BCG Against Covid-19 for Prevention and Amelioration of Severity Trial (BAC to the PAST)

Summary

The purpose of this study is to assess the efficacy of Bacille Calmette-Guérin (BCG) vaccination compared to placebo in reducing severe Covid-19 disease among elderly residents of skilled nursing facilities. The investigators hypothesize that BCG vaccination can reduce severity of Covid-19 disease. Patients who are residents of participating long-term care facilities (LTCFs), with the ability to understand and cooperate with study procedures, who agree to participate in the study will be randomly assigned to receive BCG vaccination or a placebo. Participants will be followed for up to twelve months to assess severity of Covid-19 outcomes.

Timeline

Start

2021-09

Primary completion

2022-05

Completion

2022-07

Publications

• Background Wang D, Hu B, Hu C, Zhu F, Liu X, Zhang J, Wang B, Xiang H, Cheng Z, Xiong Y, Zhao Y, Li Y, Wang X, Peng Z. Clinical Characteristics of 138 Hospitalized Patients With 2019 Novel Coronavirus-Infected Pneumonia in Wuhan, China. JAMA. 2020 Mar 17;323(11):1061-1069. doi: 10.1001/jama.2020.1585.
• Background Wu C, Chen X, Cai Y, Xia J, Zhou X, Xu S, Huang H, Zhang L, Zhou X, Du C, Zhang Y, Song J, Wang S, Chao Y, Yang Z, Xu J, Zhou X, Chen D, Xiong W, Xu L, Zhou F, Jiang J, Bai C, Zheng J, Song Y. Risk Factors Associated With Acute Respiratory Distress Syndrome and Death in Patients With Coronavirus Disease 2019 Pneumonia in Wuhan, China. JAMA Intern Med. 2020 Jul 1;180(7):934-943. doi: 10.1001/jamainternmed.2020.0994.
• Background Chen T, Wu D, Chen H, Yan W, Yang D, Chen G, Ma K, Xu D, Yu H, Wang H, Wang T, Guo W, Chen J, Ding C, Zhang X, Huang J, Han M, Li S, Luo X, Zhao J, Ning Q. Clinical characteristics of 113 deceased patients with coronavirus disease 2019: retrospective study. BMJ. 2020 Mar 26;368:m1091. doi: 10.1136/bmj.m1091.
• Background Arentz M, Yim E, Klaff L, Lokhandwala S, Riedo FX, Chong M, Lee M. Characteristics and Outcomes of 21 Critically Ill Patients With COVID-19 in Washington State. JAMA. 2020 Apr 28;323(16):1612-1614. doi: 10.1001/jama.2020.4326.
• Background Cao J, Tu WJ, Cheng W, Yu L, Liu YK, Hu X, Liu Q. Clinical Features and Short-term Outcomes of 102 Patients with Coronavirus Disease 2019 in Wuhan, China. Clin Infect Dis. 2020 Jul 28;71(15):748-755. doi: 10.1093/cid/ciaa243.
• Background Basu-Ray I, Almaddah NK, Vaqar S, Soos MP. Cardiac Manifestations of Coronavirus (COVID-19). 2024 Feb 12. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2026 Jan-. Available from http://www.ncbi.nlm.nih.gov/books/NBK556152/
• Background Danzi GB, Loffi M, Galeazzi G, Gherbesi E. Acute pulmonary embolism and COVID-19 pneumonia: a random association? Eur Heart J. 2020 May 14;41(19):1858. doi: 10.1093/eurheartj/ehaa254. No abstract available.
• Background Zhang Y, Xiao M, Zhang S, Xia P, Cao W, Jiang W, Chen H, Ding X, Zhao H, Zhang H, Wang C, Zhao J, Sun X, Tian R, Wu W, Wu D, Ma J, Chen Y, Zhang D, Xie J, Yan X, Zhou X, Liu Z, Wang J, Du B, Qin Y, Gao P, Qin X, Xu Y, Zhang W, Li T, Zhang F, Zhao Y, Li Y, Zhang S. Coagulopathy and Antiphospholipid Antibodies in Patients with Covid-19. N Engl J Med. 2020 Apr 23;382(17):e38. doi: 10.1056/NEJMc2007575. Epub 2020 Apr 8.
• Background Klok FA, Kruip MJHA, van der Meer NJM, Arbous MS, Gommers DAMPJ, Kant KM, Kaptein FHJ, van Paassen J, Stals MAM, Huisman MV, Endeman H. Incidence of thrombotic complications in critically ill ICU patients with COVID-19. Thromb Res. 2020 Jul;191:145-147. doi: 10.1016/j.thromres.2020.04.013. Epub 2020 Apr 10.
