A High Force of Plasmodium vivax Blood-Stage Infection Drives the Rapid Acquisition of Immunity in Papua New Guinean Children

et al. (2013) A High Force of Plasmodium vivax Blood-Stage Infection Drives the Rapid Acquisition of Immunity in Papua New Guinean Children. PLoS Negl Trop Dis 7(9): e2403. doi:10.1371/journal.pntd.0002403 A High Force of Plasmodium vivax Blood-Stage Infection Drives the Rapid Acquisition of Immunity in Papua New Guinean Children Cristian Koepfli 0 Kathryn L. Colborn 0 Benson Kiniboro 0 Enmoore Lin 0 Terence P. Speed 0 Peter M. Siba 0 Ingrid Felger 0 Ivo Mueller 0 James S. McCarthy, Queensland Institute for Medical Research, Australia 0 1 Swiss Tropical and Public Health Institute, Basel, Switzerland, 2 University of Basel, Basel, Switzerland, 3 Walter and Eliza Hall Institute , Parkville, Victoria , Australia , 4 University of California, Berkeley, Department of Biostatistics, Berkeley, California, United States of America, 5 Papua New Guinea Institute of Medical Research , Goroka, Eastern Highland Province , Papua New Guinea , 6 Barcelona Centre for International Health Research , Barcelona , Spain Background: When both parasite species are co-endemic, Plasmodium vivax incidence peaks in younger children compared to P. falciparum. To identify differences in the number of blood stage infections of these species and its potential link to acquisition of immunity, we have estimated the molecular force of blood-stage infection of P. vivax (molFOB, i.e. the number of genetically distinct blood-stage infections over time), and compared it to previously reported values for P. falciparum. Methods: P. vivax molFOB was estimated by high resolution genotyping parasites in samples collected over 16 months in a cohort of 264 Papua New Guinean children living in an area highly endemic for P. falciparum and P. vivax. In this cohort, P. vivax episodes decreased three-fold over the age range of 1-4.5 years. Results: On average, children acquired 14.0 new P. vivax blood-stage clones/child/year-at-risk. While the incidence of clinical P. vivax illness was strongly associated with molFOB (incidence rate ratio (IRR) = 1.99, 95% confidence interval (CI95) [1.80, 2.19]), molFOB did not change with age. The incidence of P. vivax showed a faster decrease with age in children with high (IRR = 0.49, CI95 [0.38, 0.64] p,0.001) compared to those with low exposure (IRR = 0.63, CI95[0.43, 0.93] p = 0.02). Conclusion: P. vivax molFOB is considerably higher than P. falciparum molFOB (5.5 clones/child/year-at-risk). The high number of P. vivax clones that infect children in early childhood contribute to the rapid acquisition of immunity against clinical P. vivax malaria. - Funding: The study was supported by Swiss National Science Foundation Grants 310030-134889 and 320030-125316, National Institutes of Health (AI063135), National Health & Medical Research Council (1021544 & 1003825). IM is supported by a Senior Research Fellowship from the NHMRC (1043345). This work was made possible through Victorian State Government Operational Infrastructure Support and Australian Government NHMRC IRIISS. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist. Exposure to malaria i.e. the number of blood-stage infections acquired over time determines to a large extent the frequency of disease and can also explain seasonal patterns and age trends. The number of infections acquired over time depends on transmission intensity, with frequent bites by infected mosquitoes resulting in high numbers of infections in a short period of time. In P. vivax, additional blood-stage infections are caused by relapses from dormant hypnozoites. As people who live in malaria endemic areas achieve immunity to disease after several years of exposure, newly acquired infections do not always result in clinical episodes. The speed of acquisition of immunity depends on transmission intensity [13] and also differs between parasite species, with immunity to P. vivax appearing to be acquired faster than immunity to P. falciparum [4,5]. In numerous field studies conducted in areas co-endemic for both species, the burden of P. vivax infections and disease was found to peak at a younger age than that of P. falciparum [610]. The mechanisms underlying the immunity to malaria are not entirely understood [2,11]. Whereas semi-immune people still develop blood stage parasitemia, parasite densities are considerably lower and rarely cause fever. Differences in the rate of natural acquisition of immunity to P. falciparum and P. vivax may be the result of differences in the immune responses induced by either species, and/or a consequence of different numbers of infections acquired over time. Malaria infections consist of different parasite clones that can infect individuals successively or simultaneously as multiple clone infections. Clones differ in their polymorphic surface antigens as well as in neutral genetic markers. Genotyping of such markers allows discrimination of individual parasite clones during multiple clone infections. The diversity of antigens is well documented in P. falciparum [1214] and P. vivax [15,16]. The large number of In areas where P. vivax and P. falciparum parasite species co-occur, immunity to P. vivax seems to be acquired more rapidly. This difference could be caused either by generic differences in the way immunity is acquired or by a relatively higher exposure to P. vivax blood-stage infections in early life. We found that children experienced an average of 14 new P. vivax blood-stage infections per year, and that the number of new infections acquired predicted how often children fell ill with vivax malaria by genotyping all P. vivax infections that occurred in a group of 264 children 14 years of age followed for 16 months. The burden of blood-stage infections caused by P. vivax was therefore at least twice as high as that caused by P. falciparum. This higher force-of-blood-stage infection (molFOB) caused by P. vivax is at least partially due to the ability of P. vivax hypnozoites to relapse from long-lasting liver stages. A high exposure to P. vivax blood-stage infection resulted in more rapid decrease in the incidence of P. vivax malaria. The high number of P. vivax clones that infect children in early childhood is thus likely to contribute substantially to the rapid acquisition of immunity against clinical P. vivax malaria. antigen variants is thought to allow parasites to escape the immune system, as new infections likely express alleles different from previous clones, and thus are not recognized by the present humoral response [17,18]. Immunity is thus assumed to be largely clone-specific, providing little cross-protection against heterologous clones [4,1922]. Plasmodium falciparum clones transmitted by a mosquito bite appear in the blood stream within 710 days. Albeit some of the transmitted sporozoites might not establish blood-stage infections, the num (...truncated)