{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,6]],"date-time":"2026-03-06T15:33:08Z","timestamp":1772811188381,"version":"3.50.1"},"reference-count":46,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2022,2,17]],"date-time":"2022-02-17T00:00:00Z","timestamp":1645056000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2022,2,17]],"date-time":"2022-02-17T00:00:00Z","timestamp":1645056000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["npj Vaccines"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Acellular pertussis (aP) booster vaccines are central to pertussis immunization programs, although their effectiveness varies. The Bacille Calmette-Gu\u00e9rin (BCG) vaccine is a prototype inducer of trained immunity, which enhances immune responses to subsequent infections or vaccinations. While previous clinical studies have demonstrated that trained immunity can protect against heterologous infections, its effect on aP vaccines in humans is unknown. We conducted a clinical study in order to determine the immunological effects of trained immunity on pertussis vaccination. Healthy female volunteers were randomly assigned to either receive BCG followed by a booster dose of tetanus-diphteria-pertussis inactivated polio vaccine (Tdap-IPV) 3 months later (BCG-trained), BCG\u2009+\u2009Tdap-IPV concurrently, or Tdap-IPV followed by BCG 3 months later. Primary outcomes were pertussis-specific humoral, T- and B-cell responses and were quantified at baseline of Tdap-IPV vaccination and 2 weeks thereafter. As a secondary outcome in the BCG-trained cohort, ex vivo leukocyte responses were measured in response to unrelated stimuli before and after BCG vaccination. BCG vaccination 3 months prior to, but not concurrent with, Tdap-IPV improves pertussis-specific Th1-cell and humoral responses, and also increases total memory B cell responses. These responses were correlated with enhanced IL-6 and IL-1\u03b2 production at the baseline of Tdap-IPV vaccination in the BCG-trained cohort. Our study demonstrates that prior BCG vaccination potentiates immune responses to pertussis vaccines and that biomarkers of trained immunity are the most reliable correlates of those responses.<\/jats:p>","DOI":"10.1038\/s41541-022-00438-4","type":"journal-article","created":{"date-parts":[[2022,2,17]],"date-time":"2022-02-17T11:02:53Z","timestamp":1645095773000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["BCG-induced trained immunity enhances acellular pertussis vaccination responses in an explorative randomized clinical trial"],"prefix":"10.1038","volume":"7","author":[{"given":"Joshua","family":"Gillard","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bastiaan A.","family":"Blok","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Daniel R.","family":"Garza","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Prashanna Balaji","family":"Venkatasubramanian","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Elles","family":"Simonetti","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marc J.","family":"Eleveld","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Guy A. M.","family":"Berbers","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2753-9674","authenticated-orcid":false,"given":"Pieter G. M.","family":"van Gageldonk","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Irma","family":"Joosten","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ronald","family":"de Groot","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"L. Charlotte J.","family":"de Bree","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Reinout","family":"van Crevel","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marien I.","family":"de Jonge","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6189-5491","authenticated-orcid":false,"given":"Martijn