Creation and preclinical evaluation of genetically attenuated malaria parasites arresting growth late in the liver.

Blandine Franke-Fayard; Catherin Marin-Mogollon; Fiona J A Geurten; Séverine Chevalley-Maurel; Jai Ramesar; Hans Kroeze; Els Baalbergen; Els Wessels; Ludivine Baron; Valérie Soulard; Thomas Martinson; Maya Aleshnick; Antonius T G Huijs; Amit Subudhi; Yukiko Miyazaki; Ahmad Syibli Othman; Surendra Kumar Kolli; Olivia A C Lamers; Magali Roques; Rebecca R Stanway; Sean C Murphy; Lander Foquet; Diana Moita; António M Mendes; Miguel Prudêncio; Koen J Dechering; Volker T Heussler; Arnab Pain; Brandon K Wilder; Meta Roestenberg; Chris J Janse

doi:10.1038/s41541-022-00558-x

Creation and preclinical evaluation of genetically attenuated malaria parasites arresting growth late in the liver.

Blandine Franke-Fayard, Catherin Marin-Mogollon, Fiona J A Geurten, Séverine Chevalley-Maurel, Jai Ramesar, Hans Kroeze, Els Baalbergen, Els Wessels, Ludivine Baron, Valérie Soulard, Thomas Martinson, Maya Aleshnick, Antonius T G Huijs, Amit Subudhi, Yukiko Miyazaki, Ahmad Syibli Othman, Surendra Kumar Kolli, Olivia A C Lamers, Magali Roques, Rebecca R StanwaySean C Murphy, Lander Foquet, Diana Moita, António M Mendes, Miguel Prudêncio, Koen J Dechering, Volker T Heussler, Arnab Pain, Brandon K Wilder, Meta Roestenberg, Chris J Janse

Research output: Contribution to journal › Article › peer-review

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Abstract

Whole-sporozoite (WSp) malaria vaccines induce protective immune responses in animal malaria models and in humans. A recent clinical trial with a WSp vaccine comprising genetically attenuated parasites (GAP) which arrest growth early in the liver (PfSPZ-GA1), showed that GAPs can be safely administered to humans and immunogenicity is comparable to radiation-attenuated PfSPZ Vaccine. GAPs that arrest late in the liver stage (LA-GAP) have potential for increased potency as shown in rodent malaria models. Here we describe the generation of four putative P. falciparum LA-GAPs, generated by CRISPR/Cas9-mediated gene deletion. One out of four gene-deletion mutants produced sporozoites in sufficient numbers for further preclinical evaluation. This mutant, PfΔmei2, lacking the mei2-like RNA gene, showed late liver growth arrest in human liver-chimeric mice with human erythrocytes, absence of unwanted genetic alterations and sensitivity to antimalarial drugs. These features of PfΔmei2 make it a promising vaccine candidate, supporting further clinical evaluation. PfΔmei2 (GA2) has passed regulatory approval for safety and efficacy testing in humans based on the findings reported in this study.

Original language	English (US)
Journal	npj Vaccines
Volume	7
Issue number	1
DOIs	https://doi.org/10.1038/s41541-022-00558-x
State	Published - Nov 4 2022

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10.1038/s41541-022-00558-x

https://repository.kaust.edu.sa/bitstream/10754/685566/1/s41541-022-00558-x.pdf

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Franke-Fayard, B., Marin-Mogollon, C., Geurten, F. J. A., Chevalley-Maurel, S., Ramesar, J., Kroeze, H., Baalbergen, E., Wessels, E., Baron, L., Soulard, V., Martinson, T., Aleshnick, M., Huijs, A. T. G., Subudhi, A., Miyazaki, Y., Othman, A. S., Kolli, S. K., Lamers, O. A. C., Roques, M., ... Janse, C. J. (2022). Creation and preclinical evaluation of genetically attenuated malaria parasites arresting growth late in the liver. npj Vaccines, 7(1). https://doi.org/10.1038/s41541-022-00558-x

