Yano Masahide, Pirofski Liise-anne
Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
Clin Vaccine Immunol. 2011 Jan;18(1):59-66. doi: 10.1128/CVI.00368-10. Epub 2010 Nov 10.
Streptococcus pneumoniae is the most common cause of community-acquired pneumonia in the United States and globally. Despite the availability of pneumococcal capsular polysaccharide (PPS) and protein conjugate-based vaccines, the prevalence of antibiotic-resistant pneumococcal strains, serotype (ST) replacement in nonconjugate vaccine strains, and uncertainty as to whether the PPS vaccine that is used in adults protects against pneumonia emphasize the need for continued efforts to understand the nature of protective PPS antibody responses. In this study, we generated mouse monoclonal antibodies (MAbs) to a conjugate consisting of the PPS of serotype 8 (PPS8) S. pneumoniae and tetanus toxoid. Thirteen MAbs, including four IgMs that bound to PPS8 and phosphorylcholine (PC) and five IgMs and four IgG1s that bound to PPS8 but not PC, were produced, and their nucleotide sequences, epitope and fine specificity, and efficacy against lethal challenge with ST8 S. pneumoniae were determined. MAbs that bound to PPS8 exhibited gene use that was distinct from that exhibited by MAbs that bound to PC. Only PPS8-binding MAbs that did not bind PC were protective in mice. All 13 MAbs used germ line variable-region heavy (V(H)) and light (V(L)) chain genes, with no evidence of somatic hypermutation. Our data reveal a relationship between PPS specificity and V(H) gene use and MAb efficacy in mice. These findings provide insight into the relationship between antibody molecular structure and function and hold promise for the development of novel surrogates for pneumococcal vaccine efficacy.
肺炎链球菌是美国及全球社区获得性肺炎最常见的病因。尽管有肺炎球菌荚膜多糖（PPS）和基于蛋白质结合物的疫苗，但耐抗生素肺炎球菌菌株的流行、非结合疫苗菌株中的血清型（ST）替换，以及成人使用的PPS疫苗是否能预防肺炎的不确定性，都凸显了持续努力了解保护性PPS抗体反应本质的必要性。在本研究中，我们制备了针对由8型肺炎链球菌（S. pneumoniae）的PPS（PPS8）与破伤风类毒素组成的结合物的小鼠单克隆抗体（MAb）。产生了13种MAb，包括4种与PPS8和磷酸胆碱（PC）结合的IgM、5种与PPS8但不与PC结合的IgM和4种IgG1，并确定了它们的核苷酸序列、表位和精细特异性，以及对8型肺炎链球菌致死性攻击的效力。与PPS8结合的MAb表现出与与PC结合的MAb不同的基因使用情况。只有不与PC结合的与PPS8结合的MAb在小鼠中具有保护作用。所有13种MAb都使用种系可变区重链（V(H)）和轻链（V(L)）基因，没有体细胞超突变的证据。我们的数据揭示了PPS特异性与V(H)基因使用以及小鼠中MAb效力之间的关系。这些发现为抗体分子结构与功能之间的关系提供了见解，并为开发肺炎球菌疫苗效力的新型替代指标带来了希望。
