ORIGINAL RESEARCH article
Front. Immunol.
Sec. Vaccines and Molecular Therapeutics
Volume 16 - 2025 | doi: 10.3389/fimmu.2025.1633977
This article is part of the Research TopicCommunity Series in Immune studies of SARS-CoV2 and vaccines using preclinical modeling, Volume IIView all articles
The impact of mycobacteria-induced trained immunity on SARS-CoV-2 vaccine responses
Provisionally accepted
Lidia Sánchez-Morales1
Néstor Porras González1
Andrea Pérez-Domingo1
Marta Perez-Sancho2*
Teresa García-Seco1Marta Diaz-Frutos1Aranzazu Buendia1
Inmaculada Moreno2Leydis Zamora1
Ana Balseiro3
Maria A. Risalde Moya4
Antonio Rodríguez1
Christian Gortazar5
Maria Mercedes Dominguez1
Lucas Dominguez1- 1Universidad Complutense de Madrid, Madrid, Spain
- 2Complutense University of Madrid, Madrid, Spain
- 3Universidad de Leon, Len, Spain
- 4Universidad de Cordoba, Crdoba, Spain
- 5Universidad de Castilla-La Mancha, Ciudad Real, Spain
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Introduction Beyond the role of Bacillus Calmette-Guérin (BCG) for tuberculosis prevention, BCG has demonstrated heterologous protective effects. The global health crisis caused by the SARS-CoV-2 virus led to research on whether BCG-induced trained immunity could strengthen antiviral defenses. However, studies reported quite different results on its effect against COVID-19. Methods and results In this study, we evaluated the impact of pre-existing trained immunity induced by a BCG-derived Mycobacterium bovis strain (dpB), in both live and inactivated forms, in combination with SARS-CoV-2 vaccination prior to challenge in a mouse model. While the SARS-CoV-2 vaccine was enough for protection in morbidity and mortality terms, its combination with live dpB significantly enhanced immune responses reflected in higher levels of pro-inflammatory cytokines, reduced pulmonary viral loads, and improved histopathological outcomes. Additionally, the formation of inducible bronchus-associated lymphoid tissue (iBALT) in lungs in vaccinated animals pre-exposed to live dpB points to a potential mechanism for long-term immune surveillance in the respiratory tract. Conclusions These immunological findings highlight the potential benefits of integrating trained immunity inducers with pathogen-specific vaccines to enhance immune responses and protection. Further research is needed to optimize immunomodulation strategies, dosing regimens and administration routes to maximize these synergistic effects and prevent potential negative effects.
Keywords: trained immunity, SARS-CoV-2 vaccine, mycobacteria, Innate memory, Adaptative Immunity
Received: 23 May 2025; Accepted: 18 Aug 2025.
Copyright: © 2025 Sánchez-Morales, Porras González, Pérez-Domingo, Perez-Sancho, García-Seco, Diaz-Frutos, Buendia, Moreno, Zamora, Balseiro, Risalde Moya, Rodríguez, Gortazar, Dominguez and Dominguez. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Marta Perez-Sancho, Complutense University of Madrid, Madrid, Spain
Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.