ANIMAL MODEL OF MUCOSAL IMMUNITY TO HUMAN PAPILLOMAVIRUS

这项建议解决了HPV粘膜疫苗接种在 不同的粘膜佐剂以进一步阐明其类型(分泌型， 体液，细胞)，程度(效价，分泌B细胞的抗体数量) 和质量(抗体亲和力、病毒中和效价) 诱导反应。初步研究表明，HPV-11VLP， 阴道给药加上肌肉注射，可以诱导分泌 具有潜在介导体外中和作用的免疫应答 HPV-11的传染性。两只动物都做出了可测量的反应 但只有一种动物能够调节这一过程 中和类型。以前的研究(1)已经证明 单抗介导的HPV-11体外中和作用 传染性相当于预防裸体尖锐湿疣的形成 小鼠异种移植系统(2)。这一数据表明VLP在现场 适当的粘膜佐剂会诱导高滴度的中和 粘膜组织内的抗体反应。 尽管有几项研究使用了无毒的霍乱B亚单位 粘膜佐剂毒素(CTB)增强恒河猴粘膜免疫功能 猕猴最近的数据表明，这可能不是最理想的。一 研究报告诱导显著的分泌性免疫反应 SIV p27：TY-VLP-CTB免疫恒河猴 结合物通过口服-阴道-直肠免疫途径进行。然而，最近 在这些动物身上进行的SIV挑战实验表明了这种反应 没有显著的品质来保护免受传染性疾病的挑战 SIV。相反，加州地区灵长类动物正在进行的研究 研究中心表明霍乱毒素(CT)可能是一种更多的 恒河猴模型中有效的粘膜佐剂由于其性质 CT在这些动物中是一种强大的粘膜佐剂，而不是 在人类身上观察到的伴随毒性效应(C.J.米勒，附录C)。 这项研究将有助于剖析出粘膜和胃粘膜的哪些成分 对HPV-VLP的系统免疫对于诱导强烈的 生殖器和空气消化系统内的保护性反应 非人灵长类动物模型。这应该会进一步促进理性的 人体疫苗试验的设计(和对粘膜的要求 佐剂)在体内诱导保护性和多类型免疫 粘膜组织。这项研究的目标是建立一个黄金标准 非人灵长类动物对VLP抗原的粘膜免疫应答 可以与其他HPV疫苗配方进行顺序比较 优化人乳头瘤病毒疫苗接种。

This proposal addresses HPV mucosal vaccination in the context of different mucosal adjuvants to further elucidate the type (secretory, humoral, cellular), extent (titer, number of antibody secreting B cells) and quality (antibody avidity, virus neutralization titer) of the induced response. As indicated in preliminary studies, HPV-11 VLP, administered vaginally plus intramuscularly, can induce a secretory immune response with the potential to mediate in vitro neutralization of HPV-11 infectivity. Both animals mounted a measurable response within vaginal secretions but only one animal was able to mediate this type of neutralization. Previous studies (1) have demonstrated that monoclonal antibody-mediated neutralization of HPV-11 in vitro infectivity corresponds to prevention of condyloma formation in the nude mouse xenograft system (2). This data suggests that VLP in the presence of an appropriate mucosal adjuvant will induce a high titer neutralizing antibody response within mucosal tissues. Although several studies have used the nontoxic B subunit of cholera toxin (CTB), a mucosal adjuvant, for enhanced mucosal immunity in rhesus macaques more recent data suggests it may be less than optimal. One study reported induction of significant secretory immune responses following immunization of rhesus macaques with SIV p27:Ty-VLP-CTB conjugates by oral-vaginal-rectal immunization routes. However, recent challenge experiments with SIV in these animals indicate the response was not of significant quality to protect from challenge with infectious SIV. Conversely, ongoing studies at the California Regional Primate Research Center indicate cholera toxin (CT) may serve as a more effective mucosal adjuvant within the rhesus model due to the nature of CT being a strong mucosal adjuvant in these animals without the concomitant toxic effects observed in humans (C.J. Miller, Appendix C). This study will help to dissect out which components of mucosal and systemic immunity to HPV-VLP are important for induction of a strong protective response within the genital and aero-digestive tracts in a non-human primate model. This should further promote the rational design of vaccine trials in humans (and requirement for mucosal adjuvant) to induce both protective and multi-type immunity within mucosal tissues. The goal of this study is to establish a gold standard of mucosal immune response to VLP antigens in a non-human primate against which other HPV vaccine formulations can be compared in order to optimize HPV vaccinology.