卡介苗生产中生长的变化及其与免疫反应的关联。一项随机试验中的观察性研究。

Variation of growth in the production of the BCG vaccine and the association with the immune response. An observational study within a randomised trial.

作者信息

Biering-Sørensen Sofie, Jensen Kristoffer Jarlov, Aamand Susanne Havn, Blok Bastiaan, Andersen Andreas, Monteiro Ivan, Netea Mihai G, Aaby Peter, Benn Christine Stabell, Hasløv Kaare Robert

机构信息

Research Center for Vitamins & Vaccines (CVIVA), Bandim Health Project, Statens Serum Institut, DK-2300 Copenhagen S, Denmark; Projécto de Saúde Bandim, INDEPTH Network, Codex 1004, Bissau, Guinea-Bissau; Department of Cardiovascular and Renal Research, Faculty of Health Sciences, University of Southern Denmark, DK-5000 Odense, Denmark.

出版信息

Vaccine. 2015 Apr 21;33(17):2056-65. doi: 10.1016/j.vaccine.2015.02.056. Epub 2015 Mar 10.

DOI:10.1016/j.vaccine.2015.02.056

PMID:25765965

Abstract

INTRODUCTION

Bacille Calmette-Guérin (BCG) vaccine has beneficial non-specific effects on overall survival. After BCG vaccination, positive PPD response and scar formation are associated with increased survival. During a trial randomising low-birth-weight neonates to BCG at birth or the usual delayed BCG, the manufacturer of the BCG vaccine experienced a period with relatively slow growth rate of the BCG. We investigated the association between growth rate of BCG when manufacturing the vaccine and its capability to induce immune responses in vivo and in vitro.

METHODS

1633 neonates were randomised to BCG at birth and examined for scar at 12 months; a subgroup was tested for PPD response at 2 and 6 months. The BCG batches from the Slow growth period were compared with the precedent and subsequent Normal growth batches with regard to prevalence and size of BCG scar and PPD response. We also tested the effect of batches on in vitro cytokine responses.

RESULTS

At 12 months, the Slow growth batches were associated with higher BCG scar prevalence (98.2%) than the precedent batches (92.3%, p=0.01) but the prevalence remained high after return to normal growth (98.8%, p=0.52). The Slow growth batches were associated with larger scar size (5.0mm) than precedent (4.4mm, p<0.01) and subsequent batches (4.8mm, p=0.03). Compared with Normal growth batches, the Slow growth batches were associated with a higher prevalence of positive PPD responses, and among PPD positive children, a larger PPD reaction (geometric mean ratio: 1.40 (1.20-1.63)) at 2 months. In response to secondary heterologous stimulation, monocytes primed with Slow growth batches induced higher IL-6 (p=0.03) and TNF-α responses (p=0.03) compared with Normal growth batches.

CONCLUSION

The study indicates that variations in the production of BCG vaccine may influence important immunological effects of the vaccine.

TRIAL REGISTRATION

clinicaltrials.gov (NCT00625482).

摘要

引言

卡介苗（BCG）疫苗对总体生存率具有有益的非特异性作用。接种卡介苗后，PPD反应阳性和瘢痕形成与生存率提高相关。在一项将低体重新生儿随机分为出生时接种卡介苗或常规延迟接种卡介苗的试验中，卡介苗疫苗制造商经历了卡介苗生长速度相对较慢的时期。我们研究了疫苗生产时卡介苗的生长速度与其在体内和体外诱导免疫反应能力之间的关联。

方法

1633名新生儿在出生时随机接种卡介苗，并在12个月时检查瘢痕；一个亚组在2个月和6个月时进行PPD反应检测。将生长缓慢期的卡介苗批次与之前和之后的正常生长批次在卡介苗瘢痕的发生率和大小以及PPD反应方面进行比较。我们还测试了各批次对体外细胞因子反应的影响。

结果

在12个月时，生长缓慢批次的卡介苗瘢痕发生率（98.2%）高于之前的批次（92.3%，p = 0.01），但恢复正常生长后发生率仍然很高（98.8%，p = 0.52）。生长缓慢批次的瘢痕尺寸（5.0mm）大于之前的批次（4.4mm，p < 0.01）和之后的批次（4.8mm，p = 0.03）。与正常生长批次相比，生长缓慢批次的PPD反应阳性率更高，并且在PPD阳性儿童中，2个月时的PPD反应更大（几何平均比：1.40（1.20 - 1.63））。在二次异源刺激反应中，与正常生长批次相比，用生长缓慢批次致敏的单核细胞诱导出更高的IL - 6反应（p = 0.03）和TNF - α反应（p = 0.03）。