• Background Alunno A, Carubbi F, Rodriguez-Carrio J. Storm, typhoon, cyclone or hurricane in patients with COVID-19? Beware of the same storm that has a different origin. RMD Open. 2020 May;6(1):e001295. doi: 10.1136/rmdopen-2020-001295.
• Background Salehi S, Abedi A, Balakrishnan S, Gholamrezanezhad A. Coronavirus Disease 2019 (COVID-19): A Systematic Review of Imaging Findings in 919 Patients. AJR Am J Roentgenol. 2020 Jul;215(1):87-93. doi: 10.2214/AJR.20.23034. Epub 2020 Mar 14.
• Background Stam HJ, Stucki G, Bickenbach J; European Academy of Rehabilitation Medicine. Covid-19 and Post Intensive Care Syndrome: A Call for Action. J Rehabil Med. 2020 Apr 15;52(4):jrm00044. doi: 10.2340/16501977-2677.
• Background Onder G, Rezza G, Brusaferro S. Case-Fatality Rate and Characteristics of Patients Dying in Relation to COVID-19 in Italy. JAMA. 2020 May 12;323(18):1775-1776. doi: 10.1001/jama.2020.4683. No abstract available.
• Background Richardson S, Hirsch JS, Narasimhan M, Crawford JM, McGinn T, Davidson KW; the Northwell COVID-19 Research Consortium; Barnaby DP, Becker LB, Chelico JD, Cohen SL, Cookingham J, Coppa K, Diefenbach MA, Dominello AJ, Duer-Hefele J, Falzon L, Gitlin J, Hajizadeh N, Harvin TG, Hirschwerk DA, Kim EJ, Kozel ZM, Marrast LM, Mogavero JN, Osorio GA, Qiu M, Zanos TP. Presenting Characteristics, Comorbidities, and Outcomes Among 5700 Patients Hospitalized With COVID-19 in the New York City Area. JAMA. 2020 May 26;323(20):2052-2059. doi: 10.1001/jama.2020.6775.
• Background Collaborative, T.O. OpenSAFELY: factors associated with COVID-19-related hospital death in the linked electronic health records of 17 million adult NHS patients. medRxiv, 2020.
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• Background Stensballe LG, Nante E, Jensen IP, Kofoed PE, Poulsen A, Jensen H, Newport M, Marchant A, Aaby P. Acute lower respiratory tract infections and respiratory syncytial virus in infants in Guinea-Bissau: a beneficial effect of BCG vaccination for girls community based case-control study. Vaccine. 2005 Jan 26;23(10):1251-7. doi: 10.1016/j.vaccine.2004.09.006.
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• Background Civil RH, Warren KS, Mahmoud AA. Conditions for bacille Calmette-Guerin-induced resistance to infection with Schistosoma mansoni in mice. J Infect Dis. 1978 May;137(5):550-5. doi: 10.1093/infdis/137.5.550.
• Background Smrkovski LL, Larson CL. Effect of treatment with BCG on the course of visceral leishmaniasis in BALB/c mice. Infect Immun. 1977 Apr;16(1):249-57. doi: 10.1128/iai.16.1.249-257.1977.
• Background Clark IA, Allison AC, Cox FE. Protection of mice against Babesia and Plasmodium with BCG. Nature. 1976 Jan 29;259(5541):309-11. doi: 10.1038/259309a0. No abstract available.
• Background Parra M, Liu X, Derrick SC, Yang A, Tian J, Kolibab K, Kumar S, Morris SL. Molecular analysis of non-specific protection against murine malaria induced by BCG vaccination. PLoS One. 2013 Jul 4;8(7):e66115. doi: 10.1371/journal.pone.0066115. Print 2013.
• Background van 't Wout JW, Poell R, van Furth R. The role of BCG/PPD-activated macrophages in resistance against systemic candidiasis in mice. Scand J Immunol. 1992 Nov;36(5):713-9. doi: 10.1111/j.1365-3083.1992.tb03132.x.
• Background 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.
