Data Sheet 2_Measles-mumps-rubella-vaccination at 6 months of age induces measles-specific T cell responses: a randomized controlled trial.docx

BackgroundMeasles is a highly contagious viral disease, particularly severe in infants. Protection in early life is provided by maternally transferred antibodies, but this period is shorter in infants of previously vaccinated mothers (PVMs) compared to infants of previously measles-infected mothers (PIMs). Earlier measles-mumps-rubella (MMR) vaccination may compensate for this. To evaluate immune responses, 6-month-old infants were randomized to receive early MMR or placebo. This study reports the cellular immune outcomes and summarizes serological and T-cell responses.
MethodsA double-blind, randomized trial involved 6540 Danish infants aged 5–7 months, eligible if birth weight exceeded 1000 grams and gestational age was ≥32 weeks. Participants were randomized 1:1 to receive M-M-RVaxPro or placebo. Blood samples were collected before intervention, four weeks after intervention, and four weeks after routine MMR at 15 months. Peripheral blood mononuclear cells (PBMCs) were prepared, and an IFN-γ specific ELISpot assay measured measles-specific T cells.
ResultsAmong 750 infants (341 MMR, 409 placebo) in the cellular immunogenicity trial, a significant cellular immune response was observed one-month post-intervention in the MMR group compared to placebo (geometric mean ratio [GMR]: 12.3; 95% CI: 6.9–21.9). The cellular conversion rate (CCR) in the MMR group was 45%, comparable to the previously reported seroconversion rate. However, following routine MMR at 15 months, a reduced cellular response was observed in the early MMR group (GMR: 0.6; 95% CI: 0.3–0.9). Post-routine MMR, CCRs were 66% (MMR) and 74% (placebo). The immune conversion rate (ICR, defined as seroconversion and/or T-cell response) reached 99% in both groups post-routine MMR.
ConclusionEarly MMR at 6 months elicited significant measles-specific cellular responses, though the CCR was lower than after routine MMR at 15 months. However, when combining serological and cellular responses, 99% of infants achieved immune conversion by 15 months. Early MMR could help reduce measles burden in infants in endemic settings without compromising subsequent immunizations.
Clinical trial registrationClinicalTrials.gov, identifier NCT03780179, EudraCT 2016-001901-18.

背景
麻疹是一种高度传染性的病毒性疾病，婴幼儿感染后病情尤为严重。婴幼儿早期的免疫保护由母传抗体（maternally transferred antibodies）提供，但曾接种疫苗的母亲所生婴儿（previously vaccinated mothers, PVMs）的该保护期，短于曾罹患麻疹的母亲所生婴儿（previously measles-infected mothers, PIMs）。尽早接种麻疹-腮腺炎-风疹（MMR）疫苗可弥补这一不足。为评估免疫应答，研究将6月龄婴儿随机分配接受早期MMR疫苗或安慰剂。本研究报告了细胞免疫结局，并总结了血清学与T细胞应答情况。
方法
本研究为双盲随机试验，共纳入6540名5~7月龄丹麦婴儿，纳入标准为出生体重超过1000克、胎龄≥32周。受试者以1:1的比例随机分配接受M-M-RVaxPro疫苗或安慰剂。分别于干预前、干预后4周以及15月龄常规MMR接种后4周采集血液样本。制备外周血单个核细胞（peripheral blood mononuclear cells, PBMCs），采用γ干扰素特异性酶联免疫斑点（ELISpot）试验检测麻疹特异性T细胞。
结果
在细胞免疫原性试验的750名婴儿（341名接种MMR疫苗，409名接受安慰剂）中，干预后1个月，MMR疫苗组较安慰剂组观察到显著的细胞免疫应答（几何平均比值（geometric mean ratio, GMR）：12.3；95%置信区间（95% CI）：6.9~21.9）。MMR疫苗组的细胞转换率（cellular conversion rate, CCR）为45%，与此前报道的血清转换率（seroconversion rate）相当。但在15月龄接受常规MMR接种后，早期接种MMR疫苗组的细胞应答有所降低（GMR：0.6；95%置信区间（95% CI）：0.3~0.9）。常规MMR接种后，两组的细胞转换率（CCR）分别为66%（MMR组）和74%（安慰剂组）。常规MMR接种后，免疫转换率（immune conversion rate, ICR，定义为血清转换和/或T细胞应答）在两组中均达到99%。
结论
6月龄早期接种MMR疫苗可诱导显著的麻疹特异性细胞免疫应答，尽管其细胞转换率（CCR）低于15月龄常规MMR接种后的水平。但结合血清学与细胞免疫应答来看，至15月龄时，99%的婴儿均达到了免疫转换（ICR）。在麻疹流行地区，早期接种MMR疫苗可在不影响后续免疫接种效果的前提下，帮助降低婴幼儿的麻疹疾病负担。
临床试验注册
本研究注册于ClinicalTrials.gov，注册号为NCT03780179，EudraCT注册号为2016-001901-18。