Primary objective: The primary objective of the study is to determine the effects of BCG-vaccination on the immune response induced by subsequent influenza vaccination in healthy volunteers. This will be determined by measuring the Th1/Th2 response…
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Brief title
Condition
- Immunodeficiency syndromes
- Viral infectious disorders
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The primary study endpoint is the difference in influenza antibody titres 2 and
4 weeks (±2 days) after influenza vaccination between BCG-vaccinated subjects
and subjects in the control group.
Secondary outcome
- Proportion of participants in each group who achieved seroprotection (defined
by antibody titre >=1:40), 1, 2 and 4 weeks (±2 days) after influenza
vaccination.
- Proportion of participants in each group who achieved seroconversion (defined
by a >=4-fold rise in antibody titre), 1, 2 and 4 weeks ((±2 days) after
influenza vaccination.
- IFN-gamma/IL-10 production (reflecting the Th1/Th2 immune response) of
leukocytes ex vivo stimulated with inactivated influenza virus (0.1ug HA/ml),
before BCG vaccination, before influenza vaccination, and 2 and 4 weeks after
influenza vaccination.
- Production of Type 1 IFNs, IL-17 and IL-22 by leukocytes ex vivo stimulated
with inactivated influenza virus (0.1ug HA/ml), before BCG vaccination, before
influenza vaccination, and 2 and 4 weeks after influenza vaccination.
- Production of other inflammatory mediators (including TNFα, IL-1β, IFN-gamma,
IL-10, IL-17, IL-22) by leukocytes ex vivo stimulated with m. tuberculosis
(1ug/ml end protein concentration), s. aureus (1x10e6 microorganisms/ml), C.
albicans (1x10e6 microorgansims/ml strain UC820), and inactivated influenza (
0.1ug HA/ml) , before BCG vaccination, before influenza vaccination, and 2 and
4 weeks after influenza vaccination.
- The phenotype of circulating leukocytes (expression of surface markers,
including, but not limited to CD45, CD3, CD4, CD8, CD56, CD14, CD11b, TLR4,
TLR2), before BCG vaccination, before influenza vaccination, and 2 and 4 weeks
after influenza vaccination.
- Inflammatory transcriptional pathways (by use of qPCR/microarrays) , before
BCG vaccination, before influenza vaccination, and 2 and 4 weeks after
influenza vaccination.
- Epigenetic changes in leukocytes, including H3K4 trimethylation, before BCG
vaccination, before influenza vaccination, and 4 weeks after influenza
vaccination.
- Subanalyses will include differences in all these parameters between young
and older subjects.
Background summary
Influenza virus infection leads to millions of cases of severe illnesses
worldwide and up to an estimated 500.000 deaths annually. The potential for the
sudden emergence of pandemic influenza strains represents an incessant threat
on even a larger scale. Seasonal influenza vaccination is the backbone of
influenza management. However, antibodies generated by vaccination, most often
do not effectively neutralize emergent strains due to the high mutation rate of
the influenza viral genome. In addition, although vaccination is effective in
up to 85% of healthy adults, only 40-60% of the elderly are able to mount an
protective antibody response due to an age-related decline in immune function
(so-called immunoscenescence). As a result, the protective effects of influenza
vaccination are limited, and strategies to improve host immune defenses against
influenza virus infection per se, and following influenza vaccination, are
highly warranted.
It is suggested that prior vaccination with Bacille Calmette-Guérin (BCG) could
enhance resistance to other infectious diseases in addition to protection to
tuberculosis (TBC) and, in mice, protection of prior BCG-vaccination against
influenza infection was demonstrated long ago. However, only recently
substantial evidence for these nonspecific beneficial effects of
BCG-vaccination in humans has been provided by several randomized clinical
trials. Considering these potentiating effects of BCG-vaccination, it could be
a viable strategy to improve efficacy of influenza vaccination, and/or enhance
immune defenses against influenza virus infection per se. If so, this would
have an enormous impact on clinical practice.
Study objective
Primary objective:
The primary objective of the study is to determine the effects of
BCG-vaccination on the immune response induced by subsequent influenza
vaccination in healthy volunteers. This will be determined by measuring the
Th1/Th2 response, and antibody titers induced by influenza vaccination in
seronegative healthy volunteers who are, prior to influenza vaccination,
vaccinated with either BCG or placebo in a double-blind randomized manner.
There are 6 secondary objectives:
1. To determine the effects of BCG-vaccination on ex vivo responsiveness of
leukocytes to inactivated influenza virus before and after influenza
vaccination.
2. To determine the effects of BCG-vaccination on ex vivo responsiveness of
leukocytes to various not related inflammatory stimuli following influenza
vaccination.
3. To determine the effects of BCG-vaccination on the phenotype of circulating
leukocytes following influenza vaccination (e.g. expression pattern of
cell-surface receptors by use of flow cytometry).
4. To determine the effects of BCG-vaccination on inflammatory transcriptional
pathways (determined by qPCR/microarrays) following influenza vaccination.
5. To determine the effects of BCG-vaccination on epigenetic changes, including
H3K4 trimethylation, in circulating immune cells following influenza
vaccination.
6. To determine whether age influences the immune modulating effects of
BCG-vaccination.
Study design
A randomized double-blind placebo-controlled pilot study in healthy human
volunteers. In this pilot study, we will enrol 40 healthy young (>=18 and <=35
yrs) and 32 healthy older (>=65 yrs) male volunteers. Subjects will be
randomized to receive either BCG-vaccination (n=20 young volunteers, n=16 old
volunteers) or placebo (Saline, n=20 young volunteers, n=16 old volunteers) on
day 1. Fourteen days later, all subjects will receive influenza vaccination.
Blood will be withdrawn on 6 occasions to perform analyses.
Intervention
Placebo/BCG-vaccination followed by influenza vaccination.
Study burden and risks
The risks for participation in this study are low. BCG- and influenza
vaccination are worldwide administered to millions of people, and are very well
tolerated. In total, a maximum of 280 ml blood will be obtained over a period
of 6 weeks, which is not expected to result in side effects. Therefore, we feel
that the remaining risks are acceptable and do not outweigh the scientific and
medical relevance of this study. Subjects will visit the research unit of the
Intensive Care 6 times in total.
Geert Grooteplein-Zuid 10
Nijmegen 6525 GA
NL
Geert Grooteplein-Zuid 10
Nijmegen 6525 GA
NL
Listed location countries
Age
Inclusion criteria
- Age >=18 and <=35 yrs or >=65 yrs
- Male
- Healthy
Exclusion criteria
- Prior exposure to *Influvac* influenza virus strains , measured by antibody titres. Previous exposure is defined by antibody titres >=1:40.
- History of influenza vaccination within the year prior to study entry
- History of BCG vaccination within 5 years prior to study entry
- History of Mantoux testing within the year prior to study entry
- Vaccination other than BCG or influenza, within 3 months prior to study or within study period
- Medical history of any disease associated with immune deficiency
- Clinically significant acute illness, including infections, within 4 weeks before vaccination
- Participation in a drug trial or donation of blood 3 months prior to study entry
- Use of recreational drugs within 21 days prior to experiment day
- Recent hospital admission or surgery with general anaesthesia (<3 months)
- Known chronic kidney or liver disease
- Latent or active tuberculosis infection
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2014-000966-23-NL |
| CCMO | NL48457.091.14 |
| Other | volgt |