Frontiers in Immunology · 2017 · 153 citations · 60 references
Life SciencesImmunologyInfectious DiseasesAdaptive ImmunityImmunizationInnate ImmunityAdaptive Immune ResponsesImmune Response To VaccinationInnate Immune ActivationInnate Immune ResponseVaccinationVaccine ReactogenicityAdaptive Immune Responses To Viral InfectionAdjuvant-induced ImmunityInnate Cytokine ResponsesInnate Immune Response ModelingInnate Immunity PathwaysVaccine-associated ReactogenicityVaccine-induced Adaptive ImmunityVaccine-induced Innate Immunity
The study investigates how early innate immune responses to hepatitis B surface antigen combined with various adjuvant systems influence subsequent adaptive immunity in HBV‑naïve adults. In a randomized trial of 291 adults, participants received HBsAg with AS01B, AS01E, AS03, AS04, or Alum on days 0 and 30, and blood protein, cellular, and mRNA innate markers were measured up to 7 days post‑vaccination and used in regression models to correlate with CD4⁺ T‑cell and antibody responses at day 44. All adjuvants induced transient IL‑6 and CRP peaks at 24 h, with AS01B showing increased IFN‑γ after dose 2 and AS01/AS03 upregulating IP‑10 and IFN‑inducible genes, yet no adjuvant‑specific signature emerged; modeling linked higher adaptive responses to stronger IFN‑signaling, CRP, and IL‑6 post‑dose 2, supporting that AS01 and AS03 enhance immunity through innate activation, particularly IFN signaling.
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 AS01B, AS01E, AS03, AS04 or Alum/Al(OH)3 at Day 0 and Day 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 24h post-vaccination and subsiding to baseline within 1-3 days. After the second but not the first injection, median IFN γ levels were increased in the AS01B group, and IP-10 levels and IFN-inducible genes upregulated in the AS01 and AS03 groups. No distinct marker or signature was specific to one particular AS. Innative 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 (AS01B ≥ AS01E > AS03 > AS04 > Alum), suggesting an association between magnitudes of inflammatory and vaccine responses. Modelling revealed associations between adaptive responses and specific traits of the innate response post-dose-2 (activation of the IFN-signalling 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.
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Jorma Paavonen, Paulo Naud, Jorge Salmerón et al. · The Lancet · 2009 · 1.7K citations
Medicine, Gynecology, Oncology +17