A.","family":"Huynen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2421-6052","authenticated-orcid":false,"given":"Mihai G.","family":"Netea","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7065-7807","authenticated-orcid":false,"given":"Dimitri A.","family":"Diavatopoulos","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2022,2,17]]},"reference":[{"key":"438_CR1","doi-asserted-by":"publisher","first-page":"e222","DOI":"10.1097\/INF.0000000000000795","volume":"34","author":"T Tan","year":"2015","unstructured":"Tan, T. et al. Pertussis across the globe: recent epidemiologic trends from 2000 to 2013. Pediatr. Infect. Dis. J. 34, e222\u2013e232 (2015).","journal-title":"Pediatr. Infect. Dis. J."},{"key":"438_CR2","doi-asserted-by":"publisher","first-page":"787","DOI":"10.1073\/pnas.1314688110","volume":"111","author":"JM Warfel","year":"2014","unstructured":"Warfel, J. M., Zimmerman, L. I. & Merkel, T. J. Acellular pertussis vaccines protect against disease but fail to prevent infection and transmission in a nonhuman primate model. Proc. Natl Acad. Sci. USA 111, 787\u2013792 (2014).","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"438_CR3","doi-asserted-by":"publisher","first-page":"916","DOI":"10.1016\/0264-410X(95)00257-2","volume":"14","author":"LM Huang","year":"1996","unstructured":"Huang, L. M. et al. Responses to primary and a booster dose of acellular, component, and whole-cell pertussis vaccines initiated at 2 months of age. Vaccine 14, 916\u2013922 (1996).","journal-title":"Vaccine"},{"key":"438_CR4","doi-asserted-by":"publisher","first-page":"1012","DOI":"10.1056\/NEJMoa1200850","volume":"367","author":"NP Klein","year":"2012","unstructured":"Klein, N. P., Bartlett, J., Rowhani-Rahbar, A., Fireman, B. & Baxter, R. Waning protection after fifth dose of acellular pertussis vaccine in children. New Engl. J. Med. 367, 1012\u20131019 (2012).","journal-title":"New Engl. J. Med."},{"key":"438_CR5","doi-asserted-by":"publisher","first-page":"2126","DOI":"10.1001\/jama.2012.14939","volume":"308","author":"LK Misegades","year":"2012","unstructured":"Misegades, L. K. et al. Association of childhood pertussis with receipt of 5 doses of pertussis vaccine by time since last vaccine dose, California, 2010. JAMA 308, 2126\u20132132 (2012).","journal-title":"JAMA"},{"key":"438_CR6","doi-asserted-by":"publisher","first-page":"6530","DOI":"10.1016\/j.vaccine.2009.08.052","volume":"27","author":"LH Hendrikx","year":"2009","unstructured":"Hendrikx, L. H., Berbers, G. A., Veenhoven, R. H., Sanders, E. A. & Buisman, A. M. IgG responses after booster vaccination with different pertussis vaccines in Dutch children 4 years of age: effect of vaccine antigen content. Vaccine 27, 6530\u20136536 (2009).","journal-title":"Vaccine"},{"key":"438_CR7","doi-asserted-by":"publisher","first-page":"5256","DOI":"10.1016\/j.vaccine.2017.08.009","volume":"35","author":"A Misiak","year":"2017","unstructured":"Misiak, A. et al. Addition of a TLR7 agonist to an acellular pertussis vaccine enhances Th1 and Th17 responses and protective immunity in a mouse model. Vaccine 35, 5256\u20135263 (2017).","journal-title":"Vaccine"},{"key":"438_CR8","doi-asserted-by":"publisher","first-page":"607","DOI":"10.1038\/mi.2014.93","volume":"8","author":"A Dunne","year":"2015","unstructured":"Dunne, A. et al. A novel TLR2 agonist from Bordetella pertussis is a potent adjuvant that promotes protective immunity with an acellular pertussis vaccine. Mucosal Immunol. 8, 607\u2013617 (2015).","journal-title":"Mucosal Immunol."