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 K.
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 - Publisher Copyright:
© 2022, The Author(s).
PY - 2022/12
Y1 - 2022/12
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.
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U2 - 10.1038/s41541-022-00558-x
DO - 10.1038/s41541-022-00558-x
M3 - Article
AN - SCOPUS:85141373758
SN - 2059-0105
VL - 7
JO - npj Vaccines
JF - npj Vaccines
IS - 1
M1 - 139
ER -