Preclinical development of a Pfs230-Pfs48/45 chimeric malaria transmission-blocking vaccine
Abstract 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 p...
| Main Authors: | , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Nature Portfolio
2021-10-01
|
| Series: | npj Vaccines |
| Online Access: | https://doi.org/10.1038/s41541-021-00383-8 |
| _version_ | 1827615111624261632 |
|---|---|
| author | Susheel K. Singh Jordan Plieskatt Bishwanath K. Chourasia Vandana Singh Karin Lövgren Bengtsson Jenny M. Reimer Renate C. van Daalen Karina Teelen Marga van de Vegte-Bolmer Geert-Jan van Gemert Matthijs M. Jore Michael Theisen |
| author_facet | Susheel K. Singh Jordan Plieskatt Bishwanath K. Chourasia Vandana Singh Karin Lövgren Bengtsson Jenny M. Reimer Renate C. van Daalen Karina Teelen Marga van de Vegte-Bolmer Geert-Jan van Gemert Matthijs M. Jore Michael Theisen |
| author_sort | Susheel K. Singh |
| collection | DOAJ |
| description | Abstract 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®, with or without Matrix-MTM, 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. |
| first_indexed | 2024-03-09T09:05:31Z |
| format | Article |
| id | doaj.art-d23619f475cb4d5dbe3391e5cc32c116 |
| institution | Directory Open Access Journal |
| issn | 2059-0105 |
| language | English |
| last_indexed | 2024-03-09T09:05:31Z |
| publishDate | 2021-10-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | npj Vaccines |
| spelling | doaj.art-d23619f475cb4d5dbe3391e5cc32c1162023-12-02T10:34:29ZengNature Portfolionpj Vaccines2059-01052021-10-016111110.1038/s41541-021-00383-8Preclinical development of a Pfs230-Pfs48/45 chimeric malaria transmission-blocking vaccineSusheel K. Singh0Jordan Plieskatt1Bishwanath K. Chourasia2Vandana Singh3Karin Lövgren Bengtsson4Jenny M. Reimer5Renate C. van Daalen6Karina Teelen7Marga van de Vegte-Bolmer8Geert-Jan van Gemert9Matthijs M. Jore10Michael Theisen11Department for Congenital Disorders, Statens Serum InstitutPATH’s Malaria Vaccine InitiativeDepartment for Congenital Disorders, Statens Serum InstitutDepartment for Congenital Disorders, Statens Serum InstitutNovavax ABNovavax ABDepartment of Medical Microbiology, Radboud University Medical CenterDepartment of Medical Microbiology, Radboud University Medical CenterDepartment of Medical Microbiology, Radboud University Medical CenterDepartment of Medical Microbiology, Radboud University Medical CenterDepartment of Medical Microbiology, Radboud University Medical CenterDepartment for Congenital Disorders, Statens Serum InstitutAbstract 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®, with or without Matrix-MTM, 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.https://doi.org/10.1038/s41541-021-00383-8 |
| spellingShingle | Susheel K. Singh Jordan Plieskatt Bishwanath K. Chourasia Vandana Singh Karin Lövgren Bengtsson Jenny M. Reimer Renate C. van Daalen Karina Teelen Marga van de Vegte-Bolmer Geert-Jan van Gemert Matthijs M. Jore Michael Theisen Preclinical development of a Pfs230-Pfs48/45 chimeric malaria transmission-blocking vaccine npj Vaccines |
| title | Preclinical development of a Pfs230-Pfs48/45 chimeric malaria transmission-blocking vaccine |
| title_full | Preclinical development of a Pfs230-Pfs48/45 chimeric malaria transmission-blocking vaccine |
| title_fullStr | Preclinical development of a Pfs230-Pfs48/45 chimeric malaria transmission-blocking vaccine |
| title_full_unstemmed | Preclinical development of a Pfs230-Pfs48/45 chimeric malaria transmission-blocking vaccine |
| title_short | Preclinical development of a Pfs230-Pfs48/45 chimeric malaria transmission-blocking vaccine |
| title_sort | preclinical development of a pfs230 pfs48 45 chimeric malaria transmission blocking vaccine |
| url | https://doi.org/10.1038/s41541-021-00383-8 |
| work_keys_str_mv | AT susheelksingh preclinicaldevelopmentofapfs230pfs4845chimericmalariatransmissionblockingvaccine AT jordanplieskatt preclinicaldevelopmentofapfs230pfs4845chimericmalariatransmissionblockingvaccine AT bishwanathkchourasia preclinicaldevelopmentofapfs230pfs4845chimericmalariatransmissionblockingvaccine AT vandanasingh preclinicaldevelopmentofapfs230pfs4845chimericmalariatransmissionblockingvaccine AT karinlovgrenbengtsson preclinicaldevelopmentofapfs230pfs4845chimericmalariatransmissionblockingvaccine AT jennymreimer preclinicaldevelopmentofapfs230pfs4845chimericmalariatransmissionblockingvaccine AT renatecvandaalen preclinicaldevelopmentofapfs230pfs4845chimericmalariatransmissionblockingvaccine AT karinateelen preclinicaldevelopmentofapfs230pfs4845chimericmalariatransmissionblockingvaccine AT margavandevegtebolmer preclinicaldevelopmentofapfs230pfs4845chimericmalariatransmissionblockingvaccine AT geertjanvangemert preclinicaldevelopmentofapfs230pfs4845chimericmalariatransmissionblockingvaccine AT matthijsmjore preclinicaldevelopmentofapfs230pfs4845chimericmalariatransmissionblockingvaccine AT michaeltheisen preclinicaldevelopmentofapfs230pfs4845chimericmalariatransmissionblockingvaccine |