},{"key":"438_CR9","doi-asserted-by":"publisher","first-page":"5450","DOI":"10.1016\/j.vaccine.2004.09.041","volume":"23","author":"T Sugai","year":"2005","unstructured":"Sugai, T. et al. A CpG-containing oligodeoxynucleotide as an efficient adjuvant counterbalancing the Th1\/Th2 immune response in diphtheria-tetanus-pertussis vaccine. Vaccine 23, 5450\u20135456 (2005).","journal-title":"Vaccine"},{"key":"438_CR10","doi-asserted-by":"publisher","first-page":"698","DOI":"10.1001\/jama.1994.03510330076038","volume":"271","author":"GA Colditz","year":"1994","unstructured":"Colditz, G. A. et al. Efficacy of BCG vaccine in the prevention of tuberculosis. Meta-analysis of the published literature. JAMA 271, 698\u2013702 (1994).","journal-title":"JAMA"},{"key":"438_CR11","doi-asserted-by":"publisher","first-page":"1435","DOI":"10.1136\/bmj.321.7274.1435","volume":"321","author":"I Kristensen","year":"2000","unstructured":"Kristensen, I., Aaby, P. & Jensen, H. Routine vaccinations and child survival: follow up study in Guinea-Bissau, West Africa. BMJ 321, 1435\u20131438 (2000).","journal-title":"BMJ"},{"key":"438_CR12","doi-asserted-by":"publisher","first-page":"7300","DOI":"10.1016\/j.vaccine.2012.09.035","volume":"30","author":"S Hirve","year":"2012","unstructured":"Hirve, S. et al. Non-specific and sex-differential effects of vaccinations on child survival in rural western India. Vaccine 30, 7300\u20137308 (2012).","journal-title":"Vaccine"},{"key":"438_CR13","doi-asserted-by":"publisher","first-page":"245","DOI":"10.1093\/infdis\/jir240","volume":"204","author":"P Aaby","year":"2011","unstructured":"Aaby, P. et al. Randomized trial of BCG vaccination at birth to low-birth-weight children: beneficial nonspecific effects in the neonatal period? J. Infect. Dis. 204, 245\u2013252 (2011).","journal-title":"J. Infect. Dis."},{"key":"438_CR14","doi-asserted-by":"publisher","first-page":"aaf1098","DOI":"10.1126\/science.aaf1098","volume":"352","author":"MG Netea","year":"2016","unstructured":"Netea, M. G. et al. Trained immunity: a program of innate immune memory in health and disease. Science 352, aaf1098 (2016).","journal-title":"Science"},{"key":"438_CR15","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-019-08659-3","volume":"10","author":"J Walk","year":"2019","unstructured":"Walk, J. et al. Outcomes of controlled human malaria infection after BCG vaccination. Nat. Commun. 10, 874 (2019).","journal-title":"Nat. Commun."},{"key":"438_CR16","doi-asserted-by":"publisher","first-page":"89","DOI":"10.1016\/j.chom.2017.12.010","volume":"23","author":"RJW Arts","year":"2018","unstructured":"Arts, R. J. W. et al. BCG vaccination protects against experimental viral infection in humans through the induction of cytokines associated with grained immunity. Cell Host Microbe 23, 89\u2013100 e105 (2018).","journal-title":"Cell Host Microbe"},{"key":"438_CR17","doi-asserted-by":"publisher","first-page":"1930","DOI":"10.1093\/infdis\/jiv332","volume":"212","author":"J Leentjens","year":"2015","unstructured":"Leentjens, J. et al. BCG vaccination enhances the immunogenicity of subsequent influenza vaccination in healthy volunteers: a randomized, placebo-controlled pilot study. J. Infect. Dis. 212, 1930\u20131938 (2015).","journal-title":"J. Infect. Dis."},{"key":"438_CR18","doi-asserted-by":"publisher","first-page":"547","DOI":"10.1080\/14760584.2018.1483727","volume":"17","author":"P Zimmermann","year":"2018","unstructured":"Zimmermann, P. & Curtis, N. The influence of BCG on vaccine responses - a systematic review. Expert Rev. Vaccines 17, 547\u2013554 (2018).","journal-title":"Expert Rev. Vaccines"},{"key":"438_CR19","doi-asserted-by":"publisher","first-page":"103254","DOI":"10.1016\/j.ebiom.2021.103254","volume":"65","author":"E Broset","year":"2021","unstructured":"Broset, E. et al. BCG vaccination improves DTaP immune responses in mice and is associated with lower pertussis incidence in ecological epidemiological studies. EBioMedicine 65, 103254 (2021).","journal-title":"EBioMedicine"},{"key":"438_CR20","doi-asserted-by":"publisher","first-page":"173","DOI":"10.1016\/j.ebiom.2017.07.012","volume":"22","author":"P