A Multi-Centre, Randomised, Double-Blind, Placebo-Controlled Phase III Clinical Trial Evaluating the Impact of BCG Re-Vaccination on the Incidence and Severity of SARS-CoV-2 Infections among Symptomatic Healthcare Professionals during the COVID-19 Pandemic in Poland—Evaluation of Antibody Concentrations
Abstract
:1. Introduction
2. Materials and Methods
2.1. Methods
2.2. Intervention
2.2.1. Outcome Measures
2.2.2. Allocation and Blinding
2.3. Serological Tests
2.4. Statistical Analysis
3. Results
4. Discussion
5. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
Abbreviations
BAU | Binding antibody units |
BCG | Bacillus Calmette–Guérin |
BMI | Body Mass Index |
COVID-19 | Coronavirus disease 2019 |
e-CRF | electronic Case Report Form |
ELISA | Enzyme-linked immunosorbent assay |
IgG | Immunoglobulin G |
PCR | Polymerase chain reaction |
RU | Relative units |
SARS-CoV-2 | Severe acute respiratory syndrome coronavirus 2 |
TB | Tuberculosis |
Th1 | T helper type 1 |
Th17 | T helper type 17 |
WHO | World Health Organisation |
References
- World Health Organization. Global Tuberculosis Report 2021; World Health Organization: Geneva, Switzerland, 2021. [Google Scholar]
- World Health Organization. Recommendations to Assure the Quality, Safety and Efficacy of BCG Vaccines; World Health Organization: Geneva, Switzerland, 2011. [Google Scholar]
- Zwerling, A.; Behr, M.A.; Verma, A.; Brewer, T.F.; Menzies, D.; Pai, M. The BCG World Atlas: A database of global BCG vaccination policies and practices. PLoS Med. 2011, 8, e1001012. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Magdzik, W.; Naruszewicz-Lesiuk, D.; Zieliński, A. Wakcynologia, 2nd ed.; Alfa Medica Press: Bielsko-Biała, Poland, 2007. [Google Scholar]
- Weng, C.H.; Saal, A.; Butt, W.W.; Bica, N.; Fisher, J.Q.; Tao, J.; Chan, P.A. Bacillus Calmette-Guérin vaccination and clinical characteristics and outcomes of COVID-19 in Rhode Island, United States: A cohort study. Epidemiol. Infect. 2020, 148, e140. [Google Scholar] [CrossRef] [PubMed]
- Garly, M.L.; Martins, C.L.; Balé, C.; Baldé, M.A.; Hedegaard, K.L.; Gustafson, P.; Lisse, I.M.; Whittle, H.C.; Aaby, P. BCG scar and positive tuberculin reaction associated with reduced child mortality in West Africa. A non-specific beneficial effect of BCG? Vaccine 2003, 21, 2782–2790. [Google Scholar] [CrossRef] [PubMed]
- Stensballe, L.G.; Sørup, S.; Aaby, P.; Benn, C.S.; Greisen, G.; Jeppesen, D.L.; Birk, N.M.; Kjærgaard, J.; Nissen, T.N.; Pihl, G.T.; et al. BCG vaccination at birth and early childhood hospitalisation: A randomised clinical multicentre trial. Arch. Dis. Child. 2017, 102, 224–231. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Aaby, P.; Roth, A.; Ravn, H.; Napirna, B.M.; Rodrigues, A.; Lisse, I.M.; Stensballe, L.; Diness, B.R.; Lausch, K.R.; Lund, N.; et al. Randomized trial of BCG vaccination at birth to low-birth-weight children: Beneficial nonspecific effects in the neonatal period? J. Infect. Dis. 2011, 204, 245–252. [Google Scholar] [CrossRef]
