Vaccines that induce broadly neutralizing antibodies against Human Papillomarviru

目前针对人乳头瘤病毒(HPV)的疫苗是高效的。不幸的是，这些疫苗， 基于病毒主要衣壳蛋白的病毒样颗粒，L L具有类型特异性，这意味着 它们只对与宫颈癌相关的一小部分HPV类型提供保护。在……里面 相比之下，针对病毒小衣壳蛋白L2内高度保守表位的抗体， 能够中和非常广泛的HPV类型。因此，针对L2的疫苗可能是 对致癌HPV类型具有广泛的保护作用。尽管已经尝试创建基于L2多肽的 疫苗，L2的免疫原性很差。因此，需要新的疫苗策略才能 创造基于L2的高效疫苗。 体液免疫系统对密集、重复排列的抗原反应强烈，例如 在病毒和VLP的表面。相应地，VLP可以作为分子支架来增加 异种抗原的免疫原性。VLP可用来诱导抗体反应 免疫原性差的靶点，甚至自身抗原，当在高密度下呈现时都是免疫原性的 VLP。在这项提议中，我们将通过使用来自RNA噬菌体的VLP作为靶向L2的新疫苗 我们的疫苗平台。在具体目标1中，我们将利用我们掌握的化学结合技术。 靶向先前已鉴定的源自L2的多肽。在具体目标2中，我们将使用一个新的基于VLP的 噬菌体展示技术设计和识别新的候选疫苗。在具体目标3中，我们将评估 肺部疫苗接种策略诱导系统和粘膜免疫的有效性 已建立的和新的免疫原，并评估疫苗接种是否提供了对生殖器的保护 挑战人类乳头瘤病毒。这些研究将在很大程度上利用核心B(病毒分析核心)提供的设施。 此外，体内生殖器挑战研究与项目1(PI：Michelle Ozbun)具有显著的协同作用。

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).