Characterization of potential biomarkers of reactogenicity of licensed antiviral vaccines: randomized controlled clinical trials conducted by the BIOVACSAFE consortium

• Published in: Scientific reports Vol. 9; no. 1; pp. 20362 - 14
• Main Authors: Weiner, January, Lewis, David J. M., Maertzdorf, Jeroen, Mollenkopf, Hans-Joachim, Bodinham, Caroline, Pizzoferro, Kat, Linley, Catherine, Greenwood, Aldona, Mantovani, Alberto, Bottazzi, Barbara, Denoel, Philippe, Leroux-Roels, Geert, Kester, Kent E., Jonsdottir, Ingileif, van den Berg, Robert, Kaufmann, Stefan H. E., Del Giudice, Giuseppe
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 30.12.2019; Nature Publishing Group
• Subjects: 38/61; 631/250/590; 692/53/2423; Acute-Phase Proteins; Adult; Antiviral drugs; Biomarkers; Blood; Clinical trials; Cytokines - blood; Female; Genes; Heart rate; Hematologic Tests; Hepatitis B; Humanities and Social Sciences; Humans; Immunization; Immunological memory; Inflammation; Influenza; Interferon; IP-10 protein; Lymphocytes; Male; Monocytes; multidisciplinary; Physiology; Public health; Science; Science (multidisciplinary); Symptom Assessment; Transcription activation; Transcription, Genetic; Vaccination - adverse effects; Vaccination - methods; Vaccine development; Vaccines; Varicella; Viral Vaccines - adverse effects; Viral Vaccines - immunology; Vital Signs; Young Adult
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-019-56994-8

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.