A human antibody epitope map of the malaria vaccine antigen Pfs25

Pfs25 is a leading antigen for a malaria transmission-blocking vaccine and shows moderate transmission-blocking activity and induction of rapidly decreasing antibody titers in clinical trials. A comprehensive definition of all transmission-reducing epitopes of Pfs25 will inform structure-guided design to enhance Pfs25-based vaccines, leading to potent transmission-blocking activity. Here, we compiled a detailed human antibody epitope map comprising epitope binning data and structures of multiple human monoclonal antibodies, including three new crystal structures of Pfs25 in complex with transmission-reducing antibodies from Malian volunteers immunized with Pfs25 conjugated to EPA and adjuvanted with AS01. These structures revealed additional epitopes in Pfs25 capable of reducing transmission and expanded this characterization to malaria-exposed humans. This work informs immunogen design to focus the antibody response to transmission-reducing epitopes of Pfs25, enabling development of more potent transmission-blocking vaccines for malaria.

Automated summary

Pfs25 is an important antigen for a malaria transmission-blocking vaccine, but its transmission-blocking activity and antibody potency decrease over time. This study provides a comprehensive definition of all transmission-reducing epitopes of Pfs25, using data from human antibody epitope mapping and crystal structures of Pfs25 in complex with transmission-reducing antibodies. These new structures reveal additional epitopes in Pfs25 that can reduce transmission and expand our understanding of malaria-exposed humans. This information can be used to design immunogens that specifically elicit antibodies against the transmission-reducing epitopes, leading to the development of more potent transmission-blocking vaccines for malaria.