Using BCG Vaccine to Protect Health Care Workers in the COVID-19 Pandemic
Condition: COVID-19; Non-specific Effects of Vaccines; Morbidity; Absenteeism; Heterologous Immunity
MeSH terms: COVID-19
Study type: Interventional
Phase: Phase 3

Summary: 
      Background: The COVID-19 pandemic challenges the available hospital capacity, and this will
      be augmented by absenteeism of healthcare workers (HCW). HCW are at high risk, currently HCW
      constitute 20% of all the COVID-19 cases in Denmark. Strategies to prevent absenteeism of HCW
      are urgently needed.

      Bacille Calmette-Guérin (BCG) is a vaccine against tuberculosis, with protective non-specific
      effects against other infections; significant reductions in morbidity and mortality have been
      reported, and a plausible immunological mechanism has been identified.

      We hypothesize that BCG vaccination can reduce HCW absenteeism during the COVID-19 pandemic.

      Primary objective: To reduce absenteeism among HCW with direct patient contacts during the
      COVID-19 epidemic. Secondary objective: To reduce the number of HCW that are infected with
      SARS-CoV-2 during the COVID-19 epidemic and to reduce the number of hospital admissions
      amongst HCW with direct patient contacts during the COVID-19 epidemic.

      Study design: A multi-center randomized placebo controlled trial. Study population: 1500 HCW
      with direct patient contacts; defined as nurses, physicians and other medical staff working
      at emergency rooms and wards where COVID-infected patients are treated.

      Intervention: Participants will be randomized 1:1 to intradermal administration of a standard
      dose of BCG vaccine or placebo (saline).

      Main study parameters/endpoints: Primary endpoint: Number of days of (unplanned) absenteeism
      for any reason. Secondary endpoints: Number of days of (unplanned) absenteeism because of
      documented COVID infection. Cumulative incidence of hospital admissions.

      Risk for participants and impact: 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 potential beneficial effects of BCG vaccination
      through a lower work absenteeism rate of HCW and/or a mitigated clinical course of COVID
      infection.
    

Detailed description: 
      BACKGROUND Health-care workers face an elevated risk of exposure to - and infection with -
      SARS-CoV-2. It is imperative to ensure the safety, health and fitness of hospital personnel
      in order to safeguard continuous patient care. Strategies to prevent COVID-19 or to mitigate
      its clinical consequences are urgently needed.

      Bacillus Calmette-Guérin (BCG) was developed as a vaccine against tuberculosis, but our group
      has shown that it can protect against death from other infections, it has what we have called
      non-specific effects (NSEs).[3] In clinical studies, BCG vaccination was associated with less
      child mortality, mainly as a result of reduced neonatal sepsis and respiratory infections. In
      a WHO-commissioned meta-analysis, BCG was associated with 42% (95%CI: 24-55%) lower child
      mortality.

      NSEs of BCG are not limited to children. An Indonesian trial has shown that consecutive BCG
      vaccination for 3 months reduced the incidence of acute upper tract respiratory infections by
      80% (95%CI=22-95%).

      It has been recently demonstrated that the non-specific beneficial effects of BCG vaccination
      are due to epigenetic and metabolic reprogramming of innate immune cells, a process termed
      'trained immunity'. E.g. among humans receiving yellow fever vaccine virus, those who had
      received BCG had - compared to placebo treated subjects - lower viral load, and improved
      anti-viral responses.

      We hypothesize that BCG vaccination may induce (partial) protection against susceptibility to
      and/or severity of COVID-19. This study will evaluate the efficacy of BCG to improve the
      clinical course of COVID-19 and to prevent absenteeism.

      Given the immediate threat of the COVID-19 epidemic the trial has been designed as a
      pragmatic study with a highly feasible primary endpoint, that can be continuously measured.
      We have therefore chosen unplanned absenteeism from work as primary outcome, in line with an
      ongoing clinical trial of BCG in the Netherlands.

      OBJECTIVES Primary objective: To reduce absenteeism among HCW with direct patient contacts
      during the COVID-19 epidemic. Secondary objective: To reduce the number of HCW that are
      infected with SARS-CoV-2 during the COVID-19 epidemic and to reduce the number of hospital
      admissions amongst HCW with direct patient contacts during the COVID-19 epidemic.

      HYPOTHESIS BCG vaccination of HCW will reduce absenteeism by 20% over a period of 6 months.

