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Cell-Based Systems Biology Analysis of Human AS03-Adjuvanted H5N1 Avian Influenza Vaccine Responses: A Phase I Randomized Controlled Trial
- Source :
- PLoS ONE, Vol 12, Iss 1, p e0167488 (2017), PLoS ONE
- Publication Year :
- 2017
- Publisher :
- Public Library of Science (PLoS), 2017.
-
Abstract
- BACKGROUNDVaccine development for influenza A/H5N1 is an important public health priority, but H5N1 vaccines are less immunogenic than seasonal influenza vaccines. Adjuvant System 03 (AS03) markedly enhances immune responses to H5N1 vaccine antigens, but the underlying molecular mechanisms are incompletely understood.OBJECTIVE AND METHODSWe compared the safety (primary endpoint), immunogenicity (secondary), gene expression (tertiary) and cytokine responses (exploratory) between AS03-adjuvanted and unadjuvanted inactivated split-virus H5N1 influenza vaccines. In a double-blinded clinical trial, we randomized twenty adults aged 18-49 to receive two doses of either AS03-adjuvanted (n = 10) or unadjuvanted (n = 10) H5N1 vaccine 28 days apart. We used a systems biology approach to characterize and correlate changes in serum cytokines, antibody titers, and gene expression levels in six immune cell types at 1, 3, 7, and 28 days after the first vaccination.RESULTSBoth vaccines were well-tolerated. Nine of 10 subjects in the adjuvanted group and 0/10 in the unadjuvanted group exhibited seroprotection (hemagglutination inhibition antibody titer > 1:40) at day 56. Within 24 hours of AS03-adjuvanted vaccination, increased serum levels of IL-6 and IP-10 were noted. Interferon signaling and antigen processing and presentation-related gene responses were induced in dendritic cells, monocytes, and neutrophils. Upregulation of MHC class II antigen presentation-related genes was seen in neutrophils. Three days after AS03-adjuvanted vaccine, upregulation of genes involved in cell cycle and division was detected in NK cells and correlated with serum levels of IP-10. Early upregulation of interferon signaling-related genes was also found to predict seroprotection 56 days after first vaccination.CONCLUSIONSUsing this cell-based systems approach, novel mechanisms of action for AS03-adjuvanted pandemic influenza vaccination were observed.TRIAL REGISTRATIONClinicalTrials.gov NCT01573312.
- Subjects :
- Male
0301 basic medicine
Neutrophils
medicine.medical_treatment
Gene Expression
lcsh:Medicine
NK cells
Antibodies, Viral
medicine.disease_cause
Monocytes
White Blood Cells
0302 clinical medicine
Animal Cells
Medicine and Health Sciences
Influenza A virus
Public and Occupational Health
lcsh:Science
Immune Response
Antigen Presentation
Vaccines
Multidisciplinary
Systems Biology
Immunogenicity
Vaccination
Antibody titer
Middle Aged
Vaccination and Immunization
3. Good health
Killer Cells, Natural
Influenza Vaccines
Female
Cellular Types
Adjuvant
Research Article
Adult
Adolescent
H5N1 vaccine
Immune Cells
Immunology
Biology
Young Adult
03 medical and health sciences
Adjuvants, Immunologic
Double-Blind Method
Antigen
Influenza, Human
Genetics
medicine
Humans
AS03
Blood Cells
Influenza A Virus, H5N1 Subtype
Interleukin-6
lcsh:R
Biology and Life Sciences
Dendritic Cells
Cell Biology
Hemagglutination Inhibition Tests
Virology
Chemokine CXCL10
030104 developmental biology
Antibody Formation
lcsh:Q
Preventive Medicine
030215 immunology
Subjects
Details
- ISSN :
- 19326203
- Volume :
- 12
- Database :
- OpenAIRE
- Journal :
- PLOS ONE
- Accession number :
- edsair.doi.dedup.....a1a3104a990d0a42fb8049e5e461775f