Rationally-Designed, Spontaneous-Particleized Pfs48/45 for a Multivalent Malaria Vaccine
The objective of this study is to structure-functionally design a Pfs48/45-based transmission blocking vaccine against malaria, and test the vaccine by a particulate delivery in animal studies.
A highly effective malaria vaccine is likely required to eradicate the disease. Transmission blocking vaccines (TBVs) induce antibodies that block parasite reproduction and development in the mosquito midgut and are part of the World Health Organization Malaria Vaccine Technology roadmap. This R01 response to program announcement PA-19-077: Accelerating Malaria Vaccine Discovery, which specifically encourages studies that will lead to the discovery of new vaccine candidates that interrupt malaria transmission. Pfs48/45 is a TBVcandidate antigen, and is the target of one of the most potent transmission-blocking monoclonal antibodies (85RF45.1). Pfs48/45 has not yet been tested in humans, in part due to difficulties in producing the antigen. This study will follow up recent advances in producing first-in-class, well-defined, fusion-free Pfs48/45. Serendipitously, glycosylation at a non-essential epitope of the protein led to drastically enhanced protein yield, enabling us to solve its three-dimensional structure, also revealing the target epitope of 85RF45.1. This new- found structural information will be used to guide advanced antigen design, including stabilizing mutations and antigen design that is immunofocused to the potent neutralizing epitope. Rationally optimized Pfs48/45 will be optimized in the context of a next-generation vaccine adjuvant.