Intravenous BCG Vaccination Reduces SARS-CoV-2 Severity and Promotes Extensive Reprogramming of Lung Immune Cells

Overview

Journal iScience

Publisher Cell Press

Date 2023 Sep 7

PMID 37674985

Authors

Alok K Singh

Rulin Wang

Kara A Lombardo

Monali Praharaj

C Korin Bullen

Peter Um

Manish Gupta

Geetha Srikrishna

Stephanie Davis

Oliver Komm

Peter B Illei

Alvaro A Ordonez

Melissa Bahr

Joy Huang

Anuj Gupta

Kevin J Psoter

Patrick S Creisher

Maggie Li

Andrew Pekosz

Sabra L Klein

Sanjay K Jain

Trinity J Bivalacqua

Srinivasan Yegnasubramanian

William R Bishai

Affiliations

Soon will be listed here.

Abstract

Bacillus Calmette-Guérin (BCG) confers heterologous immune protection against viral infections and has been proposed as vaccine against SARS-CoV-2 (SCV2). Here, we tested intravenous BCG vaccination against COVID-19 using the golden Syrian hamster model. BCG vaccination conferred a modest reduction on lung SCV2 viral load, bronchopneumonia scores, and weight loss, accompanied by a reversal of SCV2-mediated T cell lymphopenia, and reduced lung granulocytes. BCG uniquely recruited immunoglobulin-producing plasma cells to the lung suggesting accelerated local antibody production. BCG vaccination also recruited elevated levels of Th1, Th17, Treg, CTLs, and Tmem cells, with a transcriptional shift away from exhaustion markers and toward antigen presentation and repair. Similarly, BCG enhanced recruitment of alveolar macrophages and reduced key interstitial macrophage subsets, that show reduced IFN-associated gene expression. Our observations indicate that BCG vaccination protects against SCV2 immunopathology by promoting early lung immunoglobulin production and immunotolerizing transcriptional patterns among key myeloid and lymphoid populations.

Citing Articles

Beyond Tuberculosis: The Surprising Immunological Benefits of the Bacillus Calmette-Guérin (BCG) Vaccine in Infectious, Auto-Immune, and Inflammatory Diseases.

Jurczak M, Druszczynska M Pathogens. 2025; 14(2).

PMID: 40005571 PMC: 11857995. DOI: 10.3390/pathogens14020196.

An Update on Anti-COVID-19 Vaccines and the Challenges to Protect Against New SARS-CoV-2 Variants.

Mambelli F, de Araujo A, Farias J, de Andrade K, Ferreira L, Minoprio P Pathogens. 2025; 14(1).

PMID: 39860984 PMC: 11768231. DOI: 10.3390/pathogens14010023.

No Association Between BCG Instillations and COVID-19 Incidence in a Dutch Non-Muscle Invasive Bladder Cancer Cohort.

van Zutphen M, Kiemeney L, Oldenhof U, Maurits J, Witjes J, Joosten L Bladder Cancer. 2024; 9(4):355-363.

PMID: 38994242 PMC: 11165912. DOI: 10.3233/BLC-230088.

Neuropathological lesions in intravenous BCG-stimulated K18-hACE2 mice challenged with SARS-CoV-2.

Sanchez-Morales L, Porras N, Garcia-Seco T, Perez-Sancho M, Cruz F, Chinchilla B Vet Res. 2024; 55(1):71.

PMID: 38822398 PMC: 11143641. DOI: 10.1186/s13567-024-01325-7.

Bacterial-induced or passively administered interferon gamma conditions the lung for early control of SARS-CoV-2.

Hilligan K, Namasivayam S, Clancy C, Baker P, Old S, Peluf V Nat Commun. 2023; 14(1):8229.

PMID: 38086794 PMC: 10716133. DOI: 10.1038/s41467-023-43447-0.

References

Sacchi A, Grassi G, Bordoni V, Lorenzini P, Cimini E, Casetti R . Early expansion of myeloid-derived suppressor cells inhibits SARS-CoV-2 specific T-cell response and may predict fatal COVID-19 outcome. Cell Death Dis. 2020; 11(10):921. PMC: 7590570. DOI: 10.1038/s41419-020-03125-1. View

Shenoy A, De Ana C, Arafa E, Salwig I, Barker K, Korkmaz F . Antigen presentation by lung epithelial cells directs CD4 T cell function and regulates barrier immunity. Nat Commun. 2021; 12(1):5834. PMC: 8492657. DOI: 10.1038/s41467-021-26045-w. View

Kaufmann E, Khan N, Tran K, Ulndreaj A, Pernet E, Fontes G . BCG vaccination provides protection against IAV but not SARS-CoV-2. Cell Rep. 2022; 38(10):110502. PMC: 8858710. DOI: 10.1016/j.celrep.2022.110502. View

Lodmell D, Ewalt L . Enhanced resistance against encephalomyocarditis virus infection in mice, induced by a nonviable Mycobacterium tuberculosis oil-droplet vaccine. Infect Immun. 1978; 19(1):225-30. PMC: 414071. DOI: 10.1128/iai.19.1.225-230.1978. View

