ArticleMolecular therapy : the journal of the American Society of Gene Therapy2014
A next-generation genetically attenuated Plasmodium falciparum parasite created by triple gene deletion.
Article in Molecular therapy : the journal of the American Society of Gene Therapy, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 52 papers.
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52 citing papers in PubMed, 83 citations in OpenAlex.
- The path from early- to late-liver stage arresting genetically attenuated parasites as a malaria vaccination strategy.NPJ vaccines · 2025Review
- A Plasmodium LARC GAP provides preerythrocytic, stage and species transcending protection in mice.NPJ vaccines · 2025Article
- Genome-wide gene expression profiles throughout human malaria parasite liver stage development in humanized mice.Nature microbiology · 2025Article
- A conserved Plasmodium nuclear protein is critical for late liver stage development.Communications biology · 2024Article
- A Plasmodium late liver stage arresting GAP provides superior protection in mice.NPJ vaccines · 2024Article
- Flp/Proceedings of the National Academy of Sciences of the United States of America · 2024Article
- A replication competent Plasmodium falciparum parasite completely attenuated by dual gene deletion.EMBO molecular medicine · 2024Article
- CD8Frontiers in immunology · 2024Review
- A Critical Review on Human Malaria and Schistosomiasis Vaccines: Current State, Recent Advancements, and Developments.Vaccines · 2023Review
- Progress on innate immune evasion and live attenuated vaccine of pseudorabies virus.Frontiers in microbiology · 2023Review
- A genetically engineeredScience translational medicine · 2022Article
- AiScience · 2022Article
- The History of Live AttenuatedPathogens (Basel, Switzerland) · 2022Review
- Host-parasite interactions duringFrontiers in immunology · 2022Review
- Review
- Immune responses to malaria pre-erythrocytic stages: Implications for vaccine development.Parasite immunology · 2021Review
- Article
- [Development of malaria vaccines-state of the art].Bundesgesundheitsblatt, Gesundheitsforschung, Gesundheitsschutz · 2020Review
- Vaccination With Sporozoites: Models and Correlates of Protection.Frontiers in immunology · 2019Review
- Understanding the Liver-Stage Biology of Malaria Parasites: Insights to Enable and Accelerate the Development of a Highly Efficacious Vaccine.The American journal of tropical medicine and hygiene · 2018Article
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Authors and funding
13 authors at 3 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Immunization with live-attenuated Plasmodium sporozoites completely protects against malaria infection. Genetic engineering offers a versatile platform to create live-attenuated sporozoite vaccine candidates. We previously generated a genetically attenuated parasite (GAP) by deleting the P52 and P36 genes in the NF54 wild-type (WT) strain of Plasmodium falciparum (Pf p52(-)/p36(-) GAP). Preclinical assessment of p52(-)/p36(-) GAP in a humanized mouse model indicated an early and severe liver stage growth defect. However, human exposure to >200 Pf p52(-)/p36(-) GAP-infected mosquito bites in a safety trial resulted in peripheral parasitemia in one of six volunteers, revealing that this GAP was incompletely attenuated. We have now created a triple gene deleted GAP by additionally removing the SAP1 gene (Pf p52(-)/p36(-)/sap1(-) GAP) and employed flippase (FLP)/flippase recognition target (FRT) recombination for drug selectable marker cassette removal. This next-generation GAP was indistinguishable from WT parasites in blood stage and mosquito stage development. Using an improved humanized mouse model transplanted with human hepatocytes and human red blood cells, we show that despite a high-dose sporozoite challenge, Pf p52(-)/p36(-)/sap1(-) GAP did not transition to blood stage infection and appeared to be completely attenuated. Thus, clinical testing of Pf p52(-)/p36(-)/sap1(-) GAP assessing safety, immunogenicity, and efficacy against sporozoite challenge is warranted.
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