• Background Werner GT. The effect of BCG-vaccination on vaccinia virus infections in mice. Experientia. 1979 Nov 15;35(11):1514-5. doi: 10.1007/BF01962818.
• Background Suenaga T, Okuyama T, Yoshida I, Azuma M. Effect of Mycobacterium tuberculosis BCG infection on the resistance of mice to ectromelia virus infection: participation of interferon in enhanced resistance. Infect Immun. 1978 Apr;20(1):312-4. doi: 10.1128/iai.20.1.312-314.1978.
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• Background Larson CL, Ushijima RN, Karim R, Baker MB, Baker RE. Herpesvirus hominis type 2 infections in rabbits: effect of prior immunization with attenuated Mycobacterium bovis (BCG) cells. Infect Immun. 1972 Oct;6(4):465-8. doi: 10.1128/iai.6.4.465-468.1972.
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• 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.
• Background de Bree LCJ, Marijnissen RJ, Kel JM, Rosendahl Huber SK, Aaby P, Benn CS, Wijnands MVW, Diavatopoulos DA, van Crevel R, Joosten LAB, Netea MG, Dulos J. Bacillus Calmette-Guerin-Induced Trained Immunity Is Not Protective for Experimental Influenza A/Anhui/1/2013 (H7N9) Infection in Mice. Front Immunol. 2018 Apr 30;9:869. doi: 10.3389/fimmu.2018.00869. eCollection 2018.
• Background Kulkarni S, Mukherjee S, Pandey A, Dahake R, Padmanabhan U, Chowdhary AS. Bacillus Calmette-Guerin Confers Neuroprotection in a Murine Model of Japanese Encephalitis. Neuroimmunomodulation. 2016;23(5-6):278-286. doi: 10.1159/000452171. Epub 2017 Feb 17.
• Background LEMONDE P, CLODE M. Effect of BCG infection on leukemia and polyoma in mice and hamsters. Proc Soc Exp Biol Med. 1962 Dec;111:739-42. doi: 10.3181/00379727-111-27908. No abstract available.
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• Background Larson CL, Baker RE, Ushijima RN, Baker MB, Gillespie C. Immunotherapy of Friend disease in mice employing viable BCG vaccine. Proc Soc Exp Biol Med. 1972 Jun;140(2):700-2. doi: 10.3181/00379727-140-36534. No abstract available.
• Background Niobey FM, Duchiade MP, Vasconcelos AG, de Carvalho ML, Leal Mdo C, Valente JG. [Risk factors for death caused by pneumonia in children younger than 1 year old in a metropolitan region of southeastern Brazil. A case- control study]. Rev Saude Publica. 1992 Aug;26(4):229-38. doi: 10.1590/s0034-89101992000400004. Portuguese.
• Background Hollm-Delgado MG, Stuart EA, Black RE. Acute lower respiratory infection among Bacille Calmette-Guerin (BCG)-vaccinated children. Pediatrics. 2014 Jan;133(1):e73-81. doi: 10.1542/peds.2013-2218. Epub 2013 Dec 30.
• Background de Castro MJ, Pardo-Seco J, Martinon-Torres F. Nonspecific (Heterologous) Protection of Neonatal BCG Vaccination Against Hospitalization Due to Respiratory Infection and Sepsis. Clin Infect Dis. 2015 Jun 1;60(11):1611-9. doi: 10.1093/cid/civ144. Epub 2015 Feb 27.
• Background Chisti MJ, Salam MA, Ahmed T, Shahid AS, Shahunja KM, Faruque AS, Bardhan PK, Hossain MI, Islam MM, Das SK, Huq S, Shahrin L, Huq E, Chowdhury F, Ashraf H. Lack of BCG vaccination and other risk factors for bacteraemia in severely malnourished children with pneumonia. Epidemiol Infect. 2015 Mar;143(4):799-803. doi: 10.1017/S0950268814001368. Epub 2014 Jun 3.
• Background Muthumbi E, Lowe BS, Muyodi C, Getambu E, Gleeson F, Scott JAG. Risk factors for community-acquired pneumonia among adults in Kenya: a case-control study. Pneumonia (Nathan). 2017 Nov 25;9:17. doi: 10.1186/s41479-017-0041-2. eCollection 2017.
