Hatano K, Pier G B
Channing Laboratory, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115-5804, USA.
Infect Immun. 1998 Aug;66(8):3719-26. doi: 10.1128/IAI.66.8.3719-3726.1998.
The O antigen of the Pseudomonas aeruginosa lipopolysaccharide is the optimal target for protective antibodies, but the unusual and complex nature of their sugar substituents has made it difficult to define the range of these structures needed in an effective vaccine. Most clinical isolates of P. aeruginosa can be classified into 10 O-antigen serogroups, but slight chemical differences among O polysaccharides within a serogroup give rise to subtype epitopes. These epitopes could impact the reactivity of O-antigen-specific antibodies, as well as the susceptibility of a target strain to protective, opsonic antibodies. To define parameters of serogroup and subtype-epitope immunogenicity, antigenicity, and surface expression on P. aeruginosa cells, we prepared high-molecular-weight O-polysaccharide vaccines from strains of P. aeruginosa serogroup O2, for which eight structurally variant O antigens expressing six defined subtype epitopes (O2a to O2f) have been identified. A complex pattern of immune responses to these antigens was observed following vaccination of mice. The high-molecular-weight O polysaccharides were generally more immunogenic at low doses (1 and 10 microg) than at a high dose (50 microg) and usually elicited antibodies that opsonized the homologous strain for phagocytic killing. Some of the individual polysaccharides elicited cross-opsonic antibodies to a variable number of strains that express all of the defined serogroup O2 subtype epitopes. Combination into one vaccine of two antigens that individually elicited cross-reactive opsonic antibodies to most members of the O2 serogroup inhibited, instead of enhanced, the production of antibodies broadly reactive with most serogroup O2 subtype strains. Thus, immune responses to P. aeruginosa O antigens may be restricted to a limited range of epitopes on structurally complex O antigens, and combining multiple related antigens into a single vaccine formulation may inhibit the production of those antibodies best able to protect against most P. aeruginosa strains within a given O-antigen serogroup.
铜绿假单胞菌脂多糖的O抗原是保护性抗体的最佳靶点，但其糖取代基的异常和复杂性质使得难以确定有效疫苗所需的这些结构范围。大多数铜绿假单胞菌临床分离株可分为10个O抗原血清群，但血清群内O多糖之间的细微化学差异会产生亚型表位。这些表位可能影响O抗原特异性抗体的反应性，以及靶菌株对保护性调理素抗体的敏感性。为了确定血清群和亚型表位免疫原性、抗原性以及在铜绿假单胞菌细胞上的表面表达参数，我们从铜绿假单胞菌血清群O2的菌株制备了高分子量O多糖疫苗，已鉴定出该血清群有8种结构变异的O抗原，表达6种确定的亚型表位（O2a至O2f）。给小鼠接种疫苗后，观察到对这些抗原的免疫反应模式复杂。高分子量O多糖通常在低剂量（1和10微克）时比高剂量（50微克）时更具免疫原性，并且通常会引发能调理同源菌株进行吞噬杀伤的抗体。一些单个多糖引发了针对可变数量表达所有确定的血清群O2亚型表位菌株的交叉调理抗体。将两种分别引发对O2血清群大多数成员产生交叉反应性调理抗体的抗原组合成一种疫苗，反而抑制了而不是增强了与大多数血清群O2亚型菌株广泛反应的抗体的产生。因此，对铜绿假单胞菌O抗原的免疫反应可能局限于结构复杂的O抗原上有限范围的表位，并且将多种相关抗原组合成单一疫苗制剂可能会抑制那些最能抵御给定O抗原血清群内大多数铜绿假单胞菌菌株的抗体的产生。
