A killed whole-cell one dose cholera vaccine

灭活全细胞单剂霍乱疫苗

• 批准号: 9105678
• 负责人: WILLIAM Franklin WADE
• 金额: $ 24.3万
• 依托单位: DARTMOUTH COLLEGE
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-06 至 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9105678
• 关键词: Address; Adjuvant; Antibodies; Antibody-mediated protection; Antigens; Area; B-Lymphocytes; Biological Markers; Bone Marrow; Cells; Child; Chitosan; Cholera; Cholera Vaccine; Data; Development; Disease; Dose; Elements; Environment; Epidemic; Epithelium; Exudate; Flushield; Goals; Gram-Negative Bacteria; Haiti; Health; Home environment; Human; Immune; Immune Tolerance; Immune response; Immune system; Immunity; Immunization; Immunoglobulin A; Immunoglobulin G; Immunoglobulin M; Immunologics; Individual; Infant; Infection; Inflammation; Licensing; Life; Lymphoid Tissue; Maintenance; Memory B-Lymphocyte; Mucosal Immunity; Mucous Membrane; Mus; Nasal Epithelium; Neonatal; Nose; Nutritional status; Oral; Pakistan; Pathogenesis; Plasma Cells; Plasmablast; Process; Proteins; Protocols documentation; Research Design; Serum; Signal Transduction; Structure of mucous membrane of nose; Temperature; Testing; Vaccination; Vaccines; Vibrio cholerae; Virulent; Work; age group; aged; base; colonization factor antigens; efficacy testing; experience; immunogenic; influenza virus vaccine; killings; nanoparticle; novel; pre-clinical; protective efficacy; response; vaccine development

 DESCRIPTION (provided by applicant): Vibrio cholerae (Vc), a Gram negative bacterium that has caused over 200 years of cholera that is both an ep- idemic and endemic diarrheal disease. Endemics in Pakistan (ancient home of cholera) and epidemics in Haiti (new home of cholera) underscore the unresolved issue how to control cholera. One aspect of control in the short term is a universal vaccine. The main challenges of a universal cholera vaccine are to provide fast im- munity (˜7 days) with the longest duration using the minimal number of doses to immunize the Vc antigen (Ag) immunologically naïve or young children (2-5 years) living in endemic cholera areas. The current oral cholera vaccines (OCV) recommended by the WHO do not accomplish this in young children to a high or consistent degree. A novel experimental cholera vaccine formulation, based in part on the OCV inoculum will be tested for its ability to provide cholera immunity with one intranasal (i.n.) dose. The new additions to the existing OCV formulation are 3 proven, protective Vc Ags (TcpA, TcpF and CBP-1) that are critical for cholera pathogenesis. We showed that TcpA and TcpF were able to induce immunity after one dose. The addition of these proteins, as well as CBP-A (a less robust protective Ag) will add to the protective Ags that are part of the immunogen profile of OCV. These Ags will be targeted to the mucosal epithelia by chitosan nanoparticles (Chitnp) a pro- cess which should also optimize priming of B cells. We will also use the powerful mucosal adjuvant CT. A new CT-based adjuvants (CC-TD) is being tested in preclinical human immunization protocols. CT and other normative elements of a cholera infection are associated with better sero-conversion of young children to Vc LPS, so it makes sense to see if more Ag (associated with infection), provided in better quantity to the areas of mucosal priming with the correct attending co-stimulations signals can change an OCV into a one dose vac- cine. The hypothesis we will test is whether `maximal' induction of immunity by a reformulated, killed whole-cell (kW-C) cholera vaccine can stimulate enough protective antibody (Ab) to provide protection against cholera with just one dose. Cholera immunity is already in decline in the first year after vaccination and continues to essentially no immunity in year three for young children immunized with the Shanchol, the most widely used OCV. The long term goal for this novel OCV formulation that features 3 protective protein Ags is, the induction of broader B cell memory (a biomarker of protection against cholera) that will endure for at least 3years and perhaps longer in young children who are well known to respond to vaccine protein Ags better than vaccine-associated LPS Ags.

 描述（由申请人提供）：霍乱弧菌（Vc），一种革兰氏阴性细菌，引起霍乱超过200年，霍乱是一种流行性和地方性霍乱疾病。巴基斯坦的地方病（霍乱的古老家园）和海地的流行病（霍乱的新家园）突出了如何控制霍乱的未决问题。短期控制的一个方面是通用疫苗。通用霍乱疫苗的主要挑战是使用最少的剂量数提供最长持续时间的快速免疫（10 - 7天），以免疫Vc抗原（Ag）免疫初治儿童或生活在霍乱流行区的幼儿（2-5岁）。目前世界卫生组织推荐的口服霍乱疫苗（OCV）在幼儿中不能达到很高或一致的程度。将测试部分基于OCV接种物的新型实验性霍乱疫苗制剂用一种鼻内（i.n.）次给药结束现有OCV配方中新添加了3种经过验证的保护性Vc Ags（TcpA、TcpF和CBP-1），它们对霍乱发病机制至关重要。我们发现TcpA和TcpF能够在一次剂量后诱导免疫。添加这些蛋白质以及CBP-A（一种不太稳健的保护性Ag）将增加作为OCV免疫原谱一部分的保护性Ag。这些Ag将通过壳聚糖纳米颗粒（Chitnp）靶向粘膜上皮，该过程也应该优化B细胞的引发。我们还将使用强有力的粘膜辅助CT。一种新型基于CT的佐剂（CC-TD）正在临床前人类免疫方案中进行测试。霍乱感染的CT和其他标准要素与幼儿对Vc LPS的更好血清转化相关，因此观察更多Ag（与感染相关）是否有意义，以更好的量提供给具有正确的参与共刺激信号的粘膜引发区域，可以将OCV改变为单剂量疫苗。我们将检验的假设是，重新配制的灭活全细胞（kW-C）霍乱疫苗是否能“最大限度”诱导免疫，从而刺激足够的保护性抗体（Ab），仅用一剂疫苗就能提供抗霍乱的保护。霍乱免疫力在接种疫苗后的第一年已经下降，在接种最广泛使用的OCV-Shanchol疫苗的幼儿中，第三年基本上没有免疫力。这种具有3种保护性蛋白Ag的新型OCV制剂的长期目标是，诱导更广泛的B细胞记忆（保护免受霍乱的生物标志物），该记忆在幼儿中将持续至少3年或更长时间，众所周知，幼儿对疫苗蛋白Ag的反应优于疫苗相关LPS Ag。