• Background Stensballe LG, Ravn H, Birk NM, Kjaergaard J, Nissen TN, Pihl GT, Thostesen LM, Greisen G, Jeppesen DL, Kofoed PE, Pryds O, Sorup S, Aaby P, Benn CS. BCG Vaccination at Birth and Rate of Hospitalization for Infection Until 15 Months of Age in Danish Children: A Randomized Clinical Multicenter Trial. J Pediatric Infect Dis Soc. 2019 Jul 1;8(3):213-220. doi: 10.1093/jpids/piy029.
• Background Haahr S, Michelsen SW, Andersson M, Bjorn-Mortensen K, Soborg B, Wohlfahrt J, Melbye M, Koch A. Non-specific effects of BCG vaccination on morbidity among children in Greenland: a population-based cohort study. Int J Epidemiol. 2016 Dec 1;45(6):2122-2130. doi: 10.1093/ije/dyw244.
• Background Kjaergaard J, Birk NM, Nissen TN, Thostesen LM, Pihl GT, Benn CS, Jeppesen DL, Pryds O, Kofoed PE, Aaby P, Greisen G, Stensballe LG. Nonspecific effect of BCG vaccination at birth on early childhood infections: a randomized, clinical multicenter trial. Pediatr Res. 2016 Nov;80(5):681-685. doi: 10.1038/pr.2016.142. Epub 2016 Jul 18.
• 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.
• Background Nemes E, Geldenhuys H, Rozot V, Rutkowski KT, Ratangee F, Bilek N, Mabwe S, Makhethe L, Erasmus M, Toefy A, Mulenga H, Hanekom WA, Self SG, Bekker LG, Ryall R, Gurunathan S, DiazGranados CA, Andersen P, Kromann I, Evans T, Ellis RD, Landry B, Hokey DA, Hopkins R, Ginsberg AM, Scriba TJ, Hatherill M; C-040-404 Study Team. Prevention of M. tuberculosis Infection with H4:IC31 Vaccine or BCG Revaccination. N Engl J Med. 2018 Jul 12;379(2):138-149. doi: 10.1056/NEJMoa1714021.
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• 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.
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• Background BCG vaccines: WHO position paper - February 2018. Wkly Epidemiol Rec. 2018 Feb 23;93(8):73-96. No abstract available. English, French.
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• Background Oettinger T, Jorgensen M, Ladefoged A, Haslov K, Andersen P. Development of the Mycobacterium bovis BCG vaccine: review of the historical and biochemical evidence for a genealogical tree. Tuber Lung Dis. 1999;79(4):243-50. doi: 10.1054/tuld.1999.0206.
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• Background WALLGREN, A., INTRADERMAL VACCINATIONS WITH B C G VIRUS: PRELIMINARY NOTE. Journal of the American Medical Association, 1928. 91(24): p. 1876-1881.
• Background Chen JM, Islam ST, Ren H, Liu J. Differential productions of lipid virulence factors among BCG vaccine strains and implications on BCG safety. Vaccine. 2007 Nov 23;25(48):8114-22. doi: 10.1016/j.vaccine.2007.09.041. Epub 2007 Oct 8.
• Background Abdallah AM, Hill-Cawthorne GA, Otto TD, Coll F, Guerra-Assuncao JA, Gao G, Naeem R, Ansari H, Malas TB, Adroub SA, Verboom T, Ummels R, Zhang H, Panigrahi AK, McNerney R, Brosch R, Clark TG, Behr MA, Bitter W, Pain A. Genomic expression catalogue of a global collection of BCG vaccine strains show evidence for highly diverged metabolic and cell-wall adaptations. Sci Rep. 2015 Oct 21;5:15443. doi: 10.1038/srep15443.
• Background Taniguchi K, Miyatake Y, Hayashi D, Takami A, Itoh S, Yamamoto S, Hida S, Onozaki K, Takii T. Early-shared Mycobacterium bovis bacillus Calmette-Guerin sub-strains induce Th1 cytokine production in vivo. Microbiol Immunol. 2015 Nov;59(11):684-9. doi: 10.1111/1348-0421.12326.
