TY - JOUR
T1 - Bacillus Calmette-Guérin vaccination for protection against recurrent herpes labialis
T2 - a nested randomised controlled trial
AU - the BRACE Trial Consortium Group
AU - Pittet, Laure F.
AU - Moore, Cecilia L.
AU - McDonald, Ellie
AU - Barry, Simone
AU - Bonten, Marc
AU - Campbell, John
AU - Croda, Julio
AU - Dalcolmo, Margareth
AU - Davidson, Andrew
AU - Douglas, Mark W.
AU - Gardiner, Kaya
AU - Gwee, Amanda
AU - Jardim, Bruno
AU - Lacerda, Marcus V.G.
AU - Lucas, Michaela
AU - Lynn, David J.
AU - Manning, Laurens
AU - de Oliveira, Roberto D.
AU - Perrett, Kirsten P.
AU - Prat-Aymerich, Cristina
AU - Richmond, Peter C.
AU - Rocha, Jorge L.
AU - Rodriguez-Baño, Jesus
AU - Warris, Adilia
AU - Wood, Nicholas J.
AU - Messina, Nicole L.
AU - Curtis, Nigel
AU - Jamieson, Tenaya
AU - Messina, Nicole
AU - Morawakage, Thilanka
AU - Perlen, Susan
AU - Perrett, Kirsten
AU - Pittet, Laure
AU - Sastry, Amber
AU - Teo, Jia Wei
AU - Orsini, Francesca
AU - Lee, Katherine
AU - Moore, Cecilia
AU - Vidmar, Suzanna
AU - Ali, Rashida
AU - Dunn, Ross
AU - Edler, Peta
AU - Gell, Grace
AU - Goodall, Casey
AU - Hall, Richard
AU - Blake, Stephen
AU - Eden, Georgina
AU - Lynn, Miriam
AU - Stevens, Natalie
AU - Wesselingh, Steve
N1 - Funding Information:
The 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 , SA Health , the Insurance Advisernet Foundation , the NAB Foundation , the Calvert-Jones Foundation , the Modara Pines Charitable Foundation , the UHG Foundation Pty Ltd , Epworth Healthcare and individual donors. The funders had no role in the collection, analysis and interpretation of data or in the preparation, review or approval of the manuscript. 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 . NC is supported by a National Health and Medical Research Council (NHMRC) Investigator Grant ( GNT1197117 ). LFP is supported by the Swiss National Science Foundation (Early Postdoc Mobility Grant, P2GEP3_178155).
Funding Information:
Bill & Melinda Gates Foundation, the Minderoo Foundation, Sarah and Lachlan Murdoch, the Royal Children's Hospital Foundation, Health Services Union NSW, the Peter Sowerby Foundation, SA Health, the Insurance Advisernet Foundation, the NAB Foundation, the Calvert-Jones Foundation, the Modara Pines Charitable Foundation, the UHG Foundation Pty Ltd, Epworth Healthcare, and individual donors.We thank the trial participants and the site personnel who recruited participants and assisted with the trial (detailed in the appendix); AJ Vaccines (Copenhagen) for facilitating BCG vaccine supplies; Devon Freewheelers (UK) for UK transport; Catalent (UK) for drug management; Fiocruz Clinical Research Platform for coordination and monitoring of sites in Brazil; the Pharmacy, Pathology and Immunisation Service teams from The Royal Children's Hospital Melbourne, and the Orygen Group for their support. The 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, SA Health, the Insurance Advisernet Foundation, the NAB Foundation, the Calvert-Jones Foundation, the Modara Pines Charitable Foundation, the UHG Foundation Pty Ltd, Epworth Healthcare and individual donors. The funders had no role in the collection, analysis and interpretation of data or in the preparation, review or approval of the manuscript. 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. NC is supported by a National Health and Medical Research Council (NHMRC) Investigator Grant (GNT1197117). LFP is supported by the Swiss National Science Foundation (Early Postdoc Mobility Grant, P2GEP3_178155).