- Netea, M.G.; Joosten, L.A.; Latz, E.; Mills, K.H.; Natoli, G.; Stunnenberg, H.G.; O’Neill, L.A.; Xavier, R.J. Trained immunity: A program of innate immune memory in health and disease. Science 2016, 352, aaf1098. [Google Scholar] [CrossRef] [Green Version]
- Badurdeen, S.; Marshall, A.; Daish, H.; Hatherill, M.; Berkley, J.A. Safety and Immunogenicity of Early Bacillus Calmette-Guérin Vaccination in Infants Who Are Preterm and/or Have Low Birth Weights: A Systematic Review and Meta-analysis. JAMA Pediatr. 2019, 173, 75–85. [Google Scholar] [CrossRef]
- Leentjens, J.; Kox, M.; Stokman, R.; Gerretsen, J.; Diavatopoulos, D.A.; van Crevel, R.; Rimmelzwaan, G.F.; Pickkers, P.; Netea, M.G. BCG Vaccination Enhances the Immunogenicity of Subsequent Influenza Vaccination in Healthy Volunteers: A Randomized, Placebo-Controlled Pilot Study. J. Infect. Dis. 2015, 212, 1930–1938. [Google Scholar] [CrossRef] [Green Version]
- Hensel, J.; McAndrews, K.M.; McGrail, D.J.; Dowlatshahi, D.P.; LeBleu, V.S.; Kalluri, R. Exercising caution in correlating COVID-19 incidence and mortality rates with BCG vaccination policies due to variable rates of SARS CoV-2 testing. medRxiv 2020. [Google Scholar] [CrossRef] [Green Version]
- Czajka, H.; Zapolnik, P.; Krzych, Ł.; Kmiecik, W.; Stopyra, L.; Nowakowska, A.; Jackowska, T.; Darmochwał-Kolarz, D.; Szymański, H.; Radziewicz-Winnicki, I.; et al. A Multi-Center, Randomised, Double-Blind, Placebo-Controlled Phase III Clinical Trial Evaluating the Impact of BCG Re-Vaccination on the Incidence and Severity of SARS-CoV-2 Infections among Symptomatic Healthcare Professionals during the COVID-19 Pandemic in Poland—First Results. Vaccines 2022, 10, 314. [Google Scholar] [CrossRef]
- Clinical Trial Evaluating the Effect of BCG Vaccination on the Incidence and Severity of SARS-CoV-2 Infections Among Healthcare Professionals During the COVID-19 Pandemic in Poland. Available online: https://www.clinicaltrials.gov/ct2/show/NCT04648800 (accessed on 12 April 2022).
- Amirlak, L.; Haddad, R.; Hardy, J.D.; Khaled, N.S.; Chung, M.H.; Amirlak, B. Effectiveness of booster BCG vaccination in preventing COVID-19 infection. Hum. Vaccines Immunother. 2021, 17, 3913–3915. [Google Scholar] [CrossRef]
- Khanum, I.; Kumar, L.; Awan, S.; Jamil, B. Severity of COVID-19 in bacillus Calmette-Guérin vaccinated population. Clin. Exp. Vaccine Res. 2021, 10, 276–281. [Google Scholar] [CrossRef]
- Torun, S.; Ozkaya, S.; Şen, N.; Kanat, F.; Karaman, I.; Yosunkaya, S.; Sengoren Dikis, O.; Asan, A.; Aydogan Eroglu, S.; Semih Atal, S.; et al. The Relationship between COVID-19 Severity and Bacillus Calmette-Guérin (BCG)/ Mycobacterium tuberculosis exposure history in healthcare workers: A multi-center study. Pathog. Glob. Health 2021, 115, 405–411. [Google Scholar] [CrossRef]
