Abstract
Malaria transmission-blocking vaccines (TBVs) prevent the completion of the developmental lifecycle of malarial parasites within the mosquito vector, effectively blocking subsequent infections. The mosquito midgut protein Anopheline alanyl aminopeptidase N (AnAPN1) is the leading, mosquito-based TBV antigen. Structure-function studies identified two Class II epitopes that can induce potent transmission-blocking (T-B) antibodies, informing the design of the next-generation AnAPN1. Here, we functionally screened new immunogens and down-selected to the UF6b construct that has two glycine-linked copies of the T-B epitopes. We then established a process for manufacturing UF6b and evaluated in outbred female CD1 mice the immunogenicity of the preclinical product with the human-safe adjuvant Glucopyranosyl Lipid Adjuvant in a liposomal formulation with saponin QS21 (GLA-LSQ). UF6b:GLA-LSQ effectively immunofocused the humoral response to one of the key T-B epitopes resulting in potent T-B activity, underscoring UF6b as a prime TBV candidate to aid in malaria elimination and eradication efforts.
Highlights
Malaria was responsible for about 405,000 deaths in 2019, predominantly among children under the age of five in SubSaharan Africa[1]
The Plasmodium parasites responsible for causing malaria have an obligatory developmental cycle in the female Anopheles mosquito vector, which begins when a mosquito takes up male and female Plasmodium gametocytes in a blood meal from infected humans
Previous studies on the T-B activity of anti-AnAPN1 IgG together with data on the protein structure revealed that there are multiple epitopes on the AnAPN1 protein; these studies show that only some epitopes contribute to T-B activity, while others, such as the immunodominant decoy peptide 1, do not[7,8]
Summary
Malaria was responsible for about 405,000 deaths in 2019, predominantly among children under the age of five in SubSaharan Africa[1]. RTS,S (MosquirixTM), the most advanced malaria vaccine that has been rolled out in selected African countries, reduces clinical disease, but does not prevent new cases. While this vaccine is an important step forward in the fight against malaria, alone it cannot support malaria eradication since it does not completely prevent malaria transmission[2,3,4]. Transmission-blocking vaccines (TBVs) work by preventing parasite sporogonic development in the mosquito, thereby disrupting the transmission cycle (Fig. 1a)[2,3,4,5]. Our results highlight UF6b:GLA-LSQ as a strong TBV candidate that may be a critical component in the fight to eliminate if not eradicate malaria
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