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

Speaker:沈郁婷                             Time:15:10~16:00, Nov. 8, 2006

Commentator:張堯 老師                      Place: Room 601

Abstract:

  Recent studies of human immunodeficiency virus type 1 (HIV-1) infection in humans and of simian immunodeficiency virus (SIV) in rhesus monkeys have shown that a replication incompetent adenovirus type 5 (Ad5) vector expressing the SIV gag protein elicits the antiviral cellular immune respons in monkeys ⁽¹⁾. The recombinant adenovirus vectors (rAd5) are being studied for use in gene-based vaccine strategies. They are the best characterized and perhaps the most attractive vector for vaccine development. The rAd5 vectors cannot replicate and can be safely administered. They are capable of eliciting the two main types of immune response, secreted antibodies and disease-fighting T cells. However, the preexisting immunity against Ad5 may be a serious limitation.The pre-existing immunity to rAd5, especially Ad5-specific neutralizing Abs, is directed primarily against the Ad5 hexon protein in both humans and mice ⁽²⁾. In this study ⁽³⁾, the authors engineered rAd5 vectors to circumvent anti-Ad5 immunity. They exchanged all seven hypervariable regions on the surface of rAd5 hexon protein, the target for antibody binding, with those of the rare adenovirus serotype 48. Since the core structure of the hexon protein was not altered, the resulting HVR-chimaeric rAd5 vectors retained their ability to grow well and, importantly, theimmunogenicity of the chimaeras was comparable to that of rAd5. The data in this paper show that the mouse with anti-Ad5 immunity did not produce high-titered antibody against HIV-chimaericrAd5 virus after treatment of rAd5 HVR48 (1-7)–Gag virus. The immunogenicity of HVR-chimaeric rAd5 vectors, primary aginst Gag protein, was not suppressed in the mouse with high levels of pre-existing anti-Ad5 immunity, whereas the immunogenicity of parental rAd5 vectors was abrogated. Such chimaeric viral vectors may have important practical implications for vaccination and gene therapy.

References:

1.      Shiver, J. W. et al. Replication-incompetent adenoviral vaccine vector elicits effective anti-immunodeficiency-virus immunity. Nature 415, 331–335 (2002).

2.      Sumida, S. M. et al. Neutralizing antibodies to adenovirus serotype 5 vaccine vectors are directed primarily against the adenovirus hexon protein. J. Immunol. 174, 7179–7185 (2005).

3.      Roberts, D. M. et al. Hexon-chimaeric adenovirus serotype 5 vectors circumvent pre-existing anti-vector immunity. Nature 441, 239-243 (2006).