Abstract
Background and objectives: Because of its beneficial off-target effects against non-mycobacterial infectious diseases, bacillus Calmette–Guérin (BCG) vaccination might be an accessible early intervention to boost protection against novel pathogens. Multiple epidemiological studies and randomised controlled trials (RCTs) are investigating the protective effect of BCG against coronavirus disease 2019 (COVID-19). Using samples from participants in a placebo-controlled RCT aiming to determine whether BCG vaccination reduces the incidence and severity of COVID-19, we investigated the immunomodulatory effects of BCG on in vitro immune responses to SARS-CoV-2. Methods: This study used peripheral blood taken from participants in the multicentre RCT and BCG vaccination to reduce the impact of COVID-19 on healthcare workers (BRACE trial). The whole blood taken from BRACE trial participants was stimulated with γ-irradiated SARS-CoV-2-infected or mock-infected Vero cell supernatant. Cytokine responses were measured by multiplex cytokine analysis, and single-cell immunophenotyping was made by flow cytometry. Results: BCG vaccination, but not placebo vaccination, reduced SARS-CoV-2-induced secretion of cytokines known to be associated with severe COVID-19, including IL-6, TNF-α and IL-10. In addition, BCG vaccination promoted an effector memory phenotype in both CD4+ and CD8+ T cells, and an activation of eosinophils in response to SARS-CoV-2. Conclusions: The immunomodulatory signature of BCG’s off-target effects on SARS-CoV-2 is consistent with a protective immune response against severe COVID-19.
| Original language | English |
|---|---|
| Article number | e1387 |
| Number of pages | 15 |
| Journal | Clinical & Translational Immunology |
| Volume | 11 |
| Issue number | 4 |
| DOIs | |
| Publication status | Published - 22 Apr 2022 |
Keywords
- BCG
- COVID-19
- cytokine
- immunoregulation
- SARS-CoV-2
- T cell
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In: Clinical & Translational Immunology, Vol. 11, No. 4, e1387, 22.04.2022.
Research output: Contribution to journal › Article › Research › peer-review
TY - JOUR
T1 - Off-target effects of bacillus Calmette–Guérin vaccination on immune responses to SARS-CoV-2
T2 - implications for protection against severe COVID-19
AU - Messina, Nicole L.
AU - Germano, Susie
AU - McElroy, Rebecca
AU - Rudraraju, Rajeev
AU - Bonnici, Rhian
AU - Pittet, Laure F.
AU - Neeland, Melanie R.
AU - Nicholson, Suellen
AU - Subbarao, Kanta
AU - Curtis, Nigel
AU - Baena, Adrian Siles
AU - Teo, Jia Wei
AU - de Lima, Guilherme Teodoro
AU - Abreu, Carolinne
AU - Abruzzo, Veronica
AU - Addlem, Lynne
AU - Agius, Sophie
AU - Barbosa, Adelita Agripina Refosco
AU - Alamrousi, Ahmed
AU - da Silva dos Santos, Ayla Alcoforado
AU - Al-Hindawi, Yasmeen
AU - Silveira, Samyra Almeida Da
AU - da Cruz, Lais Alves
AU - Anderson, Jeremy
AU - Nelly, Amenyogbe
AU - Anthony, Christina