Publisher Copyright:
© 2023
PY - 2023/10
Y1 - 2023/10
N2 - Background: Recurrences of herpes simplex virus (HSV) in the orofacial region (herpes labialis or cold sores) impact quality-of-life. We aimed to study whether the bacille Calmette-Guérin (BCG) vaccine can attenuate cold sore recurrences through off-target immunomodulatory effects. Methods: In this nested randomised controlled trial within the multicentre, phase 3 BRACE trial, 6828 healthcare workers were randomised in 36 sites in Australia, the Netherlands, Spain, the United Kingdom and Brazil, to receive BCG-Denmark or no BCG (1:1 ratio using a web-based procedure) and followed for 12 months with 3-monthly questionnaires. Exclusion criteria included contraindication to BCG vaccine or previous vaccination with BCG within the past year, any other live-attenuated vaccine within the last month, or any COVID-specific vaccine. The intervention group received one intradermal dose of 0.1 mL of BCG-Denmark corresponding to 2−8 x 105 colony forming units of Mycobacterium bovis, Danish strain 1331. The primary outcome was the difference in restricted mean survival time (i.e., time to first cold-sore recurrence), in participants with frequent recurrent herpes labialis (≥4 recurrences/year), analysed by intention-to-treat. Secondary outcomes addressed additional questions, including analyses in other sub-populations. Adverse events were monitored closely during the first 3 months and were reported in all participants who received one dose of study drug according to intervention received. The BRACE trial is registered with ClinicalTrials.gov, NCT04327206. Findings: Between March 30, 2020 and February 18, 2021, 84 individuals with frequent recurrent cold sores were randomly assigned to BCG (n = 38) or control (n = 46). The average time to first cold-sore recurrence was 1.55 months longer in the BCG group (95% CI 0.27–2.82, p = 0.02) than the control group (hazard ratio 0.54, 95% CI 0.32–0.91; intention-to-treat). The beneficial effect of BCG was greater in the as-treated population (difference 1.91 months, 95% CI 0.69–3.12, p = 0.003; hazard ratio 0.45, 95% CI 0.26–0.76). In prespecified subgroup analyses, only sex modified the treatment effect (interaction p = 0.007), with benefit restricted to males. Over 12 months, a greater proportion of participants in the BCG group compared with the control group reported a decrease in duration (61% vs 21%), severity (74% vs 21%), frequency (55% vs 21%), and impact on quality of life (42% vs 15%) of cold sore recurrences. In participants who had ever had a cold sore, there was also a decrease in self-reported burden of recurrences in the BCG group. In participants who had never had a cold sore, there was an increased risk of a first episode in the BCG group (risk difference 1.4%; 95% CI 0.3–2.6%, p = 0.02). There were no safety concerns. Interpretation: BCG-Denmark vaccination had a beneficial effect on herpes labialis, particularly in males with frequent recurrences, but may increase the risk of a first cold sore. Funding: Bill & Melinda Gates Foundation, the Minderoo Foundation, Sarah and Lachlan Murdoch, the Royal Children's Hospital Foundation, Health Services Union NSW, the Peter Sowerby Foundation, SA Health, the Insurance Advisernet Foundation, the NAB Foundation, the Calvert-Jones Foundation, the Modara Pines Charitable Foundation, the UHG Foundation Pty Ltd, Epworth Healthcare, and individual donors.
AB - Background: Recurrences of herpes simplex virus (HSV) in the orofacial region (herpes labialis or cold sores) impact quality-of-life. We aimed to study whether the bacille Calmette-Guérin (BCG) vaccine can attenuate cold sore recurrences through off-target immunomodulatory effects. Methods: In this nested randomised controlled trial within the multicentre, phase 3 BRACE trial, 6828 healthcare workers were randomised in 36 sites in Australia, the Netherlands, Spain, the United Kingdom and Brazil, to receive BCG-Denmark or no BCG (1:1 ratio using a web-based procedure) and followed for 12 months with 3-monthly questionnaires. Exclusion criteria included contraindication to BCG vaccine or previous vaccination with BCG within the past year, any other live-attenuated vaccine within the last month, or any COVID-specific vaccine. The intervention group received one intradermal dose of 0.1 mL of BCG-Denmark corresponding to 2−8 x 105 colony forming units of Mycobacterium bovis, Danish strain 1331. The primary outcome was the difference in restricted mean survival time (i.e., time to first cold-sore recurrence), in participants with frequent recurrent herpes labialis (≥4 recurrences/year), analysed by intention-to-treat. Secondary outcomes addressed additional questions, including analyses in other sub-populations. Adverse events were monitored closely during the first 3 months and were reported in all participants who received one dose of study drug according to intervention received. The BRACE trial is registered with ClinicalTrials.gov, NCT04327206. Findings: Between March 30, 2020 and February 18, 2021, 84 individuals with frequent recurrent cold sores were randomly assigned to BCG (n = 38) or control (n = 46). The average time to first cold-sore recurrence was 1.55 months longer in the BCG group (95% CI 0.27–2.82, p = 0.02) than the control group (hazard ratio 0.54, 95% CI 0.32–0.91; intention-to-treat). The beneficial effect of BCG was greater in the as-treated population (difference 1.91 months, 95% CI 0.69–3.12, p = 0.003; hazard ratio 0.45, 95% CI 0.26–0.76). In prespecified subgroup analyses, only sex modified the treatment effect (interaction p = 0.007), with benefit restricted to males. Over 12 months, a greater proportion of participants in the BCG group compared with the control group reported a decrease in duration (61% vs 21%), severity (74% vs 21%), frequency (55% vs 21%), and impact on quality of life (42% vs 15%) of cold sore recurrences. In participants who had ever had a cold sore, there was also a decrease in self-reported burden of recurrences in the BCG group. In participants who had never had a cold sore, there was an increased risk of a first episode in the BCG group (risk difference 1.4%; 95% CI 0.3–2.6%, p = 0.02). There were no safety concerns. Interpretation: BCG-Denmark vaccination had a beneficial effect on herpes labialis, particularly in males with frequent recurrences, but may increase the risk of a first cold sore. Funding: Bill & Melinda Gates Foundation, the Minderoo Foundation, Sarah and Lachlan Murdoch, the Royal Children's Hospital Foundation, Health Services Union NSW, the Peter Sowerby Foundation, SA Health, the Insurance Advisernet Foundation, the NAB Foundation, the Calvert-Jones Foundation, the Modara Pines Charitable Foundation, the UHG Foundation Pty Ltd, Epworth Healthcare, and individual donors.
KW - Bacille Calmette-Guérin
KW - Cold sore
KW - Herpes labialis
KW - Herpes simplex virus
KW - Heterologous immunity
KW - Mycobacterium bovis
KW - Non-specific effects
KW - Off-target effects
KW - Prevention
KW - Secondary prophylaxis
UR - http://www.scopus.com/inward/record.url?scp=85171747032&partnerID=8YFLogxK
U2 - 10.1016/j.eclinm.2023.102203
DO - 10.1016/j.eclinm.2023.102203
M3 - Article
AN - SCOPUS:85171747032
SN - 2589-5370
VL - 64
JO - EClinicalMedicine
JF - EClinicalMedicine
M1 - 102203
ER -