Adeno-associated virus vectored immunoprophylaxsis against Plasmodium falciparum
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Date
2016-04-22
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Johns Hopkins University
Abstract
Anti-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.
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Immunoprophylaxsis: Plasmodium falciparum, malaria, vaccines