Protecutive immunity to human cholera in Bangladesh

描述(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。霍乱弧菌可引起人类严重的分泌性腹泻，是一种典型的不侵犯肠道上皮的粘膜感染，因此霍乱弧菌感染是研究粘膜免疫和疫苗接种的良好模型。不幸的是，霍乱后的保护性免疫目前尚不清楚，现有的霍乱疫苗要么不能产生充分的保护效果，要么在接种疫苗后6-36个月内诱导不太理想和相对短暂的免疫反应，降至基线水平。这与自然感染霍乱弧菌相比，后者可诱导持续3-10年的保护性免疫。血清杀弧菌和其他血清抗体反应在感染后6-12个月内减弱，表明这些现有的免疫标志物不能用作长期保护性免疫的相关因素。我们有数据表明，记忆B细胞对T依赖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非依赖抗原LPS的反应在霍乱后发展，但似乎在感染后9-12个月减弱。我们有更多的初步证据表明霍乱弧菌感染后存在CD4+T辅助细胞反应，我们假设这种反应对于粘膜表面B细胞记忆的发展和维持是必要的，T细胞反应在自然感染和霍乱疫苗接种之间可能在质量或数量上有所不同，这些差异可能解释了目前霍乱和其他黏膜感染疫苗效果较差的原因。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，重点是记忆性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)样本来评估霍乱后的粘膜先天性和获得性免疫反应，并与血液中的反应相关联；(3)评估接触家庭后早期的先天和获得性免疫反应，以确定随后对霍乱的保护性免疫的相关性；(4)评估目前灭活的RBS-WC霍乱口服疫苗接种霍乱疫苗后的免疫反应(与正在进行的和单独资助的霍乱疫苗研究协同作用)，并比较与自然霍乱疫苗接种后的反应；以及(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的研究人员正在进行的合作努力的基础上的。 相关性：全球每年有500-700万人感染霍乱，导致10万多人死亡。霍乱保护性免疫的鉴定不仅可以直接影响霍乱疫苗的接种策略，而且可以应用于针对其他黏膜病原体的改良疫苗的开发。

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.