Aaby","year":"2017","unstructured":"Aaby, P., Andersen, A., Ravn, H. & Zaman, K. Co-administration of BCG and diphtheria-tetanus-pertussis (DTP) vaccinations may reduce infant mortality more than the WHO-schedule of BCG first and then DTP. A re-analysis of demographic surveillance data from rural Bangladesh. EBioMedicine 22, 173\u2013180 (2017).","journal-title":"EBioMedicine"},{"key":"438_CR21","first-page":"455","volume":"70","author":"BA Blok","year":"2020","unstructured":"Blok, B. A. et al. Interacting, nonspecific, immunological effects of bacille calmette-guerin and tetanus-diphtheria-pertussis inactivated polio vaccinations: an explorative, randomized trial. Clin. Infect. Dis. 70, 455\u2013463 (2020).","journal-title":"Clin. Infect. Dis."},{"key":"438_CR22","doi-asserted-by":"publisher","first-page":"570","DOI":"10.1093\/trstmh\/trw073","volume":"110","author":"P Aaby","year":"2016","unstructured":"Aaby, P., Ravn, H., Fisker, A. B., Rodrigues, A. & Benn, C. S. Is diphtheria-tetanus-pertussis (DTP) associated with increased female mortality? A meta-analysis testing the hypotheses of sex-differential non-specific effects of DTP vaccine. Trans. R. Soc. Trop. Med. Hyg. 110, 570\u2013581 (2016).","journal-title":"Trans. R. Soc. Trop. Med. Hyg."},{"key":"438_CR23","doi-asserted-by":"publisher","unstructured":"van der Lee, S. et al. Enhanced Bordetella pertussis acquisition rate in adolescents during the 2012 epidemic in the Netherlands and evidence for prolonged antibody persistence after infection. Euro Surveill. https:\/\/doi.org\/10.2807\/1560-7917.ES.2017.22.47.17-00011 (2017).","DOI":"10.2807\/1560-7917.ES.2017.22.47.17-00011"},{"key":"438_CR24","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-021-23114-y","volume":"12","author":"G Berbers","year":"2021","unstructured":"Berbers, G. et al. Circulation of pertussis and poor protection against diphtheria among middle-aged adults in 18 European countries. Nat. Commun. 12, 2871 (2021).","journal-title":"Nat. Commun."},{"key":"438_CR25","doi-asserted-by":"publisher","first-page":"79","DOI":"10.1016\/j.jim.2008.02.018","volume":"335","author":"PG van Gageldonk","year":"2008","unstructured":"van Gageldonk, P. G., van Schaijk, F. G., van der Klis, F. R. & Berbers, G. A. Development and validation of a multiplex immunoassay for the simultaneous determination of serum antibodies to Bordetella pertussis, diphtheria and tetanus. J. Immunol. Methods 335, 79\u201389 (2008).","journal-title":"J. Immunol. Methods"},{"key":"438_CR26","doi-asserted-by":"publisher","first-page":"1879","DOI":"10.1128\/CVI.00277-12","volume":"19","author":"RM Schure","year":"2012","unstructured":"Schure, R. M. et al. T-cell responses before and after the fifth consecutive acellular pertussis vaccination in 4-year-old Dutch children. Clin. Vaccine Immunol. 19, 1879\u20131886 (2012).","journal-title":"Clin. Vaccine Immunol."},{"key":"438_CR27","doi-asserted-by":"publisher","first-page":"3528","DOI":"10.1128\/JVI.02393-08","volume":"83","author":"KS Mathurin","year":"2009","unstructured":"Mathurin, K. S., Martens, G. W., Kornfeld, H. & Welsh, R. M. CD4 T-cell-mediated heterologous immunity between mycobacteria and poxviruses. J. Virol. 83, 3528\u20133539 (2009).","journal-title":"J. Virol."},{"key":"438_CR28","doi-asserted-by":"publisher","first-page":"1097","DOI":"10.4049\/jimmunol.166.2.1097","volume":"166","author":"G Lertmemongkolchai","year":"2001","unstructured":"Lertmemongkolchai, G., Cai, G., Hunter, C. A. & Bancroft, G. J. Bystander activation of CD8+ T cells contributes to the rapid production of IFN-gamma in response to bacterial pathogens. J. Immunol. 166, 1097\u20131105 (2001).","journal-title":"J. Immunol."