Broad spectrum vaccines to enteric fevers in humans: cross protective immunity

最近在智利圣地亚哥进行的2项随机对照田间试验的荟萃分析， 许可的口服伤寒活疫苗Ty 21 a表明，接种不仅可提供针对沙门氏菌的保护， 伤寒症，也可对抗副伤寒B热。本申请的总体目标是研究 免疫机制，可以介导这种交叉保护。拟议的研究将侧重于 研究免疫接种引起的细胞介导免疫（CMI）和Ab应答的阵列是否 的受试者与许可的Ty 21 a伤寒疫苗，以及新的减毒沙门氏菌。伤寒疫苗 可能参与保护的候选者与S.甲型和B型副伤寒抗原。 具体而言，我们建议实现以下具体目标：目标1。测试一个定义的假设， 循环中的CMI反应集在S.伤寒菌株Ty 21 a和S. 人类副伤寒B感染。为此，我们将使用来自用Ty 21 a免疫的受试者的细胞， 评估CMI反应之间是否存在交叉反应性（例如，细胞因子产生，增殖性 反应，细胞毒活性）。伤寒沙门氏菌S.甲型副伤寒和甲型副伤寒副伤寒B。我们假设交叉反应 将主要在S之间观察。伤寒和沙门氏菌。副伤寒B，有轻微交叉反应性（如有） 链球菌甲型副伤寒抗原，Aim 2。评价在Ty 21 a中观察到的CMI反应的假设 显示出S.伤寒和沙门氏菌。还可诱发副伤寒B抗原（Aim 1 通过用新的减毒沙门氏菌口服免疫受试者，伤寒候选疫苗株CVD 908-htrA和 第909章.这些研究将评估用这些新的减毒沙门氏菌免疫的可能性。伤寒 候选疫苗株将产生广谱S.伤寒和沙门氏菌。副伤寒B型（可能还有S型）。 甲型副伤寒）疫苗和Aim 3。评估免疫接种的假设， Ty 21 a和新型减毒S.伤寒候选疫苗株CVD 908-htrA和CVD 909 血清中出现与沙门氏菌常见抗原交叉反应的抗体。伤寒 和S.副伤寒B（例如，鞭毛、OmpC、GroEL、O-多糖表位12）。这些研究将包括 循环抗体分泌细胞（ASC）、记忆B细胞（BM）和针对 常见的沙门氏菌抗原，以及IgA介导的ADCC。这些交叉反应性抗体的存在， ASC和BM细胞表明这些体液反应可能在交叉保护中发挥积极作用。

A recent meta-analysis of 2 randomized, controlled field trials conducted in Santiago, Chile, with the licensed live oral typhoid vaccine Ty21a showed that vaccination not only conferred protection against S. Typhi disease, but also against paratyphoid B fever. The overall goal of this application is to study the immunological mechanisms that could mediate this cross-protection. The proposed studies will focus on investigating whether the array of cell-mediated immunity (CMI) and Ab responses elicited by immunization of subjects with the licensed Ty21 a typhoid vaccine, as well as novel attenuated S. Typhi vaccine candidates, which are likely to be involved in protection, cross-react with S. Paratyphi A and B antigens. Specifically, we propose to address the following Specific Aims: Aim 1. Test the hypothesis that a defined set of CMI responses in circulation play a key role in cross-protection between S. Typhi strain Ty21a and S. Paratyphi B infection in humans. To this end, we will use cells from subjects immunized with Ty21a to evaluate whether there is cross-reactivity between CMI responses (e.g., cytokine production, proliferative responses, cytotoxic activity) to S. Typhi, S. Paratyphi A and S. Paratyphi B. We hypothesize that crossreactivity will be chiefly observed between S. Typhi and S. Paratyphi B, with minor, if any, cross-reactivity with S. Paratyphi A antigens, Aim 2. Evaluate the hypothesis that the CMI responses observed in Ty21a vaccinees that show cross-reactivity between S. Typhi and S. Paratyphi B antigens (Aim 1) are also elicited by oral immunization of subjects with novel attenuated S. Typhi candidate vaccine strains CVD 908-htrA and CVD 909. These studies will assess the likelihood that immunization with these novel attenuated S. Typhi candidate vaccine strains will result in a broad-spectrum S. Typhi and S. Paratyphi B (and perhaps S. Paratyphi A) vaccine against enteric fevers, and Aim 3. Evaluate the hypothesis that immunization of subjects with Ty21a and novel attenuated S. Typhi candidate vaccine strains CVD 908-htrA and CVD 909 elicits the appearance in serum ofAb that cross-react to Salmonella common antigens present in S. Typhi and S. Paratyphi B (e.g., flagella, OmpC, GroEL, O-polysaccharide epitope 12). These studies will include the measurement of circulating antibody secreting cells (ASC), memory B cells (BM) and Ab directed to common Salmonella antigens, as well as IgA-mediated ADCC. The presence of these cross-reactive Ab, ASC and BM cells will suggest that these humoral responses might play an active role in cross-protection.