Clinical trial NCT03296423: Bacillus Calmette-guérin Vaccination to Prevent Infections of the Elderly
Official title: A Randomized Clinical Trial for Enhanced Trained Immune Responses Through Bacillus Calmette-guérin Vaccination to Prevent Infections of the Elderly
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Infection
Hospitalization
Mortality
Keywords: BCG vaccination
Lead sponsor: Hellenic Institute for the Study of Sepsis
Sponsor class: OTHER
Collaborators: name: Radboud University Medical Center
First posted: 2017-09-28
Enrollment: 200
Sex: ALL
Minimum age (years): 65
Standard ages: OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Patients vaccinated with placebo or BCG
Primary purpose: PREVENTION

Brief summary: 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: 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.

Eligibility criteria: 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)

Primary outcomes:
measure: Time to first infection
timeFrame: 12 months
Secondary outcomes:
measure: Hospitalization
timeFrame: Month 12
measure: Time to first infection or sepsis episode
timeFrame: Month 12
measure: Total number of infections
timeFrame: Month 12
measure: Time to first hospitalization
timeFrame: Month 12
measure: Number of antibiotic administrations
timeFrame: Month 12
measure: Mortality
timeFrame: Month 12
measure: Cytokine stimulation
timeFrame: Month 3
measure: Epigenetic changes
timeFrame: Month 3
measure: Cost of treatment
timeFrame: Month 12
Other outcomes:
Locations:
city: Athens
country: Greece
facility: 4th Department of Internal Medicine, ATTIKON University Hospital
state: Attiki
Study officials:
affiliation: National and Kapodistrian University of Athens
name: Antonios Papadopoulos, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Leentjens J, Kox M, Stokman R, Gerretsen J, Diavatopoulos DA, van Crevel R, Rimmelzwaan GF, Pickkers P, Netea MG. BCG Vaccination Enhances the Immunogenicity of Subsequent Influenza Vaccination in Healthy Volunteers: A Randomized, Placebo-Controlled Pilot Study. J Infect Dis. 2015 Dec 15;212(12):1930-8. doi: 10.1093/infdis/jiv332. Epub 2015 Jun 12.
citation: Blok BA, Arts RJ, van Crevel R, Benn CS, Netea MG. Trained innate immunity as underlying mechanism for the long-term, nonspecific effects of vaccines. J Leukoc Biol. 2015 Sep;98(3):347-56. doi: 10.1189/jlb.5RI0315-096R. Epub 2015 Jul 6.
citation: Giamarellos-Bourboulis EJ, Tsilika M, Moorlag S, Antonakos N, Kotsaki A, Dominguez-Andres J, Kyriazopoulou E, Gkavogianni T, Adami ME, Damoraki G, Koufargyris P, Karageorgos A, Bolanou A, Koenen H, van Crevel R, Droggiti DI, Renieris G, Papadopoulos A, Netea MG. Activate: Randomized Clinical Trial of BCG Vaccination against Infection in the Elderly. Cell. 2020 Oct 15;183(2):315-323.e9. doi: 10.1016/j.cell.2020.08.051. Epub 2020 Sep 1.