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The Plasmodium falciparum circumsporozoite protein (CSP) is considered a major antimalarial vaccine target. CSP consists of an N-terminal domain, a central repeat region consisting of NANP and NVDP amino acid repeats, and a C-terminal region with a glycophosphatidylinositol anchor domain for plasma membrane anchorage. RTS,S, the most advanced malaria vaccine candidate, consists of 19 NANP repeats and the C-terminal region of CSP fused to the hepatitis B surface Ag. In humans, the immunogenicity assessments following RTS,S/AS01 immunization point toward a critical role for anti-CSP IgG Abs with specificity for the NANP repeat region and possibly CSP-specific CD4+ T cell responses.