TY - JOUR
T1 - Preclinical development of a Pfs230-Pfs48/45 chimeric malaria transmission-blocking vaccine
AU - Singh, Susheel K
AU - Plieskatt, Jordan
AU - Chourasia, Bishwanath K
AU - Singh, Vandana
AU - Bengtsson, Karin Lövgren
AU - Reimer, Jenny M
AU - van Daalen, Renate C
AU - Teelen, Karina
AU - van de Vegte-Bolmer, Marga
AU - van Gemert, Geert-Jan
AU - Jore, Matthijs M
AU - Theisen, Michael
N1 - © 2021. The Author(s).
PY - 2021
Y1 - 2021
N2 - 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.
AB - 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.
U2 - 10.1038/s41541-021-00383-8
DO - 10.1038/s41541-021-00383-8
M3 - Journal article
C2 - 34642303
VL - 6
JO - npj Vaccines
JF - npj Vaccines
SN - 2059-0105
M1 - 120
ER -