1. Characterization of potential biomarkers of reactogenicity of licensed antiviral vaccines: randomized controlled clinical trials conducted by the BIOVACSAFE consortium
- Author
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Robert A. van den Berg, Geert Leroux-Roels, David J. M. Lewis, Stefan H. E. Kaufmann, Hans-Joachim Mollenkopf, Ingileif Jonsdottir, Aldona Greenwood, Catherine Linley, Giuseppe Del Giudice, Kat Pizzoferro, Caroline L. Bodinham, Kent E. Kester, Jeroen Maertzdorf, January Weiner, Alberto Mantovani, Barbara Bottazzi, and Philippe Denoel
- Subjects
0301 basic medicine ,Trivalent influenza vaccine ,Adult ,Male ,Hepatitis B vaccine ,Transcription, Genetic ,Lymphocyte ,lcsh:Medicine ,Predictive markers ,Virus ,Article ,03 medical and health sciences ,Young Adult ,0302 clinical medicine ,medicine ,Humans ,lcsh:Science ,Vaccines ,Multidisciplinary ,Reactogenicity ,Hematologic Tests ,business.industry ,Vital Signs ,Vaccination ,lcsh:R ,Viral Vaccines ,3. Good health ,Clinical trial ,030104 developmental biology ,medicine.anatomical_structure ,Immunization ,Immunology ,Cytokines ,Female ,lcsh:Q ,Symptom Assessment ,business ,030217 neurology & neurosurgery ,Biomarkers ,Acute-Phase Proteins - Abstract
Biomarkers predictive of inflammatory events post-vaccination could accelerate vaccine development. Within the BIOVACSAFE framework, we conducted three identically designed, placebo-controlled inpatient/outpatient clinical studies (NCT01765413/NCT01771354/NCT01771367). Six antiviral vaccination strategies were evaluated to generate training data-sets of pre-/post-vaccination vital signs, blood changes and whole-blood gene transcripts, and to identify putative biomarkers of early inflammation/reactogenicity that could guide the design of subsequent focused confirmatory studies. Healthy adults (N = 123; 20–21/group) received one immunization at Day (D)0. Alum-adjuvanted hepatitis B vaccine elicited vital signs and inflammatory (CRP/innate cells) responses that were similar between primed/naive vaccinees, and low-level gene responses. MF59-adjuvanted trivalent influenza vaccine (ATIV) induced distinct physiological (temperature/heart rate/reactogenicity) response-patterns not seen with non-adjuvanted TIV or with the other vaccines. ATIV also elicited robust early (D1) activation of IFN-related genes (associated with serum IP-10 levels) and innate-cell-related genes, and changes in monocyte/neutrophil/lymphocyte counts, while TIV elicited similar but lower responses. Due to viral replication kinetics, innate gene activation by live yellow-fever or varicella-zoster virus (YFV/VZV) vaccines was more suspended, with early IFN-associated responses in naïve YFV-vaccine recipients but not in primed VZV-vaccine recipients. Inflammatory responses (physiological/serum markers, innate-signaling transcripts) are therefore a function of the vaccine type/composition and presence/absence of immune memory. The data reported here have guided the design of confirmatory Phase IV trials using ATIV to provide tools to identify inflammatory or reactogenicity biomarkers.
- Published
- 2019