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Journal of Virology, December 2006, p. 12009-12016, Vol. 80, No. 24
0022-538X/06/$08.00+0     doi:10.1128/JVI.01749-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Immunogenicity of Heterologous Recombinant Adenovirus Prime-Boost Vaccine Regimens Is Enhanced by Circumventing Vector Cross-Reactivity{triangledown}

Anna R. Thorner,1 Angelique A. C. Lemckert,2 Jaap Goudsmit,2 Diana M. Lynch,1 Bonnie A. Ewald,1 Matthew Denholtz,1 Menzo J. E. Havenga,2 and Dan H. Barouch1*

Division of Viral Pathogenesis, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215,1 Crucell Holland BV, 2301 CA, Leiden, The Netherlands2

Received 12 August 2006/ Accepted 30 September 2006

The high prevalence of preexisting immunity to adenovirus serotype 5 (Ad5) in human populations has led to the development of recombinant adenovirus (rAd) vectors derived from rare Ad serotypes as vaccine candidates for human immunodeficiency virus type 1 and other pathogens. Vaccine vectors have been constructed from Ad subgroup B, including rAd11 and rAd35, as well as from Ad subgroup D, including rAd49. However, the optimal combination of vectors for heterologous rAd prime-boost vaccine regimens and the extent of cross-reactive vector-specific neutralizing antibodies (NAbs) remain poorly defined. We have shown previously that the closely related vectors rAd11 and rAd35 elicited low levels of cross-reactive NAbs. Here we show that these cross-reactive NAbs correlated with substantial sequence homology in the hexon hypervariable regions (HVRs) and suppressed the immunogenicity of heterologous rAd prime-boost regimens. In contrast, vectors with lower hexon HVR homology, such as rAd35 and rAd49, did not elicit detectable cross-reactive vector-specific NAbs. Consistent with these findings, rAd35-rAd49 vaccine regimens proved more immunogenic than both rAd35-rAd5 and rAd35-rAd11 regimens in mice with anti-Ad5 immunity. These data suggest that optimal heterologous rAd prime-boost regimens should include two vectors that are both rare in human populations to circumvent preexisting antivector immunity as well as sufficiently immunologically distinct to avoid cross-reactive antivector immunity.

* Corresponding author. Mailing address: Research East Room 213, Division of Viral Pathogenesis, Beth Israel Deaconess Medical Center, 330 Brookline Avenue, Boston, MA 02215. Phone: (617) 667-4434. Fax: (617) 667-8210. E-mail: dbarouch{at}bidmc.harvard.edu.

{triangledown} Published ahead of print on 11 October 2006.

Journal of Virology, December 2006, p. 12009-12016, Vol. 80, No. 24
0022-538X/06/$08.00+0     doi:10.1128/JVI.01749-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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