An antigenic diversification threshold for falciparum malaria transmission at high endemicity

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 easily 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. Author summaryThe vast diversity of the falciparum malaria parasite as seen by the immune system of hosts in high transmission regions, underlies both high prevalence of asymptomatic infections and partial protection to re-infection despite previous exposure. This large antigenic diversity of the parasite challenges control and elimination efforts. We propose a threshold quantity for antigenic innovation, we call Rdiv, measuring the potential of transmission to accumulate new antigenic variants over time. When Rdiv is pushed below one by reduced transmission intensity, new genes encoding this variation can no longer accumulate, resulting in a lower number of strains and facilitating further intervention. This innovation number can be applied to other infectious diseases with fast turnover of antigens, where large standing diversity similarly opposes successful intervention.