title: Protective efficacy and safety of liver stage attenuated malaria parasites.
abstract: During the clinically silent liver stage of a Plasmodium infection the parasite replicates from a single sporozoite into thousands of merozoites. Infection of humans and rodents with large numbers of sporozoites that arrest their development within the liver can cause sterile protection from subsequent infections. Disruption of genes essential for liver stage development of rodent malaria parasites has yielded a number of attenuated parasite strains. A key question to this end is how increased attenuation relates to vaccine efficacy. Here, we generated rodent malaria parasite lines that arrest during liver stage development and probed the impact of multiple gene deletions on attenuation and protective efficacy. In contrast to P. berghei strain ANKA LISP2(-) or uis3(-) single knockout parasites, which occasionally caused breakthrough infections, the double mutant lacking both genes was completely attenuated even when high numbers of sporozoites were administered. However, different vaccination protocols showed that LISP2(-) parasites protected better than uis3(-) and double mutants. Hence, deletion of several genes can yield increased safety but might come at the cost of protective efficacy.
authors.affiliation: Integrative Parasitology Center for Infectious Diseases, Heidelberg University Medical School, Im Neuenheimer Feld 324, 69120 Heidelberg, Germany.
authors.forename: Hirdesh
authors.initials: H
authors.lastname: Kumar
authors.affiliation: Integrative Parasitology Center for Infectious Diseases, Heidelberg University Medical School, Im Neuenheimer Feld 324, 69120 Heidelberg, Germany.|Parasitology, Center for Infectious Diseases, Heidelberg University Medical School, Im Neuenheimer Feld 324, 69120 Heidelberg, Germany.
authors.forename: Julia Magdalena
authors.initials: JM
authors.lastname: Sattler
authors.affiliation: Integrative Parasitology Center for Infectious Diseases, Heidelberg University Medical School, Im Neuenheimer Feld 324, 69120 Heidelberg, Germany.
authors.forename: Mirko
authors.initials: M
authors.lastname: Singer
authors.affiliation: Parasitology, Center for Infectious Diseases, Heidelberg University Medical School, Im Neuenheimer Feld 324, 69120 Heidelberg, Germany.|MalVa GmbH Heidelberg, Germany.
authors.forename: Kirsten
authors.initials: K
authors.lastname: Heiss
authors.affiliation: Integrative Parasitology Center for Infectious Diseases, Heidelberg University Medical School, Im Neuenheimer Feld 324, 69120 Heidelberg, Germany.
authors.forename: Miriam
authors.initials: M
authors.lastname: Reinig
authors.affiliation: Parasitology, Center for Infectious Diseases, Heidelberg University Medical School, Im Neuenheimer Feld 324, 69120 Heidelberg, Germany.
authors.forename: Christiane
authors.initials: C
authors.lastname: Hammerschmidt-Kamper
authors.affiliation: Institute of Cell Biology, Balzerstrasse 4, 3012 Bern, Switzerland.
authors.forename: Volker
authors.initials: V
authors.lastname: Heussler
authors.affiliation: Parasitology, Center for Infectious Diseases, Heidelberg University Medical School, Im Neuenheimer Feld 324, 69120 Heidelberg, Germany.|German Center for Infectious Diseases, Im Neuenheimer Feld 324, 69120 Heidelberg, Germany.
authors.forename: Ann-Kristin
authors.initials: AK
authors.lastname: Mueller
authors.affiliation: Integrative Parasitology Center for Infectious Diseases, Heidelberg University Medical School, Im Neuenheimer Feld 324, 69120 Heidelberg, Germany.
authors.forename: Friedrich
authors.initials: F
authors.lastname: Frischknecht
mesh_terms: D000818:Animals; D005260:Female; D017353:Gene Deletion; D008099:Liver / Q000469:parasitology*; D008288:Malaria / Q000235:genetics* / Q000276:immunology / Q000517:prevention & control; D017780:Malaria Vaccines; D008810:Mice, Inbred C57BL; D010962:Plasmodium berghei / Q000235:genetics* / Q000276:immunology; D034101:Sporozoites / Q000235:genetics / Q000276:immunology; D014611:Vaccination
chemical_list: D017780:Malaria Vaccines