Burny Wivine, Marchant Arnaud, Hervé Caroline, Callegaro Andrea, Caubet Magalie, Fissette Laurence, Gheyle Lien, Legrand Catherine, Ndour Cheikh, Tavares Da Silva Fernanda, van der Most Robbert, Willems Fabienne, Didierlaurent Arnaud M, Yarzabal Juan
GSK, Rixensart/Wavre, Belgium.
Institute for Medical Immunology, Université libre de Bruxelles, Charleroi, Belgium.
Vaccine. 2019 Mar 28;37(14):2004-2015. doi: 10.1016/j.vaccine.2019.02.015. Epub 2019 Mar 5.
Adjuvants like AS01 increase the immunogenicity of vaccines and generally cause increased transient reactogenicity compared with Alum. A phase II randomized trial was conducted to characterize the response to AS01 and Alum adjuvanted vaccines. A post-hoc analysis was performed to examine the associations between reactogenicity and innate immune parameters.
The trial involved 60 hepatitis B-naïve adults aged 18-45 years randomized 1:1 to receive either two doses of HBsAg-AS01 on Day (D)0 and D30, or three doses of HBsAg-Alum on D0, D30, D180. Prior to vaccination, all subjects received placebo injection in order to differentiate the impact of injection process and the vaccination. Main outcomes included reactogenicity symptoms, vital signs, blood cytokines, biochemical and hematological parameters after vaccination. Associations were explored using linear regression.
The vaccine with AS01 induced higher HBsAg-specific antibody levels than Alum. Local and systemic symptoms were more frequent in individuals who received HBsAg AS01/Alum vaccine or placebo, but were mild and short-lived. Blood levels of C-reactive protein (CRP), bilirubin, leukocyte, monocyte and neutrophil counts increased rapidly and transiently after AS01 but not after Alum or placebo. Lymphocyte counts decreased in the AS01 group and lactate dehydrogenase levels decreased after Alum. Modelling revealed associations between systemic symptoms and increased levels of CRP and IL-6 after the first HBsAg-AS01 or HBsAg-Alum immunization. Following the second vaccine dose, CRP, IL-6, IP-10, IFN-γ, MIP-1β and MCP-2 were identified as key parameters associated with systemic symptoms. These observations were confirmed using an independent data set extracted from a previous study of the immune response to HBsAg-adjuvanted vaccines (NCT00805389).
IL-6 and IFN-γ signals were associated with systemic reactogenicity following administration of AS01-adjuvanted vaccine. These signals were similar to those previously associated with antibody and T-cell responses induced by HBsAg-adjuvanted vaccines, suggesting that similar innate immune signals may underlie adjuvant reactogenicity and immunogenicity.
www.clinicaltrials.gov NCT01777295.
与铝盐佐剂相比，AS01等佐剂可增强疫苗的免疫原性，通常会导致更强的短暂反应原性。开展了一项II期随机试验，以描述对AS01和铝盐佐剂疫苗的反应。进行了一项事后分析，以研究反应原性与先天免疫参数之间的关联。
该试验纳入60名18至45岁未感染过乙型肝炎的成年人，按1:1随机分组，分别在第0天（D0）和第30天接种两剂HBsAg-AS01，或在D0、D30、D180接种三剂HBsAg-铝盐。在接种疫苗前，所有受试者均接受安慰剂注射，以区分注射过程和疫苗接种的影响。主要结局包括接种疫苗后的反应原性症状、生命体征、血液细胞因子、生化和血液学参数。使用线性回归探索关联。
与铝盐佐剂疫苗相比，AS01佐剂疫苗诱导的HBsAg特异性抗体水平更高。接受HBsAg AS01/铝盐佐剂疫苗或安慰剂的个体出现局部和全身症状的频率更高，但症状轻微且持续时间短。AS01接种后，血液中C反应蛋白（CRP）、胆红素、白细胞、单核细胞和中性粒细胞计数迅速且短暂升高，而铝盐佐剂疫苗或安慰剂接种后未出现此现象。AS01组淋巴细胞计数下降，铝盐佐剂疫苗接种后乳酸脱氢酶水平下降。模型显示，首次接种HBsAg-AS01或HBsAg-铝盐佐剂疫苗后，全身症状与CRP和IL-6水平升高之间存在关联。第二次接种疫苗后，CRP、IL-6、IP-10、IFN-γ、MIP-1β和MCP-2被确定为与全身症状相关的关键参数。使用从先前一项关于HBsAg佐剂疫苗免疫反应的研究（NCT00805389）中提取的独立数据集证实了这些观察结果。
IL-6和IFN-γ信号与AS01佐剂疫苗接种后的全身反应原性相关。这些信号与先前与HBsAg佐剂疫苗诱导的抗体和T细胞反应相关的信号相似，表明类似的先天免疫信号可能是佐剂反应原性和免疫原性的基础。
www.clinicaltrials.gov NCT01777295。