@article{22243d39585d449b8b0c619778bde85f,

title = "Creation and preclinical evaluation of genetically attenuated malaria parasites arresting growth late in the liver.",

abstract = "Whole-sporozoite (WSp) malaria vaccines induce protective immune responses in animal malaria models and in humans. A recent clinical trial with a WSp vaccine comprising genetically attenuated parasites (GAP) which arrest growth early in the liver (PfSPZ-GA1), showed that GAPs can be safely administered to humans and immunogenicity is comparable to radiation-attenuated PfSPZ Vaccine. GAPs that arrest late in the liver stage (LA-GAP) have potential for increased potency as shown in rodent malaria models. Here we describe the generation of four putative P. falciparum LA-GAPs, generated by CRISPR/Cas9-mediated gene deletion. One out of four gene-deletion mutants produced sporozoites in sufficient numbers for further preclinical evaluation. This mutant, PfΔmei2, lacking the mei2-like RNA gene, showed late liver growth arrest in human liver-chimeric mice with human erythrocytes, absence of unwanted genetic alterations and sensitivity to antimalarial drugs. These features of PfΔmei2 make it a promising vaccine candidate, supporting further clinical evaluation. PfΔmei2 (GA2) has passed regulatory approval for safety and efficacy testing in humans based on the findings reported in this study.",

author = "Blandine Franke-Fayard and Catherin Marin-Mogollon and Geurten, {Fiona J A} and S{\'e}verine Chevalley-Maurel and Jai Ramesar and Hans Kroeze and Els Baalbergen and Els Wessels and Ludivine Baron and Val{\'e}rie Soulard and Thomas Martinson and Maya Aleshnick and Huijs, {Antonius T G} and Amit Subudhi and Yukiko Miyazaki and Othman, {Ahmad Syibli} and Kolli, {Surendra Kumar} and Lamers, {Olivia A C} and Magali Roques and Stanway, {Rebecca R} and Murphy, {Sean C} and Lander Foquet and Diana Moita and Mendes, {Ant{\'o}nio M} and Miguel Prud{\^e}ncio and Dechering, {Koen J} and Heussler, {Volker T} and Arnab Pain and Wilder, {Brandon K} and Meta Roestenberg and Janse, {Chris J}",

note = "KAUST Repository Item: Exported on 2022-12-12 Acknowledged KAUST grant number(s): BAS/1/1020-01-01 Acknowledgements: We acknowledge the critical contribution of the late Dr Shahid Khan to the design of these studies. We are grateful to Pr Jude Przyborski for the anti- P. falciparum EXP-1 antibody. This work was supported by LUMC internal funds. CM-M was, in part, supported by Colciencias Ph.D. fellowship (Call 568 from 2012 Resolution 01218 Bogot{\'a}, Colombia) and LUF project grant, Den Dulk-Moermans Fonds (grant reference number: W19374-2-32, 2019-2021). A.O. is supported by a Skim Latihan Akademik IPTA-SLAI (Ministry of Higher Education, Malaysia). A.P. acknowledges the Faculty Baseline funding (BAS/1/1020-01-01) from King Abdullah University of Science and Technology (KAUST).",

year = "2022",

month = nov,

day = "4",

doi = "10.1038/s41541-022-00558-x",

language = "English (US)",

volume = "7",

journal = "npj Vaccines",

issn = "2059-0105",

publisher = "Nature Publishing Group",

number = "1",

}

Franke-Fayard, B, Marin-Mogollon, C, Geurten, FJA, Chevalley-Maurel, S, Ramesar, J, Kroeze, H, Baalbergen, E, Wessels, E, Baron, L, Soulard, V, Martinson, T, Aleshnick, M, Huijs, ATG, Subudhi, A, Miyazaki, Y, Othman, AS, Kolli, SK, Lamers, OAC, Roques, M, Stanway, RR, Murphy, SC, Foquet, L, Moita, D, Mendes, AM, Prudêncio, M, Dechering, KJ, Heussler, VT, Pain, A, Wilder, BK, Roestenberg, M & Janse, CJ 2022, 'Creation and preclinical evaluation of genetically attenuated malaria parasites arresting growth late in the liver.', npj Vaccines, vol. 7, no. 1. https://doi.org/10.1038/s41541-022-00558-x

TY - JOUR

T1 - Creation and preclinical evaluation of genetically attenuated malaria parasites arresting growth late in the liver.

