Neutralization-Resistant Adenovirus Vaccine Vector

描述(申请人提供)：编码SIV Gag的腺病毒疫苗载体已被用于在恒河猴体内诱导对SIV感染和疾病的有效免疫。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的载体显示出巨大的前景。 然而，许多成年人已经接触了常见的腺病毒，并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。已经在动物和人类志愿者中发现了能够中和腺病毒的预先存在的抗体，以抑制腺病毒载体诱导HIV特异性免疫反应的有效性。这个问题的一个可能的解决方案是使用腺病毒载体--例如那些来自黑猩猩C68腺病毒的载体--人类从未接触过；C68载体抵抗人血清的中和，即使在具有高水平Ad5中和抗体的动物中也是有效的疫苗载体。然而，C68的有限经验及其致病潜力，以及对其可能毒性的担忧，可能会推迟其临床应用。中和抗体是血清型特异性的，识别主要的腺病毒衣壳蛋白六邻体的表面。中和表位包含在表面环中，其序列在不同的腺病毒血清型中差异很大；相反，组成六邻体碱基和内部的序列是高度保守的。 我们建议用C68取代Ad5六邻体的可变表面环(以现有的六邻体晶体结构为指导的实验方法)。这种六邻体嵌合病毒在生物学和遗传特性上应该与Ad5几乎相同--因此很可能适合于临床试验，但对现有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艾滋病毒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.