Department of Pediatric Newborn Medicine, Brigham and Women's Hospital, Boston, MA, United States.
Department of Medicine, Division of Infectious Diseases, Boston Children's Hospital, Boston, MA, United States.
Front Immunol. 2018 Jan 24;9:29. doi: 10.3389/fimmu.2018.00029. eCollection 2018.
Immunization is key to protecting term and preterm infants from a heightened risk of infection. However, preterm immunity is distinct from that of the term, limiting its ability to effectively respond to vaccines routinely given at birth, such as hepatitis B vaccine (HBV). As part of the Expanded Program on Immunization, HBV is often given together with the live-attenuated vaccine Bacille Calmette-Guérin (BCG), known to activate multiple pattern-recognition receptors. Of note, some clinical studies suggest BCG can enhance efficacy of other vaccines in term newborns. However, little is known about whether BCG can shape Th-polarizing cytokine responses to HBV nor the age-dependency of such effects, including whether they may extend to the preterm. To characterize the effects of BCG on HBV immunogenicity, we studied individual and combined administration of these vaccines to cord newborn and adult human whole blood and mononuclear cells and to neonatal and adult mice . Compared to either BCG or HBV alone, (BCG + HBV) synergistically enhanced whole blood production of IL-1β, while (BCG + HBV) also promoted production of several cytokines/chemokines in all age groups, age-specific enhancement included IL-12p70 in the preterm and GM-CSF in the preterm and term. In human mononuclear cells, (BCG + HBV) enhanced mRNA expression of several genes including , which contributed to clustering of genes by vaccine treatment principle component analysis. To assess the impact of BCG on HBV immunization, mice of three different age groups were immunized subcutaneously with, BCG, HBV, (BCG + HBV) into the same site; or BCG and HBV injected into separate sites. Whether injected into a separate site or at the same site, co-administration of BCG with HBV significantly enhanced anti-HBV IgG titers in mice immunized on day of life-0 or -7, respectively, but not in adult mice. In summary, our data demonstrate that innate and adaptive vaccine responses of preterm and term newborns are immunologically distinct. Furthermore, BCG or "BCG-like" adjuvants should be further studied as a promising adjuvantation approach to enhance immunogenicity of vaccines to protect these vulnerable populations.
免疫接种是保护足月和早产儿免受感染风险增加的关键。然而，早产儿的免疫与足月婴儿不同，限制了其有效应对常规出生时接种的疫苗（如乙型肝炎疫苗[HBV]）的能力。作为扩大免疫规划的一部分，HBV 通常与减毒活疫苗卡介苗（BCG）一起接种，已知 BCG 可以激活多种模式识别受体。值得注意的是，一些临床研究表明，BCG 可以增强足月新生儿中其他疫苗的功效。然而，对于 BCG 是否可以影响 HBV 的 Th 极化细胞因子反应以及这些影响的年龄依赖性，包括它们是否可能扩展到早产儿，知之甚少。为了描述 BCG 对 HBV 免疫原性的影响，我们研究了单独和联合使用这些疫苗对脐带新生儿和成人全血和单核细胞以及新生和成年小鼠的影响。与单独使用 BCG 或 HBV 相比，（BCG+HBV）协同增强了全血中 IL-1β 的产生，而（BCG+HBV）也促进了所有年龄组中几种细胞因子/趋化因子的产生，包括早产儿的 IL-12p70 和早产儿和足月婴儿的 GM-CSF。在人类单核细胞中，（BCG+HBV）增强了包括在内的几个基因的 mRNA 表达，这有助于通过疫苗处理的主成分分析对基因进行聚类。为了评估 BCG 对 HBV 免疫接种的影响，三个不同年龄组的小鼠分别通过皮下免疫接种、BCG、HBV、（BCG+HBV）到同一部位；或 BCG 和 HBV 注射到不同部位。无论是在单独的部位还是在同一部位注射，BCG 与 HBV 联合给药均可显著提高在生后第 0 天或第 7 天免疫接种的小鼠的抗 HBV IgG 滴度，但在成年小鼠中则不然。总之，我们的数据表明，早产儿和足月儿的先天和适应性疫苗反应在免疫学上是不同的。此外，BCG 或“BCG 样”佐剂应作为一种有前途的佐剂方法进一步研究，以增强疫苗的免疫原性，从而保护这些脆弱人群。
