**3. Innate and acquired immunity**

Decreasing frequency and severity of malaria episodes with age among endemic populations is the best indicator that people do acquire immunity to malaria following repeated exposure. However, because both the truly protective immune response to malaria and those that simply reflect exposure to malaria increase concurrently with age, many putative in vitro measure of "immunity" to malaria show no correlation with protection against malaria. As such disentangling protective responses from non-protective ones in the complex milieu of responses provoked by malaria parasites is a major objective of malaria immunity studies. Unfortunately, differences in study methodology, polymorphism of target antigens or epitopes and other factors, such as variation in transmission in different study settings and even microvariations in transmission within a given study setting makes it difficult to develop a consistent picture of the efficacy of a given natural or vaccineinduced immune response in protecting against malaria (Bejon *et al* 2009, Kinyanjui *et al* 2009, Marsh and Kinyanjui 2006).

The Immunology of Malaria 179

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

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* 

Although both cellular and humoral immunity are thought to be involved in malaria immunity, the relative importance of each in protection against malaria is not yet well established. In particular much of the data on cellular immunity comes from animal models. However, many of these animals are poor models of human malaria. Furthermore, data from different animal species and between different strains of same species often vary considerably making it difficult to generate definitive conclusion regarding immune effector

CD8+ T cells are also referred to as cytotoxic T-cells (CTL) because they can kill infected cells directly by various cytotoxicity mechanisms. Because hepatocytes express class 1 HLA, the receptor for CD8+ T cells, the liver stage of malaria parasites is thought to be capable of inducing CTL responses. The role of CTL in the protection against malaria was first demonstrated in the classical experiments involving the immunization of animals and human with irradiated sporozoites. Such immunization resulted in complete, though short-

that antigen (Gupta and Hill 1995, Recker *et al* 2008, Recker *et al* 2004).

**4. Immune effector mechanisms in malaria immunity** 

**3.2 Strain specificity of malaria immunity** 

*al* 2008, Recker *et al* 2004).

mechanisms in malaria.

**4.1 CD8+ T-cells (CTL)** 

#### **3.1 Natural history of acquired immunity to malaria**

As shown in figure 1, in areas of stable malaria transmission, the majority of severe disease and death due to malaria occur mainly in children but parasite prevalence continue to rise well beyond childhood (Roca-Feltrer *et al* 2010, Snow *et al* 1997, Snow *et al* 1994). This has led to the suggestion that acquisition of immunity to malaria may be biphasic with immunity to disease being acquired before immunity to infection. Observations from experimental infection studies lend support to this suggestion. Records from malariotherapy in the 1940s which involved deliberate infection of syphilis patients with malaria so that the fever induced can kill syphilis spirochetes, show that in most patients, fever and high parasitaemia occurred in the first 25 days after which a low-density asymptomatic infection persisted for many months (Collins and Jeffery 1999b). More recently some modelling have suggested that immunity to severe disease may develop after only one or two episodes of disease (Gupta *et al* 1999a, Gupta *et al* 1999b). In reality, there is an overlap between the two phases of immunity otherwise anti-disease immunity acting in the absence of anti-parasite immunity would not prevent the parasites from multiplying and eventually overwhelming the patient. Furthermore, the risk of disease is proportional to parasite density (Rougemont *et al* 1991, Smith *et al* 1994) therefore immune mechanisms that clear parasites will also reduce the risk of disease.

Fig. 1. A typical age pattern for incidence of severe and mild malaria and prevalence of asymptomatic malaria infection in an area of high (upper graph) and low (lower graph ) malaria transmission

As shown in figure 1, in areas of stable malaria transmission, the majority of severe disease and death due to malaria occur mainly in children but parasite prevalence continue to rise well beyond childhood (Roca-Feltrer *et al* 2010, Snow *et al* 1997, Snow *et al* 1994). This has led to the suggestion that acquisition of immunity to malaria may be biphasic with immunity to disease being acquired before immunity to infection. Observations from experimental infection studies lend support to this suggestion. Records from malariotherapy in the 1940s which involved deliberate infection of syphilis patients with malaria so that the fever induced can kill syphilis spirochetes, show that in most patients, fever and high parasitaemia occurred in the first 25 days after which a low-density asymptomatic infection persisted for many months (Collins and Jeffery 1999b). More recently some modelling have suggested that immunity to severe disease may develop after only one or two episodes of disease (Gupta *et al* 1999a, Gupta *et al* 1999b). In reality, there is an overlap between the two phases of immunity otherwise anti-disease immunity acting in the absence of anti-parasite immunity would not prevent the parasites from multiplying and eventually overwhelming the patient. Furthermore, the risk of disease is proportional to parasite density (Rougemont *et al* 1991, Smith *et al* 1994) therefore immune mechanisms that clear parasites will also

Fig. 1. A typical age pattern for incidence of severe and mild malaria and prevalence of asymptomatic malaria infection in an area of high (upper graph) and low (lower graph )

**3.1 Natural history of acquired immunity to malaria** 

reduce the risk of disease.

malaria transmission
