Bacillus Calmette-guérin Vaccination to Prevent Infections of the Elderly

Study Overview
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Brief Summary
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One small recent trial in elderly volunteers showed that BCG vaccination can protect against infectious complications, while several studies have demonstrated an increased capacity of innate immune responses to react against pathogens. This process, also called trained immunity, generates the hypothesis that BCG vaccination can prevent or delay new infections in the elderly patients and is studied in the ACTIVATE trial

Detailed Description
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In an era of antimicrobial resistance, where the already existing antimicrobials are not sufficient, the development of new strategies for the prevention and treatment of infections is of great interest. This approach becomes more and more mandatory in our current era of the financial crisis where bacterial infections by multidrug-resistant emerge and impose heavily on the financial burden of the disease. These infections occur more frequently among elderly patients leading to prolonged hospitalization where unfavorable outcome is not infrequent1. Vaccination is the traditional approach of infection prevention. A classic example focusing on the need to prevent morbid re-infection is vaccination with pneumococcal vaccine the incidence of pneumococcal pneumonia and bacteremia is enormously increasing among the elderly2. The principle of vaccination is to develop memory B-lymphocytes so that early and adequate antibody titers are produced upon re-exposure to the same antigen. This is called the memory function of the adaptive immune system. Well before adaptive immunity develops proper recognition of a bacterial pathogen is done through binding of well-preserved structures known as pathogen-associated molecular patterns (PAMPs) on pattern-recognition receptors (PRRs) of the innate immune system and mainly of blood monocytes and tissue macrophages. Through a series of experiments in cell systems and animals, it was found that exposure of macrophages to small amounts of PAMPs like the β-glucan of Candida albicans and constituents of Mycobacterium tuberculosis may prevent death upon re-exposure to lethal bacterial challenges like C.albicans and Staphylococcus aureus3-6. Initial exposure to small amounts of PAMPs leads to epigenetic changes that induce the capacity of macrophages and monocytes to produce high amounts of pro-inflammatory cytokines like tumour necrosis factor-alpha (TNFα) and interferon-gamma (IFNγ) that clear efficiently the pathogen3. This enhancement of the immune cells reaction after appropriate priming to stimuli totally different from the initial ones is called trained immunity and it could be a potential pathway of preventing serious infections without having severe adverse effects. The concept has also been tested in healthy volunteers that were vaccinated with placebo or BCG (Baccillus Calmette Guérin) vaccine. These volunteers were injected 14 days latter a tri-valent influenza A vaccine. Volunteers previous vaccinated by BCG developed significantly greater titers against hemagglutinin A of the influenza A virus whereas their circulating monocytes were more potent for the production of IFNγ7. Finally, a small study has recently reported that BCG vaccination of the elderly may protect against infections8, but larger studies are necessary to confirm these findings. This generates hopes that vaccination by BCG may increase immune resistance and/or tolerance of elderly patients upon exposure to bacterial infections. This generates hopes that vaccination by BCG may increase immune tolerance of elderly patients upon exposure to bacterial diseases. The aim of the study is to demonstrate in a double-blind, placebo-controlled approach if vaccination of elderly patients with BCG vaccine may modulate their disease susceptibility for bacterial diseases. This will be validated using both clinical and immunological criteria.

Official Title
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A Randomized Clinical Trial for Enhanced Trained Immune Responses Through Bacillus Calmette-guérin Vaccination to Prevent Infections of the Elderly

Conditions
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Infection, Hospitalization, Mortality

Intervention / Treatment
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* Biological: Vaccination
* Biological: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female Age more than or equal to 65 years based on the precise date of birth Discharge from hospital after hospitalization for a medical cause. All medical causes make patients eligible for enrolment with the only exception of medical causes mentioned in the exclusion criteria Exclusion Criteria: Failure to obtain written informed consent Solid organ malignancy or lymphoma diagnosed the last five years Treatment with oral or intravenous steroids defined as daily doses of 10mg prednisone or equivalent for longer than 3 months Severely immunocompromised patients. This exclusion category comprises: a) patients with known infection by the human immunodeficiency virus (HIV-1); b) neutropenic patients with less than 500 neutrophils/mm3; c) patients with solid organ transplantation; d) patients with bone marrow transplantation; e) patients under chemotherapy; f) patients with primary immunodeficiency; g) severe lymphopenia with less than 400 lymphocytes/mm3; h) treatment with any anti-cytokine therapies Positive Interferon-gamma Release Assay (IGRA)

Ages Eligible for Study
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Minimum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Patients vaccinated with placebo or BCG
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo<br>One intradermal injection of 0.1ml of sodium chloride 0.9% | Biological: Placebo<br>* Patients discharged from hospital will be vaccinated with one intradermal injection of 0.1ml of sodium chloride 0.9%<br>* Other names: Saline;|
| Active Comparator: Vaccination<br>One intradermal injection of 0.1ml of BCG (BCG vaccine Bulgaria strain 1331; Intervax) | Biological: Vaccination<br>* Patients discharged from hospital will be vaccinated with one intradermal injection of 0.1ml of BCG vaccine<br>* Other names: Intervax;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to first infection | The time interval to the first infection post hospital discharge between the two groups of treatment. | 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Hospitalization | The rate of hospitalizations will be compared between the two groups of treatment | Month 12 | 
| Time to first infection or sepsis episode | The time to first infection or sepsis episode will be compared between the two groups of treatment | Month 12 | 
| Total number of infections | The total number of infections will be compared between the two groups of treatment | Month 12 | 
| Time to first hospitalization | The time to first hospitalization will be compared between the two groups of treatment | Month 12 | 
| Number of antibiotic administrations | The number of antibiotic administrations will be compared between the two groups of treatment | Month 12 | 
| Mortality | Mortality will be compared between the two groups of treatment | Month 12 | 
| Cytokine stimulation | Cytokine stimulation from peripheral blood monuclear cells will be compared between the two groups of treatment | Month 3 | 
| Epigenetic changes | Epigenetic changes of circulating monocytes will be compared between the two groups of treatment | Month 3 | 
| Cost of treatment | The effect of BCG vaccination on cost of treatment for infections will be compared between the two groups of treatment | Month 12 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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BCG vaccination