Generation of a Peptide Vaccine Candidate against Falciparum Placental Malaria Based on a Discontinuous Epitope

• Published in: Vaccines (Basel) Vol. 8; no. 3; p. 392
• Main Authors: Mitran, Catherine J, Higa, Lauren M, Good, Michael F, Yanow, Stephanie K
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 18.07.2020; MDPI
• Subjects: Antibodies; Antigens; Chemical bonds; Clinical trials; Communication; Design; Disulfide bonds; Epitopes; Erythrocytes; Immunization; Malaria; Monoclonal antibodies; Parasites; peptide; Peptides; Placenta; placental malaria; Plasmodium falciparum; Plasmodium vivax; Pregnancy; Proteins; PvDBP; vaccine; Vaccines; Vector-borne diseases; Canada; United States > US; Netherlands; Plasmodium falciparum; Plasmodium vivax; PvDBP; peptide; vaccine; placental malaria; VAR2CSA
• ISSN: 2076-393X; 2076-393X
• DOI: 10.3390/vaccines8030392

In pregnant women, infected red blood cells adhere to the placenta via the parasite protein VAR2CSA. Two vaccine candidates based on VAR2CSA are currently in clinical trials; however, these candidates failed to elicit strain-transcending antibody responses. We previously showed that a cross-reactive monoclonal antibody (3D10) raised against the antigen PvDBP targets epitopes in VAR2CSA. We now aim to design a peptide vaccine against VAR2CSA based on the epitope that generated 3D10. We mapped the epitope to subdomain 1 (SD1) of PvDBP and identified a peptide that contained the minimal sequence. However, this peptide did not elicit cross-reactive VAR2CSA antibodies in mice. When tested against a broader, overlapping peptide array spanning SD1, 3D10 in fact recognized a discontinuous epitope consisting of three segments of SD1. These findings presented the challenge to generate this larger structural epitope as a synthetic peptide since it is stabilized by two pairs of disulfide bonds. We overcame this using a synthetic scaffold to conformationally constrain the SD1 peptide and coupled it to keyhole limpet hemocyanin (KLH). The SD1-KLH conjugate elicited antibodies in mice that cross-reacted with VAR2CSA. This strategy successfully recapitulated a discontinuous epitope with a synthetic peptide and represents the first heterologous vaccine candidate against VAR2CSA.