Use of BCG Vaccine as a Preventive Measure for COVID-19 in Health Care Workers (ProBCG)

• ClinicalTrials.gov Identifier: NCT04659941
• Recruitment Status: Active, not recruiting
• First Posted: December 9, 2020
• Last Update Posted: May 24, 2022
• Sponsor: Universidade Federal do Rio de Janeiro
• Collaborator: Ministry of Science and Technology, Brazil
• Information provided by (Responsible Party): JOSE ROBERTO LAPA E SILVA, Universidade Federal do Rio de Janeiro

Study Description

Brief Summary:

The disease promoted by coronavirus (COVID-19) is caused by Severe Acute Respiratory Syndrome (SARS) caused by Coronavirus type 2 (CoV2), being the first cases identified in December 2019 in China after exposure to the animal market in Wuhan city, China. From the first case to the present day, the COVID-19 epidemic has been identified in 185 countries, with the notification of 2,666,154 cases and 186,144 deaths. In Brazil, more than 45,757 cases and 2,906 confirmed deaths by COVID-19 have been confirmed (Visualized on Apr 23 2020). In our country, to date, testing for COVID-19 occurs only in severe cases and few centers offer the service to health care workers, a population at high risk of infection. BCG is a vaccine produced from a live attenuated strain derived from a Mycobacterium bovis isolate and is widely used worldwide as a tuberculosis (TB) vaccine, but there are studies demonstrating non-specific immunotherapeutic mechanisms of this vaccine that signal a possible relationship with the lowest morbidity and mortality associated with COVID-19 infections worldwide. The present study aims to analyze the role of BCG in the prevention of SARS-CoV-2 infection and also in the occurrence of severe forms of COVID-19 in addition to evaluating the immune response mediated by this vaccine in voluntary health care workers.

Condition or disease	Intervention/treatment	Phase
COVID 19 Vaccine	Biological: BCG vaccine; Biological: 0.9% sodium chloride (NaCl) saline solution	Phase 2

Detailed Description:

Study detailed description can be seen on the protocol attached.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 752 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Care Provider)
• Primary Purpose: Prevention
• Official Title: Use of BCG Vaccine as a Preventive Measure for COVID-19 in Health Care Workers
• Actual Study Start Date: October 1, 2020
• Actual Primary Completion Date: October 1, 2021
• Estimated Study Completion Date: October 1, 2022

Arms and Interventions

Arm	Intervention/treatment
Experimental: BCG vaccine; 0.1 ml of the reconstituted vaccine to be administered intradermally in the lower insertion of the deltoid muscle, preferably on the right side, in only one occasion	Biological: BCG vaccine; Using aseptic methods, 1 mL of Sterile Water for Injection, is added to one vial of vaccine. Gently swirl the vial until a homogenous suspension is obtained. Avoid forceful agitation which may cause clumping of the mycobacteria. Drop the immunizing dose of 0.1 mL of BCG VACCINE from the syringe and needle onto the cleansed surface of the skin.
Placebo Comparator: 0.9% sodium chloride (NaCl) saline solution; 0.1 ml of 0.9% NaCl saline solution to be administered intradermally in the lower insertion of the deltoid muscle, preferably on the right side, in only one occasion	Biological: 0.9% sodium chloride (NaCl) saline solution; A 0.1 ml of 0.9% NaCl saline solution applied intradermally in the lower insertion of the deltoid muscle of the right arm will be used as placebo, except contraindications or impossibilities.

Outcome Measures

Primary Outcome Measures :

1. Compare the cumulative incidence of SARS-CoV-2 infection [ Time Frame: 6 months ]
   It is estimated that it will take 376 individuals in each of the comparison groups to ensure a statistical power of 85% for the detection of a risk difference of 5%, considering that the 6 months of follow-up, for a type I error of 5%.
2. Compare the cumulative incidence of severe forms of COVID-19 [ Time Frame: 6 months ]
   With 376 individuals in each of the comparison groups the study will have a statistical power of approximately 75% for the detection of a risk difference of 2%, considering that the control group will have an accumulated incidence of more severe forms of COVID-19 of 2.5% after 6 months of follow-up, for a type I error of 5%.
3. Assess the BCG vaccine-mediated immune response in health care workers [ Time Frame: 6 months ]
   SARS-CoV2 infection is estimated to occur in approximately 10% of BCG-vaccinated healthcare professionals (experimental group) and in 30% of non-BCG-vaccinated healthcare professionals (placebo group) In this scenario, with the bearing of 372 health professionals in each arm, SARS-CoV2 infection is expected to be detected in 50 BCG-vaccinated professionals and 150 professionals not vaccinated with BCG. For each subgroup (vaccinated and not vaccinated with BCG) it will be possible to identify the predictive biomarkers of infection by comparing infected professionals with those who were not infected with SARS-CoV2.

