Placental
malaria is a major health problem for both pregnant women and their fetuses in
malaria endemic regions. It is triggered by the accumulation of Plasmodium falciparum-infected erythrocytes (IE) in the intervillous spaces of the placenta and is associated with foetal growth restriction and maternal
anemia. IE accumulation is supported by the binding of the parasite-expressed
protein VAR2CSA to placental
chondroitin sulfate A (CSA). Defining specific CSA-binding
epitopes of VAR2CSA, against which to target the immune response, is essential for the development of a
vaccine aimed at blocking IE adhesion. However, the development of a VAR2CSA adhesion-blocking
vaccine remains challenging due to (i) the large size of VAR2CSA and (ii) the extensive immune selection for polymorphisms and thereby non-neutralizing
B-cell epitopes. Camelid heavy-chain-only
antibodies (HcAbs) are known to target
epitopes that are less immunogenic to classical
IgG and, due to their small size and protruding
antigen-binding loop, able to reach and recognize cryptic, conformational
epitopes which are inaccessible to conventional
antibodies. The variable heavy chain (VHH) domain is the
antigen-binding site of camelid HcAbs, the so called Nanobody, which represents the smallest known (15 kDa) intact, native
antigen-binding fragment. In this study, we have used the Nanobody technology, an approach new to
malaria research, to generate small and functional
antibody fragments recognizing unique
epitopes broadly distributed on VAR2CSA.