Evaluation of Novel Preerythrocytic Anti-infection Malaria Vaccine Candidates

National Institute Of Allergy And Infectious Diseases

Investigators

Linked publications & trials

Abstract

From our collaborative publication this year, we report the following advances in FY2022: 1. Duffy PE. Making a good malaria vaccine better. 2021. Trends in Parasitology. Nov 30. In 2021, the World Health Organization (WHO) recommended widespread use of RTS,S/AS01 vaccine to prevent malaria in young African children, noting its 30% reduction in deadly severe malaria. In a recent report, Das et al. described antibody effector functions that may contribute to RTS,S efficacy and thereby guide vaccine improvements. In this publication, we synthesized recent findings from antibody studies of the CSP-based malaria vaccine to discern patterns of responses to different CSP domains that can inform the improved design of anti-infection malaria vaccines. Our unpublished progress during this reporting period includes the following advances: In FY2022, we focused on production and immunogenicity of our 2 PfPEVA candidates PfSHMT and PfTBP. Full-length PfSHMT was expressed as insoluble protein in E. coli. Refolding conditions were screened and further optimized to promote stability and suppress aggregation. Production of PfSHMT was scaled up and refolded material was further purified using by size-exclusion chromatography (SEC). The purified PfSHMT had an SEC elution profile consistent with a monomeric and soluble protein. PfSHMT formulated in a clinically relevant adjuvant AS01E was highly immunogenic in mice. Efforts to make full-length PfTBP were met with challenges that included poor expression levels and toxicity to the recombinant system. Therefore, we employed in silico and structural prediction to design a construct that improves recombinant expression and may focus B cell responses. PfTBP was produced in E. coli and purified to a high level using mixed mode chromatography. Mice were immunized with PfCSP-EPA conjugate and either PfSHMT and/or PfTBP and then challenged with a Pb parasite expressing PfCSP instead of native PbCSP. Sterile protection induced by PfCSP was not reduced when co-immunized with one or both PfPEVA, suggesting PfPEVA does not interfere with PfCSP protection.