},{"key":"438_CR29","doi-asserted-by":"publisher","first-page":"3735","DOI":"10.1016\/j.vaccine.2019.03.016","volume":"37","author":"P Zimmermann","year":"2019","unstructured":"Zimmermann, P. et al. The influence of neonatal Bacille Calmette-Guerin (BCG) immunisation on heterologous vaccine responses in infants. Vaccine 37, 3735\u20133744 (2019).","journal-title":"Vaccine"},{"key":"438_CR30","doi-asserted-by":"publisher","first-page":"3098","DOI":"10.1016\/j.vaccine.2013.03.059","volume":"31","author":"N Ritz","year":"2013","unstructured":"Ritz, N., Mui, M., Balloch, A. & Curtis, N. Non-specific effect of Bacille Calmette-Guerin vaccine on the immune response to routine immunisations. Vaccine 31, 3098\u20133103 (2013).","journal-title":"Vaccine"},{"key":"438_CR31","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.trivac.2013.11.004","volume":"3","author":"DH Libraty","year":"2014","unstructured":"Libraty, D. H. et al. Neonatal BCG vaccination is associated with enhanced T-helper 1 immune responses to heterologous infant vaccines. Trials Vaccinol. 3, 1\u20135 (2014).","journal-title":"Trials Vaccinol."},{"key":"438_CR32","doi-asserted-by":"publisher","first-page":"e0152710","DOI":"10.1371\/journal.pone.0152710","volume":"11","author":"WJ du Plessis","year":"2016","unstructured":"du Plessis, W. J. et al. The functional response of B cells to antigenic stimulation: a preliminary report of latent tuberculosis. PLoS ONE 11, e0152710 (2016).","journal-title":"PLoS ONE"},{"key":"438_CR33","doi-asserted-by":"publisher","first-page":"2056","DOI":"10.1016\/j.vaccine.2015.02.056","volume":"33","author":"S Biering-Sorensen","year":"2015","unstructured":"Biering-Sorensen, S. et al. Variation of growth in the production of the BCG vaccine and the association with the immune response. An observational study within a randomised trial. Vaccine 33, 2056\u20132065 (2015).","journal-title":"Vaccine"},{"key":"438_CR34","doi-asserted-by":"publisher","first-page":"239","DOI":"10.3389\/fcimb.2017.00239","volume":"7","author":"H Ru","year":"2017","unstructured":"Ru, H. et al. The impact of Genome Region of Difference 4 (RD4) on Mycobacterial virulence and BCG efficacy. Front. Cell. Infect. Microbiol. 7, 239 (2017).","journal-title":"Front. Cell. Infect. Microbiol."},{"key":"438_CR35","doi-asserted-by":"publisher","first-page":"2454","DOI":"10.1080\/21645515.2021.1885280","volume":"17","author":"T Cho","year":"2021","unstructured":"Cho, T. et al. A review of the BCG vaccine and other approaches toward tuberculosis eradication. Hum. Vaccin. Immunother. 17, 2454\u20132470 (2021).","journal-title":"Hum. Vaccin. Immunother."},{"key":"438_CR36","doi-asserted-by":"publisher","first-page":"5596","DOI":"10.1073\/pnas.0700869104","volume":"104","author":"R Brosch","year":"2007","unstructured":"Brosch, R. et al. Genome plasticity of BCG and impact on vaccine efficacy. Proc. Natl Acad. Sci. USA 104, 5596\u20135601 (2007).","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"438_CR37","doi-asserted-by":"publisher","first-page":"1055","DOI":"10.1128\/CVI.00131-10","volume":"17","author":"SA Plotkin","year":"2010","unstructured":"Plotkin, S. A. Correlates of protection induced by vaccination. Clin. Vaccin. Immunol. 17, 1055\u20131065 (2010).","journal-title":"Clin. Vaccin. Immunol."},{"key":"438_CR38","doi-asserted-by":"publisher","first-page":"e1003264","DOI":"10.1371\/journal.ppat.1003264","volume":"9","author":"PJ Ross","year":"2013","unstructured":"Ross, P. J. et al. Relative contribution of Th1 and Th17 cells in adaptive immunity to Bordetella pertussis: towards the rational design of an improved acellular pertussis vaccine. PLoS Pathog. 9, e1003264 (2013).","journal-title":"PLoS Pathog."