Targeted Nanoparticle Vaccine Approach for Protection Against Encapsulated Pathogens

 描述（由申请方提供）：大多数成功的人用疫苗都会引发保护性抗体。CD4+ T细胞辅助对于强抗体应答是必不可少的，特别是针对免疫原性差的多糖抗原。为了实现这一点，多糖抗原通常与高免疫原性T细胞表位缀合。不幸的是，这种方法是昂贵的，只针对一个子集的荚膜多糖抗原，并依赖于等位变异的CD4+ T细胞的帮助。我们和其他人最近发现了一种新的帮助B细胞的来源，可以利用它来克服这些限制，即不变的自然杀伤T（iNKT）细胞。iNKT细胞是一种先天性糖脂特异性T细胞淋巴细胞亚群，局限于非多态性抗原呈递分子CD1d，激活后可快速产生细胞因子。由于CD1d是非多态性的，或者在所有人中都是一样的，所以iNKT细胞对糖脂的反应应该在每个人中都一样好。此外，糖脂对人类是绝对安全的，并且可以用作共同施用的蛋白质和多糖抗原的稳健佐剂，特别是当掺入纳米颗粒中时。纳米颗粒疫苗可以由安全的、充分研究的、可生物降解的聚合物制成，将包封的糖脂佐剂的活性增强1000倍，并且可以包埋有B细胞抗原以促进它们被相关B细胞亚群靶向和摄取。该提案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囊病原体的全身感染。在目的1中，我们将用糖脂加多糖包埋的纳米颗粒接种小鼠，以评估哪种给药途径诱导高滴度的类别转换抗体，并最好地保护免受两种不同的肺炎链球菌感染的体内小鼠模型。在目的2中，我们将使用小鼠来比较可溶性与纳米颗粒包埋的糖脂如何增强由当前人S.肺炎多糖疫苗。我们还将培养人外周血细胞，以测试哪种形式的糖脂佐剂最能增强人多糖特异性B细胞应答。如果成功，这一系列研究将推动广泛适用的iNKT细胞靶向疫苗策略的开发，鉴于CD1d的非多态性，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，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.