**3.2 Strain specificity of malaria immunity**

It has been suggested that the reason why immunity to malaria takes so long to acquire is because malaria is transmitted as a construct of many independent "strains" and one needs to accumulate immunity to all the circulating strains (Gupta and Day 1994, Gupta and Hill 1995). The observations in malariotherapy that infection with a given strain gave considerably more protection against re-infection by the same strain than by a different strain (Collins and Jeffery 1999a, Jeffery 1966) points to strain-specific immunity. However, unlike in the laboratory where cloned lines can be physically separated, maintaining such a population structure in the field despite sexual mixing is difficult (Babiker *et al* 1994, Hill and Babiker 1995, Ranford-Cartwright *et al* 1993). Nonetheless a number of models suggest that efficient immunity responses directed against a polymorphic antigenic determinant could constrain parasite populations into discrete non-overlapping strains with respect to that antigen (Gupta and Hill 1995, Recker *et al* 2008, Recker *et al* 2004).

Immune responses against the variant parasite antigens (VSA) exported to the surface of infected red cells, of which PfEMP1 is the best characterised, are an example of immunity that might be sufficiently efficient to structure malaria parasite population into "strains". These antigens are highly polymorphic and undergo clonal antigenic variation (Brannan *et al* 1994, Recker *et al* 2011, Roberts *et al* 1992). Antibodies to VSA provide variant-specific protection against malaria (Bull *et al* 1999, Bull *et al* 1998, Marsh *et al* 1989, Newbold *et al* 1992). The number of VSA variants against which an individual has antibodies increases with age (Bull *et al* 1998, Iqbal *et al* 1993, Reeder *et al* 1994). Thus, acquisition of immunity to malaria might, in part, involve the accumulation of antibodies against the circulating repertoire of VSA variants. It is thought that the variation of these antigens serve as an parasite immune evasion mechanism and therefore the need to avoid the generation of cross-reactive responses might provide the selection pressure necessary to maintain the circulation of distinct variants within a parasite population (Gupta and Hill 1995, Recker *et al* 2008, Recker *et al* 2004).
