4.6 Article

Preclinical development of a Pfs230-Pfs48/45 chimeric malaria transmission-blocking vaccine

Journal

NPJ VACCINES
Volume 6, Issue 1, Pages -

Publisher

NATURE PORTFOLIO
DOI: 10.1038/s41541-021-00383-8

Keywords

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Funding

  1. European Union's Horizon 2020 research and innovation program of the European and Developing Countries Clinical Trials Partnership [733273, RIA2018SV-2311]
  2. PATH's Malaria Vaccine Initiative from the Bill & Melinda Gates Foundation [OPP1108403]
  3. [NNF14CC0001]
  4. Bill and Melinda Gates Foundation [OPP1108403] Funding Source: Bill and Melinda Gates Foundation

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The modified construct ProC6C successfully improved expression levels, paving the way for further clinical evaluation. A scalable process in the Lactococcus lactis expression system was developed, along with a panel of analytical assays for release and stability. Immunogenicity studies in mice demonstrated that ProC6C can induce functional antibodies that reduce transmission to mosquitoes and invasion of human hepatocytes.
The Plasmodium falciparum Pfs230 and Pfs48/45 proteins are leading candidates for a malaria transmission-blocking vaccine (TBV). Previously, we showed that a Pfs230-Pfs48/45 fusion protein elicits higher levels of functional antibodies than the individual antigens, but low yields hampered progression to clinical evaluation. Here we identified a modified construct (ProC6C) with a circumsporozoite protein (CSP) repeat-linker sequence that enhances expression. A scalable and reproducible process in the Lactococcus lactis expression system was developed and ProC6C was successfully transferred for manufacturing under current Good Manufacturing Practices (cGMP). In addition, a panel of analytical assays for release and stability were developed. Intact mass spectrometry analysis and multiangle light scattering showed that the protein contained correct disulfide bonds and was monomeric. Immunogenicity studies in mice showed that the ProC6C adsorbed to Alhydrogel(R), with or without Matrix-M-TM, elicited functional antibodies that reduced transmission to mosquitoes and sporozoite invasion of human hepatocytes. Altogether, our data support manufacture and clinical evaluation of ProC6C as a multistage malaria-vaccine candidate.

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