title: Clinically immune hosts as a refuge for drug-sensitive malaria parasites.
abstract: BACKGROUND
  Mutations in Plasmodium falciparum that confer resistance to first-line antimalarial drugs have spread throughout the world from a few independent foci, all located in areas that were likely characterized by low or unstable malaria transmission. One of the striking differences between areas of low or unstable malaria transmission and hyperendemic areas is the difference in the size of the population of immune individuals. However, epidemiological models of malaria transmission have generally ignored the role of immune individuals in transmission, assuming that they do not affect the fitness of the parasite. This model reconsiders the role of immunity in the dynamics of malaria transmission and its impact on the evolution of antimalarial drug resistance under the assumption that immune individuals are infectious.
  
  
  METHODS
  The model is constructed as a two-stage susceptible-infected-susceptible (SIS) model of malaria transmission that assumes that individuals build up clinical immunity over a period of years. This immunity reduces the frequency and severity of clinical symptoms, and thus their use of drugs. It also reduces an individual's level of infectiousness, but does not impact the likelihood of becoming infected.
  
  
  RESULTS
  Simulations found that with the introduction of resistance into a population, clinical immunity can significantly alter the fitness of the resistant parasite, and thereby impact the ability of the resistant parasite to spread from an initial host by reducing the effective reproductive number of the resistant parasite as transmission intensity increases. At high transmission levels, despite a higher basic reproductive number, R0, the effective reproductive number of the resistant parasite may fall below the reproductive number of the sensitive parasite.
  
  
  CONCLUSIONS
  These results suggest that high-levels of clinical immunity create a natural ecological refuge for drug-sensitive parasites. This provides an epidemiological rationale for historical patterns of resistance emergence and suggests that future outbreaks of resistance are more likely to occur in low- or unstable-transmission settings. This finding has implications for the design of drug policies and the formulation of malaria control strategies, especially those that lower malaria transmission intensity.
authors.affiliation: Resources for the Future, 1616 P St., NW, Washington, DC 20036, USA. ramanan@rff.org
authors.forename: Eili Y
authors.initials: EY
authors.lastname: Klein
authors.forename: David L
authors.initials: DL
authors.lastname: Smith
authors.forename: Maciej F
authors.initials: MF
authors.lastname: Boni
authors.forename: Ramanan
authors.initials: R
authors.lastname: Laxminarayan
mesh_terms: D000818:Animals; D003198:Computer Simulation; D004351:Drug Resistance / Q000235:genetics*; D019353:Endemic Diseases; D006801:Humans; D008288:Malaria / Q000453:epidemiology / Q000276:immunology* / Q000469:parasitology / Q000635:transmission*; D008962:Models, Theoretical; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000235:genetics / Q000302:isolation & purification*