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dc.contributor.authorLow, Leanne M
dc.contributor.authorSsemaganda, Aloysious
dc.contributor.authorLiu, Xue Q
dc.contributor.authorHo, Mei-Fong
dc.contributor.authorOzberk, Victoria
dc.contributor.authorFink, James
dc.contributor.authorSundac, Lana
dc.contributor.authorAlcorn, Kylie
dc.contributor.authorMorrison, Amy
dc.contributor.authorO'Callaghan, Kevin
dc.contributor.authorGerrard, John
dc.contributor.authorStanisic, Danielle I
dc.contributor.authorGood, Michael F
dc.date.accessioned2019-07-05T12:32:17Z
dc.date.available2019-07-05T12:32:17Z
dc.date.issued2019
dc.identifier.issn0019-9567
dc.identifier.doi10.1128/IAI.00587-18
dc.identifier.urihttp://hdl.handle.net/10072/383797
dc.description.abstractNaturally acquired immunity to malaria is robust and protective against all strains of the same species of Plasmodium. This develops as a result of repeated natural infection, taking several years to develop. Evidence suggests that apoptosis of immune lymphocytes due to uncontrolled parasite growth contributes to the slow acquisition of immunity. To hasten and augment the development of natural immunity, we studied controlled infection immunization (CII) using low-dose exposure to different parasite species (Plasmodium chabaudi, P. yoelii, or P. falciparum) in two rodent systems (BALB/c and C57BL/6 mice) and in human volunteers, with drug therapy commencing at the time of initiation of infection. CIIs with infected erythrocytes and in conjunction with doxycycline or azithromycin, which are delayed death drugs targeting the parasite’s apicoplast, allowed extended exposure to parasites at low levels. In turn, this induced strong protection against homologous challenge in all immunized mice. We show that P. chabaudi/P. yoelii infection initiated at the commencement of doxycycline therapy leads to cellular or antibody-mediated protective immune responses in mice, with a broad Th1 cytokine response providing the best correlate of protection against homologous and heterologous species of Plasmodium. P. falciparum CII with doxycycline was additionally tested in a pilot clinical study (n = 4) and was found to be well tolerated and immunogenic, with immunological studies primarily detecting increased cell-associated immune responses. Furthermore, we report that a single dose of the longer-acting drug, azithromycin, given to mice (n = 5) as a single subcutaneous treatment at the initiation of infection controlled P. yoelii infection and protected all mice against subsequent challenge.
dc.description.peerreviewedYes
dc.languageEnglish
dc.language.isoeng
dc.publisherAMER SOC MICROBIOLOGY
dc.relation.ispartofpagefrom1
dc.relation.ispartofpageto24
dc.relation.ispartofissue1
dc.relation.ispartofjournalINFECTION AND IMMUNITY
dc.relation.ispartofvolume87
dc.subject.fieldofresearchBiological sciences
dc.subject.fieldofresearchMicrobiology
dc.subject.fieldofresearchBiomedical and clinical sciences
dc.subject.fieldofresearchImmunology
dc.subject.fieldofresearchMedical microbiology
dc.subject.fieldofresearchcode31
dc.subject.fieldofresearchcode3107
dc.subject.fieldofresearchcode32
dc.subject.fieldofresearchcode3204
dc.subject.fieldofresearchcode3207
dc.subject.keywordsMalaria
dc.titleControlled Infection Immunization Using Delayed Death Drug Treatment Elicits Protective Immune Responses to Blood-Stage Malaria Parasites
dc.typeJournal article
dc.type.descriptionC1 - Articles
dc.type.codeC - Journal Articles
gro.rights.copyright© 2019 American Society for Microbiology. The attached file is reproduced here in accordance with the copyright policy of the publisher. Please refer to the journal's website for access to the definitive, published version.
gro.hasfulltextFull Text
gro.griffith.authorGood, Michael F.
gro.griffith.authorStanisic, Danielle
gro.griffith.authorOzberk, Victoria


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