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1.
Front Immunol ; 11: 613496, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-33613536

RESUMEN

Systems vaccinology has been applied to detect signatures of human vaccine induced immunity but its ability, together with high definition in vivo clinical imaging is not established to predict vaccine reactogenicity. Within two European Commission funded high impact programs, BIOVACSAFE and ADITEC, we applied high resolution positron emission tomography/computed tomography (PET/CT) scanning using tissue-specific and non-specific radioligands together with transcriptomic analysis of muscle biopsies in a clinical model systematically and prospectively comparing vaccine-induced immune/inflammatory responses. 109 male participants received a single immunization with licensed preparations of either AS04-adjuvanted hepatitis B virus vaccine (AHBVV); MF59C-adjuvanted (ATIV) or unadjuvanted seasonal trivalent influenza vaccine (STIV); or alum-OMV-meningococcal B protein vaccine (4CMenB), followed by a PET/CT scan (n = 54) or an injection site muscle biopsy (n = 45). Characteristic kinetics was observed with a localized intramuscular focus associated with increased tissue glycolysis at the site of immunization detected by 18F-fluorodeoxyglucose (FDG) PET/CT, peaking after 1-3 days and strongest and most prolonged after 4CMenB, which correlated with clinical experience. Draining lymph node activation peaked between days 3-5 and was most prominent after ATIV. Well defined uptake of the immune cell-binding radioligand 11C-PBR28 was observed in muscle lesions and draining lymph nodes. Kinetics of muscle gene expression module upregulation reflected those seen previously in preclinical models with a very early (~6hrs) upregulation of monocyte-, TLR- and cytokine/chemokine-associated modules after AHBVV, in contrast to a response on day 3 after ATIV, which was bracketed by whole blood responses on day 1 as antigen presenting, inflammatory and innate immune cells trafficked to the site of immunization, and on day 5 associated with activated CD4+ T cells. These observations confirm the use of PET/CT, including potentially tissue-, cell-, or cytokine/chemokine-specific radioligands, is a safe and ethical quantitative technique to compare candidate vaccine formulations and could be safely combined with biopsy to guide efficient collection of samples for integrated whole blood and tissue systems vaccinology in small-scale but intensive human clinical models of immunization and to accelerate clinical development and optimisation of vaccine candidates, adjuvants, and formulations.


Asunto(s)
Adyuvantes Inmunológicos/metabolismo , Fluorodesoxiglucosa F18/metabolismo , Ganglios Linfáticos/metabolismo , Músculos/metabolismo , Transcriptoma/inmunología , Vacunas/metabolismo , Adolescente , Adulto , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD4-Positivos/metabolismo , Citocinas/inmunología , Femenino , Humanos , Inmunización/métodos , Cinética , Ganglios Linfáticos/inmunología , Masculino , Persona de Mediana Edad , Músculos/inmunología , Tomografía Computarizada por Tomografía de Emisión de Positrones/métodos , Vacunación/métodos , Vacunas/inmunología , Adulto Joven
2.
Sci Rep ; 9(1): 20362, 2019 12 30.
Artículo en Inglés | MEDLINE | ID: mdl-31889148

RESUMEN

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.


Asunto(s)
Biomarcadores , Vacunas Virales/efectos adversos , Proteínas de Fase Aguda , Adulto , Citocinas/sangre , Femenino , Pruebas Hematológicas , Humanos , Masculino , Evaluación de Síntomas , Transcripción Genética , Vacunación/efectos adversos , Vacunación/métodos , Vacunas Virales/inmunología , Signos Vitales , Adulto Joven
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