Pre-clinical evaluation of a P. berghei-based whole-sporozoite malaria vaccine candidate

Mendes, A. M. et al. (2018) Pre-clinical evaluation of a P. berghei-based whole-sporozoite malaria vaccine candidate. npj Vaccines, 3(1), 54. (doi: 10.1038/s41541-018-0091-3) (PMID:30510775) (PMCID:PMC6258718)

Abstract

Whole-sporozoite vaccination/immunization induces high levels of protective immunity in both rodent models of malaria and in humans. Recently, we generated a transgenic line of the rodent malaria parasite P. berghei (Pb) that expresses the P. falciparum (Pf) circumsporozoite protein (PfCS), and showed that this parasite line (PbVac) was capable of (1) infecting and developing in human hepatocytes but not in human erythrocytes, and (2) inducing neutralizing antibodies against the human Pf parasite. Here, we analyzed PbVac in detail and developed tools necessary for its use in clinical studies. A microbiological contaminant-free Master Cell Bank of PbVac parasites was generated through a process of cyclic propagation and clonal expansion in mice and mosquitoes and was genetically characterized. A highly sensitive qRT-PCR-based method was established that enables PbVac parasite detection and quantification at low parasite densities in vivo. This method was employed in a biodistribution study in a rabbit model, revealing that the parasite is only present at the site of administration and in the liver up to 48 h post infection and is no longer detectable at any site 10 days after administration. An extensive toxicology investigation carried out in rabbits further showed the absence of PbVac-related toxicity. In vivo drug sensitivity assays employing rodent models of infection showed that both the liver and the blood stage forms of PbVac were completely eliminated by Malarone® treatment. Collectively, our pre-clinical safety assessment demonstrates that PbVac possesses all characteristics necessary to advance into clinical evaluation.

• Item Type: Articles
• Additional Information: AMM and MP would like to acknowledge Fundação para a Ciência e Tecnologia, Portugal for grants SFRH/BPD/80693/2011 and Investigador FCT 2013. This work was supported by PATH’s Malaria Vaccine Initiative to IMM and RUMC, by the Bill & Melinda Gates Foundation’s grant OPP1025364 to IMM, by the Wellcome Trust grants WT 098051 to the Sanger Institute and 104792/Z/14/Z to CN, and by Fundação para a Ciência e Tecnologia (FCT-Portugal)’s grant PTDC/BBB-BMD/2695/2014 to IMM.
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Otto, Professor Thomas
• Authors: Mendes, A. M., Reuling, I. J., Andrade, C. M., Otto, T. D., Machado, M., Teixeira, F., Pissarra, J., Gonçalves-Rosa, N., Bonaparte, D., Sinfrónio, J., Sanders, M., Janse, C. J., Khan, S. M., Newbold, C. I., Berriman, M., Lee, C. K., Wu, Y., Ockenhouse, C. F., Sauerwein, R. W., and Prudêncio, M.
• College/School: College of Medical Veterinary and Life Sciences > School of Infection & Immunity
• Journal Name: npj Vaccines
• Publisher: Nature Publishing Group
• ISSN: 2059-0105
• ISSN (Online): 2059-0105
• Copyright Holders: Copyright © 2018 The Authors
• First Published: First published in npj Vaccines 3(1):54
• Publisher Policy: Reproduced under a Creative Commons License