Different Adjuvants Induce Common Innate Pathways That Are Associated with Enhanced Adaptive Responses against a Model Antigen in Humans
Different Adjuvants Induce Common Innate Pathways That Are Associated with Enhanced Adaptive Responses against a Model Antigen in Humans
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DOI：
10.3389/fimmu.2017.00943
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发表时间：
2017-08-14
影响因子：
7.3
通讯作者：
Didierlaurent, Arnaud M.
中科院分区：
文献类型：
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作者：
Burny, Wivine;Callegaro, Andrea;Didierlaurent, Arnaud M.
为了阐明先天性应答在疫苗免疫原性中的作用，我们比较了健康HBV初治成人对B病毒（HBV）表面抗原（HBsAg）联合不同佐剂系统（AS）的早期应答，并将这些参数纳入适应性应答的多参数模型。共有291名18-45岁的受试者以1：1：1：1：1的比例随机分配，在第0天和第30天接受HBsAg与AS 01（B）、AS 01（E）、AS 03、AS 04或明矾/Al（OH）（3）联合治疗（ClinicalTrials.gov：NCT 00805389）。在早期时间点和疫苗接种后7天内评估血液蛋白、细胞和mRNA先天应答，并与反应原性症状一起用于线性回归分析，评价其与第44天的抗-CD 4（+）T细胞和抗体应答的相关性。所有AS均诱导瞬时先天性应答，包括白细胞介素（IL）-6和C反应蛋白（CRP），大多数在接种后24 h达到峰值，并在1-3天内消退至基线。第二次注射后，AS 01 B组的干扰素（IFN）-γ水平中位数增加，AS 01和AS 03组的IFN-γ诱导蛋白-10水平和IFN-诱导基因上调。没有明显的标记或签名是特定于一个特定的AS。AS 01 B、AS 01 E和AS 03组之间以及AS 04和明矾组之间的固有特征相当。AS组在适应性和先天性反应水平以及反应原性患病率方面的排名相似（AS 01（B）>= AS 01（E）> AS 03> AS 04>明矾），表明炎症反应程度与疫苗反应之间存在关联。建模揭示了适应性反应与第2次给药后先天反应的特定特征（IFN信号通路、CRP和IL-6反应的激活）之间的关联。总之，AS 01和AS 03增强对共同施用HBsAg的适应性应答的能力可能与其激活先天免疫，特别是IFN信号传导途径的能力有关。
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-naive 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(B), AS01(E), AS03, AS04, or Alum/Al(OH)(3) 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)-gamma levels were increased in the AS01B group, and IFN-gamma-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 AS01B, AS01E, and AS03 groups, and between AS04 and Alum groups. AS group rankings within adaptive and innate response levels and reactogenicity prevalence were similar (AS01(B) >= AS01(E) > 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 postdose 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.