      METHODS

      Study design and follow-up:

      A multi-center randomized placebo-controlled trial.

      STUDY POPULATION As the COVID-19 epidemic has already started in Denmark, our intention is to
      start as soon as possible. Recruitment of study participants will take place at participating
      hospitals, at departments were COVID-19 patients are treated and, thus, the risk of exposure
      to SARS-CoV-2 is high.

      Participating hospitals Hospital PI Odense University Hospital Isik Somuncu Johansen Sygehus
      Lillebælt, Kolding Poul-Erik Kofoed Hvidovre Hospital Thomas Lars Benfield Nordsjællands
      Hospital Ellen Løkkegaard Aarhus University Hospital Christian Wejse Herning Hospital Lars
      Skov Dalgaard Sygehus Sønderjylland Christian B. Mogensen

      TREATMENT OF SUBJECTS Participants will be randomized 1:1 to receiving one intradermal BCG
      vaccine or placebo. Participants that are randomized in the active arm will receive a BCG
      vaccine (BCG-Denmark, AJ Vaccines). Placebo will be 0.1 ml sterile 0.9 % NaCl, which has a
      similar color as the resuspended BCG vaccine.

      STUDY PROCEDURES Day 0: Participants fill in a short questionnaire regarding baseline
      characteristics. A blood sample will be drawn for subsequent testing for SARS-CoV-2
      antibodies. Participants will be randomised to BCG or placebo in a 1:1 ratio. Randomisation
      will be done centrally using the REDCap tool with stratification per hospital and by age
      groups (+/- 45 years of age) in blocks of 8.

      Participants will be blinded to treatment. The physicians administering the BCG vaccine or
      placebo will not be blinded. In case of serious adverse events, the participant can be
      unblinded after consultation with the coordinating PI or sponsor.

      The end of the trial is defined as whichever comes latest: the last patient's last
      registration in the online data collection, or 180 days.

      Day 0 till end of trial (weekly): Short electronic questionnaire regarding work absenteeism,
      symptoms and side effects through REDCap. In case a participant reports acute respiratory
      symptoms indicating COVID-19, he or she will be tested depending on test availability.

      End of trial: Participants are asked to fill in a final questionnaire. A blood sample will be
      drawn for subsequent testing for SARS-CoV-2 antibodies.

      STATISTICAL ANALYSIS All analyses will be performed from the intention-to-treat principle.
      The primary endpoint will be analysed as counts per week (i.e. multiple observations per
      subject) using a Bayesian negative binomial regression. Similar regression models will be
      used for secondary endpoints: Number of days of unplanned absenteeism because of documented
      COVID; number of days of self-reported fever. Documented COVID, death for any reason, death
      due to documented COVID, cumulative incidence of Intensive Care Admission for any reason,
      cumulative incidence of Intensive Care Admission due to documented COVID, cumulative
      incidence of Hospital Admission for any reason, cumulative incidence of Hospital Admission
      due to documented COVID will be analysed in Cox proportional hazards models.

      Participants will be followed until a new vaccine is given (but data will also be analyzed
      after receipt of a new vaccine type, to study potential interactions).

      When applicable (i.e. in the event that one or more participants have died during the
      follow-up period) a competing events analysis will be performed in addition.

      Interim analysis Every month, an interim analysis will be conducted by the independent
      statistician of the trial. The parallel Dutch trial will enable combined analysis that will
      strengthen the conclusions and increase the power to analyse the secondary outcomes and more
      rare outcomes as intensive hospitalization.

      ETHICAL CONSIDERATIONS The study has ben approved by the Ethics Committee and by the Danish
      Medicines Agency.
    

Intervention name(s): BCG-Denmark; Saline
Intervention type(s): Biological; Biological
Intervention description(s): Participants randomized to receive BCG will receive one 0.1 ml dose of Mycobacterium bovis BCG live attenuated BCG-Denmark vaccine (AJ Vaccines, Copenhagen, Denmark) by intradermal injection in the left deltoid region.; Participants randomized to the control group will receive one 0.1 ml dose sterile 0.9 % NaCl by intradermal injection in the left deltoid region.
Allocation: Randomized
Intervention model: Parallel Assignment
Intervention model description: A multi-center randomized placebo-controlled trial
Masking: Double (Participant, Outcomes Assessor)
Primary purpose: Prevention