AU - dos Reis Pereira, Andrea Antonia Souza de Almeida
AU - de las Revillas Almajano, Francisco Arnaiz
AU - Arnold, Annabelle
AU - Arrowsmith, Beth
AU - Azzopardi, Kristy
AU - Marti, Cristina Badia
AU - Bahaduri, Twinkle
AU - Bannister, Samantha
AU - Barney, Sarah
AU - Barrera, Lydia
AU - Barriocanal, Anabel
AU - Barros, Dayanne
AU - Barry, Simone
AU - Bartlett, Adam
AU - Batista, Lilian
AU - Muranaka, Silva
AU - Baulman, Therese
AU - Bealing, Morgan
AU - Beardsley, Justin
AU - Gutierrez, Ana Belen Martin
AU - Bell, Jason
AU - Benson, Saoirse
AU - Rym, Benothman
AU - Bennett-Wood, Vicki
AU - Bergant, Nikki
AU - Barbosa, Fabiane Bianca
AU - Bijllaardt, Wouter
AU - Bimboese, Patricia
AU - de Andrade, Camila Bitencourt
AU - Blake, Stephen
AU - Blauwendraat, Kitty
AU - Boersma, Wim
AU - Garcia, Pilar Bohedo
AU - Bonten, Marc
AU - Boon, Anne
AU - Bourke, Anna
AU - Bowes, Kirsty
AU - Brasil, Larissa
AU - Brophy, Clare
AU - Botten, Rochelle
AU - Buchanan, Sandy
AU - Bucholc, Jess
AU - Burns, Alison
AU - Burrell, Emma
AU - Bustos, Natalia
AU - Byrne, Bridie
AU - Byrne, Anthony
AU - Calbo, Esther
AU - Montes, Jorge Calvo
AU - Camesella, Beatriz
AU - Campbell, John
AU - Cangas, Atsegiñe
AU - Carlin, John
AU - Roque, Maria Carmen
AU - Diogo, Roberta Carolina Pereira
AU - Carvalho, Estela
AU - Casas, Irma
AU - Castro, Erika
AU - Castro, Ramon
AU - Catterick, Helen
AU - Escobar, Rodrigo Cezar Dutra
AU - Chan, Joyce
AU - Cheah, Jo
AU - Chern, Tee Yee
AU - Chengodu, Thilakavathi
AU - Ciaverella, Marianna
AU - Clark, Sharon
AU - Espindola, Marie Alix Clement
AU - Cobbledick, Annie
AU - Colaco, Clinton
AU - Collopy, Simone
AU - Comella, Patricia
AU - Corbett, Mary
AU - Castro, Gabriela Correa E.
AU - Costa, Erlane
AU - Coya, Raquel
AU - Crawford, Nigel
AU - Croda, Julio
AU - Cruz, Alda
AU - Maxwell, Curtis
AU - Cushnahan, Jac
AU - Czajko, Anna
AU - da Costa Silva, Renato
AU - Daitiri, Bouchra
AU - Dalcolmo, Margareth
AU - Dalton, Karen
AU - Dang, Thanh
AU - Dao, Aiken
AU - Davidson, Andrew
AU - Dawe, Phoebe
AU - Dawson, Diane
AU - de Jesus Costa, Miriam
AU - De La Cruz, Karina
AU - de la Serna, Almudena
AU - de Morais Batista, Fabiani
AU - de Oliveira, Adriely
AU - del Alba Rey Morillo, Rocio
AU - Desylva, Maria
AU - Dijkstra, Helga
AU - Dixon, Rachel
AU - del Toro Lopez, Maria Dolores
AU - Dominguez, Jose
AU - Doran, Catriona
AU - Castellano, Angel Dominguez
AU - Santos, Glauce Dos
AU - dos Santos Lencina, Joyce
AU - dos Santos Silva, Débora
AU - Douglas, Mark
AU - Dunn, Ross
AU - Dunn, Andrew
AU - Dunnill, Jemma
AU - Eden, Georgina
AU - Peta, Edler
AU - Edmund, Harriet
AU - Eiffler, Nat
AU - Elborough, Hannah
AU - Elia, Sonja
AU - Elkington, Olivia
AU - England, Michelle
AU - Ayala, Wellyngthon Espindola
AU - Esteve, Maria
AU - Evans, Nick
AU - Evans, Sue
AU - Ewe, Krist
AU - Álvarez, María Carmen Fariñ
AU - Fahey, Kieran
AU - Fairweather, Jill
AU - Faustman, Denise
AU - Silva, Erica Fernandes
AU - Fernandez, Monique
AU - Fidler, Galina
AU - Filius, P. M.G.
