classification , Plasmodium falciparum/isolation & purification , Polymerase Chain Reaction/standards , Polymorphism, Restriction Fragment Length , Protozoan Proteins/genetics , Sensitivity and SpecificityABSTRACT
Immigration-death models are proposed to analyse the infection dynamics in longitudinal studies of panels of heavily parasitized human hosts where parasites have been typed at regular intervals by PCR. Immigration refers to the acquisition of a new parasitic genotype, occurring at rate lambda, and death refers to the clearance of a parasitic genotype (with rate mu). The models assume that corresponding to each observed process which is the detection or failure to detect a parasitic genotype, is an underlying true process which is hidden as a result of imperfect detection. We consider: (i) a model in which no distinction is made between the different members of the human population, who collectively represent the habitat of the parasites, and (ii) a model that allows for the accrual of infections with age. The models are fitted to a panel data set of malaria genotype of parasites belonging to the msp2 FC27 and 3D7 allelic families from a study of the dynamics of Plasmodium falciparum in Northern Ghana. Maximum likelihood estimates suggest that on average any individual residing in this holo-endemic area will acquire 16 new infections per year (95 per cent CI, 15-18) (defined by their single locus genotypes) and that infection with any of these genotypes lasts on average 152 days (95 per cent CI, 138-169). We estimate that an average of 47 per cent (95 per cent CI, 42-51) of the parasite types present in the host are detected in a finger-prick blood sample. This model provides a basis for analyses of how these quantities vary with the age, and hence the immune status of the host.
Subject(s)
Malaria, Falciparum/parasitology , Models, Biological , Models, Statistical , Plasmodium falciparum/genetics , Adolescent , Adult , Age Factors , Animals , Antigens, Protozoan/chemistry , Antigens, Protozoan/genetics , Child , Child, Preschool , Computer Simulation , DNA, Protozoan/chemistry , DNA, Protozoan/genetics , Endemic Diseases , Genotype , Ghana/epidemiology , Humans , Infant , Likelihood Functions , Longitudinal Studies , Malaria, Falciparum/blood , Malaria, Falciparum/epidemiology , Markov Chains , Middle Aged , Monte Carlo Method , Polymerase Chain Reaction , Protozoan Proteins/chemistry , Protozoan Proteins/geneticsABSTRACT
We reviewed the use of simple mathematical models to estimate the duration of Plasmodium falciparum infection after transmission has been interrupted. We then fit an exponential decay model to repeated cross-sectional survey data collected from three historical trials of indoor residual spraying against malaria: one from two contiguous districts in Tanzania-Kenya (Pare Taveta) carried out in 1954, the others in West Papua (1953), and the Garki project in northern Nigeria (1972-1973). A cross-sectional analysis of these datasets gave overall estimates of 602 days (95% confidence interval [CI] = 581-625) for the infection duration in Pare Taveta, 734 days (95% CI = 645-849) in West Papua, and 1,329 days (95% CI =1,193-1,499) for Garki. These estimates are much greater than the most widely quoted figures for the duration of untreated P. falciparum infections. Although these may be exaggerated because some reinfections occurred despite intensive vector control, prevalence was still decreasing when all these projects ended. Longitudinal survival analysis of the Garki data gave much shorter estimates of duration (186 days, 95% CI = 181-191), but effects of imperfect detection of parasites by microscopy severely bias these estimates. Estimates of infection duration for different age groups showed considerable variation but no general age trend. There was also no clear relationship between malaria endemicity and infection duration. Analyses of successive sampling from the same individuals with parasite typing are needed to obtain more reliable estimates of infection duration in endemic areas. Periods of several years may be required to evaluate long-term effects of interventions on malaria prevalence.
