Randall Arlo Z, Conti Valentino, Nakakana Usman, Liang Xiaowu, Teng Andy A, Di Pasquale Antonio Lorenzo, Kapulu Melissa, Frenck Robert, Launay Odile, Ferruzzi Pietro, Sciré Antonella Silvia, Marchetti Elisa, Obiero Christina, Pablo Jozelyn V, Edgar Joshua, Bejon Philip, Shandling Adam D, Campo Joseph J, Yee Angela, Martin Laura B, Podda Audino, Micoli Francesca
Antigen Discovery, Inc. (ADI), Irvine, California, USA.
GSK Vaccines Institute for Global Health, Siena, Italy.
mSphere. 2025 May 27;10(5):e0105724. doi: 10.1128/msphere.01057-24. Epub 2025 Apr 16.
is a leading cause of diarrheal morbidity and mortality in young children from low- and middle-income countries. Here, we aimed to verify the ability of the generalized modules for membrane antigens (GMMA)-based candidate vaccine 1790GAHB to elicit an anti-protein antibody response. Serum samples from previous clinical trials in adults (a dose-escalation study and its extension in France, a vaccine efficacy study after human challenge in the United States, and a study in Kenya) were investigated using pan-proteome microarrays consisting of 3,150 full-length or fragmented proteins. Pre-/post-vaccination comparisons identified subsets of proteins that were highly immunoreactive and largely overlapped across all trials; the T3SS lipochaperone family protein (expressed on GMMA) was the most reactive in all studies. Responses to several microarray antigens correlated well with LPS serum IgG antibody levels. Overall, we confirmed the ability of GMMA to elicit an anti-protein IgG/IgA response; however, no association with protection against shigellosis was identified. In the challenge study, IgG response to seven antigens (IpaC, IpaB, IpaA, IpaD, IpaH, IpgC, and MxiD; not expressed on GMMA) was associated with a decreased risk of shigellosis. These antigens were observed to also have high IgG responses at baseline in individuals naturally exposed to and could constitute targets for future vaccine development.IMPORTANCE remains a major cause of diarrheal disease, especially in children aged under 5 years from low-to-middle-income countries. No vaccine against shigellosis is yet widely available despite the high public health need. An ideal vaccine would provide protection against the most prevalent species, and ; therefore, it could be relevant to identify common antigens. We developed a microarray containing 3,150 full-length or fragmented proteins selected across species. Sera collected in four clinical trials conducted in three countries of varying endemicity to evaluate a GMMA-based candidate vaccine were tested against these proteins. We identified several proteins (IpaC, IpaB, IpaA, IpaD, IpaH, IpgC, MxiD) that induced robust antibody response following experimental challenge or natural infection. These proteins correlated with a reduced risk of shigellosis after the challenge. We found no apparent role for anti-GMMA proteins' IgG or IgA response in protection against shigellosis.
在低收入和中等收入国家，是幼儿腹泻发病率和死亡率的主要原因。在此，我们旨在验证基于膜抗原通用模块（GMMA）的候选疫苗1790GAHB引发抗蛋白抗体反应的能力。使用由3150种全长或片段化蛋白质组成的全蛋白质组微阵列，对先前在成人中进行的临床试验（法国的剂量递增研究及其扩展、美国人体激发后的疫苗效力研究以及肯尼亚的一项研究）的血清样本进行了调查。接种疫苗前后的比较确定了在所有试验中具有高免疫反应性且大部分重叠的蛋白质亚组；T3SS脂伴侣蛋白家族（在GMMA上表达）在所有研究中反应性最强。对几种微阵列抗原的反应与LPS血清IgG抗体水平密切相关。总体而言，我们证实了GMMA引发抗蛋白IgG/IgA反应的能力；然而，未发现与预防志贺氏菌病的保护作用相关联。在激发研究中，对七种抗原（IpaC、IpaB、IpaA、IpaD、IpaH、IpgC和MxiD；不在GMMA上表达）的IgG反应与志贺氏菌病风险降低相关。观察到这些抗原在自然暴露个体的基线时也有高IgG反应，并且可能构成未来疫苗开发的靶点。重要性仍然是腹泻病的主要原因，特别是在低收入至中等收入国家5岁以下的儿童中。尽管有很高的公共卫生需求，但尚无针对志贺氏菌病的疫苗广泛可用。理想的疫苗应能预防最常见的菌种，因此，识别共同抗原可能是有意义的。我们开发了一种微阵列，包含从多种菌种中选择的3150种全长或片段化蛋白质。在三个不同地方性流行程度的国家进行的四项临床试验中收集的血清，针对这些蛋白质进行了检测，以评估一种基于GMMA的候选疫苗。我们鉴定了几种蛋白质（IpaC、IpaB、IpaA、IpaD、IpaH、IpgC、MxiD），它们在实验激发或自然感染后诱导了强烈的抗体反应。这些蛋白质与激发后志贺氏菌病风险降低相关。我们发现抗GMMA蛋白的IgG或IgA反应在预防志贺氏菌病中没有明显作用。
