Age is a key risk factor associated with the severity of symptoms caused by SARS-CoV-2, and there is an urgent need to reduce COVID-19 morbidity and mortality in elderly individuals. We discuss evidence suggesting that trained immunity elicited by BCG vaccination may improve immune responses and can serve as a strategy to combat COVID-19 in this population.

Department for Genomics and Immunoregulation Life and Medical Sciences Institute University of Bonn Bonn Germany

Department of Cardiology 1 Coronary and Peripheral Vascular Disease Heart Failure University Hospital Münster Münster Germany

Department of Internal Medicine and Radboud Centre of Infectious Diseases Radboud University Medical Centre Nijmegen the Netherlands

Institutes of Molecular Genetics of the Czech Academy of Sciences Prague Czechia

Núcleo de Pesquisa da Faculdade da Polícia Militar do Estado de Goiás Goiânia Goiás Brazil

See more in PubMed

Sohrabi Y., Dos Santos J.C., Dorenkamp M., Findeisen H., Godfrey R., Netea M.G., Joosten L.A. Trained immunity as a novel approach against COVID-19 with a focus on Bacillus Calmette-Guérin vaccine: mechanisms, challenges and perspectives. Clin. Transl. Immunology. 2020;9:e1228. doi: 10.1002/cti2.1228. PubMed DOI PMC

Rydyznski Moderbacher C., Ramirez S.I., Dan J.M., Grifoni A., Hastie K.M., Weiskopf D., Belanger S., Abbott R.K., Kim C., Choi J., et al. Antigen-Specific Adaptive Immunity to SARS-CoV-2 in Acute COVID-19 and Associations with Age and Disease Severity. Cell. 2020;183:996–1012. doi: 10.1016/j.cell.2020.09.038. PubMed DOI PMC

Santesmasses D., Castro J.P., Zenin A.A., Shindyapina A.V., Gerashchenko M.V., Zhang B., Kerepesi C., Yim S.H., Fedichev P.O., Gladyshev V.N. COVID-19 is an emergent disease of aging. Aging Cell. 2020;19:e13230. doi: 10.1111/acel.13230. PubMed DOI PMC

Catanzaro M., Fagiani F., Racchi M., Corsini E., Govoni S., Lanni C. Immune response in COVID-19: addressing a pharmacological challenge by targeting pathways triggered by SARS-CoV-2. Signal Transduct. Target. Ther. 2020;5:84. doi: 10.1038/s41392-020-0191-1. PubMed DOI PMC

Quinn K.M., Fox A., Harland K.L., Russ B.E., Li J., Nguyen T.H.O., Loh L., Olshanksy M., Naeem H., Tsyganov K., et al. Age-Related Decline in Primary CD8+ T Cell Responses Is Associated with the Development of Senescence in Virtual Memory CD8+ T Cells. Cell Rep. 2018;23:3512–3524. doi: 10.1016/j.celrep.2018.05.057. PubMed DOI

Glynn J.R., Moss P.A.H. Systematic analysis of infectious disease outcomes by age shows lowest severity in school-age children. Sci. Data. 2020;7:329. doi: 10.1038/s41597-020-00668-y. PubMed DOI PMC

Del Giudice G., Goronzy J.J., Grubeck-Loebenstein B., Lambert P.H., Mrkvan T., Stoddard J.J., Doherty T.M. Fighting against a protean enemy: immunosenescence, vaccines, and healthy aging. NPJ Aging Mech. Dis. 2017;4:1. doi: 10.1038/s41514-017-0020-0. PubMed DOI PMC

Bulut O., Kilic G., Domínguez-Andrés J., Netea M.G. Overcoming immune dysfunction in the elderly: trained immunity as a novel approach. Int. Immunol. 2020;32:741–753. doi: 10.1093/intimm/dxaa052. PubMed DOI PMC

Steinman J.B., Lum F.M., Ho P.P., Kaminski N., Steinman L. Reduced development of COVID-19 in children reveals molecular checkpoints gating pathogenesis illuminating potential therapeutics. Proc. Natl. Acad. Sci. USA. 2020;117:24620–24626. doi: 10.1073/pnas.2012358117. PubMed DOI PMC

Escobar L.E., Molina-Cruz A., Barillas-Mury C. BCG vaccine protection from severe coronavirus disease 2019 (COVID-19) Proc. Natl. Acad. Sci. USA. 2020;117:17720–17726. doi: 10.1073/pnas.2008410117. PubMed DOI PMC

Giamarellos-Bourboulis E.J., Tsilika M., Moorlag S., Antonakos N., Kotsaki A., Dominguez-Andres J., Kyriazopoulou E., Gkavogianni T., Adami M.E., Damoraki G., et al. Activate: Randomized Clinical Trial of BCG Vaccination against Infection in the Elderly. Cell. 2020;183:315–323. doi: 10.1016/j.cell.2020.08.051. PubMed DOI PMC

Cirovic B., de Bree L.C.J., Groh L., Blok B.A., Chan J., van der Velden W., Bremmers M.E.J., van Crevel R., Handler K., Picelli S., et al. BCG Vaccination in Humans Elicits Trained Immunity via the Hematopoietic Progenitor Compartment. Cell Host Microbe. 2020;28:322–334. doi: 10.1016/j.chom.2020.05.014. PubMed DOI PMC

Kleinnijenhuis J., Quintin J., Preijers F., Joosten L.A., Jacobs C., Xavier R.J., van der Meer J.W., van Crevel R., Netea M.G. BCG-induced trained immunity in NK cells: Role for non-specific protection to infection. Clin. Immunol. 2014;155:213–219. doi: 10.1016/j.clim.2014.10.005. PubMed DOI PMC

Koeken V.A., de Bree L.C.J., Mourits V.P., Moorlag S.J., Walk J., Cirovic B., Arts R.J., Jaeger M., Dijkstra H., Lemmers H., et al. BCG vaccination in humans inhibits systemic inflammation in a sex-dependent manner. J. Clin. Invest. 2020;130:5591–5602. doi: 10.1172/JCI133935. PubMed DOI PMC

Zimmermann P., Donath S., Perrett K.P., Messina N.L., Ritz N., Netea M.G., Flanagan K.L., van der Klis F.R.M., Curtis N., MIS BAIR group The influence of neonatal Bacille Calmette-Guérin (BCG) immunisation on heterologous vaccine responses in infants. Vaccine. 2019;37:3735–3744. doi: 10.1016/j.vaccine.2019.03.016. PubMed DOI

Improving reproducibility and translational potential of mouse models: lessons from studying leishmaniasis