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dc.contributor.advisorKetner, Gary W.
dc.creatorElizabeth Joseph, Renuka
dc.date.accessioned2016-12-15T07:05:17Z
dc.date.available2016-12-15T07:05:17Z
dc.date.created2016-05
dc.date.issued2016-04-22
dc.date.submittedMay 2016
dc.identifier.urihttp://jhir.library.jhu.edu/handle/1774.2/39481
dc.description.abstractAnti-Circumsporozoite protein (CSP) monoclonal antibodies (mAbs) can neutralize Plasmodium sporozoites in vitro and passively transferred mAb against P. falciparum CSP can block liver invasion by sporozoites of a transgenic rodent parasite that expresses chimeric P. falciparum CSP (Pb-Pf), preventing infection in mice. Despite this, attempts at targeting CSP for a vaccine have fallen short of expectations, mainly since a single un-neutralized sporozoite can cause disease, necessitating sustained high-titer neutralizing antibodies which current vaccines have been unable to achieve. Recently, David Baltimore’s laboratory developed adeno-associated virus type 8 (AAV8) platform that efficiently delivers pre-formed mAb genes in vivo and directs sustained, high-level mAb production. We have adopted this technology to express humanized mAbs against the N-terminal region of the CSP protein of P. falciparum in mice. Mice developed high titer human IgG antibodies as early as one week post-transduction, and levels have remained constant for more than six weeks at 800 to 1000 µg of IgG/mL. Mice transduced with humanized CSP mAb 5D5 (5D5-AAV) and challenged intravenously with 104 transgenic P.berghei parasite expressing complete P.falciparum CSP (Pb-PfCSP) sporozoites, exhibited a statistically significant decrease in liver parasite burden. Unexpectedly, no protection or delay to parasitemia was observed in mice challenged by infective Pb-PfCSP mosquito bites. Neutralizing antibodies against the vector used in mAb delivery (Vectored Immunoprophylaxis; VIP) can inhibit expression of mAb. Neutralizing antibodies in the sera of Aotus monkeys previously transduced with AAV1, -7 and -8 vectors were detected using an AAV-luciferase assay. Based on the results of the assay, a correlation between high pre-existing neutralizing anti-AAV antibodies titers and inhibition of AAV vectored mAb expression was noted. Our results recommend the prescreening of animals for neutralizing anti-AAV antibodies before VIP administration.
dc.format.mimetypeapplication/pdf
dc.languageen
dc.publisherJohns Hopkins University
dc.subjectImmunoprophylaxsis: Plasmodium falciparum
dc.subjectmalaria
dc.subjectvaccines
dc.titleAdeno-associated virus vectored immunoprophylaxsis against Plasmodium falciparum
dc.typeThesis
thesis.degree.disciplinenot listed
thesis.degree.grantorJohns Hopkins University
thesis.degree.grantorBloomberg School of Public Health
thesis.degree.levelMasters
thesis.degree.nameSc.M.
dc.date.updated2016-12-15T07:05:17Z
dc.type.materialtext
thesis.degree.departmentMolecular Microbiology and Immunology
dc.contributor.committeeMemberSinnis, Photini
dc.publisher.countryUSA
dc.creator.orcid0000-0001-5409-7272


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