The Incidence and Differential Seasonal Patterns of Plasmodium vivax Primary Infections and Relapses in a Cohort of Children in Papua New Guinea

Abstract

Plasmodium vivax has the ability to relapse from dormant parasites in the liver weeks or months after inoculation, causing further blood-stage infection and potential onward transmission. Estimates of the force of blood-stage infections arising from primary infections and relapses are important for designing intervention strategies. However, in endemic settings their relative contributions are unclear. Infections are frequently asymptomatic, many individuals harbor multiple infections, and while high-resolution genotyping of blood samples enables individual infections to be distinguished, primary infections and relapses cannot be identified. We develop a model and fit it to longitudinal genotyping data from children in Papua New Guinea to estimate the incidence and seasonality of P vivax primary infection and relapse. The children, aged one to three years at enrolment, were followed up over 16 months with routine surveys every two months. Blood samples were taken at the routine visits and at other times if the child was ill. Samples positive by microscopy or a molecular method for species detection were genotyped using high-resolution capillary electrophoresis for P vivax MS16 and msp1F3, and P falciparum msp2. The data were summarized as longitudinal patterns of success or failure to detect a genotype at each routine time-point (eg 001000001). We assume that the seasonality of P vivax primary infection is similar to that of P falciparum since they are transmitted by the same vectors and, because P falciparum does not have the ability to relapse, the seasonality can be estimated. Relapses occurring during the study period can be a consequence of infections occurring prior to the study: we assume that the seasonal pattern of primary infections repeats over time. We incorporate information from parasitological and entomology studies to gain leverage for estimating the parameters, and take imperfect detection into account. We estimate the force of P vivax primary infections to be 11.5 (10.5, 12.3) for a three-year old child per year and the mean number of relapses per infection to be 4.3 (4.0, 4.6) over 16 months. The peak incidence of relapses occurred in the two month interval following the peak interval for primary infections: the contribution to the force of blood-stage infection from relapses is between 71% and 90% depending on the season. Our estimates contribute to knowledge of the P vivax epidemiology and have implications for the timing of intervention strategies targeting different stages of the life cycle.

Fig 1. Example of the structure of the data.

The diagram represents the data for a child who had no missing visits. The time of the routine visits is shown by red triangles: the timepoints were spaced two months apart with two visits 24 hours apart for all but the first and last timepoints. The child had had a sample taken at each routine visit. Eighteen distinct genotypes were detected, each is shown with blue rectangles representing the visits where the genotypes where detected. The timing of an illness visit (light blue rectangle) and recorded treatments (dark blue rectangle) is shown below. The column for observed patterns shows how the data are represented for the analysis: 0 indicates that the genotype was not detected at that routine time-point and 1 that it was detected. The pairs of routine visits 24 hours apart were combined, and the detectability was taken into account. The observed pattern ID is the distinct number assigned to the specific pattern.

Fig 2. Estimated seasonal pattern of P falciparum infections (a) estimated pattern during study follow-up (b) seasonal pattern extended to time preceding the study period.

Circles (a): estimated seasonal pattern of P falciparum infections (95% CI) during the study period. Solid line (b): inferred seasonal pattern of P vivax primary infections during the study period. Dashed line (b): assumed seasonal pattern of P vivax primary infections prior to the study period.

Fig 3. Predicted P vivax relapse and primary infection for a three-year-old girl.

(a) Estimated incidence of relapse per infection by two month interval from the primary infection. (b) Estimated incidence of primary infection and of relapses subsequent to primary infections one, two and six intervals earlier. Red circles: The incidence of primary infections prior to (dotted line) and during (solid line) the study period. Blue lines: The incidence of relapses subsequent to primary infections occurring one (light blue triangles), two (mid-blue squares) and six (dark blue diamonds) intervals earlier. (c) Estimated force of blood-stage infection from primary infections and relapses. Red circles: primary infections, blue diamonds: relapses. Shaded area is the warm-up period prior to the study, unshaded area is the study period itself. (d) Estimated proportion of the force of blood-stage infection from primary infections and relapses during the study period. Red triangles: primary infections, blue diamonds: relapses. The predictions are for a three-year old girl in Ilaita village with no ITN use using the results for MS16.