Immunization with attenuated Plasmodium falciparum sporozoites (PfSPZs) has been shown to be protective against
malaria, but the features of the antibody response induced by this treatment remain unclear. To investigate this response in detail, we isolated
IgM and
IgG monoclonal antibodies from Tanzanian volunteers who were immunized with repeated injection of Sanaria PfSPZ
Vaccine and who were found to be protected from controlled human
malaria infection with infectious homologous PfSPZs. All isolated
IgG monoclonal antibodies bound to P. falciparum circumsporozoite
protein (PfCSP) and recognized distinct
epitopes in its N terminus, NANP-repeat region, and C terminus. Strikingly, the most effective
antibodies, as determined in a humanized mouse model, bound not only to the repeat region, but also to a minimal
peptide at the PfCSP N-terminal junction that is not in the RTS,S
vaccine. These dual-specific
antibodies were isolated from different donors and were encoded by VH3-30 or VH3-33 alleles that encode
tryptophan or
arginine at position 52. Using structural and mutational data, we describe the elements required for germline recognition and affinity maturation. Our study provides potent
neutralizing antibodies and relevant information for lineage-targeted
vaccine design and immunization strategies.