Impact of a new group 6 serotype on pneumococcal vaccines

描述（由申请方提供）：肺炎球菌，包括具有6A或6B型荚膜多糖（PS）的肺炎球菌，是重要的人类病原体。6A和6B血清型产生结构相似但血清学上不同的荚膜PS。我们发现了6A血清型（命名为6A？（6A）？用单克隆抗体和发现的等位基因wciN（命名为wciN？和wciN？），一个假定的荚膜糖基转移酶基因位点。6A？代表经典的6A，并且似乎具有wciN？。虽然比6Aa菌株更不常见，但6A？菌株在世界范围内发现，可能是致病性的，并且似乎具有wciN？。此外，目前的肺炎球菌疫苗，其中含有6B？PS，似乎引发交叉调理抗体6A？但不是6A。(We用wciN？而WCIN？如6B？6B？分别6B？未观察到菌株）。从6A开始？可能能够避免疫苗诱导的宿主免疫，6A？菌株可能取代6Aa菌株，继续使用疫苗，导致疫苗效力降低。为了研究这种可能性，我们假设血清组6有两个新的血清型（6A？（6B）？与wciN有关联吗等位基因，新的血清型产生新的荚膜PS，目前的肺炎球菌疫苗覆盖不足，并可能随着疫苗的使用而增加患病率。为了检验我们的假设，我们将：（A）研究wciN的作用？6A上的等位基因6B？通过测定6A？荚膜基因位点的DNA序列进行血清型鉴定，通过替换wciN 6Aa等位基因与wciN？等位基因6A？，并阐明了6A？PS和生化分析。(B)评价肺炎球菌疫苗诱导能够调理6A？的抗体的能力，6A？6B？6B？血清型中老年人和幼儿，并评估6A？PS的能力，引发调理抗体的四种血清型。(C)研究肺炎球菌疫苗接种对6A？亚型，通过确定6A？在临床使用7价结合疫苗之前和之后在世界各地获得的分离株。我们的研究兴趣一直是肺炎球菌疫苗诱导的交叉保护的研究。在上一个资助期，我们预测疫苗可能不会对某些血清型产生交叉保护。在我们发现6A的基础上？血清型，我们将研究未识别的血清型对疫苗诱导的交叉保护的影响。我们的研究将增加对肺炎球菌疫苗接种后血清型变化和替代的理解，这是一种重要的国家卫生保健工具。此外，我们的研究6A？应该产生一个优雅的模型，显示新出现的病原体如何出现，传播和对宿主免疫力改变的反应。

DESCRIPTION (provided by applicant): Pneumococci, including those with capsular polysaccharides (PSs) of types 6A or 6B are significant human pathogens. 6A and 6B serotypes produce structurally similar but serologically distinct capsular PSs. We discovered subtypes within 6A serotype (named 6A? and 6A?) with monoclonal antibodies and discovered alleles of wciN (named wciN? and wciN?), a putative glycosyl transferase in capsule gene locus. 6A? represents the classical 6A and appears to have wciN?. Although less common than 6Aa strains, 6A? strains are found worldwide, can be pathogenic, and appear to have wciN?. Further, current pneumococcal vaccines, which contain 6B? PS, appear to elicit cross-opsonic antibodies to 6A? regularly but not to 6A?. (We labeled the 6B strains with wciN? and wciN? as 6B? and 6B?, respectively. 6B? strains have not been observed.) Since 6A? may be able to avoid vaccine-induced host immunity, 6A? strains may replace 6Aa strains with continued vaccine use with resulting reduction in vaccine efficacy. To investigate this potential, we hypothesize that serogroup 6 has two new serotypes (6A? and 6B?) associated with the wciN? allele and that the new serotypes produce new capsular PSs, are poorly covered by current pneumococcal vaccines, and may increase in prevalence with vaccine use. To examine our hypothesis, we will: (A) Study the role of the wciN? allele on the 6A? and 6B? serotypes by determining the DNA sequence of the capsule gene locus of 6A?, by replacing the wciN? allele of 6Aa with the wciN? allele of 6A?, and by elucidating the molecular structure of 6A? PS with biochemical analyses. (B) Evaluate pneumococcal vaccines for their abilities to elicit antibodies capable of opsonizing the 6A?, 6A?, 6B?, and 6B? serotypes among elderly adults and young children, and evaluate 6A? PS for its ability to elicit opsonic antibodies to the four serotypes. (C) Study the effect of pneumococcal vaccination on the 6A? subtype by determining the prevalence and evolutionary relationship of 6A? isolates obtained in various parts of the world before and after clinical use of a 7-valent conjugate vaccine. Our research interest has been the study of cross-protection induced by pneumococcal vaccines. In the last funding period, we predicted vaccines may not elicit cross-protection to some serotypes. Building on our discovering the 6A? serotype, we will investigate the effect of unrecognized serotypes on vaccine-induced cross-protection. Our study will increase the understanding of the serotype shifts and replacements that follow pneumococcal vaccination, an important national health care tool. Also, our studies of 6A? should yield an elegant model showing how an emerging pathogen can appear, spread, and react to altered host immunity.