Pre-clinical evaluation of a P. berghei-based whole-sporozoite malaria vaccine candidate
| Autor: | Mandy Sanders, António M. Mendes, Cynthia K. Lee, Filipa Teixeira, Shahid M. Khan, Christian F. Ockenhouse, Thomas D. Otto, Carolina M. Andrade, Chris J. Janse, Chris I. Newbold, Nataniel Goncalves-Rosa, Dolores Bonaparte, Marta Machado, Isaie J. Reuling, João Sinfrónio, Yimin Wu, Miguel Prudêncio, Robert W. Sauerwein, Joana Pissarra, Matthew Berriman |
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| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
lcsh:Immunologic diseases. Allergy Immunology lnfectious Diseases and Global Health Radboud Institute for Molecular Life Sciences [Radboudumc 4] lcsh:RC254-282 03 medical and health sciences 0302 clinical medicine All institutes and research themes of the Radboud University Medical Center In vivo parasitic diseases medicine Parasite hosting Pharmacology (medical) Pharmacology biology Malaria vaccine medicine.disease lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens Virology 3. Good health Vaccination Circumsporozoite protein 030104 developmental biology Infectious Diseases biology.protein Antibody Cell bank lcsh:RC581-607 030217 neurology & neurosurgery Malaria |
| Zdroj: | npj Vaccines, 3 Npj Vaccines, 3 npj Vaccines, Vol 3, Iss 1, Pp 1-12 (2018) npj Vaccines |
| ISSN: | 2059-0105 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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