Impact of a new group 6 serotype on pneumococcal vaccines

新的 6 组血清型对肺炎球菌疫苗的影响

• 批准号: 7914795
• 负责人: Moon H. Nahm
• 金额: $ 1.3万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-01 至 2010-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7914795
• 关键词: Adult; Alleles; Antibodies; Base Sequence; Biochemical; Chemicals; Child; Clinical; Code; Complement component C1s; Conjugate Vaccines; DNA Sequence; Elderly; Funding; Galactose; Genes; Healthcare; Human; Immunity; Label; Mass Fragmentography; Measures; Modeling; Molecular Structure; Monoclonal Antibodies; Monosaccharides; Moods; Mutation; Names; Pneumococcal conjugate vaccine; Pneumococcal vaccine; Polysaccharides; Population; Prevalence; Reporting; Research; Research Personnel; Rhamnose; Ribitol; Role; Serotyping; Serum; South Africa; Streptococcus pneumoniae; Transferase; Transferase Gene; Vaccination; Vaccines; capsule; interest; pathogen; programs; tool; vaccine efficacy; young adult

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.

描述（由申请人提供）：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不同的荚膜PS。我们用单克隆抗体发现了 6A 血清型内的亚型（命名为 6A？和 6A？），并发现了 wciN 的等位基因（命名为 wciN？和 wciN？），这是荚膜基因座中的一种假定的糖基转移酶。 6A？代表经典的 6A 并且似乎有 wciN?。虽然不如 6Aa 菌株常见，但 6A?该菌株在世界各地都有发现，可能具有致病性，并且似乎具有 wciN?。此外，目前的肺炎球菌疫苗，其中含有6B？ PS，似乎会引发针对 6A 的交叉调理抗体？定期但不到6A？ （我们将带有wciN？和wciN？的6B菌株分别标记为6B？和6B？。尚未观察到6B？菌株。）由于6A？也许能够避免疫苗引起的宿主免疫，6A？继续使用疫苗可能会取代 6Aa 菌株，从而导致疫苗功效降低。为了研究这种潜力，我们假设血清组 6 有两种与 wciN? 相关的新血清型（6A？和 6B？）。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很难覆盖，并且可能会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？和6B？通过确定 6A? 荚膜基因座的 DNA 序列，通过替换 wciN? 来确定血清型。 6Aa 的等位基因与 wciN？ 6A？的等位基因，并通过阐明6A？的分子结构PS 与生化分析。 (B) 评估肺炎球菌疫苗引发能够调理 6A?、6A?、6B? 和 6B? 的抗体的能力。老年人和幼儿的血清型，并评估6A？ PS 因其能够引发针对四种血清型的调理性抗体。 (C) 研究肺炎球菌疫苗接种对 6A 的影响？通过确定6A的流行程度和进化关系来确定亚型？临床使用七价结合疫苗之前和之后在世界各地获得的分离株。我们的研究兴趣是肺炎球菌疫苗诱导的交叉保护的研究。在上一个资助期间，我们预测疫苗可能不会对某些血清型产生交叉保护。以我们发现 6A 为基础？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。我们的研究将增进对肺炎球菌疫苗接种（一种重要的国家医疗保健工具）后血清型转变和替代的了解。还有，我们对6A的研究？应该产生一个优雅的模型，展示新出现的病原体如何出现、传播以及如何对改变的宿主免疫力做出反应。