Devi S J, Robbins J B, Schneerson R
Laboratory of Developmental and Molecular Immunity, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892.
Proc Natl Acad Sci U S A. 1991 Aug 15;88(16):7175-9. doi: 10.1073/pnas.88.16.7175.
Meningitis and other systemic infections caused by group B Neisseria meningitidis and Escherichia coli K1 remain important problems. The capsular polysaccharides (CPs) of these pathogens (poly[(2----8)-alpha-N-acetylneuraminic acid] or poly(alpha 2-8NeuNAc] are identical and are virulence factors and protective antigens for both. CP vaccines for these pathogens are not available because poly(alpha 2-8NeuNAc) alone, as a complex or a conjugate, is poorly immunogenic. Because oligomers of poly(alpha 2-8NeuNAc) in fetal brain and other tissues bind antibodies in vitro, it has been suggested that antibodies to this CP might be pathologic. We synthesized conjugates of this CP with tetanus toxoid under conditions that avoid lactone formation. Using this scheme, we also synthesized conjugates of group C meningococcal CP (poly[(2----9)-alpha-N-acetylneuraminic acid] or poly(alpha 2-9NeuNAc] and of E. coli K92 CP [poly(alpha 2-8, alpha 2-9NeuNAc)]. When injected s.c. in saline into mice, conjugates of poly(alpha 2-8NeuNAc) or poly(alpha 2-9NeuNAc) elicited homologous antibodies. E. coli K92 conjugates elicited both poly(alpha 2-8NeuNAc) and poly(alpha 2-9NeuNAc) antibodies. Both components of the conjugates expressed T-dependent immunologic properties under conditions and dosages acceptable for clinical evaluation. Poly(alpha 2-8NeuNAc) antibodies elicited by the homologous or the K92 conjugates had lower binding activities at 37 degrees C than at 22 degrees C. "Natural" poly(alpha 2-8NeuNAc) antibodies were present in almost all matched pairs of human maternal and cord sera; most cord levels were higher than in corresponding maternal sera. These findings suggest that increased levels of poly(alpha 2-8NeuNAc) IgG antibodies elicited by our conjugates will confer protective immunity to group B meningococci and E. coli K1 and will not be pathologic.
由B群脑膜炎奈瑟菌和大肠杆菌K1引起的脑膜炎及其他全身感染仍然是重要问题。这些病原体的荚膜多糖（CPs）（聚[(2→8)-α-N-乙酰神经氨酸]或聚(α2-8NeuNAc)）是相同的，并且都是毒力因子和保护性抗原。目前尚无针对这些病原体的CP疫苗，因为单独的聚(α2-8NeuNAc)，无论是作为复合物还是偶联物，免疫原性都很差。由于胎儿脑和其他组织中的聚(α2-8NeuNAc)寡聚体在体外能结合抗体，因此有人提出针对这种CP的抗体可能具有致病性。我们在避免内酯形成的条件下合成了这种CP与破伤风类毒素的偶联物。利用该方案，我们还合成了C群脑膜炎球菌CP（聚[(2→9)-α-N-乙酰神经氨酸]或聚(α2-9NeuNAc)）和大肠杆菌K92 CP[聚(α2-8,α2-9NeuNAc)]的偶联物。当将聚(α2-8NeuNAc)或聚(α2-9NeuNAc)的偶联物经皮下注射到盐水中的小鼠体内时，能引发同源抗体。大肠杆菌K92偶联物能引发聚(α2-8NeuNAc)和聚(α2-9NeuNAc)两种抗体。在临床评估可接受的条件和剂量下，偶联物的两种成分均表现出T细胞依赖性免疫特性。同源或K92偶联物引发的聚(α2-8NeuNAc)抗体在37℃时的结合活性低于22℃时的结合活性。几乎所有配对的人类母血和脐血血清中都存在“天然”的聚(α2-8NeuNAc)抗体；大多数脐血中的水平高于相应母血中的水平。这些发现表明，我们的偶联物引发的聚(α2-8NeuNAc) IgG抗体水平升高将赋予对B群脑膜炎球菌和大肠杆菌K1的保护性免疫，且不会具有致病性。
