AUTHOR=Burny Wivine , Callegaro Andrea , Bechtold Viviane , Clement Frédéric , Delhaye Sophie , Fissette Laurence , Janssens Michel , Leroux-Roels Geert , Marchant Arnaud , van den Berg Robert A. , Garçon Nathalie , van der Most Robbert , Didierlaurent Arnaud M. ,  On Behalf of the ECR-002 Study Group , Bechtold Viviane , Burny Wivine , Callegaro Andrea , Carletti Isabelle , Clement Frédéric  , Delhaye Sophie , Didierlaurent Arnaud , Esen Meral , Fissette Laurence , Gabor Julian , Garçon Nathalie , Haelterman Edwige , Hervé Caroline , Horsmans Yves , Janssens Michel , Kremsner Peter , Leroux-Roels Geert , Marchant Arnaud , Moris Philippe , Schwarz Tino F , da Silva Fernanda Tavares , Van Belle Pascale , Van Damme Pierre , van den Berg Robert A. , van der Most Robbert , Zuchner Dirk 

TITLE=Different Adjuvants Induce Common Innate Pathways That Are Associated with Enhanced Adaptive Responses against a Model Antigen in Humans

JOURNAL=Frontiers in Immunology

VOLUME=8

YEAR=2017

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2017.00943

DOI=10.3389/fimmu.2017.00943

ISSN=1664-3224

ABSTRACT=<p>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 AS01<sub>B</sub>, AS01<sub>E</sub>, AS03, AS04, or Alum/Al(OH)<sub>3</sub> at days 0 and 30 (<uri xlink:href="http://ClinicalTrials.gov" xmlns:xlink="http://www.w3.org/1999/xlink">ClinicalTrials.gov</uri>: 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<sup>+</sup> 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)-γ levels were increased in the AS01<sub>B</sub> group, and IFN-γ-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 AS01<sub>B</sub>, AS01<sub>E</sub>, and AS03 groups, and between AS04 and Alum groups. AS group rankings within adaptive and innate response levels and reactogenicity prevalence were similar (AS01<sub>B</sub> ≥ AS01<sub>E</sub> &gt; AS03 &gt; AS04 &gt; Alum), suggesting an association between magnitudes of inflammatory and vaccine responses. Modeling revealed associations between adaptive responses and specific traits of the innate response post-dose 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.</p>