• Background Ritz N, Dutta B, Donath S, Casalaz D, Connell TG, Tebruegge M, Robins-Browne R, Hanekom WA, Britton WJ, Curtis N. The influence of bacille Calmette-Guerin vaccine strain on the immune response against tuberculosis: a randomized trial. Am J Respir Crit Care Med. 2012 Jan 15;185(2):213-22. doi: 10.1164/rccm.201104-0714OC. Epub 2011 Nov 3.
• Background Darrah PA, Patel DT, De Luca PM, Lindsay RW, Davey DF, Flynn BJ, Hoff ST, Andersen P, Reed SG, Morris SL, Roederer M, Seder RA. Multifunctional TH1 cells define a correlate of vaccine-mediated protection against Leishmania major. Nat Med. 2007 Jul;13(7):843-50. doi: 10.1038/nm1592. Epub 2007 Jun 10.
• Background Davids V, Hanekom WA, Mansoor N, Gamieldien H, Gelderbloem SJ, Hawkridge A, Hussey GD, Hughes EJ, Soler J, Murray RA, Ress SR, Kaplan G. The effect of bacille Calmette-Guerin vaccine strain and route of administration on induced immune responses in vaccinated infants. J Infect Dis. 2006 Feb 15;193(4):531-6. doi: 10.1086/499825. Epub 2006 Jan 13.
• Background Brosch R, Gordon SV, Garnier T, Eiglmeier K, Frigui W, Valenti P, Dos Santos S, Duthoy S, Lacroix C, Garcia-Pelayo C, Inwald JK, Golby P, Garcia JN, Hewinson RG, Behr MA, Quail MA, Churcher C, Barrell BG, Parkhill J, Cole ST. Genome plasticity of BCG and impact on vaccine efficacy. Proc Natl Acad Sci U S A. 2007 Mar 27;104(13):5596-601. doi: 10.1073/pnas.0700869104. Epub 2007 Mar 19.
• Background Schaltz-Buchholzer F, Bjerregaard-Andersen M, Oland CB, Golding C, Stjernholm EB, Monteiro I, Aaby P, Benn CS. Early Vaccination With Bacille Calmette-Guerin-Denmark or BCG-Japan Versus BCG-Russia to Healthy Newborns in Guinea-Bissau: A Randomized Controlled Trial. Clin Infect Dis. 2020 Nov 5;71(8):1883-1893. doi: 10.1093/cid/ciz1080.
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• Background Guerin N, Teulieres L, Noba A, Schlumberger M, Bregere P, Chauvin P. Comparison of the safety and immunogenicity of the lyophilized Merieux seed and the World Health Organization working reference BCG vaccines in school-aged children in Senegal. Vaccine. 1999 Jan;17(2):105-9. doi: 10.1016/s0264-410x(98)00186-8.
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• Background Gallagher, J., C. Watson, and M. Ledwidge, Association of Bacille Calmette-Guérin (BCG), Adult Pneumococcal and Adult Seasonal Influenza Vaccines with Covid-19 Adjusted Mortality Rates in Level 4 European countries. medRxiv, 2020: p. 2020.06.03.20121624.
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• Background Totura AL, Whitmore A, Agnihothram S, Schafer A, Katze MG, Heise MT, Baric RS. Toll-Like Receptor 3 Signaling via TRIF Contributes to a Protective Innate Immune Response to Severe Acute Respiratory Syndrome Coronavirus Infection. mBio. 2015 May 26;6(3):e00638-15. doi: 10.1128/mBio.00638-15.
• Background Xu Z, Shi L, Wang Y, Zhang J, Huang L, Zhang C, Liu S, Zhao P, Liu H, Zhu L, Tai Y, Bai C, Gao T, Song J, Xia P, Dong J, Zhao J, Wang FS. Pathological findings of COVID-19 associated with acute respiratory distress syndrome. Lancet Respir Med. 2020 Apr;8(4):420-422. doi: 10.1016/S2213-2600(20)30076-X. Epub 2020 Feb 18. No abstract available.
• Background Netea MG, Dominguez-Andres J, Barreiro LB, Chavakis T, Divangahi M, Fuchs E, Joosten LAB, van der Meer JWM, Mhlanga MM, Mulder WJM, Riksen NP, Schlitzer A, Schultze JL, Stabell Benn C, Sun JC, Xavier RJ, Latz E. Defining trained immunity and its role in health and disease. Nat Rev Immunol. 2020 Jun;20(6):375-388. doi: 10.1038/s41577-020-0285-6. Epub 2020 Mar 4.
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