Structural basis for recognition of the malaria vaccine candidate Pfs48/45 by a transmission blocking antibody

• Published in: Nature communications 2018-09, Vol.9 (1), p.3822-11, Article 3822
• Main Authors: Lennartz, Frank, Brod, Florian, Dabbs, Rebecca, Miura, Kazutoyo, Mekhaiel, David, Marini, Arianna, Jore, Matthijs M., Søgaard, Max M., Jørgensen, Thomas, de Jongh, Willem A., Sauerwein, Robert W., Long, Carole A., Biswas, Sumi, Higgins, Matthew K.
• Format: Article
• Language: English
• Subjects: 101/1; 631/250/2152/2153/1291; 631/326/590; 631/535/1266; 692/699/255/1629; 82/1; Animals; Antibodies, Blocking - immunology; Antibodies, Monoclonal - immunology; Aquatic insects; Blocking antibodies; Epitopes; Epitopes - chemistry; Epitopes - immunology; Humanities and Social Sciences; Immunization; Immunoglobulins; Infectious diseases; Malaria; Malaria - immunology; Malaria - transmission; Malaria Vaccines - immunology; Membrane Glycoproteins - chemistry; Membrane Glycoproteins - immunology; Mice; Molecular structure; Monoclonal antibodies; multidisciplinary; Protein Domains; Protein Interaction Mapping; Proteins; Protozoan Proteins - chemistry; Protozoan Proteins - immunology; Science; Science (multidisciplinary); Vaccines; Vector-borne diseases
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-018-06340-9

The quest to develop an effective malaria vaccine remains a major priority in the fight against global infectious disease. An approach with great potential is a transmission-blocking vaccine which induces antibodies that prevent establishment of a productive infection in mosquitos that feed on infected humans, thereby stopping the transmission cycle. One of the most promising targets for such a vaccine is the gamete surface protein, Pfs48/45. Here we establish a system for production of full-length Pfs48/45 and use this to raise a panel of monoclonal antibodies. We map the binding regions of these antibodies on Pfs48/45 and correlate the location of their epitopes with their transmission-blocking activity. Finally, we present the structure of the C-terminal domain of Pfs48/45 bound to the most potent transmission-blocking antibody, and provide key molecular information for future structure-guided immunogen design. Pfs48/45 is a promising component for a transmission-blocking malaria vaccine. Here, the authors develop a system to produce full-length Pfs48/45 for immunisation, characterise a panel of monoclonal antibodies and determine the structure of a potent transmission-blocking epitope.