Using BCG Vaccine to Protect Health Care Workers in the COVID-19 Pandemic

NCT04373291 | Completed Phase 3

• 2 other identifiers: BCG-DENMARK-COVID2020-001888-90
• Study Type: interventional
• Target: 1,293
• Locations: 1 country
• Sites: 1

Brief 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.

Conditions

COVID-19; Non-specific Effects of Vaccines; Morbidity; Absenteeism; Heterologous Immunity

Outcome Measures

Primary Outcomes (1)

• Number of days of unplanned absenteeism for any reason

  6 months

Secondary Outcomes (17)

• The cumulative incidence of documented COVID

  6 months

• Cumulative incidence of all-cause and infectious hospital admissions, in particular respiratory infections

  6 months

• The number of days of unplanned absenteeism, because of documented COVID

  6 months

• Number of days of (unplanned) absenteeism due to infections

  6 months

• Number of days of (unplanned) absenteeism due to respiratory infections

  6 months

Study Arms (2)

BCG vaccine

ACTIVE COMPARATOR

Participants that are randomized in the active arm will receive an adult 0.1 ml dose of BCG vaccine (BCG-Denmark, AJ Vaccines) in the skin covering the left upper deltoid muscle. Each 0.1 ml vaccine contains between 200000 to 800000 colony forming units of the live attenuated strain of Mycobacterium bovis (BCG), Danish strain 1331.

Biological: BCG-Denmark

Control

PLACEBO COMPARATOR

Placebo will be 0.1 ml sterile 0.9 % NaCl, which has a similar color as the resuspended BCG vaccine.

Biological: Saline

Interventions

BCG-Denmark BIOLOGICAL

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.

BCG vaccine

Saline BIOLOGICAL

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.

Control

Eligibility Criteria

• Age: 18 Years - 100 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• In order to be eligible to participate in this study, a subject must meet the following criteria:
• Adult (≥18 years);
• Hospital personnel caring for patients with COVID-19.

You may not qualify if:

• Known allergy to (components of) the BCG vaccine or serious adverse events to prior BCG administration
• Known active or latent infection with Mycobacterium tuberculosis (M. tuberculosis) or other mycobacterial species
• Previous M. tuberculosis infection
• Previous confirmed COVID-19 infection
• Fever (\>38 C) within the past 24 hours
• Suspicion of active viral or bacterial infection
• Pregnancy
• Active solid or non-solid malignancy or lymphoma within the prior two years;
• Direct involvement in the design or the execution of the BCG-DENMARK-COVID study
• Employed to the hospital \< 22 hours per week
• Not in possession of a smartphone/tablet.

Sponsors & Collaborators

• Bandim Health Project: lead
• University of Southern Denmark: collaborator

Study Sites (1)

University of Southern Denmark

Odense, Region Syddanmark, 5000, Denmark

Location

Related Publications (13)

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  PMID: 31986264 BACKGROUND

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  PMID: 25232810 BACKGROUND

• Biering-Sorensen S, Aaby P, Napirna BM, Roth A, Ravn H, Rodrigues A, Whittle H, Benn CS. Small randomized trial among low-birth-weight children receiving bacillus Calmette-Guerin vaccination at first health center contact. Pediatr Infect Dis J. 2012 Mar;31(3):306-8. doi: 10.1097/INF.0b013e3182458289.

  PMID: 22189537 BACKGROUND

• Kristensen I, Aaby P, Jensen H. Routine vaccinations and child survival: follow up study in Guinea-Bissau, West Africa. BMJ. 2000 Dec 9;321(7274):1435-8. doi: 10.1136/bmj.321.7274.1435.

  PMID: 11110734 BACKGROUND

• Aaby P, Roth A, Ravn H, Napirna BM, Rodrigues A, Lisse IM, Stensballe L, Diness BR, Lausch KR, Lund N, Biering-Sorensen S, Whittle H, Benn CS. Randomized trial of BCG vaccination at birth to low-birth-weight children: beneficial nonspecific effects in the neonatal period? J Infect Dis. 2011 Jul 15;204(2):245-52. doi: 10.1093/infdis/jir240.

  PMID: 21673035 BACKGROUND

• Higgins JP, Soares-Weiser K, Lopez-Lopez JA, Kakourou A, Chaplin K, Christensen H, Martin NK, Sterne JA, Reingold AL. Association of BCG, DTP, and measles containing vaccines with childhood mortality: systematic review. BMJ. 2016 Oct 13;355:i5170. doi: 10.1136/bmj.i5170.

  PMID: 27737834 BACKGROUND

• Wardhana, Datau EA, Sultana A, Mandang VV, Jim E. The efficacy of Bacillus Calmette-Guerin vaccinations for the prevention of acute upper respiratory tract infection in the elderly. Acta Med Indones. 2011 Jul;43(3):185-90.

