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

January Weiner,Kat Pizzoferro,Jeroen Maertzdorf,Geert Leroux-Roels,Caroline Bodinham,Ingileif Jonsdottir,Kent E Kester,Robert Van Den Berg,Catherine Linley,Stefan H E Kaufmann,Hans-Joachim Mollenkopf,David J M Lewis,Aldona Greenwood,Giuseppe Del Giudice,Philippe Denoel,Alberto Mantovani,Barbara Bottazzi

doi:10.1038/s41598-019-56994-8

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.

Highlights

We report the vital signs data, blood changes and, importantly, the gene transcripts detected in whole blood before and after vaccination, as generated in these clinical trials
In saline placebo-controlled studies, we evaluated live yellow fever virus (YFV) and varicella zoster virus (VZV) vaccines in YFV-naive and VZV-primed subjects respectively (Study A); a prime-boost-boost regimen with aluminum-hydroxide-adjuvanted subunit hepatitis B virus (HBV) surface antigen vaccine in initially HBV-naive subjects (Study B); and non-adjuvanted or MF59-adjuvanted subunit trivalent influenza vaccine (TIV or adjuvanted trivalent influenza vaccine (ATIV) respectively) in subjects assumed to have been exposed previously to circulating seasonal influenza viruses (Study C); see Table 1
The scores obtained for the ATIV group were considered the most informative for future use in systems biology analyses

Summary

Objectives

The study objective was to generate an exploratory ‘training’ set of data characterising reactogenicity as well as physiological and innate immune responses following immunisation with licensed vaccines. This data set would be used to identify putative biomarkers of vaccine reactogenicity in subsequent research phases, that could guide the design of follow-on large-scale non-residential confirmatory studies, using selected vaccines and time points

Methods

Results

Conclusion