- Netea, M.G.; Giamarellos-Bourboulis, E.J.; Domínguez-Andrés, J.; Curtis, N.; van Crevel, R.; van de Veerdonk, F.L.; Bonten, M. Trained Immunity: A Tool for Reducing Susceptibility to and the Severity of SARS-CoV-2 Infection. Cell 2020, 181, 969–977. [Google Scholar] [CrossRef]
- Rivas, M.N.; Ebinger, J.E.; Wu, M.; Sun, N.; Braun, J.; Sobhani, K.; Van Eyk, J.E.; Cheng, S.; Arditi, M. BCG vaccination history associates with decreased SARS-CoV-2 seroprevalence across a diverse cohort of health care workers. J. Clin. Investig. 2021, 131, e145157. [Google Scholar] [CrossRef]
- Tsilika, M.; Taks, E.; Dolianitis, K.; Kotsaki, A.; Leventogiannis, K.; Damoulari, C.; Kostoula, M.; Paneta, M.; Adamis, G.; Papanikolaou, I.C.; et al. Activate-2: A Double-Blind Randomized Trial of Bcg Vaccination Against COVID19 in Individuals at Risk. medRxiv 2021. [Google Scholar] [CrossRef]
- Uysal, E.B.; Gümüş, S.; Bektöre, B.; Bozkurt, H.; Gözalan, A. Evaluation of antibody response after COVID-19 vaccination of healthcare workers. J. Med. Virol. 2022, 94, 1060–1066. [Google Scholar] [CrossRef]
- Dos Anjos, L.R.B.; da Costa, A.C.; Cardoso, A.D.R.O.; Guimarães, R.A.; Rodrigues, R.L.; Ribeiro, K.M.; Borges, K.C.M.; Carvalho, A.C.O.; Dias, C.I.S.; Rezende, A.O.; et al. Efficacy and Safety of BCG Revaccination with M. bovis BCG Moscow to Prevent COVID-19 Infection in Health Care Workers: A Randomized Phase II Clinical Trial. Front. Immunol. 2022, 13, 841868. [Google Scholar] [CrossRef]
- Jalalizadeh, M.; Buosi, K.; Dionato, F.A.V.; Dal Col, L.S.B.; Giacomelli, C.F.; Ferrari, K.L.; Pagliarone, A.C.; Leme, P.A.F.; Maia, C.L.; Yadollahvandmiandoab, R.; et al. Randomized clinical trial of BCG vaccine in patients with convalescent COVID-19: Clinical evolution, adverse events, and humoral immune response. J. Intern Med. 2022, 292, 654–666. [Google Scholar] [CrossRef]
- Dionato, F.A.V.; Jalalizadeh, M.; Buosi, K.; Visacri, M.B.; Dal Col, L.S.B.; Giacomelli, C.F.; Leme, P.A.F.; Maia, C.L.; Moriel, P.; Reis, L. BCG vaccine safety in COVID-19 convalescent adults: BATTLE a randomized controlled trial. Vaccine 2022, 40, 4603–4608. [Google Scholar] [CrossRef]
- Moorlag, S.J.C.F.M.; Taks, E.; Ten Doesschate, T.; van der Vaart, T.W.; Janssen, A.B.; Müller, L.; Ostermann, P.; Dijkstra, H.; Lemmers, H.; Simonetti, E.; et al. Efficacy of BCG Vaccination Against Respiratory Tract Infections in Older Adults During the Coronavirus Disease 2019 Pandemic. Clin. Infect Dis. 2022, 75, e938–e946. [Google Scholar] [CrossRef] [PubMed]
- Ten Doesschate, T.; van der Vaart, T.W.; Debisarun, P.A.; Taks, E.; Moorlag, S.J.C.F.M.; Paternotte, N.; Boersma, W.G.; Kuiper, V.P.; Roukens, A.H.E.; Rijnders, B.J.A.; et al. Bacillus Calmette-Guérin vaccine to reduce healthcare worker absenteeism in COVID-19 pandemic, a randomized controlled trial. Clin. Microbiol. Infect. 2022, 28, 1278–1285. [Google Scholar] [CrossRef] [PubMed]
