ANIMAL MODEL OF MUCOSAL IMMUNITY TO HUMAN PAPILLOMAVIRUS

人乳头瘤病毒粘膜免疫动物模型

• 批准号: 2631426
• 负责人: MARGARET E HITCHCOCK
• 金额: $ 11.56万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-04-15 至 2000-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2631426
• 关键词: Macaca mulatta; active immunization; antibody neutralization test; athymic mouse; cell mediated lymphocytolysis test; cellular immunity; disease /disorder model; dosage; drug administration routes; drug screening /evaluation; enzyme linked immunosorbent assay; genetic strain; human papillomavirus; human tissue; humoral immunity; immunoglobulin isotypes; immunomodulators; microorganism immunology; mucosal immunity; nonhuman therapy evaluation; secretory immune system; vaccine development; viral vaccines; viruslike particle; xenotransplantation

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.

该提案在以下背景下解决了HPV粘膜疫苗接种问题： 不同的粘膜佐剂以进一步阐明类型（分泌型， 体液、细胞）、程度（滴度、抗体分泌B细胞数量） 和质量（抗体亲合力，病毒中和滴度）， 诱导反应。 如初步研究所示，HPV-11 VLP， 阴道给药加肌肉注射，可以诱导分泌 具有介导体外中和潜力的免疫应答 HPV-11的感染性。 两种动物都有明显的反应 在阴道分泌物中，但只有一只动物能够介导这一点 中和的类型。 以前的研究（1）已经证明， 单克隆抗体介导的体外中和HPV-11 感染性对应于预防裸体中的湿疣形成 小鼠异种移植系统（2）。 这一数据表明，VLP在存在 适当的粘膜佐剂将诱导高滴度中和 粘膜组织内的抗体反应。 尽管有几项研究使用了霍乱的无毒B亚单位 CTB是一种粘膜佐剂，用于增强恒河猴的粘膜免疫 猕猴最近的数据表明，它可能不是最佳的。 一 一项研究报告了诱导显著的分泌性免疫应答 用SIV p27：Ty-VLP-CTB免疫恒河猴后 通过口服-阴道-直肠免疫途径制备缀合物。 但最近的 在这些动物中进行的SIV攻击实验表明， 没有显著的质量来保护免受感染性 SIV 相反，在加州地区灵长类动物中心正在进行的研究 研究中心表示，霍乱毒素（CT）可能是一种 在恒河猴模型中有效的粘膜佐剂 CT在这些动物中是一种强粘膜佐剂， 在人体中观察到的伴随毒性作用（C.J.米勒，附录C）。 这项研究将有助于解剖出哪些组成部分的粘膜和 对HPV-VLP系统性免疫对于诱导强的 保护性反应内的生殖器和呼吸消化道在一个 非人类灵长类动物模型 这将进一步促进理性 人体疫苗试验的设计（以及粘膜免疫的要求） 佐剂）以诱导保护性和多型免疫， 粘膜组织 这项研究的目的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 其他HPV疫苗制剂可以与之进行比较， 优化HPV疫苗学。