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， 获得许可的口服伤寒活疫苗Ty21a表明，接种疫苗不仅对沙门氏菌有保护作用。 伤寒，还能对抗副伤寒B热。这个应用程序的总体目标是研究 可以调节这种交叉保护的免疫机制。拟议的研究将集中于 研究细胞免疫(CMI)和抗体反应阵列是否由免疫引起 使用获得许可的伤寒A型疫苗以及新型伤寒减毒疫苗的受试者 候选甲型副伤寒沙门氏菌与甲型副伤寒沙门氏菌和甲型副伤寒沙门氏菌B抗原发生交叉反应。 具体地说，我们建议解决以下具体目标：目标1.测试定义的 循环中的一组CMI应答在伤寒沙门氏菌Ty21a株与S. 人类感染乙型副伤寒。为此，我们将使用来自Ty21a免疫受试者的细胞来 评估CMI反应之间是否存在交叉反应(例如，细胞因子产生、增殖 对伤寒沙门氏菌、甲型副伤寒沙门氏菌和乙型副伤寒沙门氏菌的反应)。我们假设这种交叉反应 将主要在伤寒沙门氏菌和副伤寒沙门氏菌B之间观察到，如果有交叉反应的话，也是很少的 使用副伤寒沙门氏菌A抗原，目的2.评估在Ty21a中观察到的CMI反应的假设 表现出伤寒沙门氏菌和副伤寒沙门氏菌B抗原(目标1)交叉反应的疫苗接种者也会被激发。 通过口服接种新型伤寒沙门氏菌候选减毒株CVD908-htrA和 CVD909。这些研究将评估这些新型减毒伤寒沙门氏菌免疫的可能性 候选疫苗株将导致广谱伤寒沙门氏菌和副伤寒沙门氏菌B(可能还有S。 甲型副伤寒)疫苗，以及目标3.评估甲型副伤寒疫苗免疫的假设 Ty21a和新型伤寒沙门氏菌候选减毒疫苗株CVD908-htrA和CVD909的研究对象 在血清中出现与伤寒沙门氏菌常见抗原交叉反应的OFAB 和副伤寒沙门氏菌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)和抗体的检测 常见的沙门氏菌抗原，以及IgA介导的ADCC。这些交叉反应抗体的存在， ASC和BM细胞将提示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.