Lindenbach B . Measuring HCV infectivity produced in cell culture and in vivo. Methods Mol Biol. 2008; 510:329-36. DOI: 10.1007/978-1-59745-394-3_24. View

Arunachalam P, Wimmers F, Mok C, Perera R, Scott M, Hagan T . Systems biological assessment of immunity to mild versus severe COVID-19 infection in humans. Science. 2020; 369(6508):1210-1220. PMC: 7665312. DOI: 10.1126/science.abc6261. View

Upton C, Van Wijk R, Mockeliunas L, Simonsson U, McHarry K, van den Hoogen G . Safety and efficacy of BCG re-vaccination in relation to COVID-19 morbidity in healthcare workers: A double-blind, randomised, controlled, phase 3 trial. EClinicalMedicine. 2022; 48:101414. PMC: 9098089. DOI: 10.1016/j.eclinm.2022.101414. View

Koeken V, van der Pasch E, Leijte G, Mourits V, de Bree L, Moorlag S . The effect of BCG vaccination on alveolar macrophages obtained from induced sputum from healthy volunteers. Cytokine. 2020; 133:155135. PMC: 8850675. DOI: 10.1016/j.cyto.2020.155135. View

Farr L, Ghosh S, Moonah S . Role of MIF Cytokine/CD74 Receptor Pathway in Protecting Against Injury and Promoting Repair. Front Immunol. 2020; 11:1273. PMC: 7325688. DOI: 10.3389/fimmu.2020.01273. View

10.

Eggenhuizen P, Ng B, Chang J, Fell A, Cheong R, Wong W . BCG Vaccine Derived Peptides Induce SARS-CoV-2 T Cell Cross-Reactivity. Front Immunol. 2021; 12:692729. PMC: 8374943. DOI: 10.3389/fimmu.2021.692729. View

11.

Leentjens J, Kox M, Stokman R, Gerretsen J, Diavatopoulos D, van Crevel R . BCG Vaccination Enhances the Immunogenicity of Subsequent Influenza Vaccination in Healthy Volunteers: A Randomized, Placebo-Controlled Pilot Study. J Infect Dis. 2015; 212(12):1930-8. DOI: 10.1093/infdis/jiv332. View

12.

Wu Y, Cai M, Ma J, Teng X, Tian M, Bassuoney E . Heterologous Boost Following Reduces the Late Persistent, Rather Than the Early Stage of Intranasal Tuberculosis Challenge Infection. Front Immunol. 2018; 9:2439. PMC: 6218689. DOI: 10.3389/fimmu.2018.02439. View

13.

Counoupas C, Johansen M, Stella A, Nguyen D, Ferguson A, Aggarwal A . A single dose, BCG-adjuvanted COVID-19 vaccine provides sterilising immunity against SARS-CoV-2 infection. NPJ Vaccines. 2021; 6(1):143. PMC: 8633321. DOI: 10.1038/s41541-021-00406-4. View

14.

Arts R, Carvalho A, La Rocca C, Palma C, Rodrigues F, Silvestre R . Immunometabolic Pathways in BCG-Induced Trained Immunity. Cell Rep. 2016; 17(10):2562-2571. PMC: 5177620. DOI: 10.1016/j.celrep.2016.11.011. View

15.

Nouailles G, Wyler E, Pennitz P, Postmus D, Vladimirova D, Kazmierski J . Temporal omics analysis in Syrian hamsters unravel cellular effector responses to moderate COVID-19. Nat Commun. 2021; 12(1):4869. PMC: 8357947. DOI: 10.1038/s41467-021-25030-7. View

16.

Moorlag S, Arts R, van Crevel R, Netea M . Non-specific effects of BCG vaccine on viral infections. Clin Microbiol Infect. 2019; 25(12):1473-1478. DOI: 10.1016/j.cmi.2019.04.020. View

17.

Chua W, Truscott S, Eickhoff C, Blazevic A, Hoft D, Hansen T . Polyclonal mucosa-associated invariant T cells have unique innate functions in bacterial infection. Infect Immun. 2012; 80(9):3256-67. PMC: 3418730. DOI: 10.1128/IAI.00279-12. View

18.

Harvey W, Carabelli A, Jackson B, Gupta R, Thomson E, Harrison E . SARS-CoV-2 variants, spike mutations and immune escape. Nat Rev Microbiol. 2021; 19(7):409-424. PMC: 8167834. DOI: 10.1038/s41579-021-00573-0. View

19.

White A, Sibley L, Sarfas C, Morrison A, Bewley K, Churchward C . Influence of Aerosol Delivered BCG Vaccination on Immunological and Disease Parameters Following SARS-CoV-2 Challenge in Rhesus Macaques. Front Immunol. 2022; 12:801799. PMC: 8863871. DOI: 10.3389/fimmu.2021.801799. View

20.

Arts R, Moorlag S, Novakovic B, Li Y, Wang S, Oosting M . BCG Vaccination Protects against Experimental Viral Infection in Humans through the Induction of Cytokines Associated with Trained Immunity. Cell Host Microbe. 2018; 23(1):89-100.e5. DOI: 10.1016/j.chom.2017.12.010. View