Thorner Anna R, Lemckert Angelique A C, Goudsmit Jaap, Lynch Diana M, Ewald Bonnie A, Denholtz Matthew, Havenga Menzo J E, Barouch Dan H
Research East Room 213, Division of Viral Pathogenesis, Beth Israel Deaconess Medical Center, 330 Brookline Avenue, Boston, MA 02215, USA.
J Virol. 2006 Dec;80(24):12009-16. doi: 10.1128/JVI.01749-06. Epub 2006 Oct 11.
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.
人群中对5型腺病毒（Ad5）的预先存在的免疫的高流行率已导致开发源自罕见Ad血清型的重组腺病毒（rAd）载体，作为1型人类免疫缺陷病毒和其他病原体的候选疫苗。疫苗载体已由B亚组腺病毒构建，包括rAd11和rAd35，以及由D亚组腺病毒构建，包括rAd49。然而，用于异源rAd初免-加强疫苗方案的载体的最佳组合以及交叉反应性载体特异性中和抗体（NAbs）的程度仍不清楚。我们之前已经表明，密切相关的载体rAd11和rAd35诱导出低水平的交叉反应性NAbs。在这里我们表明，这些交叉反应性NAbs与六邻体高变区（HVRs）中的大量序列同源性相关，并抑制了异源rAd初免-加强方案的免疫原性。相比之下，六邻体HVR同源性较低的载体，如rAd35和rAd49，不会诱导出可检测到的交叉反应性载体特异性NAbs。与这些发现一致，在具有抗Ad5免疫的小鼠中，rAd35-rAd49疫苗方案比rAd35-rAd5和rAd35-rAd11方案更具免疫原性。这些数据表明，最佳的异源rAd初免-加强方案应包括两种在人群中都很罕见的载体，以规避预先存在的抗载体免疫，以及在免疫学上足够不同以避免交叉反应性抗载体免疫。
