Performance Evaluation of BCG Vaccination in Healthcare Personnel to Reduce the Severity of COVID-19 Infection.

COVID-19 Clinical Trial

Official title:

Performance Evaluation of BCG Vaccination in Healthcare Personnel to Reduce the Severity of SARS-COV-2 Infection in Medellín, Colombia, 2020

Clinical Trial Details — Status: Withdrawn

Administrative data

• NCT number: NCT04362124
• Other study ID #: PEC03_2020
• Status: Withdrawn
• Phase: Phase 3
• Start date: August 2020
• Est. completion date: November 2021

Study information

• Verified date: April 2020
• Source: Universidad de Antioquia
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

Until the first half of April, Colombia has more than 2,800 infected cases and a hundred deaths as a result of COVID-19, with Antioquia being the third department with the highest number of cases. Official records indicate that, in Colombia, the first case was diagnosed on March 6, 2020, corresponding to a patient from Italy. However, in conversations with several infectologists and intensivists from Medellín, it was agreed that clinical cases similar to the clinical presentation that is now recognized as COVID-19 had arisen since the end of 2019 when it was still unknown to everyone. The previous suggests that the virus was already circulating in the country since before March 6, 2020. But at that moment, there were no tools to make a clinical identification, nor to diagnose it from the laboratory's point of view.

Considering as real the hypothesis that the infection has been circulating in the country since before the first official diagnosis, the question arises: Why does not the country still has the same healthcare and humanitarian chaos that countries such as Italy and Spain are suffering at this time? To answer this question may be that there are differences in vaccination rates with BCG (Bacille Calmette-Guérin or tuberculosis vaccine), which is significantly higher in Latin America compared to those in Europe. This finding could explain to some extent the situation in the country, since previous studies have shown the influence that this vaccine can have on the immune response against various other pathogens, including viruses.

Among the population at risk of infection, health-care workers due to their permanent contact with patients are the population group with the highest risk of contracting SARS-Cov-2 and developing COVID-19 in any of its clinical manifestations, and currently there are no vaccines or proven preventive interventions available to protect them.

For this reason, this research study aims to demonstrate whether the centennial vaccine against tuberculosis (BCG), a bacterial disease, can activate the human immune system in a broad way, allowing it to better combat the coronavirus that causes COVID-19 and, perhaps, prevents the complications that lead the patient to the intensive care unit and death.

In the future, and if these results are as expected, they may be the basis for undertaking a population vaccination campaign that improves clinical outcomes in the general population.

Description:

Problem Statement

To date, Colombia has more than 2,800 infected cases and a hundred deaths as a result of COVID-19, with Antioquia being the third department with the highest number of cases (1). Official records indicate that, in Colombia, the first case was diagnosed on March 6, 2020, corresponding to a patient from Italy. However, in conversations with several infectologists and intensivists from Medellín, it was agreed that clinical cases similar to the clinical presentation that is now recognized as COVID-19 had arisen since the end of 2019 when it was still unknown to everyone. The previous suggests that the virus was already circulating in the country since before March 6, 2020. But at that moment, there were no tools to make a clinical identification, nor to diagnose it from the laboratory's point of view. This theory has been gathering momentum in other latitudes, demonstrating how the asymptomatic infected individuals are responsible for spreading the infection .

Considering as real the hypothesis that the infection has been circulating in the country since before the first official diagnosis, the question arises: Why does not the country still has the same healthcare and humanitarian chaos that countries such as Italy and Spain are suffering at this time? To answer this question, an extensive literature search of factors that differentiate Europeans from Latin Americans was carried out. Finding, in addition to genetic factors specific to race, differences in the number of ACEI receptors (binding site of the coronavirus to the alveolus), and differences in vaccination rates with BCG (Bacille Calmette-Guérin or tuberculosis vaccine), which is significantly higher in Latin America compared to those in Europe (3). This last finding could explain to some extent the situation in the country, since previous studies have shown the influence that this vaccine can have on the immune response against various other pathogens, including viruses (4,5).

Among the population at risk of infection, health-care workers due to their permanent contact with patients are the population group with the highest risk of contracting SARS-Cov-2 and developing COVID-19 in any of its clinical manifestations.

Currently, there are no vaccines or proven preventive interventions available to protect health-care workers. However, researchers from Germany, the Netherlands, Australia, and France are working on a clinical trial with an unorthodox approach to combat this new virus. This research study aims to demonstrate whether the centennial vaccine against tuberculosis (BCG), a bacterial disease, can activate the human immune system in a broad way, allowing it to better combat the coronavirus that causes COVID-19 and, perhaps, prevents the complications that lead the patient to the intensive care unit and death. Initially, studies in these four countries will be carried out on doctors and nurses, since they are the ones with a higher risk of becoming infected compared to the general population.

