Immunofocusing humoral immunity potentiates the functional efficacy of the AnAPN1 malaria transmission-blocking vaccine antigen

Abstract

Malaria transmission-blocking vaccines (TBVs) are a critical tool for disease elimination. TBVs prevent 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 and structure-function studies have identified two Class II epitopes that induce potent transmission-blocking (T-B) antibodies. 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 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 was immunogenic and immunofocused the humoral response to one of the key T-B epitopes resulting in potent T-B activity and establishing UF6b as a prime TBV candidate to aid in malaria elimination and eradication efforts.

Host-parasite interactions during Plasmodium infection: Implications for immunotherapies

“…Vaccination of mice with recombinant P. falciparum cell-traversal protein for ookinetes and sporozoites, PfCelTOS (a P. falciparum TBV candidate) along with TLR-based adjuvant, elicited specific anti-PfCelTOS antibody-mediated immune response, which has been shown to induce transmission-reducing activity in mosquito (162). Recently, a mosquito midgut protein, namely anopheline alanyl aminopeptidase N 1 (AnAPN1), has been shown to induce potent transmission-blocking antibodies and may prove to be a potential TBV candidate (163). Moreover, Bender et al designed a vaccine construct, UF6B, from AnAPN1 protein.…”

“…The immunogenicity of UF6B was evaluated in mice, wherein mice were immunized with UF6B along with human safe adjuvant, GLA-LSQ. Vaccination with UF6b:GLA-LSQ induced humoral immune response against a potent transmission-blocking epitope indicating that UF6b vaccine construct could be a TBV candidate for malaria elimination (163). A list of various stage specific malaria vaccine candidates is presented in Table 2.…”