Hexon-chimaeric adenovirus serotype 5 vectors circumvent pre-existing anti-vector immunity View Full Text


Ontology type: schema:ScholarlyArticle     


Article Info

DATE

2006-05

AUTHORS

Diane M. Roberts, Anjali Nanda, Menzo J. E. Havenga, Peter Abbink, Diana M. Lynch, Bonnie A. Ewald, Jinyan Liu, Anna R. Thorner, Patricia E. Swanson, Darci A. Gorgone, Michelle A. Lifton, Angelique A. C. Lemckert, Lennart Holterman, Bing Chen, Athmanundh Dilraj, Angela Carville, Keith G. Mansfield, Jaap Goudsmit, Dan H. Barouch

ABSTRACT

A common viral immune evasion strategy involves mutating viral surface proteins in order to evade host neutralizing antibodies. Such immune evasion tactics have not previously been intentionally applied to the development of novel viral gene delivery vectors that overcome the critical problem of anti-vector immunity. Recombinant, replication-incompetent adenovirus serotype 5 (rAd5) vector-based vaccines for human immunodeficiency virus type 1 and other pathogens have proved highly immunogenic in preclinical studies but will probably be limited by the high prevalence of pre-existing anti-Ad5 immunity in human populations, particularly in the developing world. Here we show that rAd5 vectors can be engineered to circumvent anti-Ad5 immunity. We constructed novel chimaeric rAd5 vectors in which the seven short hypervariable regions (HVRs) on the surface of the Ad5 hexon protein were replaced with the corresponding HVRs from the rare adenovirus serotype Ad48. These HVR-chimaeric rAd5 vectors were produced at high titres and were stable through serial passages in vitro. HVR-chimaeric rAd5 vectors expressing simian immunodeficiency virus Gag proved comparably immunogenic to parental rAd5 vectors in naive mice and rhesus monkeys. In the presence of high levels of pre-existing anti-Ad5 immunity, the immunogenicity of HVR-chimaeric rAd5 vectors was not detectably suppressed, whereas the immunogenicity of parental rAd5 vectors was abrogated. These data demonstrate that functionally relevant Ad5-specific neutralizing antibodies are focused on epitopes located within the hexon HVRs. Moreover, these studies show that recombinant viral vectors can be engineered to circumvent pre-existing anti-vector immunity by removing key neutralizing epitopes on the surface of viral capsid proteins. Such chimaeric viral vectors may have important practical implications for vaccination and gene therapy. More... »

PAGES

239

Journal

TITLE

Nature

ISSUE

7090

VOLUME

441

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  • Identifiers

    URI

    http://scigraph.springernature.com/pub.10.1038/nature04721

    DOI

    http://dx.doi.org/10.1038/nature04721

    DIMENSIONS

    https://app.dimensions.ai/details/publication/pub.1050800201

    PUBMED

    https://www.ncbi.nlm.nih.gov/pubmed/16625206


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