Currently, the available evidence supports the hypothesis that BCG vaccination has beneficial heterologous effects against viral, bacterial, and fungal infections. The basis of these effects has been little explored in humans; however, this knowledge opens the door to future research to explore the effect of "trained immunity" associated with this vaccine, both for diseases in hosts with immunological disorders, and for autoinflammatory diseases, in which there is an inappropriate activation of inflammation (21). All of the findings described have considerable potential to aid in the design of new therapeutic strategies, such as the use of old and new vaccines that combine classical immune memory, and the activation of innate immunity by "trained immunity," for prevention and treatment of infections, and modulation of exaggerated inflammation in autoinflammatory diseases.

A multicenter, double-blind, randomized, phase III clinical trial will be carried out. 1000 healthy healthcare workers (doctors, nurses, and nursing assistants) with a negative test for COVID-19 and asymptomatic for the disease will be randomly assigned to receive one dose of BGC vaccine or placebo (saline solution). Volunteers will be followed for one year.

Hypothesis Healthcare workers who have negative SARS-Cov-2 serology and who receive the BCG vaccine, have a better clinical outcome if they become infected with COVID-19, in terms of not getting sick, requiring hospitalization or dying, than those who do not receive the vaccine.

Objectives

Overall Objective

Evaluate the performance of BCG vaccination in reducing the severity of SARS-COV-2 infection compared to the placebo, in healthcare personnel from Medellín, Colombia.

. Specific Objectives

• Determine if there are differences in the clinical outcome in terms of not getting sick, requiring hospitalization, or dying in both treatment groups.

• Estimate previous exposure of healthcare personnel to SARS-Cov-2 by conducting rapid tests that measure IgG and IgM immunity.

• Assess the safety (frequency, seriousness, and severity of adverse events) of BCG vaccination in an adult population.

• Estimate SARS-Cov-2 infection in healthcare personnel at the end of the study, by performing rapid tests that measure IgG and IgM immunity.

Recruitment information / eligibility

• Status: Withdrawn
• Enrollment: 0
• Est. completion date: November 2021
• Est. primary completion date: June 2021
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 18 Years to 65 Years

Eligibility

Inclusion criteria

• Men and women

• Between =18 and = 65 years old

• Healthcare workers (doctors, nurses and nursing assistants) from clinics and hospitals in Medellín, who are directly involved in the care of patients with COVID-19

• A negative test for COVID-19 and being asymptomatic at baseline

• Are able and willing to give signed informed consent (Subjects whom the investigator believes are able to understand and are willing to comply with the requirements of the protocol)

Exclusion Criteria

• Have a previous diagnosis (probable or confirmed) of COVID-19

• Immunosuppression (pharmacological or clinical)

• Are taking immunosuppressive medications

• Pregnant or lactating women; or women of childbearing age who do not agree to take contraceptives during the month following vaccination.

• Have received any live or replicative vaccine one month before the time of screening.

• Permanent teleworking activity.

• History of active tuberculosis

• Currently are receiving Hydroxychloroquine, Chloroquine, Lopinavir/ritonavir, Tocilizumab, or Azithromycin.

• Known or suspected history of hypersensitivity to vaccines.

• Patients who do not wish to attend or who cannot keep up with the follow-up visits.

Related Conditions & MeSH terms

• COVID-19
• Infection

Intervention

Biological:
• vaccine BCG
Performance evaluation of a single dose of BCG vaccine in reducing the severity of SARS-COV-2 infection compared to placebo, in healthcare personnel.

Other:
• Placebo
A single dose intradermal application of normal saline solution.

Locations

Country	Name	City	State
Colombia	Program for Research and Control in Tropical Diseases - PECET	Medellín	Antioquia

Sponsors (1)

Lead Sponsor	Collaborator
Universidad de Antioquia

Country where clinical trial is conducted

Colombia, 

References & Publications (18)

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. — View Citation

Bekkering S, Blok BA, Joosten LA, Riksen NP, van Crevel R, Netea MG. In Vitro Experimental Model of Trained Innate Immunity in Human Primary Monocytes. Clin Vaccine Immunol. 2016 Dec 5;23(12):926-933. Print 2016 Dec. Erratum in: Clin Vaccine Immunol. 2017 May 5;24(5):. — View Citation

Benn CS, Netea MG, Selin LK, Aaby P. A small jab - a big effect: nonspecific immunomodulation by vaccines. Trends Immunol. 2013 Sep;34(9):431-9. doi: 10.1016/j.it.2013.04.004. Epub 2013 May 14. Review. — View Citation

Brandau S, Riemensberger J, Jacobsen M, Kemp D, Zhao W, Zhao X, Jocham D, Ratliff TL, Böhle A. NK cells are essential for effective BCG immunotherapy. Int J Cancer. 2001 Jun 1;92(5):697-702. — View Citation

