Broad-Spectrum HPV Vaccine Based on Recombinant Measles

人乳头瘤病毒（HPV）通常诱导皮肤和粘膜的良性乳头瘤。“高危”类型的持续感染会导致肛门生殖道癌（特别是宫颈癌）和口咽癌，并与非黑色素瘤皮肤癌（NMSC）的发展有关。许可的疫苗基于从主要衣壳蛋白L1自组装的病毒样颗粒（VLP）。疫苗接种保护免受粘膜HPV感染，从而诱导肿瘤形成，仅限于需要在接种疫苗的女性中继续进行宫颈筛查的相应疫苗基因型，并且不靶向皮肤类型。RG 1-VLP是由在组装的VLP表面上展示HPV 16 L2次要衣壳蛋白的交叉中和表位“RG 1”的HPV 16 L1融合蛋白组成的候选疫苗。疫苗接种在体外和动物攻击模型中提供低滴度交叉型免疫和对广谱高风险和低风险粘膜和皮肤HPV类型的保护。然而，在体内保护的持续时间和广度是未知的。活减毒复制麻疹疫苗诱导持久的体液和细胞免疫应答。重组麻疹病毒（MV）已被开发作为针对外国病原体（西尼罗河病毒、登革热病毒等）的疫苗平台。我们建议开发一种经济的下一代HPV疫苗，以预防所有生殖器致癌性和低风险HPV，这可能会克服尽管获得许可的疫苗仍需要继续进行宫颈PAP筛查的负担，并进一步显着减少宫颈癌和HPV诱导的其他肿瘤的发生。在常规麻疹疫苗接种活动中的实施尤其有利于低收入和中等收入国家，这些国家承担着宫颈癌的主要负担，免疫抑制患者特别容易感染HPV并诱发包括NMSC在内的肿瘤。此外，我们将确定诱导记忆B细胞、长寿浆细胞和平台抗体滴度的关键特征，其是生殖道中消除免疫力的主要效应物。我们还将研究MV疫苗平台和紧密间隔的HPV抗原展示是否协同作用，共同激发针对HPV的强大和持久的交叉保护性体液免疫，并评估诱导细胞介导免疫的机制及其对新型动物疾病模型保护的贡献。Reinhard Kirnbauer是授权HPV疫苗的共同发明者，并开发了HPV 16 RG 1-VLP，该疫苗正在临床开发中，作为下一代广谱HPV疫苗候选物。Michael Mühlebach使用MV疫苗平台开发现代疫苗，特别是通过诱导有效的体液和细胞免疫应答来靶向MERS-CoV感染或CLDN 6阳性肿瘤的疫苗。他们的实验室拥有协同和互补的专业知识，为跨境DACH项目提供所需的关键附加价值。

Human Papillomaviruses (HPV) induce generally benign papillomas of skin and mucosa. Persistent infection with ‘high-risk’ types causes carcinomas of the ano-genital tract (in particular cervical cancer) and the oro-pharynx, and has been implicated in development of non-melanoma skin cancer (NMSC). Licensed vaccines are based on virus-like particles (VLP) self-assembled from the major capsid protein L1. Vaccinations protect against mucosal HPV infection and thereby induced neoplasia limited to the respective vaccine genotypes requiring continued cervical screening in vaccinated women, and do not target skin types.RG1-VLP is a vaccine candidate composed of fusion protein of HPV16 L1 displaying the cross-neutralization epitope ‚RG1’ of the HPV16 L2 minor capsid protein on the assembled VLP surface. Vaccinations provide low-titer cross-type immunity and protection to a broad spectrum of high-risk and low-risk mucosal and cutaneous HPV types in vitro and in animal challenge models. However, duration and breadth of protection in vivo are unknown.Live attenuated replicating measles vaccine induces long lasting humoral and cellular immune responses. Recombinant measles virus (MV) has been developed as vaccine platform against foreign pathogens (West Nile, Dengue, etc).We propose to generate an economic next generation HPV vaccine to protect against all genital oncogenic and low-risk HPV, which may overcome the burden of continued cervical PAP screening despite licensed vaccines and yield further significant reduction of cervical cancers and other neoplasias induced by HPV. Implementation in routine measles vaccination campaigns could particularly benefit low- and middle-income countries, which carry the major burden of cervical cancers, and immunosuppressed patients, who are particularly prone to HPV infections and induced neoplasias including NMSC.In addition, we will determine crucial features for induction of memory B-cells, long-lived plasma cells, and plateau antibody titers, which are the main effectors for sterilizing immunity in the genital tract. We will also examine whether the MV vaccine platform and closely spaced HPV antigen-display act synergistically together for provoking robust and long-lasting cross-protective humoral immunity against HPV, and evaluate mechanisms for induction of cell-mediated immunity and its contribution to protection in novel animal disease models. Reinhard Kirnbauer is a co-inventor of licensed HPV vaccines and has developed HPV16 RG1-VLP, which is in clinical development as next generation broad-spectrum HPV vaccine candidate. Michael Mühlebach has used the MV vaccine platform for development of modern vaccines, in particular for a vaccine targeting MERS-CoV infections or CLDN6-positive tumors by inducing both effective humoral and cellular immune responses. Their laboratories have synergistic and complementing expertise, that provide critical additional value required for a cross-border DACH project.