Vaccines that induce broadly neutralizing antibodies against Human Papillomarviru

目前针对人乳头瘤病毒（HPV）的疫苗非常有效。不幸的是，这些疫苗， 基于病毒主要衣壳蛋白L1的病毒样颗粒（VLP）是类型特异性的，这意味着 它们仅提供针对与宫颈癌相关的HPV类型的一小部分的保护。在 相反，对病毒次要衣壳蛋白，L2， 能够中和非常广泛的HPV类型。因此，靶向L2的疫苗可以是 对致癌HPV类型具有广泛的保护作用。尽管已经尝试产生基于L2肽的 疫苗，L2免疫原性差。因此，需要新的疫苗策略，以 以L2为基础研发高效疫苗。 体液免疫系统对以密集、重复阵列展示的抗原作出强烈反应，例如 在病毒和VLP的表面。相应地，VLP可以用作分子支架以增加细胞内的细胞粘附。 异源抗原的免疫原性。VLP可用于诱导针对以下的抗体应答： 免疫原性差的靶标，甚至自身抗原在以高密度呈递于细胞表面时也是免疫原性的。 贵宾在本提案中，我们将使用源自RNA噬菌体的VLP开发针对L2的新疫苗， 疫苗平台。在具体目标1中，我们将利用我们掌握的化学缀合技术 靶向先前鉴定的源自L2的肽。在具体目标2中，我们将使用一种新的基于VLP的 噬菌体展示技术，设计和鉴定新的候选疫苗。具体目标3： 肺疫苗接种策略诱导全身和粘膜免疫的有效性， 建立和新的免疫原，并评估疫苗接种是否提供保护，从生殖器 HPV的挑战这些研究将大量利用核心B（病毒检测核心）提供的设施。 此外，体内生殖器激发研究与项目1（PI：Michelle Ozbun）具有显著协同作用。

Current vaccines against Human Papillomavirus (HPV) are highly effective. Unfortunately, these vaccines, based on the virus-like particles (VLP) of the viral major capsid protein, L l , are type-specific, meaning that they provide protection against only a small subset of HPV types associated with cervical cancer. In contrast, antibodies that are specific for highly conserved epitopes within the viral minor capsid protein, L2, are able to neutralize a remarkably broad range of HPV types. Thus, a vaccine targeting L2 could be broadly protective against oncogenic HPV types. Although attempts have been made to create L2 peptidebased vaccines, L2 is poorly immunogenic. Therefore, novel vaccine strategies are required in order to create highly effective vaccines based on L2. The humoral immune system responds vigorously to antigens displayed in a dense, repetitive array, such as on the surface of viruses and VLPs. Correspondingly, VLPs can be used as molecular scaffolds to increase the immunogenicity of heterologous antigens. VLPs can be used to induce antibody responses against poorly immunogenic targets, and even self-antigens are immunogenic when presented at high density on VLPs. In this proposal we will develop new vaccines targeting L2 by using VLPs derived from RNA phage as our vaccine platform. In specific aim 1, we will exploit the chemical conjugation technologies at our disposal to target previously identified peptides derived from L2. In specific aim 2, we will use a new VLP-based phage display technology to design and identify new candidate vaccines. In specific aim 3, we will assess the effectiveness of a pulmonary vaccination strategy to induce systemic and mucosal immunity against established and novel immunogens, and assess whether vaccination provides protection from genital challenge with HPVs. These studies will draw heavily on facilities provided by Core B (the Viral Assay Core). Moreover, the in vivo genital challenge studies have significant synergy with Project 1 (PI: Michelle Ozbun).