The development of an effective malaria vaccine remains a major public health challenge. Merozoite surface protein (MSP)-1 of Plasmodium falciparum is being developed as a vaccine candidate to protect against the erythrocytic stages of the malaria parasite [1, 2]. Much of the work has been focused on the 19 kDa C-terminal region of MSP1 (called MSP119). Protection against challenge infection following immunization in rodent and monkey models of malaria has been reported [4–11]. However, sero-epidemiological studies [12–16] and vaccine trials  in human populations have given conflicting results concerning the protective role of anti-MSP1 antibodies, which may be explained by differences in the fine specificities of the MSP119-specific antibodies [18, 19]. It can be concluded from these studies that in the humoral control of malaria infection, the fine specificity of the antibody response may be crucial to inhibit erythrocyte invasion by merozoites.
The MSP1 precursor is cleaved into four fragments on the merozoite surface and at invasion the C-terminal 42 kDa fragment (MSP142) is processed further into two smaller fragments: a 33 kDa polypeptide (MSP133) and the C-terminal MSP119, which remains on the parasite surface during invasion of red blood cells (RBC). MSP1 has been reported to elicit three types of antibody that can bind MSP142[2, 20, 21]. These are a) inhibitory antibodies, which inhibit the cleavage of MSP142 and thus invasion of RBC; b) blocking antibodies, which have overlapping specificities and compete with inhibitory antibodies for binding to the antigen, thereby allowing processing and invasion to occur even in the presence of inhibitory antibodies; and c) neutral antibodies that are neither inhibitory nor blocking. Significantly, it has been shown that all these types of MSP119-specific antibodies are part of the natural immune response to MSP1 in malaria-exposed individuals [22, 23]. Thus, the rational design of an MSP1-based malaria vaccine for the preferential induction of processing-inhibitory antibodies with the appropriate specificities is an important goal. The relative abundance of these protective antibodies in relation to the detrimental (blocking) antibodies in any infection is one of the important factors that may determine the outcome of that infection [2, 3, 20, 22].
The MSP119 epitopes recognized by inhibitory and blocking monoclonal antibodies (mAbs) have been mapped using site-directed mutagenesis, PEPSCAN, and nuclear magnetic resonance (NMR) [21, 24, 25]. A number of single and multiple amino acid substitutions in MSP119 has been made, which had either no effect, or reduced, or completely abolished the binding of individual mAbs . Recent data have shown that polyclonal antibodies in sera obtained from individuals living in a malaria endemic area recognize and bind to the modified antigens [22, 23]. A vaccine based on one of these modified proteins could be designed to induce inhibitory but not blocking Abs and thus provide a focused polyclonal antibody response to inhibit RBC invasion and cleavage of MSP1 [21, 22].
CD4+ T-cell responses, providing help for MSP1-specific B-cell responses, are essential for protective immunity in rodent models of malaria, in protective immunity induced by immunization with MSP119. Since it is possible that the amino acid substitutions may alter the pattern and kinetics of MSP119 antigen processing of within the MHC class II pathway, and thus the peptides presented, it will be important to determine whether the variant MSP1 molecules are recognized by immune cells obtained from individuals naturally primed by malaria infection. Some reports have suggested that T-cell responses to MSP1 in malaria-exposed donors are poor [27, 28], possibly because of the difficulty in processing the highly disulfide bonded globular MSP119 [27, 29, 30]. Also, the common occurrence of high background responses in both unexposed and exposed donors makes it difficult to demonstrate T-cell responses in field samples. The study described here was carried out to determine whether modified MSP119 antigens were recognized by immune cells from naturally exposed and immune individuals living in a malaria endemic area, and whether modification of the critical T cell epitopes of MSP119 would enhance or compromise cellular responses. Results from this study show that variant MSP119 with two or more amino acid substitutions not only stimulated PBMC from exposed individuals but also induced proliferative responses in vitro of greater magnitude than the wild-type (WT) antigen. These results suggest that these modified MSP1 proteins may be suitable candidates for a malaria vaccine that would induce both protective antibodies and suitable cellular responses.