AU - Franke-Fayard, Blandine

AU - Marin-Mogollon, Catherin

AU - Geurten, Fiona J A

AU - Chevalley-Maurel, Séverine

AU - Ramesar, Jai

AU - Kroeze, Hans

AU - Baalbergen, Els

AU - Wessels, Els

AU - Baron, Ludivine

AU - Soulard, Valérie

AU - Martinson, Thomas

AU - Aleshnick, Maya

AU - Huijs, Antonius T G

AU - Subudhi, Amit

AU - Miyazaki, Yukiko

AU - Othman, Ahmad Syibli

AU - Kolli, Surendra Kumar

AU - Lamers, Olivia A C

AU - Roques, Magali

AU - Stanway, Rebecca R

AU - Murphy, Sean C

AU - Foquet, Lander

AU - Moita, Diana

AU - Mendes, António M

AU - Prudêncio, Miguel

AU - Dechering, Koen J

AU - Heussler, Volker T

AU - Pain, Arnab

AU - Wilder, Brandon K

AU - Roestenberg, Meta

AU - Janse, Chris J

N1 - KAUST Repository Item: Exported on 2022-12-12 Acknowledged KAUST grant number(s): BAS/1/1020-01-01 Acknowledgements: We acknowledge the critical contribution of the late Dr Shahid Khan to the design of these studies. We are grateful to Pr Jude Przyborski for the anti- P. falciparum EXP-1 antibody. This work was supported by LUMC internal funds. CM-M was, in part, supported by Colciencias Ph.D. fellowship (Call 568 from 2012 Resolution 01218 Bogotá, Colombia) and LUF project grant, Den Dulk-Moermans Fonds (grant reference number: W19374-2-32, 2019-2021). A.O. is supported by a Skim Latihan Akademik IPTA-SLAI (Ministry of Higher Education, Malaysia). A.P. acknowledges the Faculty Baseline funding (BAS/1/1020-01-01) from King Abdullah University of Science and Technology (KAUST).

PY - 2022/11/4

Y1 - 2022/11/4

N2 - Whole-sporozoite (WSp) malaria vaccines induce protective immune responses in animal malaria models and in humans. A recent clinical trial with a WSp vaccine comprising genetically attenuated parasites (GAP) which arrest growth early in the liver (PfSPZ-GA1), showed that GAPs can be safely administered to humans and immunogenicity is comparable to radiation-attenuated PfSPZ Vaccine. GAPs that arrest late in the liver stage (LA-GAP) have potential for increased potency as shown in rodent malaria models. Here we describe the generation of four putative P. falciparum LA-GAPs, generated by CRISPR/Cas9-mediated gene deletion. One out of four gene-deletion mutants produced sporozoites in sufficient numbers for further preclinical evaluation. This mutant, PfΔmei2, lacking the mei2-like RNA gene, showed late liver growth arrest in human liver-chimeric mice with human erythrocytes, absence of unwanted genetic alterations and sensitivity to antimalarial drugs. These features of PfΔmei2 make it a promising vaccine candidate, supporting further clinical evaluation. PfΔmei2 (GA2) has passed regulatory approval for safety and efficacy testing in humans based on the findings reported in this study.

AB - Whole-sporozoite (WSp) malaria vaccines induce protective immune responses in animal malaria models and in humans. A recent clinical trial with a WSp vaccine comprising genetically attenuated parasites (GAP) which arrest growth early in the liver (PfSPZ-GA1), showed that GAPs can be safely administered to humans and immunogenicity is comparable to radiation-attenuated PfSPZ Vaccine. GAPs that arrest late in the liver stage (LA-GAP) have potential for increased potency as shown in rodent malaria models. Here we describe the generation of four putative P. falciparum LA-GAPs, generated by CRISPR/Cas9-mediated gene deletion. One out of four gene-deletion mutants produced sporozoites in sufficient numbers for further preclinical evaluation. This mutant, PfΔmei2, lacking the mei2-like RNA gene, showed late liver growth arrest in human liver-chimeric mice with human erythrocytes, absence of unwanted genetic alterations and sensitivity to antimalarial drugs. These features of PfΔmei2 make it a promising vaccine candidate, supporting further clinical evaluation. PfΔmei2 (GA2) has passed regulatory approval for safety and efficacy testing in humans based on the findings reported in this study.

UR - http://hdl.handle.net/10754/685566

UR - https://www.nature.com/articles/s41541-022-00558-x

UR - http://www.scopus.com/inward/record.url?scp=85141373758&partnerID=8YFLogxK

U2 - 10.1038/s41541-022-00558-x

DO - 10.1038/s41541-022-00558-x

M3 - Article

C2 - 36333336

SN - 2059-0105

VL - 7

JO - npj Vaccines

JF - npj Vaccines

IS - 1

ER -

Creation and preclinical evaluation of genetically attenuated malaria parasites arresting growth late in the liver.

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