Channing Laboratory, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
Nat Med. 2011 Nov 20;17(12):1602-9. doi: 10.1038/nm.2535.
Glycoconjugate vaccines have provided enormous health benefits globally, but they have been less successful in some populations at high risk for developing disease. To identify new approaches to enhancing glycoconjugate effectiveness, we investigated molecular and cellular mechanisms governing the immune response to a prototypical glycoconjugate vaccine. We found that in antigen-presenting cells a carbohydrate epitope is generated upon endolysosomal processing of group B streptococcal type III polysaccharide coupled to a carrier protein. In conjunction with a carrier protein-derived peptide, this carbohydrate epitope binds major histocompatibility class II (MHCII) and stimulates carbohydrate-specific CD4(+) T cell clones to produce interleukins 2 and 4-cytokines essential for providing T cell help to antibody-producing B cells. An archetypical glycoconjugate vaccine that we constructed to maximize the presentation of carbohydrate-specific T cell epitopes is 50-100 times more potent and substantially more protective in a neonatal mouse model of group B Streptococcus infection than a vaccine constructed by methods currently used by the vaccine industry. Our discovery of how glycoconjugates are processed resulting in presentation of carbohydrate epitopes that stimulate CD4(+) T cells has key implications for glycoconjugate vaccine design that could result in greatly enhanced vaccine efficacy.
糖缀合物疫苗在全球范围内带来了巨大的健康益处，但在某些疾病高发人群中的效果却不尽如人意。为了寻找增强糖缀合物效果的新方法，我们研究了控制针对典型糖缀合物疫苗的免疫反应的分子和细胞机制。我们发现，在抗原呈递细胞中，B 族链球菌 III 型多糖与载体蛋白偶联后，在内体溶酶体处理过程中会产生一个碳水化合物表位。与载体蛋白衍生的肽结合后，该碳水化合物表位与主要组织相容性复合体 II（MHCII）结合，并刺激碳水化合物特异性 CD4+T 细胞克隆产生白细胞介素 2 和 4——这些细胞因子对于为产生抗体的 B 细胞提供 T 细胞帮助至关重要。我们构建的一种典型糖缀合物疫苗，通过最大限度地展示碳水化合物特异性 T 细胞表位，其在 B 族链球菌感染的新生小鼠模型中的效力比目前疫苗行业使用的方法构建的疫苗高 50-100 倍，且具有更好的保护作用。我们发现了糖缀合物是如何被加工以呈现刺激 CD4+T 细胞的碳水化合物表位的，这对糖缀合物疫苗设计具有重要意义，可能会极大地增强疫苗的效果。