Jensen KJ, Larsen N, Biering-Sørensen S, Andersen A, Eriksen HB, Monteiro I, Hougaard D, Aaby P, Netea MG, Flanagan KL, Benn CS. Heterologous immunological effects of early BCG vaccination in low-birth-weight infants in Guinea-Bissau: a randomized-controlled trial. J Infect Dis. 2015 Mar 15;211(6):956-67. doi: 10.1093/infdis/jiu508. Epub 2014 Sep 9. — View Citation

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. — View Citation

Kleinnijenhuis J, Quintin J, Preijers F, Joosten LA, Ifrim DC, Saeed S, Jacobs C, van Loenhout J, de Jong D, Stunnenberg HG, Xavier RJ, van der Meer JW, van Crevel R, Netea MG. Bacille Calmette-Guerin induces NOD2-dependent nonspecific protection from reinfection via epigenetic reprogramming of monocytes. Proc Natl Acad Sci U S A. 2012 Oct 23;109(43):17537-42. doi: 10.1073/pnas.1202870109. Epub 2012 Sep 17. — View Citation

Kleinnijenhuis J, van Crevel R, Netea MG. Trained immunity: consequences for the heterologous effects of BCG vaccination. Trans R Soc Trop Med Hyg. 2015 Jan;109(1):29-35. doi: 10.1093/trstmh/tru168. Review. — View Citation

Li R, Pei S, Chen B, Song Y, Zhang T, Yang W, Shaman J. Substantial undocumented infection facilitates the rapid dissemination of novel coronavirus (SARS-CoV-2). Science. 2020 May 1;368(6490):489-493. doi: 10.1126/science.abb3221. Epub 2020 Mar 16. — View Citation

Moorlag SJCFM, Arts RJW, van Crevel R, Netea MG. Non-specific effects of BCG vaccine on viral infections. Clin Microbiol Infect. 2019 Dec;25(12):1473-1478. doi: 10.1016/j.cmi.2019.04.020. Epub 2019 May 2. Review. — View Citation

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. Review. — View Citation

Rusek P, Wala M, Druszczynska M, Fol M. Infectious Agents as Stimuli of Trained Innate Immunity. Int J Mol Sci. 2018 Feb 3;19(2). pii: E456. doi: 10.3390/ijms19020456. Review. — View Citation

Sakuma T, Suenaga T, Yoshida I, Azuma M. Mechanisms of enhanced resistance of Mycobacterium bovis BCG-treated mice to ectromelia virus infection. Infect Immun. 1983 Nov;42(2):567-73. — View Citation

Sher NA, Chaparas SD, Greenberg LE, Bernard S. Effects of BCG, Corynebacterium parvum, and methanol-extration residue in the reduction of mortality from Staphylococcus aureus and Candida albicans infections in immunosuppressed mice. Infect Immun. 1975 Dec;12(6):1325-30. — View Citation

Tribouley J, Tribouley-Duret J, Appriou M. [Effect of Bacillus Callmette Guerin (BCG) on the receptivity of nude mice to Schistosoma mansoni]. C R Seances Soc Biol Fil. 1978;172(5):902-4. French. — View Citation

Uthayakumar D, Paris S, Chapat L, Freyburger L, Poulet H, De Luca K. Non-specific Effects of Vaccines Illustrated Through the BCG Example: From Observations to Demonstrations. Front Immunol. 2018 Dec 4;9:2869. doi: 10.3389/fimmu.2018.02869. eCollection 2018. Review. — View Citation

Yamazaki-Nakashimada MA, Unzueta A, Berenise Gámez-González L, González-Saldaña N, Sorensen RU. BCG: a vaccine with multiple faces. Hum Vaccin Immunother. 2020 Aug 2;16(8):1841-1850. doi: 10.1080/21645515.2019.1706930. Epub 2020 Jan 29. — View Citation

Zwerling A, Behr MA, Verma A, Brewer TF, Menzies D, Pai M. The BCG World Atlas: a database of global BCG vaccination policies and practices. PLoS Med. 2011 Mar;8(3):e1001012. doi: 10.1371/journal.pmed.1001012. Epub 2011 Mar 22. — View Citation

* Note: There are 18 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Primary outcome	Incidence of COVID-19 cases confirmed or probable in the study population	From date of randomization to 360 day of the study
Secondary	Secondary outcome	Incidence of severe or critical infection in COVID-19 cases	From date to diagnosis to 1 month after
Secondary	Secondary outcome	Lethality of the infection in both groups	From date to diagnosis to 1 month after
Secondary	Secondary outcome	Assess the safety (frequency, seriousness, and severity of adverse events) of BCG vaccination	From date of randomization to 7 day of the study
Secondary	Secondary outcome	Prevalence of SARS-Cov-2 infection	At baseline evaluation

External Links

•   official report of the coronavirus in colombia