The complex relationship of exposure to new Plasmodium infections and incidence of clinical malaria in Papua New Guinea

Abstract

The molecular force of blood-stage infection (molFOB) is a quantitative surrogate metric for malaria transmission at population level and for exposure at individual level. Relationships between molFOB, parasite prevalence and clinical incidence were assessed in a treatment-to-reinfection cohort, where P.vivax (Pv) hypnozoites were eliminated in half the children by primaquine (PQ). Discounting relapses, children acquired equal numbers of new P. falciparum (Pf) and Pv blood-stage infections/year (Pf-molFOB = 0-18, Pv-molFOB = 0-23) resulting in comparable spatial and temporal patterns in incidence and prevalence of infections. Including relapses, Pv-molFOB increased >3 fold (relative to PQ-treated children) showing greater heterogeneity at individual (Pv-molFOB = 0-36) and village levels. Pf- and Pv-molFOB were strongly associated with clinical episode risk. Yearly Pf clinical incidence rate (IR = 0.28) was higher than for Pv (IR = 0.12) despite lower Pf-molFOB. These relationships between molFOB, clinical incidence and parasite prevalence reveal a comparable decline in Pf and Pv transmission that is normally hidden by the high burden of Pv relapses.

Clinical trial registration: ClinicalTrials.gov NCT02143934.

Keywords: p. falciparum; Papua New Guinea; Plasmodium vivax; epidemiology; global health; human; immunity; immunology; malaria; transmission.

Conflict of interest statement

No competing interests declared.

Figures

Figure 1.. P. falciparum and P. vivax molFOB (A), prevalence by qPCR (B) and LM (C) by week of follow-up.

Blue lines, P. falciparum; red lines, P. vivax; solid lines, placebo arm; dashed lines, PQ arm. Open circles in (B) mark enrolment qPCR prevalence for each species.

Figure 1—figure supplement 1.. Definition of new infections for calculating molFOB.

Definition of P. falciparum new infections in two exemplary children is shown. The study design and timelines of follow-up are shown in upper panel: enrolment visit (‘E’), followed by radical treatment (black bar ‘T’) and 235 days of follow-up. The presence of P. falciparum clones by sampling visit is visualized below. Columns represent sampling visits, rows represent P. falciparum msp2 alleles, that is distinct P. falciparum clones. Grey solid circles, P. falciparum negative sample, grey open circle, missing sample due to missed follow-up visit; red circle: sample positive for respective Pf-msp2 allele. New infections were defined as a positive sample preceded by two samples negative for this allele (black rectangles), excluding missed samples (see Child 2, allele F, days 120–200). The time point of new infections is marked by arrows for the two children.

Figure 1—figure supplement 2.. P. ovale and P. malariae prevalence by qPCR during follow-up.

Purple lines, P. ovale; green lines, P. malariae; solid lines, Placebo arm; dashed lines, PQ arm. Open circles mark enrolment qPCR prevalence for each species.

Figure 2.. Distribution of P.falciparum molFOB (A) and P. vivax molFOB by treatment arm (B).

Relative frequencies among the 466 children are shown.

Figure 3.. Heterogeneity in molFOB (A, B) and clinical episode risk (C, D) of P.falciparum (A, C) and P. vivax (B, D).

Upper panels show the kriging fit of model predictions of molFOB and clinical episode risk of children in both treatment arms. Lower panels show the standard error relative to the kriging estimate. Dots represent study participants’ houses and are color-coded according to village. Black lines: vehicle-accessible road; dark grey lines: vehicle-inaccessible road; light grey lines: river; red/white cross: health center or aid post; grey square: school or enrolment location. Maps were prepared using ArcGIS 10.2 (Esri, USA).

Figure 4.. The incidence of P.falciparum (A) and P. vivax (B) clinical episodes relative to molFOB.

Mean clinical episode incidence is shown as bars (left axis) and proportion of clinical episode incidence divided by molFOB as connected dots (right axis). Error bars represent 95% CIs. p-values refer to the differences between groups in the proportion of clinical episodes and new infections, assessed by Chi2 or Fisher’s exact test.