- Faustman, D.L.; Lee, A.; Hostetter, E.R.; Aristarkhova, A.; Ng, N.C.; Shpilsky, G.F.; Tran, L.; Wolfe, G.; Takahashi, H.; Dias, H.F.; et al. Multiple BCG vaccinations for the prevention of COVID-19 and other infectious diseases in type 1 diabetes. Cell. Rep. Med. 2022, 3, 100728. [Google Scholar] [CrossRef] [PubMed]
- Pittet, L.F.; Messina, N.L.; Gardiner, K.; Orsini, F.; Abruzzo, V.; Bannister, S.; Bonten, M.; Campbell, J.L.; Croda, J.; Dalcolmo, M.; et al. BCG vaccination to reduce the impact of COVID-19 in healthcare workers: Protocol for a randomised controlled trial (BRACE trial). BMJ Open. 2021, 11, e052101. [Google Scholar] [CrossRef] [PubMed]
- Netea, M.G.; van der Meer, J.W.; van Crevel, R. BCG vaccination in health care providers and the protection against COVID-19. J. Clin. Investig. 2021, 131, e145545. [Google Scholar] [CrossRef]
- Moreno Fernández-Ayala, D.J.; Navas, P.; López-Lluch, G. Age-related mitochondrial dysfunction as a key factor in COVID-19 disease. Exp. Gerontol. 2020, 142, 111147. [Google Scholar] [CrossRef]
- Gibellini, L.; De Biasi, S.; Paolini, A.; Borella, R.; Boraldi, F.; Mattioli, M.; Lo Tartaro, D.; Fidanza, L.; Caro-Maldonado, A.; Meschiari, M.; et al. Altered bioenergetics and mitochondrial dysfunction of monocytes in patients with COVID-19 pneumonia. EMBO Mol. Med. 2020, 12, e13001. [Google Scholar] [CrossRef]
- Gvozdjakova, A.; Klauco, F.; Kucharska, J.; Sumbalova, Z. Is mitochondrial bioenergetics and coenzyme Q10 the target of a virus causing COVID-19? Br. Lek Listy 2020, 121, 775–778. [Google Scholar] [CrossRef]
- Rashidzadeh, H.; Danafar, H.; Rahimi, H.; Mozafari, F.; Salehiabar, M.; Rahmati, M.A.; Rahamooz-Haghighi, S.; Mousazadeh, N.; Mohammadi, A.; Ertas, Y.N.; et al. Nanotechnology against the novel coronavirus (severe acute respiratory syndrome coronavirus 2): Diagnosis, treatment, therapy and future perspectives. Nanomedicine 2021, 16, 497–516. [Google Scholar] [CrossRef]
Groups of Patients | Number of Participants from V6 | Mean from V6 [BAU/mL] | SD from V6 [BAU/mL] | Number of Participants from V7 | Mean from V7 [BAU/mL] | SD from V7 [BAU/mL] |
---|---|---|---|---|---|---|
Group 1 (RT23+) Group 2 (BCG) Group 3 (Placebo) | 156 | 1277.39 | 1550.63 | 88 | 482.22 | 1432.77 |
100 | 1344.88 | 1728.23 | 55 | 446.87 | 787.49 | |
96 | 1172.91 | 1099.58 | 57 | 336.93 | 304.54 | |
Total | 352 | 1268.07 | 1495.21 | 200 | 431.09 | 1046.71 |
Age | Number of Participants from V6 | Mean from V6 [BAU/mL] | SD from V6 [BAU/mL] | Number of Participants from V7 | Mean from V7 [BAU/mL] | SD from V7 [BAU/mL] |
---|---|---|---|---|---|---|
<35 35–50 >50 | 92 | 1261.38 | 959.50 | 44 | 321.81 | 254.83 |
126 | 1117.29 | 1348.51 | 71 | 337.95 | 571.73 | |
134 | 1414.44 | 1875.62 | 85 | 565.47 | 1502.68 | |
Total | 352 | 1268.07 | 1495.21 | 200 | 431.09 | 1046.71 |