AU - Finn, Adam
AU - Finucane, Carolyn
AU - Firth, Stephanie
AU - Fletcher, Emily
AU - Flynn, Catherine
AU - Flynn, Lorraine
AU - Fouracre, Liam
AU - Fowler, Sarah
AU - Freitas, Thamires
AU - Furtado, Ana Carolina
AU - Oliveira, Maria Gabriela
AU - Santos, Anna Gabriela
AU - Gonçalves, Leandro Galdino Cavalcanti
AU - Galletta, Laura
AU - Gama, Larissa
AU - Gamage, Dinusha
AU - Ganpat, Radhika
AU - García, Carlos
AU - Croda, Mariana Garcia
AU - Gardiner, Kaya
AU - Gardiner, Evangeline
AU - Gell, Grace
AU - de Oliveira, Aline Gerhardt
AU - Germano, Susie
AU - Gibbons, Michael
AU - Gibson, Camille
AU - Gifford, Alison
AU - Poderos, Teresa Giménez
AU - Ginsberg, Ann
AU - Gisolf, Jet
AU - Gladanac, Bojana
AU - Glenn, Penny
AU - Godinho, Vanessa
AU - dos Santos, Mayara Góes
AU - Goikoetxea, Josune
AU - Goldenberg, Telma
AU - Gomes, Adriano
AU - Marcos, Susana Gonzalez
AU - Rico, Claudia González
AU - Goodall, Casey
AU - Goodchild, Louise
AU - Gordon, Victoria
AU - Greven, Frances
AU - Capella, Ana Greyce
AU - Griffith, Liddy
AU - Guo, Christina
AU - Campos, David Gutierrez
AU - Cuadra, Manuel Gutierrez
AU - Gwee, Amanda
AU - Hall, Richard
AU - Hall, Lydia
AU - Hamilton, Kate
AU - Hannan, Matthew
AU - Harbech, Houda
AU - Harding, Alex
AU - Harker, Neil
AU - Harrison, Robert
AU - Hassing, Robert Jan
AU - da Rosa, Thaynara Haynara Souza
AU - Haywood, Zaheerah
AU - Heath, Christine
AU - Henare, Nadine
AU - Andrade, Paulo Henrique
AU - Herrmann, Susan
AU - Hill, Erin
AU - Hilton, Sam
AU - Huijbens, Danique
AU - Hutton, Heidi
AU - James, Jane
AU - Jamieson, Tenaya
AU - Janssen, Axel
AU - Jardim, Bruno
AU - Jardim, Tyane
AU - Jarvis, Lance
AU - Jenkins, Narelle
AU - Jones, Jane
AU - Jones, Jan
AU - Jones, Karen
AU - Jorge, Leticia
AU - Vilegas, Maria Jose Rios
AU - Joshi, Sri
AU - Joyce, Rosemary
AU - Junior, Joel
AU - Kandasamy, Rama
AU - Karunanayake, Anushka
AU - Karuppasamy, Hana
AU - Keeble, Tom
AU - Kent, Jennifer
AU - Kloeg, Paul
AU - Korman, Tony
AU - Mazarakis, Nadia
AU - Wesselingh, Steve
AU - the BRACE trial
N1 - Funding Information: The Murdoch Children’s Research Institute (MCRI) leads the BRACE trial across 36 sites in five countries. It is supported by the Victorian Government’s Operational Infrastructure Support Programme. The BRACE trial is supported by the Bill & Melinda Gates Foundation (INV-017302), the Minderoo Foundation (COV-001), Sarah and Lachlan Murdoch, the Royal Children's Hospital Foundation (2020-1263 BRACE Trial), Health Services Union NSW, the Peter Sowerby Foundation, the Ministry of Health Government of South Australia, the NAB Foundation, the Calvert-Jones Foundation, the Modara Pines Charitable Foundation, the UHG Foundation Pty Ltd, Epworth Healthcare and individual donors. NC is supported by the National Health and Medical Research Council (NHMRC; Investigator Grant GNT1197117). Funding Information: The Murdoch Children’s Research Institute (MCRI) leads the BRACE trial across 36 sites in five countries. It is supported by the Victorian Government’s Operational Infrastructure Support Programme. The BRACE trial is supported by the Bill & Melinda Gates Foundation (INV‐017302), the Minderoo Foundation (COV‐001), Sarah and Lachlan Murdoch, the Royal Children's Hospital Foundation (2020‐1263 BRACE Trial), Health Services Union NSW, the Peter Sowerby Foundation, the Ministry of Health Government of South Australia, the NAB Foundation, the Calvert‐Jones Foundation, the Modara Pines Charitable Foundation, the UHG Foundation Pty Ltd, Epworth Healthcare and individual donors. NC is supported by the National Health and Medical Research Council (NHMRC; Investigator Grant GNT1197117). LFP is supported by the Swiss National Science Foundation (Early Postdoc. Mobility grant number P2GEP3_178155). The Melbourne WHO Collaborating Centre for Reference and Research on Influenza is supported by the Australian Government Department of Health. KS is supported by an NHMRC Investigator grant and has received support from the Victorian Government Department of Health, Jack Ma Foundation and the A2 Milk Company. Publisher Copyright: © 2022 The Authors. Clinical & Translational Immunology published by John Wiley & Sons Australia, Ltd on behalf of Australian and New Zealand Society for Immunology, Inc.
