COS 193-1 - Antigenic diversity and strain structure influence falciparum malaria resilience to transmission-reducing intervention

Abstract: Parasites compete for hosts in a frequency-dependent manner through patterns of cross-protection conferred by hosts’ immune memory. Negative frequency-dependent selection arising from such competition can lead to limiting similarity and high diversity of coexisting parasites on the basis of antigenic traits. In high-transmission regions, the malaria parasite Plasmodium falciparum exhibits such strain structure and hyper-diversity from the perspective of the multigene family known as var, which encodes for the major surface antigen of the blood stage of infection. These features allow hosts to remain susceptible to reinfection throughout their lifetime (incomplete immunity), enabling a high asymptomatic prevalence despite high transmission (high host occupancy despite high competition). The role of such large antigenic diversity and associated strain structure in the response of disease population dynamics to major perturbations remains, however, poorly understood. We address this role here in the ability of the transmission system to rebound from transmission-reducing intervention. We specifically ask whether a threshold response occurs at which the transmission system loses its resilience, and whether molecular indicators related to antigenic diversity and associated strain structure provide information on approaching this rapid change. To address these questions, we extend a stochastic agent-based model that incorporates the interplay of malaria population dynamics and parasite evolution. For pulse and press perturbations (transient or sustained transmission reductions), a sharp transition occurs across a narrow region of intervention intensity in the capacity of the system to rapidly rebound to high prevalence. Above this region, the system returns to high prevalence within a few years following perturbation. Within or below this region, the system remains at low prevalence, with a weak and delayed rebound. We show that rapid recovery is enabled by the concomitant recovery of high (antigenic) diversity and associated strain structure, whereas the slow prevalence rebound is accompanied by a loss of both these features. We identify molecular indicators that provide information on fragility and distance from the transition region of the perturbed system. We illustrate these indicators with longitudinal epidemiological and molecular data from northern Ghana across multiple seasons. The indicators can guide adjustment of control efforts to achieve local parasite extinction. Our results establish a link between the population dynamics of the disease and observations of parasite population genomics. The findings should be more generally relevant to other pathogens with similar immune evasion strategies whose large transmission reservoirs and resilience to control efforts are enabled by vast strain diversity.