BMI | Number of Participants from V6 | Mean from V6 [BAU/mL] | SD from V6 [BAU/mL] | Number of Participants from V7 | Mean from V7 [BAU/mL] | SD from V7 [BAU/mL] |
---|---|---|---|---|---|---|
<18.5 18.5–24.99 25–29.99 | 13.00 | 943.02 | 753.94 | 5.00 | 414.94 | 398.73 |
196.00 | 1273.79 | 1336.41 | 102.00 | 283.27 | 375.96 | |
93.00 | 1292.84 | 1910.24 | 60.00 | 649.88 | 1765.92 | |
Total | 352 | 1268.07 | 1495.21 | 200 | 431.09 | 1046.71 |
BMI/Gender | Number of Participants from V6 | Mean from V6 [BAU/mL] | SD from V6 [BAU/mL] | Number of Participants from V7 | Mean from V7 [BAU/mL] | SD from V7 [BAU/mL] |
---|---|---|---|---|---|---|
<18.5 | 13.00 | 943.02 | 753.94 | 5.00 | 414.94 | 398.73 |
Women | 12.00 | 947.04 | 787.32 | 5.00 | 414.94 | 398.73 |
Men | 1.00 | 894.78 | - | - | - | - |
18.5–24.99 | 196.00 | 1273.79 | 1336.41 | 102.00 | 283.27 | 375.96 |
Women | 172.00 | 1318.35 | 1397.67 | 94.00 | 293.06 | 389.06 |
Men | 24.00 | 954.42 | 704.98 | 8.00 | 168.24 | 109.09 |
25–29.99 | 93.00 | 1292.84 | 1910.24 | 60.00 | 649.88 | 1765.92 |
Women | 67.00 | 1356.79 | 2152.80 | 46.00 | 774.45 | 2000.45 |
Men | 26,00 | 1128.03 | 1074.22 | 14.00 | 240.60 | 255.80 |
>30 | 50.00 | 1284.09 | 1373.70 | 33.00 | 492.65 | 659.00 |
Women | 37.00 | 1319.34 | 1522.36 | 24.00 | 524.64 | 744.98 |
Men | 13.00 | 1183.78 | 859.10 | 9.00 | 407.33 | 360.91 |
Total | 352.00 | 1268.07 | 1495.21 | 200.00 | 431.09 | 1046.71 |
Age/BMI/Gender | Number of Participants from V6 | Mean from V6 [BAU/mL] | SD from V6 [BAU/mL] | Number of Participants from V7 | Mean from V7 [BAU/mL] | SD from V7 [BAU/mL] |
---|---|---|---|---|---|---|
<35 | 92 | 1261.38 | 959.50 | 44 | 321.81 | 254.83 |
<18.5 | 9 | 1008.14 | 736.35 | 3 | 601.88 | 421.18 |
Women | 8 | 1022.31 | 785.88 | 3 | 601.88 | 421.18 |
Men | 1 | 894.78 | - | - | - | - |
18.5–24.99 | 69 | 1312.76 | 1021.79 | 31 | 305.68 | 244.79 |
Women | 57 | 1359.62 | 1067.24 | 27 | 317.84 | 257.14 |
Men | 12 | 1090.16 | 768.17 | 4 | 223.66 | 125.92 |
25–29.99 | 10 | 1175.19 | 575.39 | 7 | 263.55 | 197.79 |
Women | 6 | 885.99 | 448.30 | 4 | 234.27 | 203.88 |
Men | 4 | 1608.99 | 489,98 | 3 | 302.60 | 225.87 |
>30 | 4 | 1160.26 | 1237.03 | 3 | 344.32 | 261.23 |
Women | 1 | 400.00 | - | - | - | - |
Men | 3 | 1413.67 | 1382.04 | 3 | 344.32 | 261.23 |
35–50 | 126 | 1117.29 | 1348.51 | 71 | 337.95 | 571.73 |
<18.5 | 3 | 1012,11 | 949.11 | 1 | 232.17 | - |
0 | 3 | 1012.11 | 949.11 | 1 | 232.17 | - |
18.5–24.99 | 70 | 1029.84 | 915.13 | 37 | 212.02 | 154.34 |
Women | 62 | 1032.03 | 944.84 | 34 | 218.41 | 159.35 |
Men | 8 | 1012.82 | 689.23 | 3 | 139.63 | 35.68 |
25–29.99 | 30 | 1291.84 | 2258.60 | 16 | 539.74 | 1117.97 |
Women | 21 | 1380.08 | 2682.26 | 13 | 552.58 | 1235.48 |
Men | 9 | 1085.95 | 661.59 | 3 | 484.12 | 458.15 |
>30 | 23 | 1169.50 | 910.56 | 17 | 428.31 | 343.43 |
Women | 17 | 1143.50 | 955.37 | 12 | 397.72 | 313.33 |
Men | 6 | 1243.15 | 847.70 | 5 | 501.75 | 438.45 |
>50 | 134 | 1414.44 | 1875.62 | 85 | 565.47 | 1502.68 |