  PMID: 21979284 BACKGROUND

• Netea MG, Joosten LA, Latz E, Mills KH, Natoli G, Stunnenberg HG, O'Neill LA, Xavier RJ. Trained immunity: A program of innate immune memory in health and disease. Science. 2016 Apr 22;352(6284):aaf1098. doi: 10.1126/science.aaf1098. Epub 2016 Apr 21.

  PMID: 27102489 BACKGROUND

• Spencer JC, Ganguly R, Waldman RH. Nonspecific protection of mice against influenza virus infection by local or systemic immunization with Bacille Calmette-Guerin. J Infect Dis. 1977 Aug;136(2):171-5. doi: 10.1093/infdis/136.2.171.

  PMID: 894076 BACKGROUND

• Arts RJW, Moorlag SJCFM, Novakovic B, Li Y, Wang SY, Oosting M, Kumar V, Xavier RJ, Wijmenga C, Joosten LAB, Reusken CBEM, Benn CS, Aaby P, Koopmans MP, Stunnenberg HG, van Crevel R, Netea MG. BCG Vaccination Protects against Experimental Viral Infection in Humans through the Induction of Cytokines Associated with Trained Immunity. Cell Host Microbe. 2018 Jan 10;23(1):89-100.e5. doi: 10.1016/j.chom.2017.12.010.

  PMID: 29324233 BACKGROUND

• Hatherill M, Geldenhuys H, Pienaar B, Suliman S, Chheng P, Debanne SM, Hoft DF, Boom WH, Hanekom WA, Johnson JL. Safety and reactogenicity of BCG revaccination with isoniazid pretreatment in TST positive adults. Vaccine. 2014 Jun 30;32(31):3982-8. doi: 10.1016/j.vaccine.2014.04.084. Epub 2014 May 9.

  PMID: 24814553 BACKGROUND

• Sovik WLM, Madsen AMR, Aaby P, Nielsen S, Benn CS, Schaltz-Buchholzer F. The association between BCG scars and self-reported chronic diseases: A cross-sectional observational study within an RCT of Danish health care workers. Vaccine. 2024 Mar 19;42(8):1966-1972. doi: 10.1016/j.vaccine.2024.02.049. Epub 2024 Feb 19.

  PMID: 38378387 DERIVED

• Madsen AMR, Schaltz-Buchholzer F, Benfield T, Bjerregaard-Andersen M, Dalgaard LS, Dam C, Ditlev SB, Faizi G, Johansen IS, Kofoed PE, Kristensen GS, Loekkegaard ECL, Mogensen CB, Mohamed L, Ostenfeld A, Oedegaard ES, Soerensen MK, Wejse C, Jensen AKG, Nielsen S, Krause TG, Netea MG, Aaby P, Benn CS. Using BCG vaccine to enhance non-specific protection of health care workers during the COVID-19 pandemic: A structured summary of a study protocol for a randomised controlled trial in Denmark. Trials. 2020 Sep 17;21(1):799. doi: 10.1186/s13063-020-04714-3.

  PMID: 32943115 DERIVED

Related Links

• Novel Coronavirus (2019-nCoV) situation reports

MeSH Terms

Conditions

COVID-19

Interventions

Sodium Chloride

Condition Hierarchy (Ancestors)

Pneumonia, Viral; Pneumonia; Respiratory Tract Infections; Infections; Virus Diseases; Coronavirus Infections; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Lung Diseases; Respiratory Tract Diseases

Intervention Hierarchy (Ancestors)

Chlorides; Hydrochloric Acid; Chlorine Compounds; Inorganic Chemicals; Sodium Compounds

Study Officials

• Frederik Schaltz-Buchholzer, MD

  Bandim Health Project, University of Southern Denmark

  PRINCIPAL INVESTIGATOR

• Anne Marie Rosendahl Madsen, MD

  Bandim Health Project, University of Southern Denmark

  PRINCIPAL INVESTIGATOR

• Christine Stabell Benn, Professor

  Bandim Health Project, University of Southern Denmark

  STUDY CHAIR

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, OUTCOMES ASSESSOR
• Masking Details: 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.
• Purpose: PREVENTION
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: A multi-center randomized placebo-controlled trial

Study Record Dates

• First Submitted: May 1, 2020
• First Posted: May 4, 2020
• Study Start: May 18, 2020
• Primary Completion: July 31, 2021
• Study Completion: October 1, 2021
• Last Updated: October 8, 2021

Record last verified: 2021-10

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF, CSR, ANALYTIC CODE
• Time Frame: When follow-up has been completed and the dataset have been closed
• Access Criteria: Non-identifiable individual data can be shared on the basis of a data sharing proposal sent to cbenn@health.sdu.dk

Locations

DK (1)