PY - 2022/4/22
Y1 - 2022/4/22
N2 - Background and objectives: Because of its beneficial off-target effects against non-mycobacterial infectious diseases, bacillus Calmette–Guérin (BCG) vaccination might be an accessible early intervention to boost protection against novel pathogens. Multiple epidemiological studies and randomised controlled trials (RCTs) are investigating the protective effect of BCG against coronavirus disease 2019 (COVID-19). Using samples from participants in a placebo-controlled RCT aiming to determine whether BCG vaccination reduces the incidence and severity of COVID-19, we investigated the immunomodulatory effects of BCG on in vitro immune responses to SARS-CoV-2. Methods: This study used peripheral blood taken from participants in the multicentre RCT and BCG vaccination to reduce the impact of COVID-19 on healthcare workers (BRACE trial). The whole blood taken from BRACE trial participants was stimulated with γ-irradiated SARS-CoV-2-infected or mock-infected Vero cell supernatant. Cytokine responses were measured by multiplex cytokine analysis, and single-cell immunophenotyping was made by flow cytometry. Results: BCG vaccination, but not placebo vaccination, reduced SARS-CoV-2-induced secretion of cytokines known to be associated with severe COVID-19, including IL-6, TNF-α and IL-10. In addition, BCG vaccination promoted an effector memory phenotype in both CD4+ and CD8+ T cells, and an activation of eosinophils in response to SARS-CoV-2. Conclusions: The immunomodulatory signature of BCG’s off-target effects on SARS-CoV-2 is consistent with a protective immune response against severe COVID-19.
AB - Background and objectives: Because of its beneficial off-target effects against non-mycobacterial infectious diseases, bacillus Calmette–Guérin (BCG) vaccination might be an accessible early intervention to boost protection against novel pathogens. Multiple epidemiological studies and randomised controlled trials (RCTs) are investigating the protective effect of BCG against coronavirus disease 2019 (COVID-19). Using samples from participants in a placebo-controlled RCT aiming to determine whether BCG vaccination reduces the incidence and severity of COVID-19, we investigated the immunomodulatory effects of BCG on in vitro immune responses to SARS-CoV-2. Methods: This study used peripheral blood taken from participants in the multicentre RCT and BCG vaccination to reduce the impact of COVID-19 on healthcare workers (BRACE trial). The whole blood taken from BRACE trial participants was stimulated with γ-irradiated SARS-CoV-2-infected or mock-infected Vero cell supernatant. Cytokine responses were measured by multiplex cytokine analysis, and single-cell immunophenotyping was made by flow cytometry. Results: BCG vaccination, but not placebo vaccination, reduced SARS-CoV-2-induced secretion of cytokines known to be associated with severe COVID-19, including IL-6, TNF-α and IL-10. In addition, BCG vaccination promoted an effector memory phenotype in both CD4+ and CD8+ T cells, and an activation of eosinophils in response to SARS-CoV-2. Conclusions: The immunomodulatory signature of BCG’s off-target effects on SARS-CoV-2 is consistent with a protective immune response against severe COVID-19.
KW - BCG
KW - COVID-19
KW - cytokine
KW - immunoregulation
KW - SARS-CoV-2
KW - T cell
UR - http://www.scopus.com/inward/record.url?scp=85133973951&partnerID=8YFLogxK
U2 - 10.1002/cti2.1387
DO - 10.1002/cti2.1387
M3 - Article
AN - SCOPUS:85133973951
SN - 2050-0068
VL - 11
JO - Clinical & Translational Immunology
JF - Clinical & Translational Immunology
IS - 4
M1 - e1387
ER -