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The world's first malaria vaccine RTS,S provides only partial protection against Plasmodium falciparum infections. The explanation for such low efficacy is unclear. This study examined the associations of parasite genetic variations with binding affinity to human immunological proteins including human leukocyte antigen (HLA) and T cell receptors (TCR) involved in RTS,S-induced immune responses. Multiplicity of infections was determined by amplicon deep sequencing of merozoite surface protein 1 (PfMSP1). Genetic variations in the C-terminal of circumsporozoite protein (PfMSP1) gene were examined across 88 samples of P. falciparum collected from high and low transmission settings of Ghana. Binding interactions of PfMSP1 variants and HLA/TCR were analyzed using NetChop} and HADDOCK predictions. Anti-CSP IgG levels were measured by ELISA in a subset of 10 samples. High polyclonality was detected among P. falciparum infections. A total 27 CSP haplotypes were detected among samples. A significant correlation was detected between the CSP and MSP multiplicity of infection (MOI). No clear clustering of haplotypes was observed by geographic regions. The number of genetic differences in PfCSP between 3D7 and non-3D7 variants does not influence binding interactions to HLA/T cells nor anti-CSP IgG levels. Nevertheless, PfCSP peptide length significantly affects its molecular weight and binding affinity to the HLA. The presence of multiple non-3D7 strains among P. falciparum infections in Ghana impact the effectiveness of RTS,S. Longer PfCSP peptides may elicit a stronger immune response and should be considered in future version RTS,S. The molecular mechanisms of RTS,S cell-mediated immune responses related to longer CSP peptides warrants further investigations.

A wide deployment of malaria control tools have significantly reduced malaria morbidity and mortality across Africa. However, in the last five to seven years, there has been a resurgence of malaria in several African countries, raising the questions of whether and why current control mechanisms are failing. Since the first Plasmodium falciparum reference genome was published in 2002, few thousands more representing a broad range of geographical isolates have been sequenced. These advances in parasite genomics have improved our understanding of mutational changes, molecular structure, and genetic mechanisms associated with diagnostic testing, antimalarial resistance, and preventive measures such as vaccine development. In this chapter, we summarize the current progress on: (1) genomic characteristics of P. falciparum; (2) novel biomarkers and revolutionary techniques for diagnosing malaria infections; and (3) current vaccine targets and challenges for developing efficacious and long-lasting malaria vaccines.

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