<18.5 | 1 | 149.71 | - | 1 | 36.89 | - |
0 | 1 | 149.71 | - | 1 | 36.89 | - |
18.5–24.99 | 57 | 1526.21 | 1943.78 | 34 | 340.36 | 585.33 |
Women | 53 | 1608.91 | 1991.09 | 33 | 349.70 | 591.83 |
Men | 4 | 430.39 | 298.82 | 1 | 32.41 | - |
25–29.99 | 53 | 1315.60 | 1884.29 | 37 | 770.60 | 2129.36 |
Women | 40 | 1415.18 | 2022.37 | 29 | 948.41 | 2382.63 |
Men | 13 | 1009.18 | 1399.46 | 8 | 126.03 | 70.05 |
>30 | 23 | 1420.23 | 1768.99 | 13 | 611.01 | 981.27 |
Women | 19 | 1525.05 | 1924.32 | 12 | 651.57 | 1013.46 |
Men | 4 | 922.31 | 574.54 | 1 | 124.30 | - |
Total | 352 | 1268.07 | 1495.21 | 200 | 431.09 | 1046.71 |
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content. |
© 2022 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
Share and Cite
Zapolnik, P.; Kmiecik, W.; Nowakowska, A.; Krzych, Ł.J.; Szymański, H.; Stopyra, L.; Jackowska, T.; Darmochwał-Kolarz, D.; Mazur, A.; Czajka, H. A Multi-Centre, Randomised, Double-Blind, Placebo-Controlled Phase III Clinical Trial Evaluating the Impact of BCG Re-Vaccination on the Incidence and Severity of SARS-CoV-2 Infections among Symptomatic Healthcare Professionals during the COVID-19 Pandemic in Poland—Evaluation of Antibody Concentrations. Vaccines 2023, 11, 75. https://doi.org/10.3390/vaccines11010075
Zapolnik P, Kmiecik W, Nowakowska A, Krzych ŁJ, Szymański H, Stopyra L, Jackowska T, Darmochwał-Kolarz D, Mazur A, Czajka H. A Multi-Centre, Randomised, Double-Blind, Placebo-Controlled Phase III Clinical Trial Evaluating the Impact of BCG Re-Vaccination on the Incidence and Severity of SARS-CoV-2 Infections among Symptomatic Healthcare Professionals during the COVID-19 Pandemic in Poland—Evaluation of Antibody Concentrations. Vaccines. 2023; 11(1):75. https://doi.org/10.3390/vaccines11010075
Chicago/Turabian StyleZapolnik, Paweł, Wojciech Kmiecik, Anna Nowakowska, Łukasz Jerzy Krzych, Henryk Szymański, Lidia Stopyra, Teresa Jackowska, Dorota Darmochwał-Kolarz, Artur Mazur, and Hanna Czajka. 2023. "A Multi-Centre, Randomised, Double-Blind, Placebo-Controlled Phase III Clinical Trial Evaluating the Impact of BCG Re-Vaccination on the Incidence and Severity of SARS-CoV-2 Infections among Symptomatic Healthcare Professionals during the COVID-19 Pandemic in Poland—Evaluation of Antibody Concentrations" Vaccines 11, no. 1: 75. https://doi.org/10.3390/vaccines11010075
APA StyleZapolnik, P., Kmiecik, W., Nowakowska, A., Krzych, Ł. J., Szymański, H., Stopyra, L., Jackowska, T., Darmochwał-Kolarz, D., Mazur, A., & Czajka, H. (2023). A Multi-Centre, Randomised, Double-Blind, Placebo-Controlled Phase III Clinical Trial Evaluating the Impact of BCG Re-Vaccination on the Incidence and Severity of SARS-CoV-2 Infections among Symptomatic Healthcare Professionals during the COVID-19 Pandemic in Poland—Evaluation of Antibody Concentrations. Vaccines, 11(1), 75. https://doi.org/10.3390/vaccines11010075