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We investigated whether anti-merozoite surface protein-1 (MSP1) block 2 antibodies mediate the monocyte-dependent antibody-mediated cellular inhibition (ADCI) of Plasmodium falciparum. This study was performed because soluble molecules have been shown to trigger ADCI and because MSP1 block 2 is released following processing and is the target of cytophilic IgG3 responses in exposed populations. We assessed human anti-MSP1 block 2 antibodies against 4 P. falciparum strains that carry the 3 main block 2 sequence alleles. These antibodies were able to inhibit in vitro growth of P. falciparum only in cooperation with human monocytes, whereas no direct inhibition was observed. However, the ADCI effect was strictly allele specific. Our findings highlight a new mechanism involving MSP1 in the protection against malaria. [ABSTRACT FROM AUTHOR]