},{"key":"438_CR39","doi-asserted-by":"publisher","first-page":"e018594","DOI":"10.1136\/bmjopen-2017-018594","volume":"7","author":"H de Graaf","year":"2017","unstructured":"de Graaf, H. et al. Investigating Bordetella pertussis colonisation and immunity: protocol for an inpatient controlled human infection model. BMJ Open 7, e018594 (2017).","journal-title":"BMJ Open"},{"key":"438_CR40","doi-asserted-by":"publisher","first-page":"3853","DOI":"10.1172\/JCI121309","volume":"128","author":"R da Silva Antunes","year":"2018","unstructured":"da Silva Antunes, R. et al. Th1\/Th17 polarization persists following whole-cell pertussis vaccination despite repeated acellular boosters. J. Clin. Investig. 128, 3853\u20133865 (2018).","journal-title":"J. Clin. Investig."},{"key":"438_CR41","doi-asserted-by":"publisher","first-page":"106","DOI":"10.1016\/j.pep.2005.01.014","volume":"41","author":"M Hijnen","year":"2005","unstructured":"Hijnen, M., van Gageldonk, P. G., Berbers, G. A., van Woerkom, T. & Mooi, F. R. The Bordetella pertussis virulence factor P.69 pertactin retains its immunological properties after overproduction in Escherichia coli. Protein Expr. Purif. 41, 106\u2013112 (2005).","journal-title":"Protein Expr. Purif."},{"key":"438_CR42","doi-asserted-by":"publisher","first-page":"1986","DOI":"10.1038\/leu.2012.122","volume":"26","author":"T Kalina","year":"2012","unstructured":"Kalina, T. et al. EuroFlow standardization of flow cytometer instrument settings and immunophenotyping protocols. Leukemia 26, 1986\u20132010 (2012).","journal-title":"Leukemia"},{"key":"438_CR43","doi-asserted-by":"publisher","first-page":"2208","DOI":"10.1016\/j.jaci.2018.02.017","volume":"141","author":"E Blanco","year":"2018","unstructured":"Blanco, E. et al. Age-associated distribution of normal B-cell and plasma cell subsets in peripheral blood. J. Allergy Clin. Immunol. 141, 2208\u20132219. e2216 (2018).","journal-title":"J. Allergy Clin. Immunol."},{"key":"438_CR44","doi-asserted-by":"publisher","first-page":"1","DOI":"10.18637\/jss.v067.i01","volume":"67","author":"D Bates","year":"2015","unstructured":"Bates, D., Machler, M., Bolker, B. M. & Walker, S. C. Fitting linear mixed-effects models Using lme4. J. Stat. Softw. 67, 1\u201348 (2015).","journal-title":"J. Stat. Softw."},{"key":"438_CR45","doi-asserted-by":"crossref","unstructured":"Lenth, R. Emmeans: estimated marginal means, aka least-squares means (2018).","DOI":"10.32614\/CRAN.package.emmeans"},{"key":"438_CR46","doi-asserted-by":"publisher","first-page":"1","DOI":"10.18637\/jss.v028.i05","volume":"28","author":"M Kuhn","year":"2008","unstructured":"Kuhn, M. Building predictive models in R using the caret Package. J. Stat. Softw. 28, 1\u201326 (2008).","journal-title":"J. Stat. Softw."}],"container-title":["npj Vaccines"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41541-022-00438-4.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41541-022-00438-4","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41541-022-00438-4.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,9,18]],"date-time":"2024-09-18T20:28:53Z","timestamp":1726691333000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41541-022-00438-4"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,2,17]]},"references-count":46,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2022,12]]}},"alternative-id":["438"],"URL":"https:\/\/doi.org\/10.1038\/s41541-022-00438-4","relation":{},"ISSN":["2059-0105"],"issn-type":[{"value":"2059-0105","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,2,17]]},"assertion":[{"value":"19 July 2021","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"14 December 2021","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"17 February 2022","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"M.G.N. has a patent Nanobiologics to inhibit trained immunity licensed to TTxD, and a patent nanobiologics to stimulate trained immunity licensed to TTxD. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"21"}}