Rationale: Covid-19 spreads rapidly throughout the world. A large epidemic in the Netherlands would seriously challenge the available hospital capacity, and this would be augmented by absenteeism of healthcare workers (HCW). Strategies to prevent absenteeism of HCW are, therefore, desperately needed to safeguard continuous patient care. Bacille Calmette-Guérin (BCG) is a vaccine against tuberculosis, with protective non-specific effects against other respiratory tract infections in in vitro and in vivo studies, and reported significant reductions in morbidity and mortality. The hypothesis is that BCG vaccination can reduce HCW absenteeism during the epidemic phase of Covid-19. Objective: Primary objective: To reduce absenteeism among HCW with direct patient contacts during the epidemic phase of Covid-19. Secondary objective: To reduce hospital admission, ICU admission or death in HCW with direct patient contacts during the epidemic phase of Covid-19. Study design: A placebo-controlled adaptive multi-centre randomized controlled trial. Study population: HCW with direct patient contacts among which nurses and physicians working at emergency rooms and wards where Covid-19-infected patients are treated. Intervention: Participants will be randomized between intracutaneous administration of BCG vaccine or placebo in a 1:1 ratio. Main study parameters/endpoints: Primary endpoint: number of days of (unplanned) absenteeism for any reason. Secondary endpoints include the number of days of (unplanned) absenteeism because of documented Covid-19 infection, and the cumulative incidence of hospital admission, Intensive Care Admission, and death. Nature and extent of the burden and risks associated with participation, benefit and group relatedness: Based on previous experience and randomized controlled trials in adult and elderly individuals, the risks of BCG vaccination are considered low. The objective of this trial is to evaluate the beneficial effects of BCG vaccination through a lower work absenteeism rate of HCW and/or a mitigated clinical course of Covid-19 infection. The primary endpoint and the adaptive design with frequent interim analyses facilitate maximum efficiency of the trial, so that results can inform policy making during the ongoing epidemic.
Since the beginning of 2020, SARS-CoV-2 spread rapidly throughout China and the rest of the
world, with on 27 February 2020 the first detected case in the Netherlands.
According to the WHO, Health-care workers (HCW) face an elevated risk of exposure to - and
infection of Covid-19.
Bacillus Calmette-Guérin (BCG) was developed as a vaccine against tuberculosis, but studies
have shown its ability to induce potent protection against other infectious diseases: the so
called non-specific effects (NSEs). A favorable in vitro or in vivo effect has been observed
in studies for distinct viral pathogens, e.g. respiratory syncytial virus, yellow fever,
herpes simplex virus; human papilloma virus.
Based on the capacity of BCG to reduce the incidence of respiratory tract infections in
children, to exert antiviral effects in experimental models; and to reduce viremia in an
experimental human model of viral infection, the hypothesis is that BCG vaccination induces
(partial) protection against susceptibility to and/or severity of Covid-19 infection. This
study evaluates the efficacy of BCG to improve the clinical course of Covid-19 infection and
to prevent absenteeism in order to safeguard continuous patient care.
This randomized controlled trial has been designed as a pragmatic study with a highly
feasible primary endpoint, which is unplanned absenteeism, that can be continuously measured
on a bi-weekly basis). This allows for the most rapid identification of a beneficial outcome
that would allow other HCWs to also benefit from the intervention if and as soon as it has
been demonstrated to be effective.
Drug: BCG Vaccine
Intracutaneously 0.1ml BCG vaccine, which accounts for 0.075mg of attenuated Mycobacterium bovis
Other Name: Danish strain 1331
Drug: Placebo
Intracutaneously 0.1ml NaCl 0,9%
Other Name: NaCl 0,9%
Inclusion Criteria:
- Adult (≥18 years)
- Male or female
- Hospital personnel (expected to) taking care for patients with SARS CoV-2 infection
Exclusion Criteria:
- Known allergy to (components of) the BCG vaccine or serious adverse events to prior
BCG administration
- Known active or latent Mycobacterium tuberculosis or with another mycobacterial
species. A history with- or a suspicion of M. tuberculosis infection.
- Fever (>38 C) within the past 24 hours
- Pregnancy
- Suspicion of active viral or bacterial infection
- Vaccination in the past 4 weeks or expected vaccination during the study period,
independent of the type of vaccination.
- Severely immunocompromised subjects. This exclusion category comprises: a) subjects
with known infection by the human immunodeficiency virus (HIV-1); b) neutropenic
subjects with less than 500 neutrophils/mm3; c) subjects with solid organ
transplantation; d) subjects with bone marrow transplantation; e) subjects under
chemotherapy; f) subjects with primary immunodeficiency; g) severe lymphopenia with
less than 400 lymphocytes/mm3; h) treatment with any anti-cytokine therapies. i)
treatment with oral or intravenous steroids defined as daily doses of 10mg prednisone
or equivalent for longer than 3 months, or probable use of oral or intravenous
steroids in the following four weeks
- Active solid or non-solid malignancy or lymphoma within the prior two years
- Direct involvement in the design or the execution of the BCG-CORONA study
- Expected absence from work of ≥4 of the following 12 weeks due to any reason
(holidays, maternity leave, retirement, planned surgery etc)
- Employed to the hospital < 22 hours per week
- Not in possession of a smartphone
Jeroen Bosch ziekenhuis
Den Bosch, Brabant, Netherlands
Canisius Wilhelmina Ziekenhuis
Nijmegen, Gelderland, Netherlands
Radboud UMC
Nijmegen, Gelderland, Netherlands
Sint Maartenskliniek
Nijmegen, Gelderland, Netherlands
Noordwest Ziekenhuisgroep locatie Alkmaar
Alkmaar, Noord Holland, Netherlands
Hagaziekenhuis
Den Haag, Zuid-Holland, Netherlands
Leiden University Medical Center
Leiden, Zuid-Holland, Netherlands
Erasmus Medical Center
Rotterdam, Zuid-Holland, Netherlands
University Medical Center Utrecht
Utrecht, Netherlands
Marc Bonten, MD, PhD, Principal Investigator
UMC Utrecht