Burny Wivine, Callegaro Andrea, Bechtold Viviane, Clement Frédéric, Delhaye Sophie, Fissette Laurence, Janssens Michel, Leroux-Roels Geert, Marchant Arnaud, van den Berg Robert A, Garçon Nathalie, van der Most Robbert, Didierlaurent Arnaud M
GSK, Rixensart, Belgium.
Center for Vaccinology, Ghent University, Ghent University Hospital, Ghent, Belgium.
Front Immunol. 2017 Aug 14;8:943. doi: 10.3389/fimmu.2017.00943. eCollection 2017.
To elucidate the role of innate responses in vaccine immunogenicity, we compared early responses to hepatitis B virus (HBV) surface antigen (HBsAg) combined with different Adjuvant Systems (AS) in healthy HBV-naïve adults, and included these parameters in multi-parametric models of adaptive responses. A total of 291 participants aged 18-45 years were randomized 1:1:1:1:1 to receive HBsAg with AS01, AS01, AS03, AS04, or Alum/Al(OH) at days 0 and 30 (ClinicalTrials.gov: NCT00805389). Blood protein, cellular, and mRNA innate responses were assessed at early time-points and up to 7 days after vaccination, and used with reactogenicity symptoms in linear regression analyses evaluating their correlation with HBs-specific CD4 T-cell and antibody responses at day 44. All AS induced transient innate responses, including interleukin (IL)-6 and C-reactive protein (CRP), mostly peaking at 24 h post-vaccination and subsiding to baseline within 1-3 days. After the second but not the first injection, median interferon (IFN)-γ levels were increased in the AS01 group, and IFN-γ-inducible protein-10 levels and IFN-inducible genes upregulated in the AS01 and AS03 groups. No distinct marker or signature was specific to one particular AS. Innate profiles were comparable between AS01, AS01, and AS03 groups, and between AS04 and Alum groups. AS group rankings within adaptive and innate response levels and reactogenicity prevalence were similar (AS01 ≥ AS01 > AS03 > AS04 > Alum), suggesting an association between magnitudes of inflammatory and vaccine responses. Modeling revealed associations between adaptive responses and specific traits of the innate response post-dose 2 (activation of the IFN-signaling pathway, CRP and IL-6 responses). In conclusion, the ability of AS01 and AS03 to enhance adaptive responses to co-administered HBsAg is likely linked to their capacity to activate innate immunity, particularly the IFN-signaling pathway.
为阐明固有免疫反应在疫苗免疫原性中的作用，我们比较了健康的未感染乙肝病毒（HBV）成年人对乙肝病毒表面抗原（HBsAg）与不同佐剂系统（AS）组合的早期反应，并将这些参数纳入适应性免疫反应的多参数模型中。共有291名年龄在18至45岁的参与者按1:1:1:1:1随机分组，在第0天和第30天分别接受与AS01、AS01、AS03、AS04或铝盐/氢氧化铝（Alum/Al(OH)）联合的HBsAg（ClinicalTrials.gov：NCT00805389）。在早期时间点以及接种疫苗后长达7天评估血液中的蛋白质、细胞和mRNA固有免疫反应，并将其与反应原性症状一起用于线性回归分析，以评估它们与第44天HBs特异性CD4 T细胞和抗体反应的相关性。所有佐剂系统均诱导了短暂的固有免疫反应，包括白细胞介素（IL）-6和C反应蛋白（CRP），大多在接种疫苗后24小时达到峰值，并在1至3天内降至基线水平。在第二次而非第一次注射后，AS01组的干扰素（IFN）-γ水平中位数升高，AS01组和AS03组中IFN-γ诱导蛋白-10水平及IFN诱导基因上调。没有特定的标志物或特征是某一种特定佐剂系统所特有的。AS01、AS01和AS03组之间以及AS04和铝盐组之间的固有免疫反应特征具有可比性。在适应性免疫反应水平、固有免疫反应水平和反应原性发生率方面，佐剂系统的排名相似（AS01≥AS01＞AS03＞AS04＞铝盐），这表明炎症反应程度与疫苗反应之间存在关联。模型分析揭示了适应性免疫反应与第2剂后固有免疫反应的特定特征（IFN信号通路的激活、CRP和IL-6反应）之间的关联。总之，AS01和AS03增强对共同给药的HBsAg的适应性免疫反应的能力可能与其激活固有免疫，特别是IFN信号通路的能力有关。
