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Publication Details
AFRICAN RESEARCH NEXUS
SHINING A SPOTLIGHT ON AFRICAN RESEARCH
general
Hexon-chimaeric adenovirus serotype 5 vectors circumvent pre-existing anti-vector immunity
Nature, Volume 441, No. 7090, Year 2006
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Description
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 studies1,2 but will probably be limited by the high prevalence of pre-existing anti-Ad5 immunity in human populations, particularly in the developing world 3-6. 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. © 2006 Nature Publishing Group.
Authors & Co-Authors
Roberts, Diane M.
United States, Boston
Harvard Medical School
Nanda, Anjali
United States, Boston
Harvard Medical School
Havenga, Menzo J.E.
Netherlands, Leiden
Crucell nv
Abbink, Peter
United States, Boston
Harvard Medical School
Lynch, Diana M.
United States, Boston
Harvard Medical School
Ewald, Bonnie A.
United States, Boston
Harvard Medical School
Liu, Jinyan
United States, Boston
Harvard Medical School
Thorner, Anna R.
United States, Boston
Harvard Medical School
Swanson, Patricia E.
United States, Boston
Harvard Medical School
Gorgone, Darci A.
United States, Boston
Harvard Medical School
Lifton, Michelle A.
United States, Boston
Harvard Medical School
Lemckert, Angelique A.C.
Netherlands, Leiden
Crucell nv
Holterman, Lennart
Netherlands, Leiden
Crucell nv
Chen, Bing
United States, Boston
Harvard Medical School
Dilraj, Athmanundh
South Africa, Tygerberg
South African Medical Research Council
Carville, Angela A.L.
United States, Southborough
New England Regional Primate Research Center
Mansfield, Keith G.
United States, Southborough
New England Regional Primate Research Center
Goudsmit, Jaap
Netherlands, Leiden
Crucell nv
Barouch, Dan H.
United States, Boston
Harvard Medical School
Statistics
Citations: 496
Authors: 19
Affiliations: 4
Identifiers
Doi:
10.1038/nature04721
ISSN:
00280836
e-ISSN:
14764687
Research Areas
Genetics And Genomics
Study Design
Cross Sectional Study