Protective antibodies target cryptic epitope unmasked by cleavage of malaria sporozoite protein

The most advanced monoclonal antibodies (mAbs) and vaccines against
malaria target the central repeat region or closely related sequences
within the Plasmodium falciparum circumsporozoite protein
(PfCSP). Here, using an antigen-agnostic strategy to interrogate human
antibody responses to whole sporozoites, we identify a class of mAbs that
target a cryptic PfCSP epitope that is only exposed after cleavage and
subsequent pyroglutamylation (pGlu) of the newly formed N-terminus. This
pGlu-CSP epitope is not targeted by current anti-PfCSP mAbs and is not
included in the licensed malaria vaccines. MAD21-101, the most potent mAb
in this class, confers sterile protection against Pf infection in a human
liver-chimeric mouse model. These findings reveal a site of vulnerability
on the sporozoite surface that can be targeted by next-generation
antimalarial interventions.