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Dissection-independent production of a protective whole-sporozoite malaria vaccine

View ORCID ProfileJoshua Blight, Katarzyna A. Sala, Erwan Atcheson, Holger Kramer, View ORCID ProfileAadil El-Turabi, View ORCID ProfileEliana Real, View ORCID ProfileFarah A. Dahalan, View ORCID ProfilePaulo Bettencourt, Emma Dickinson, Eduardo Alves, View ORCID ProfileAhmed M. Salman, View ORCID ProfileChris J. Janse, View ORCID ProfileFrances Ashcroft, View ORCID ProfileAdrian V. S. Hill, View ORCID ProfileArturo Reyes-Sandoval, View ORCID ProfileAndrew M. Blagborough, View ORCID ProfileJake Baum
doi: https://doi.org/10.1101/2020.06.22.164756
Joshua Blight
1Department of Life Sciences, Imperial College London, Sir Alexander Fleming Building, Exhibition Road, South Kensington, London, SW7 2AZ, UK
2The Jenner Institute, Nuffield Department of Medicine, University of Oxford, The Henry Wellcome Building for Molecular Physiology, Roosevelt Drive, Oxford, OX3 7BN, UK
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Katarzyna A. Sala
1Department of Life Sciences, Imperial College London, Sir Alexander Fleming Building, Exhibition Road, South Kensington, London, SW7 2AZ, UK
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Erwan Atcheson
2The Jenner Institute, Nuffield Department of Medicine, University of Oxford, The Henry Wellcome Building for Molecular Physiology, Roosevelt Drive, Oxford, OX3 7BN, UK
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Holger Kramer
3Department of Physiology, Anatomy & Genetics, Henry Wellcome Building for Gene Function, University of Oxford, South Parks Road, Oxford, OX3 7BN, UK
4MRC London Institute of Medical Sciences, Imperial College London, Hammersmith Hospital, Du Cane Road, London, W12 0NN
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Aadil El-Turabi
2The Jenner Institute, Nuffield Department of Medicine, University of Oxford, The Henry Wellcome Building for Molecular Physiology, Roosevelt Drive, Oxford, OX3 7BN, UK
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Eliana Real
1Department of Life Sciences, Imperial College London, Sir Alexander Fleming Building, Exhibition Road, South Kensington, London, SW7 2AZ, UK
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Farah A. Dahalan
1Department of Life Sciences, Imperial College London, Sir Alexander Fleming Building, Exhibition Road, South Kensington, London, SW7 2AZ, UK
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Paulo Bettencourt
2The Jenner Institute, Nuffield Department of Medicine, University of Oxford, The Henry Wellcome Building for Molecular Physiology, Roosevelt Drive, Oxford, OX3 7BN, UK
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Emma Dickinson
2The Jenner Institute, Nuffield Department of Medicine, University of Oxford, The Henry Wellcome Building for Molecular Physiology, Roosevelt Drive, Oxford, OX3 7BN, UK
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Eduardo Alves
2The Jenner Institute, Nuffield Department of Medicine, University of Oxford, The Henry Wellcome Building for Molecular Physiology, Roosevelt Drive, Oxford, OX3 7BN, UK
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Ahmed M. Salman
2The Jenner Institute, Nuffield Department of Medicine, University of Oxford, The Henry Wellcome Building for Molecular Physiology, Roosevelt Drive, Oxford, OX3 7BN, UK
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Chris J. Janse
5Leiden Malaria Research Group, Department of Parasitology, Center of Infectious Diseases, Leiden University Medical Center, (LUMC, L4-Q), Albinusdreef 2, 2333 ZA Leiden, The Netherlands
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Frances Ashcroft
3Department of Physiology, Anatomy & Genetics, Henry Wellcome Building for Gene Function, University of Oxford, South Parks Road, Oxford, OX3 7BN, UK
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Adrian V. S. Hill
2The Jenner Institute, Nuffield Department of Medicine, University of Oxford, The Henry Wellcome Building for Molecular Physiology, Roosevelt Drive, Oxford, OX3 7BN, UK
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Arturo Reyes-Sandoval
2The Jenner Institute, Nuffield Department of Medicine, University of Oxford, The Henry Wellcome Building for Molecular Physiology, Roosevelt Drive, Oxford, OX3 7BN, UK
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Andrew M. Blagborough
1Department of Life Sciences, Imperial College London, Sir Alexander Fleming Building, Exhibition Road, South Kensington, London, SW7 2AZ, UK
6Department of Pathology, University of Cambridge, Tennis Court Road, Cambridge, CB2 1QP, UK
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Jake Baum
1Department of Life Sciences, Imperial College London, Sir Alexander Fleming Building, Exhibition Road, South Kensington, London, SW7 2AZ, UK
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  • For correspondence: jake.baum@imperial.ac.uk
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Abstract

Complete protection against human malaria challenge has been achieved using infected mosquitoes as the delivery route for immunization with Plasmodium parasites. Strategies seeking to replicate this efficacy with either a manufactured whole-parasite or subunit vaccine, however, have shown only limited success. A major roadblock to whole parasite vaccine progress and understanding of the human infective sporozoite form in general, is reliance on manual dissection for parasite isolation from infected mosquitoes. We report here the development of a four-step process based on whole mosquito homogenization, slurry and density-gradient filtration, combined with free-flow electrophoresis that is able to rapidly produce a pure, aseptic sporozoite inoculum from hundreds of mosquitoes. Murine P. berghei or human-infective P. falciparum sporozoites produced in this way are 2-3-fold more infective with in vitro hepatocytes and can confer sterile protection when immunized intravenously with subsequent challenge using a mouse malaria model. Critically, we can also demonstrate for the first time 60-70% protection when the same parasites are administered via intramuscular (i.m.) route. In developing a process amenable to industrialisation and demonstrating efficacy by i.m. route these data represent a major advancement in capacity to produce a whole parasite malaria vaccine at scale.

One-Sentence Summary A four-step process for isolating pure infective malaria parasite sporozoites at scale from homogenized whole mosquitoes, independent of manual dissection, is able to produce a whole parasite vaccine inoculum that confers sterilizing protection.

Competing Interest Statement

J.Blight, KAS, AR-S, AMB and J.Baum are inventors on a patent application filed internationally covering parts of this work. All other authors declare no competing interests.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY 4.0 International license.
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Posted June 22, 2020.
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Dissection-independent production of a protective whole-sporozoite malaria vaccine
Joshua Blight, Katarzyna A. Sala, Erwan Atcheson, Holger Kramer, Aadil El-Turabi, Eliana Real, Farah A. Dahalan, Paulo Bettencourt, Emma Dickinson, Eduardo Alves, Ahmed M. Salman, Chris J. Janse, Frances Ashcroft, Adrian V. S. Hill, Arturo Reyes-Sandoval, Andrew M. Blagborough, Jake Baum
bioRxiv 2020.06.22.164756; doi: https://doi.org/10.1101/2020.06.22.164756
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Dissection-independent production of a protective whole-sporozoite malaria vaccine
Joshua Blight, Katarzyna A. Sala, Erwan Atcheson, Holger Kramer, Aadil El-Turabi, Eliana Real, Farah A. Dahalan, Paulo Bettencourt, Emma Dickinson, Eduardo Alves, Ahmed M. Salman, Chris J. Janse, Frances Ashcroft, Adrian V. S. Hill, Arturo Reyes-Sandoval, Andrew M. Blagborough, Jake Baum
bioRxiv 2020.06.22.164756; doi: https://doi.org/10.1101/2020.06.22.164756

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