Bartoloni A, Norelli F, Ceccarini C, Rappuoli R, Costantino P
IRIS, Biocine Research Center, Siena, Italy.
Vaccine. 1995 Apr;13(5):463-70. doi: 10.1016/0264-410x(94)00007-a.
Vaccine development against Group B Neisseria meningitidis is complicated by the nature of the capsular polysaccharide, which is alpha 2-8-linked poly-sialic acid, identical in structure to the poly-sialic acid found in many mammalian tissues during development. To test the feasibility of a vaccine based on this polysaccharide, we synthesized several conjugates of meningococcal B polysaccharide linked to a carrier protein (tetanus toxoid or diphtheria CRM197), via an adipic acid dihydrazide (ADH) spacer. All conjugates induced a strong immune response. However, most of the antibodies were not directed against the Meningococcus B polysaccharide and could not be inhibited by the purified polysaccharide alone. Further investigations showed that the antibodies recognized an epitope composed by the junction between the spacer and the polysaccharide and protein, that is not present in the native polysaccharide and is generated during the coupling reaction. This epitope becomes immunodominant with respect to the poorly immunogenic polysaccharide. While the majority of the immune response is directed against the above epitope, the conjugates induced also an immune response against the Meningococcus B polysaccharide. The anti-Meningococcus B antibodies elicited are of the IgM and IgG class and are inhibitable by the polysaccharide. Moreover, they are bactericidal, thus suggesting that they would induce protection against disease.
针对B群脑膜炎奈瑟菌的疫苗研发因荚膜多糖的性质而变得复杂，该多糖是α2-8连接的聚唾液酸，其结构与许多哺乳动物组织发育过程中发现的聚唾液酸相同。为了测试基于这种多糖的疫苗的可行性，我们通过己二酸二酰肼（ADH）间隔物合成了几种与载体蛋白（破伤风类毒素或白喉CRM197）连接的脑膜炎球菌B多糖缀合物。所有缀合物均诱导了强烈的免疫反应。然而，大多数抗体并非针对B群脑膜炎球菌多糖，且不能仅被纯化的多糖所抑制。进一步研究表明，这些抗体识别的表位由间隔物与多糖及蛋白质之间的连接组成，该表位不存在于天然多糖中，而是在偶联反应过程中产生的。相对于免疫原性较差的多糖而言，这个表位成为了免疫显性表位。虽然大多数免疫反应针对上述表位，但缀合物也诱导了针对B群脑膜炎球菌多糖的免疫反应。所引发的抗B群脑膜炎球菌抗体属于IgM和IgG类别，且可被多糖抑制。此外，它们具有杀菌作用，因此表明它们可诱导对疾病的保护作用。
