Inflammatory parameters associated with systemic reactogenicity following vaccination with adjuvanted hepatitis B vaccines in humans.

Background: 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.

Methods: 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.

Findings: 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).

Conclusions: 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.

Trial Registration: www.clinicaltrials.gov NCT01777295.