Neutralization-Resistant Adenovirus Vaccine Vector

描述（由申请人提供）：编码SIV gag 的腺病毒疫苗载体已用于在恒河猴中诱导针对SHIV感染和疾病的有效免疫力。在正在进行的临床试验中，基于腺病毒的 HIV 疫苗在人类受试者中诱导 HIV gag 特异性 CD8 和 CD4 淋巴细胞反应。因此，腺病毒载体作为艾滋病毒疫苗接种的载体显示出巨大的前景。 然而，许多成年人已经接触过常见的腺病毒，并且对目前使用的腺病毒 5 (Ad5) 和 Ad2 载体具有预先存在的免疫力。在动物和人类志愿者中，已经发现预先存在的能够中和腺病毒的抗体可以抑制腺病毒载体诱导 HIV 特异性免疫反应的有效性。解决这个问题的一个可能的办法是使用腺病毒载体，例如源自黑猩猩腺病毒 C68 的载体，人类尚未接触过这种载体； C68 载体可抵抗人血清的中和作用，并且即使在具有高水平 Ad5 中和抗体的动物中也能有效地作为疫苗载体。然而，对 C68 及其致病潜力的经验有限，以及对其可能的毒性的担忧，可能会推迟其临床应用。 中和抗体具有血清型特异性，可识别主要腺病毒衣壳蛋白六邻体的表面。中和表位包含在表面环内，其序列在腺病毒血清型之间高度可变；相比之下，构成六邻体的底部和内部的序列是高度保守的。 我们建议用 C68 的可变表面环替换 Ad5 六邻体的可变表面环（在可用六邻体晶体结构指导的实验方法中）。这种六邻体嵌合病毒的生物学和遗传特性实际上与 Ad5 相同，因此可能适合临床试验，但对预先存在的抗体的中和具有抵抗力。这种嵌合载体可以解决使用腺病毒载体进行HIV免疫的主要障碍之一。

DESCRIPTION (provided by applicant): Adenovirus vaccine vectors encoding SIV gag have been used to induce effective immunity against SHIV infection and disease in rhesus macaques. In ongoing clinical trials, adenovirus-based HIV vaccines induce HIV gag-specific CD8 and CD4 lymphocyte responses in human subjects. Adenovirus vectors thus show great promise as vehicles for HIV vaccination. However, many adults have been exposed to common adenoviruses, and have preexisting immunity to the adenovirus 5 (Ad5) and Ad2 vectors in present use. Preexisting antibody capable of adenovirus neutralization has been seen - both in animals and in human volunteers - to inhibit the effectiveness of adenovirus vectors in inducing HIV-specific immune responses. A possible solution to this problem is to use adenovirus vectors-- such as those derived from the chimpanzee adenovirus C68-- to which humans have not been exposed; C68-vectors resist neutralization by human sera, and have been effective as vaccine vehicles even in animals with high levels of Ad5-neutalizing antibody. However, the limited experience with C68 and its pathogenic potential, and concerns about its possible toxicities, may delay its clinical application. Neutralizing antibodies are serotype-specific, and recognize the surface of the major adenovirus capsid protein, hexon. The neutralizing epitopes are contained within surface loops whose sequences are highly variable among adenovirus serotypes; in contrast, the sequences that make up the base and interior of the hexon are highly conserved. We propose to replace the variable surface loops of the Ad5 hexon with those of C68 (in an experimental approach guided by available hexon crystal structures). This hexon-chimeric virus should be virtually identical to Ad5 in its biological and genetic properties-- and thus likely to be appropriate for clinical trial but resistant to neutralization by preexisting antibodies. Such a chimeric vector could solve one of the major obstacles to the use of adenovirus vectors for HIV immunization.