Abstract
In malaria and several other important infectious diseases, high prevalence occurs concomitantly with incomplete immunity. This apparent paradox poses major challenges to malaria elimination in highly endemic regions, where asymptomatic Plasmodium falciparum infections are present across all age classes creating a large reservoir that maintains transmission. This reservoir is in turn enabled by extreme antigenic diversity of the parasite and turnover of new variants. We present here the concept of a threshold in local pathogen diversification that defines a sharp transition in transmission intensity below which new antigen-encoding genes generated by either recombination or migration cannot establish. Transmission still occurs below this threshold, but diversity of these genes can neither accumulate nor recover from interventions that further reduce it. An analytical expectation for this threshold is derived and compared to numerical results from a stochastic individual-based model of malaria transmission that incorporates the major antigen-encoding multigene family known as var. This threshold corresponds to an “innovation” number we call Rdiv; it is different from, and complementary to, the one defined by the classic basic reproductive number of infectious diseases, R0, which does not readily is better apply under large and dynamic strain diversity. This new threshold concept can be exploited for effective malaria control and applied more broadly to other pathogens with large multilocus antigenic diversity.
Highlights
High transmission endemic areas present a significant challenge to the control and elimination of falciparum malaria due to the large reservoir of chronic asymptomatic infections sustaining transmission
Large reservoirs of chronic asymptomatic infection arise not just from high transmission rates per se, and from accompanying nonsterile specific immunity to pathogens with extreme antigenic variation encoded by multigene families [4, 5]
We introduce the concept for infectious agents in general, derive an analytical expectation for the rate of generation of “successful” new genes for the var system in P. falciparum, and demonstrate the existence of the predicted analytical threshold in numerical simulations of a stochastic agent-based model that incorporates var genes and the acquisition of immunity by individual hosts
Summary
High transmission endemic areas present a significant challenge to the control and elimination of falciparum malaria due to the large reservoir of chronic asymptomatic infections sustaining transmission. Large reservoirs of chronic asymptomatic infection arise not just from high transmission rates per se, and from accompanying nonsterile specific immunity to pathogens with extreme antigenic variation encoded by multigene families [4, 5]. One important multigene family in the malaria parasite P. falciparum is known as var It encodes for the major antigen of the blood stage of infection, the protein PfEMP1, exported to the surface of infected blood cells upon expression. Local parasite populations exhibit a large pool of gene variants reaching the tens of thousands [8, 9]. This vast genetic diversity is generated primarily by ectopic recombination. Spatial diversity in var genes has been documented [8, 9, 12], indicating that migration from surrounding areas contributes to new diversity and to the immunological challenge
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
