Targeted Nanoparticle Vaccine Approach for Protection Against Encapsulated Pathogens

 描述(由申请人提供)：大多数成功的人类疫苗都能引起保护性抗体。CD4+T细胞有助于产生强大的抗体反应，尤其是对免疫原性差的多糖类抗原。为了做到这一点，多糖抗原通常连接到高度免疫原性的T细胞表位。遗憾的是，这种方法价格昂贵，只针对囊膜多糖抗原的一小部分，并且依赖于等位基因可变的CD4+T细胞的帮助。我们和其他人最近发现了一种帮助B细胞的新来源，可以利用这种来源来克服这些限制，即不变自然杀伤T细胞(iNKT细胞)。INKT细胞是一种天然的糖脂特异性T细胞亚群，受非多形性抗原提呈分子CD1d的限制，当被激活时，CD1d会迅速产生细胞因子。由于CD1d是非多态的，或者在所有人中都是相同的，iNKT细胞对糖脂的反应应该在每个人身上都一样好。此外，糖脂对人类是压倒性的安全，可以作为联合注射蛋白质和多糖抗原的强效佐剂，特别是在纳米颗粒中加入时。纳米颗粒疫苗可以由安全的、经过充分研究的可生物降解的聚合物制成，将包裹的糖脂佐剂的活性提高1000倍，并可以嵌入B细胞抗原，以促进它们被相关的B细胞亚群靶向和摄取。这项建议的总体目标是使用糖脂佐剂加多糖B细胞抗原的纳米颗粒递送来保护小鼠免受包裹的病原体的全身感染。在目标1中，我们将用糖脂加多糖包埋纳米颗粒接种小鼠，以评估哪种给药途径可以诱导高滴度的类别转换抗体，并对两种不同的体内肺炎链球菌感染小鼠模型具有最好的保护作用。在目标2中，我们将使用小鼠来比较可溶性糖脂和纳米颗粒包埋糖脂如何很好地增强当前人类肺炎链球菌多糖基疫苗诱导的保护性抗体反应。我们还将培养人类外周血细胞，以测试哪种形式的糖脂佐剂最能增强人类多糖特异性B细胞反应。如果成功，这一系列研究将推动开发一种广泛适用的iNKT细胞靶向疫苗策略，鉴于CD1d的非多态性质，该策略可能对所有人普遍有效。反过来，这种疫苗可以保护和改善人类健康，减轻疾病负担，并提高国家的经济福祉。

 DESCRIPTION (provided by applicant): Most successful human vaccines elicit protective antibodies. CD4+ T cell help is essential for a strong antibody response, especially against poorly immunogenic polysaccharide antigens. To accomplish this, polysaccharide antigens are typically conjugated to highly immunogenic T cell epitopes. Unfortunately, this approach is expensive, only targets a subset of capsular polysaccharide antigens, and depends on allelically variable CD4+ T cell help. We and others have recently identified a new source for help for B cells which can be harnessed to overcome these limitations, the invariant Natural Killer T (iNKT) cells. iNKT cells are an innate glycolipid-specific lymphocyte subset of T cells restricted to the non-polymorphic antigen presenting molecule CD1d which rapidly produce cytokines when activated. Because CD1d is non-polymorphic, or the same in all people, iNKT cells should respond to glycolipids equally well in everyone. Furthermore, glycolipids are overwhelmingly safe for humans and can serve as robust adjuvants for co-administered protein and polysaccharide antigens, especially when incorporated in nanoparticles. Nanoparticle vaccines can be made of safe, well-studied, biodegradable polymers, enhance the activity of encapsulated glycolipid adjuvants 1000 fold, and can be embedded with B cell antigens to facilitate their targeting and uptake by a relevant B cell subpopulation. The overall objective of this proposal is to use nanoparticle delivery of glycolipid adjuvant plus polysaccharide B cell antigen to protect mice against systemic infection with an encapsulated pathogen. In Aim 1 we will vaccinate mice with glycolipid plus polysaccharide embedded nanoparticles to assess which route of administration induces high titer class-switched antibodies, and protects best against two different in vivo murine models of Streptococcus pneumoniae infection. In Aim 2 we will use mice to compare how well soluble vs nanoparticle-embedded glycolipids enhance protective antibody responses induced by current human S. pneumoniae polysaccharide-based vaccines. We will also culture human peripheral blood cells to test which form of glycolipid adjuvant best enhances human polysaccharide-specific B cell responses. If successful, this line of research will drive the development of a widely applicable iNKT cell-targeted vaccine strategy which, given the non-polymorphic nature of CD1d, may be universally effective in all people. In turn, this vaccine can protect and improve human health, reduce the burdens of illness, and enhance the nation's economic well-being.