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Criteria

Inclusion Criteria:

1. Individuals aged 18 ≥, male or female, not infected with SARS-CoV-2
2. Agreement to participate in the study by signing the Free Informed Consent (FIC)
3. Not being pregnant (in case of women able to become pregnant)
4. Have not received a specific vaccine against COVID-19 or, if vaccinated against SARS-CoV-2, have received the complete immunization schedule only with vaccines approved by ANVISA and implemented by the National Immunization Program, (including the second dose) within a minimum of 15 days prior to the date of inclusion in the study
5. If the participant have not received a specific vaccine against COVID-19 approved by ANVISA, be aware and agree to be able to receive them only 15 days after the intervention proposed in this study

Exclusion Criteria:

1. Professionals with a history of SARS-CoV-2 confirmed infection through RT-PCR or who have already presented clinical and molecular diagnosis of COVID-19 prior to the study
2. Individuals who have not underwent confirmatory tests for COVID-19
3. Breastfeeding
4. Individuals with primary or acquired immunodeficiency
5. Individuals affected by malignant neoplasms
6. Patients treated with high-dose corticosteroids (equivalent to the prednisone dose of 20 mg/day or more) for more than two weeks
7. Patients using other immunosuppressive therapies (antineoplastic chemotherapy, radiotherapy, among others)
8. Individuals with autoimmune diseases
9. Dermatological conditions at the vaccine site or generalized
10. Individuals under treatment for active tuberculosis
11. Individuals with a history of previous tuberculosis treatment
12. Individuals with febrile symptoms [body temperature ≥ 37.5 celsius degree (ºC) in the last 48h]
13. Participation in other prevention clinical trials for COVID-19 (vaccines already approved by ANVISA for use by the National Immunization Program are not included in this item)
14. Report of vaccination with live microorganism administered in the month prior to randomization
15. Require that, if another vaccination with live microorganism is required, it is administered in the month following randomisation (If the other live vaccine can be administered on the same day, this exclusion criterion does not apply)
16. Known anaphylactic reaction to any ingredient in BCG vaccine
17. Adverse reaction prior to BCG vaccine [significant local reaction (abscess) or suppurative lymphadenitis]
18. BCG vaccine administered in the last year

Contacts and Locations

Locations

Brazil

Universidade Federal do Rio de Janeiro

Rio De Janeiro, RJ, Brazil, 21941-590

Sponsors and Collaborators

Universidade Federal do Rio de Janeiro

Ministry of Science and Technology, Brazil

Investigators

• Principal Investigator: Fernanda Carvalho de Q Mello, PHD; Universidade Federal do Rio de Janeiro

  Study Documents (Full-Text)

Documents provided by JOSE ROBERTO LAPA E SILVA, Universidade Federal do Rio de Janeiro:

Study Protocol and Statistical Analysis Plan  [PDF] September 30, 2021

Informed Consent Form  [PDF] September 30, 2021

More Information

Publications:

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.

Goodridge HS, Ahmed SS, Curtis N, Kollmann TR, Levy O, Netea MG, Pollard AJ, van Crevel R, Wilson CB. Harnessing the beneficial heterologous effects of vaccination. Nat Rev Immunol. 2016 Jun;16(6):392-400. doi: 10.1038/nri.2016.43. Epub 2016 May 9.

Kleinnijenhuis J, Quintin J, Preijers F, Benn CS, Joosten LA, Jacobs C, van Loenhout J, Xavier RJ, Aaby P, van der Meer JW, van Crevel R, Netea MG. Long-lasting effects of BCG vaccination on both heterologous Th1/Th17 responses and innate trained immunity. J Innate Immun. 2014;6(2):152-8. doi: 10.1159/000355628. Epub 2013 Oct 30.

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.

Channappanavar R, Zhao J, Perlman S. T cell-mediated immune response to respiratory coronaviruses. Immunol Res. 2014 Aug;59(1-3):118-28. doi: 10.1007/s12026-014-8534-z.

Netea MG, Giamarellos-Bourboulis EJ, Dominguez-Andres J, Curtis N, van Crevel R, van de Veerdonk FL, Bonten M. Trained Immunity: a Tool for Reducing Susceptibility to and the Severity of SARS-CoV-2 Infection. Cell. 2020 May 28;181(5):969-977. doi: 10.1016/j.cell.2020.04.042. Epub 2020 May 4.

Ozdemir C, Kucuksezer UC, Tamay ZU. Is BCG vaccination affecting the spread and severity of COVID-19? Allergy. 2020 Jul;75(7):1824-1827. doi: 10.1111/all.14344. Epub 2020 May 12. No abstract available.

Urashima M, Otani K, Hasegawa Y, Akutsu T. BCG Vaccination and Mortality of COVID-19 across 173 Countries: An Ecological Study. Int J Environ Res Public Health. 2020 Aug 3;17(15):5589. doi: 10.3390/ijerph17155589.

• Responsible Party: JOSE ROBERTO LAPA E SILVA, MD, MSc, PhD, Universidade Federal do Rio de Janeiro
• ClinicalTrials.gov Identifier: NCT04659941
• Other Study ID Numbers: 31942220.8.1001.5257
• First Posted: December 9, 2020
• Last Update Posted: May 24, 2022
• Last Verified: May 2022

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: No

Keywords provided by JOSE ROBERTO LAPA E SILVA, Universidade Federal do Rio de Janeiro:

COVID 19; BCG vaccine

Additional relevant MeSH terms:

COVID-19; BCG Vaccine; Respiratory Tract Infections; Infections; Pneumonia, Viral; Pneumonia; Virus Diseases; Coronavirus Infections; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Lung Diseases; Respiratory Tract Diseases; Adjuvants, Immunologic; Immunologic Factors; Physiological Effects of Drugs