感染儿童（MARVIC）中记忆B细胞与疫苗抗体应答伴反复感染：一项前瞻性观察性研究方案

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中文摘要

背景： 反复感染是儿科实践中的常见问题，可能促使对潜在先天性免疫缺陷进行评估，尤其是当感染严重、持续、不寻常或反复发生时。反复的鼻窦肺部感染，如肺炎、鼻窦炎和中耳炎，可能提示体液免疫缺陷，因为抗体缺陷是最常见的先天性免疫缺陷之一。实验室检查通常包括测定血清免疫球蛋白（免疫球蛋白G [IgG]、免疫球蛋白A [IgA]和免疫球蛋白M [IgM]）及IgG亚类（IgG1、IgG2、IgG3和IgG4）、评估疫苗特异性抗体应答以及计数B细胞亚群。这些检查共同评估体液免疫的定量和功能组成部分。然而，马来西亚尚未建立这些免疫学参数的儿科参考区间。
目的： 本研究旨在描述马来西亚反复感染儿童的体液免疫参数特征，将这些参数与健康儿童进行比较，并在健康儿科人群中建立年龄特异性参考值。
方法： MARVIC（感染儿童中记忆B细胞与疫苗抗体应答）研究是一项前瞻性观察性比较研究，纳入反复感染儿童和年龄匹配的健康对照，并包含疫苗挑战随访。符合条件的参与者将接受基线评估，使用散射比浊法测定血清免疫球蛋白和IgG亚类浓度，使用流式细胞术测定B细胞亚群，并使用酶联免疫吸附试验测定疫苗特异性抗体应答。随后他们将接种破伤风类毒素和23价肺炎球菌多糖疫苗，并在28至30天后再次采血以评估功能性抗体应答。共同主要结局是反复感染儿童与健康对照之间IgG亚类浓度、疫苗特异性抗体应答和B细胞亚群的组间差异。次要结局是在健康儿童中建立这些免疫学参数的年龄特异性参考区间。
结果： 本研究于2024年12月获得资助，参与者招募和数据收集正在进行中。截至2026年5月，共招募145名参与者，包括60名（41.4%）反复感染儿童和85名（58.6%）健康对照，所有参与者均已完成疫苗接种后随访采样。数据收集和分析预计于2026年12月完成，研究结果预计于2027年5月发表。
结论： 本研究将对马来西亚反复感染儿童的体液免疫特征进行全面评估。研究结果可能改善临床相关抗体缺陷的识别，并支持马来西亚儿科免疫学检查结果的解读。

英文摘要

BACKGROUND: Recurrent infections are a common concern in pediatric practice and may prompt evaluation for an underlying inborn error of immunity, particularly when infections are severe, persistent, unusual, or recurrent. Recurrent sinopulmonary infections such as pneumonia, sinusitis, and otitis media may indicate a humoral immune defect, as antibody deficiencies are among the most common inborn errors of immunity. Laboratory tests typically include measurement of serum immunoglobulins (immunoglobulin G [IgG], immunoglobulin A [IgA], and immunoglobulin M [IgM]) and IgG subclasses (IgG1, IgG2, IgG3, and IgG4), assessment of vaccine-specific antibody responses, and enumeration of B-cell subsets. Together, these tests assess the quantitative and functional components of humoral immunity. However, pediatric reference intervals for these immunological parameters have not been established in Malaysia.
OBJECTIVE: This study aims to characterize humoral immune parameters among Malaysian children with recurrent infections, compare these parameters with those of healthy children, and establish age-specific reference values in a healthy pediatric population.
METHODS: The MARVIC (Memory B Cells and Antibody Responses to Vaccines in Infected Children) study is a prospective observational comparative study incorporating a vaccine challenge follow-up in children with recurrent infections and age-matched healthy controls. Eligible participants will undergo baseline assessment of serum immunoglobulins and IgG subclass concentrations using nephelometry, B-cell subsets using flow cytometry, and vaccine-specific antibody responses using enzyme-linked immunosorbent assays. They will then receive the tetanus toxoid and 23-valent pneumococcal polysaccharide vaccines, followed by repeat blood sampling 28 to 30 days later to evaluate functional antibody responses. The co-primary outcomes are between-group differences in IgG subclass concentrations, vaccine-specific antibody responses, and B-cell subsets between children with recurrent infections and healthy controls. The secondary outcome is the establishment of age-specific reference intervals for these immunological parameters among healthy children.
RESULTS: This study was funded in December 2024, and participant recruitment and data collection are ongoing. As of May 2026, a total of 145 participants had been recruited, comprising 60 (41.4%) children with recurrent infections and 85 (58.6%) healthy controls, all of whom had completed postvaccination follow-up sampling. Data collection and analysis are expected to be completed by December 2026, with publication of the findings anticipated in May 2027.
CONCLUSIONS: This study will provide a comprehensive evaluation of the humoral immune profile of Malaysian children with recurrent infections. The findings may improve the identification of clinically relevant antibody deficiencies and support the interpretation of pediatric immunological investigations in Malaysia.