Based on findings of the interim analysis of the ACTIVATE study showing 53% decrease of the incidence of all new infections with BCG vaccination, a new trial is designed aiming to validate if BCG can protect against COVID-19 (Corona Virus Disease-19).The aim of the study is to demonstrate in a double-blind, placebo-controlled approach if vaccination of participants susceptible to COVID-19 with BCG vaccine may modulate their disease susceptibility for COVID-19. This will be validated using both clinical and immunological criteria. At the same time, a sub-study will be conducted and the mechanism of benefit from BCG vaccination by assessing its effect on vascular endothelial function and mononuclear blood cells will be studied
Infection by the novel SARS-CoV-2 virus (also known as COVID-19) has tremendous social
impact. Most of Western societies are at major or part lock-down whatever brings
unpredictable financial and societal consequences. The urgent need for the reversal of this
situation can only be met through the generation of an immune defence shield to protect the
society from COVID-19. Many efforts for the development of a vaccine are under way without
any specific outcome so for.
The stimulation of trained immune responses seems the only alternative to bridge the gap from
the turn-on of the society until the entrance of a specific vaccine in the market. Trained
immunity stands for the non-specific raise of defense shield for severe infections coming
once tissue macrophages recognize a universal pathogen. The concept was successfully tested
in healthy volunteers that were vaccinated with placebo or BCG (Bacillus Calmette-Guérin)
vaccine. These volunteers were injected 14 days latter a tri-valent influenza A vaccine.
Volunteers previously 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 interferon-gamma.
It is proposed that this BCG vaccination triggering trained immune responses may play a role
of protection against the COVID-19 pandemic. A solid background on this rationale came
recently from the interim analysis of the ACTIVATE trial. ACTIVATE (A randomized Clinical
trial for enhanced Trained Immune responses through Bacillus Calmette-Guérin VAccination to
prevenT infections of the Elderly) was a prospective randomized open-label controlled trial
conducted among patients hospitalized at the 4th Department of Internal Medicine of ATTIKON
University General Hospital in Greece. The protocol was approved by the National Ethics
Committee of Greece and the National Organization for Medicine of Greece (EudraCT number,
2017-000596-87; ClinicalTrials.gov NCT03296423). The trial is conducted and funded by the
Hellenic Institute for the Study of Sepsis. In this trial hospitalized elderly patients were
vaccinated on the day of hospital discharge with single doses of placebo or BCG. Every
patient is under follow-up for 12 months. The last visit of the last patient is scheduled for
August 2020. An interim analysis took place on April 29th 2020 by an independent committee of
experts. The full interim analysis focused on the study primary endpoint that was the
comparative time to a new infection between the two groups of treatment. Infections counting
against this primary endpoint were respiratory or viral infections necessitating medical
treatment, community-acquired pneumonias, hospital-acquired pneumonias, intraabdominal
infections, urinary tract infections, soft tissue infections and bloodstream infections.
Analysis revealed 53% decrease of the incidence of new infections in the BCG group compared
to the placebo group. This decrease reached 80% for all respiratory tract infections.
Multivariate analysis showed that most of benefit was for patients with coronary heart
disease (CHD) and chronic obstructive pulmonary disease (COPD). This interim analysis clearly
enhances the concept that BCG can be protective against COVID-19.
Biological: BCG vaccine
Patients susceptible to SARS-CoV-2 infection will be vaccinated with one intradermal injection of 0.1ml of BCG vaccine
Other Name: BCG Vaccine (Freeze Dried)
Biological: Placebo
Patients susceptible to SARS-CoV-2 infection will be vaccinated with one intradermal injection of 0.1ml of sodium chloride 0.9%
Other Name: Saline
Inclusion Criteria:
1. Written informed consent
2. Male or female
3. Age more than or equal to 50 years based on the precise date of birth. Female
participants are allowed on the premise that they are post-menopausal.
4. History of at least one of the following:
1. coronary heart disease;
2. chronic obstructive pulmonary disease;
3. Charlson's comorbidity index (CCI) more than 3
5. Negative serum testing for immunoglobulin G and M against SARS-CoV-2
6. Skin tuberculin test diameter less than 10mm
Exclusion Criteria:
- Deny to written informed consent
- Age less than 50 years
- Known infection by the Human Immunodeficiency Virus-1 (HIV-1)
- Severely immunocompromised patients. This exclusion category comprises:
- History of congenital immunodeficiency
- History of solid organ transplantation
- History of bone marrow transplantation
- Intake of chemotherapy the last two months
- Intake of radiotherapy the last two months
- Active hematological or solid tumor malignancy
- History of any anti-cytokine therapies
- History of oral or intravenous steroids defined as daily doses of 10mg prednisone
or equivalent for longer than the last 3 months
General Hospital of Argolida - Nafplion Unit
Náfplio, Argos, Greece
2nd Department of Internal Medicine, University General Hospital of Alexandroupolis
Alexandroupolis, Greece
Department of Therapeutics, Alexandra General Hospital
Athens, Greece
1st Department of Internal Medicine, General Hospital of Athens G. GENNIMATAS
Athens, Greece
2nd University Department of Internal Medicine, IPPOKRATEION General Hospital of Athens
Athens, Greece
3rd University Department of Internal Medicine, General Hospital of Chest Diseases of Athens I SOTIRIA
Athens, Greece
4th Department of Internal Medicine, "Attikon" University Hospital, National and Kapodistrian University of Athens, Medical School
Athens, Greece
Department of Pulmonary Medicine- General Hospital of Kerkyra
Corfu, Greece
1st Department of Internal Medicine, General University Hospital of Ioannina
Ioánnina, Greece
Department of Internal Medicine, General Hospital of Karditsa
Kardítsa, Greece
General Hospital of Korinthos
Kórinthos, Greece
Department of Internal Medicine, Patras University Hospital
Patras, Greece
General Hospital of Ptolemaida MPODOSAKEIO
Ptolemaḯda, Greece
1st Department of Internal Medicine, AHEPA University General Hospital of Thessaloniki
Thessaloníki, Greece
General Hospital of Imathia - Veria Unit
Véria, Greece
Antonios Papadopoulos, MD, PhD, Principal Investigator
National Kapodistrian University of Athens, Medical School