**4. Variant-specific immunity**

240 Malaria Parasites

combination with MSP3 [140], Liver Stage Antigen 1 (LSA1) being developed as a component of the ME-TRAP vaccine [168] and as a single component vaccine [169]; and MSP4 [170]. More recently discovered antigens demonstrate significant potential as vaccine candidates including members of the Rh family of proteins (Rh1, 2a, 2b, 4 and 5) [171, 172] and the Rh-interacting protein, RIPr [173], Serine repeat antigen 5 (SERA5, reviewed in [174]); MSP6 [175], MSP7 [176] and the pregnancy-associated malaria vaccine candidate, *var2csa* [177-179]. For some of these antigens, diversity is a significant issue that needs to be

Combinations of antigens from different *P. falciparum* lifecycle stages have also been tested. Trials for Spf66, a synthetic combination of peptides from including CSP, MSP1 and two others of unknown origin have now been halted after it was shown to have no effect on malaria [180], NMRC-M3V-Ad-PfCA which is a combination of CSP and AMA1 and is currently in phase 2 trials in the USA [51], GMZ2 which was mentioned above (MSP3 and GLURP, [140]) and the EBA/Rh vaccine candidate, which consists of EBA175 (RIII-V) and Rh2a/b, Rh5 and RIPr binding regions [181]. This vaccine candidate is still undergoing preclinical testing and aims to target different invasion pathways used by the merozoite

The increasing recognition of the importance of *Plasmodium vivax*, both as a significant cause of severe malaria and as a major obstacle to malaria control and elimination has exposed some major gaps in our knowledge of this parasite [182]. The vaccine development pipeline is lagging well behind that of *P.falciparum* and while work is progressing on vaccines targeted at the *P.vivax* Duffy-binding protein (DBP, [183]), which has long had a human genetic correlate (Duffy negative individuals have a greatly reduced risk of infection) [184], relatively little has been done on the blood-stage antigens homologous to those being intensively tested for *P.falciparum* [39]. Underlying this lack of development is an urgent need to understand more about the biology of the transmission of the parasite, the extent of

its diversity at a population level, and the mechanism of acquiring immunity to it.

One major obstacle impeding *P.vivax* research is the fact that presently, *P.vivax* cannot be maintained in long-term culture or at high parasitaemias. In addition, infected individuals typically present with low parasitemia and therefore parasite material is less available than for *P. falciparum* [185]. Recombinant *P.vivax* proteins for use in immunoepidemiological studies and vaccine development therefore are often isolated from reference strains, such as

Many *P. vivax* vaccine candidates currently being investigated are orthologues of *P. falciparum* vaccine candidate antigens [38, 39]. However, these two species have distinct biological features, the most obvious being the ability of *P. vivax* to form dormant liver stages, and also their variable transmission in different regions across the globe. Therefore it is difficult to base conclusions for *P.vivax*, on what is known for *P.falciparum*. Many experts believe that a malaria vaccine will need to contain a combination of both *P. falciparum* and *P. vivax* antigens to be globally effective, since many regions of the world are burdened with

evaluated.

[172].

**3.2** *Plasmodium vivax* 

Sal1 (Salvador).

both species [38].

Naturally acquired immunity to malaria develops only after years of exposure to infection by Plasmodium parasites. The extensive genetic diversity that is characteristic of malaria surface antigens provides one explanation for this, especially because immune responses are variant-specific. Eventually, antibodies to all of the variants in the parasite population are acquired or reach a threshold whereby protection against clinical episodes is achieved (reviewed in [190]).
