Table6_An innate immune signature induced by AS01- or AS03-adjuvanted vaccines predicts the antibody response magnitude and quality consistently over time.xlsx

BackgroundAntibody-mediated protection can depend on mechanisms varying from neutralization to Fc-dependent innate immune-cell recruitment. Adjuvanted vaccine development relies on a holistic understanding of how adjuvants modulate the quantity/titer and quality of the antibody response.
MethodsA Phase 2 trial (ClinicalTrials.gov: NCT00805389) evaluated hepatitis B vaccines formulated with licensed adjuvants (AS01B, AS01E, AS03, AS04 or Alum) in antigen-naïve adults. The trial investigated the role of adjuvants in shaping antibody-effector functions, and identified an innate transcriptional response shared by AS01B, AS01E and AS03. We integrated previously reported data on the innate response (gene expression, cytokine/C-reactive protein levels) and on quantitative/qualitative features of the mature antibody response (Fc-related parameters, immunoglobulin titers, avidity). Associations between the innate and humoral parameters were explored using systems vaccinology and a machine-learning framework.
ResultsA dichotomy in responses between AS01/AS03 and AS04/Alum (with the former two contributing most to the association with the humoral response) was observed across all timepoints of this longitudinal study. The consistent patterns over time suggested a similarity in the impacts of the two-dose immunization regimen, year-long interval, and non-adjuvanted antigenic challenge given one year later. An innate signature characterized by interferon pathway-related gene expression and secreted interferon-γ-induced protein 10 and C-reactive protein, which was shared by AS01 and AS03, consistently predicted both the qualitative antibody response features and the titers. The signature also predicted from the antibody response quality, the group of adjuvants from which the administered vaccine was derived.
ConclusionAn innate signature induced by AS01- or AS03-adjuvanted vaccines predicts the antibody response magnitude and quality consistently over time.

研究背景
抗体介导的免疫保护可依赖多种机制，涵盖从中和作用到依赖Fc段的先天免疫细胞招募（Fc-dependent innate immune-cell recruitment）等不同途径。佐剂疫苗（adjuvanted vaccine）的开发依赖于对佐剂如何调控抗体应答的数量/滴度与质量的全面认知。

研究方法
本项II期临床试验（Phase 2 trial，临床试验注册平台ClinicalTrials.gov编号：NCT00805389）在抗原初治成年人（antigen-naïve adults）中评估了采用获批佐剂（AS01B、AS01E、AS03、AS04或明矾（Alum））配制的乙型肝炎疫苗。本试验探究了佐剂在塑造抗体效应功能（antibody-effector functions）中的作用，并鉴定出AS01B、AS01E与AS03共有的先天转录应答（innate transcriptional response）特征。我们整合了已发表的先天应答相关数据（基因表达、细胞因子/C反应蛋白（C-reactive protein）水平）以及成熟抗体应答的定量/定性特征数据（Fc相关参数、免疫球蛋白滴度（immunoglobulin titers）、抗体亲和力（avidity））。采用系统疫苗学（systems vaccinology）与机器学习框架（machine-learning framework）探究了先天应答参数与体液免疫参数之间的关联。

研究结果
本项纵向研究的所有时间节点均观察到，AS01/AS03组与AS04/明矾组的免疫应答存在二分性，其中前两组与体液免疫应答的关联度更高。随时间推移呈现的一致模式提示，两剂免疫程序、1年间隔接种以及1年后给予的非佐剂抗原攻击的影响具有相似性。AS01与AS03共有的先天特征以干扰素通路相关基因表达、分泌型干扰素γ诱导蛋白10及C反应蛋白为表征，该特征可稳定预测抗体应答的定性特征与滴度水平。此外，该特征还可通过抗体应答质量预测疫苗所使用的佐剂组别。

研究结论
AS01或AS03佐剂疫苗诱导的先天特征，可在整个随访周期内稳定预测抗体应答的强度与质量。