Protecutive immunity to human cholera in Bangladesh

描述（由申请人提供）：腹泻病是全球五岁以下儿童死亡的第二大常见原因，感染性腹泻是全球发病率的第二大原因。霍乱弧菌在人类中引起严重的分泌性腹泻，并且是一种不侵入肠上皮的典型粘膜感染;因此，霍乱弧菌感染作为研究粘膜免疫和疫苗接种的极好模型。不幸的是，霍乱后的保护性免疫目前还不清楚，现有的霍乱疫苗要么不能产生完全的保护效力，要么诱导低于最佳和相对短暂的免疫应答，在接种疫苗后6-36个月内降至基线。这与自然感染霍乱弧菌相比，霍乱弧菌诱导持续3-10年的保护性免疫。血清杀弧菌和其他血清抗体应答在感染后6-12个月内减弱，表明这些目前的免疫学标志物不能用作长期保护性免疫的相关物。我们有数据表明，记忆B细胞对T依赖性蛋白抗原的反应在霍乱弧菌感染后发展，并持续至少一年，而记忆B细胞对T非依赖性抗原LPS的反应在霍乱后发展，但在感染后9-12个月似乎减弱。我们有额外的初步证据表明，霍乱弧菌感染后存在CD 4 + T辅助细胞应答，我们假设这种应答对于粘膜表面B细胞记忆的发展和维持是必要的，自然感染和霍乱疫苗接种之间的T细胞应答可能在质或量上不同，这些差异可能解释了目前霍乱和其他粘膜感染疫苗效力的降低。为了解决这些问题，我们提出了五个具体目标：（1）表征自然霍乱后血液中的免疫反应，重点是记忆B细胞和T细胞反应的发展和维持;（2）使用内窥镜获得的十二指肠（EGD）样本评估霍乱后粘膜的先天性和获得性免疫反应，并与血液中观察到的反应相关联;（3）评估家庭接触者接触霍乱后的早期先天和后天免疫反应，以确定随后对霍乱的保护性免疫的相关性;（4）评估用目前的灭活口服rBS-WC霍乱疫苗接种霍乱疫苗后的免疫应答（5）评估影响霍乱易感性和免疫反应的宿主因素。这项建议是建立在马萨诸塞州总医院-哈佛大学和孟加拉国达卡的ICDDR，B的研究人员之间正在进行的合作努力的基础上。 相关性：霍乱每年影响500万至700万人，在全球范围内造成10万多人死亡。确定针对霍乱的保护性免疫不仅可以直接影响霍乱疫苗接种策略，而且可以适用于针对其他粘膜病原体的改进疫苗的开发。

DESCRIPTION (provided by applicant): Diarrheal disease is the second most common cause of death among children under five years of age globally, and infectious diarrhea is the second leading cause of global morbidity. Vibrio cholerae causes severe secretory diarrhea in humans, and is a prototypical mucosal infection that does not invade the intestinal epithelium; V. cholerae infection thus serves as an excellent model for the study of mucosal immunity and vaccination. Unfortunately, protective immunity following cholera is not currently understood, and available cholera vaccines either fail to produce full protective efficacy or induce less than optimal and relatively short-lived immune responses that fall to baseline within 6-36 months of vaccination. This is in comparison to natural infection with V. cholerae that induces protective immunity that lasts for 3-10 years. Serum vibriocidal and other serum antibody responses wane within 6-12 months of infection, suggesting that these current immunologic markers cannot be used as correlates of longer-term protective immunity. We have data to suggest that memory B cell responses to T-dependent protein antigens develop following V. cholerae infection and persist for at least one year, while memory B cell responses to a T-independent antigen, LPS, develop following cholera, but appear to wane by 9-12 months following infection. We have additional preliminary evidence of a CD4+ T helper cell response following V. cholerae infection, and we hypothesize that this response is necessary for the development and maintenance of B cell memory at the mucosal surface, that the T cell response may be qualitatively or quantitatively different between natural infection and cholera vaccination, and that these differences may explain the lessened efficacy of current vaccines for cholera and other mucosal infections. To address these questions, we propose five specific aims: (1) Characterize immune responses in blood following natural cholera, focusing on development and maintenance of memory B cell and T cell responses; (2) Evaluate mucosal innate and acquired immune responses following cholera using endoscopically obtained duodenal (EGD) samples, and correlate with responses seen in blood; (3) Assess innate and acquired immune responses early after exposure in household contacts to determine correlates of subsequent protective immunity to cholera; (4) Assess immune responses following cholera vaccination with the current killed oral rBS-WC cholera vaccine (synergizing with an on-going and separately funded cholera vaccine study), and compare responses to those following natural cholera; and (5) Evaluate host factors influencing susceptibility and immune responses to cholera. This proposal is built upon an on-going collaborative effort between researchers at the Massachusetts General Hospital-Harvard University and the ICDDR,B in Dhaka, Bangladesh. RELEVANCE: Cholera affects 5-7 million individuals each year, killing over 100,000, globally. Identification of protective immunity against cholera could not only directly affect cholera vaccination strategies, but could be applicable to the development of improved vaccines against other mucosal pathogens.