{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T21:13:28Z","timestamp":1790802808616,"version":"4.1.0"},"reference-count":57,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2018,6,29]],"date-time":"2018-06-29T00:00:00Z","timestamp":1530230400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2018,6,29]],"date-time":"2018-06-29T00:00:00Z","timestamp":1530230400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100002428","name":"Austrian Science Fund","doi-asserted-by":"publisher","award":["SFB1814"],"award-info":[{"award-number":["SFB1814"]}],"id":[{"id":"10.13039\/501100002428","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002428","name":"Austrian Science Fund","doi-asserted-by":"publisher","award":["SFB1814"],"award-info":[{"award-number":["SFB1814"]}],"id":[{"id":"10.13039\/501100002428","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Investigator initiated grant by Novartis, and Medical University Vienna"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Immunosenescence is characterised by reduced B and T cell responses. Evidence shows that booster vaccinations are less effective in elderly people, but data on the efficacy of primary immunisation are sparse. We conducted a monocentric, open label, phase IV trial to compare immune responses to primary vaccinations using the inactivated, adjuvanted Japanese Encephalitis vaccine by 30 elderly people (mean 69, range 61\u201378\u2009years) and 30 younger people (mean 24, range 18\u201330\u2009years). Humoral and cellular immune responses were analysed in relation to age and cytomegalovirus (CMV) seropositivity. Vaccine-specific antibody titres were significantly lower in elderly participants and 47% of them were non- or low responders after the two doses of the vaccine neo-antigen. The reduced humoral immune responses in elderly people correlated with reduced cytokine production, such as interferon gamma (IFN-\u03b3) <jats:italic>in vitro<\/jats:italic>, as well as higher frequencies of late-differentiated effector and effector memory T cells and T regulatory cells. These cellular changes and lower antibody titres were particularly prominent in CMV-seropositive elderly participants. If primary vaccination before the age of 60 is not possible, elderly patients may require different vaccination strategies to ensure sufficient long-lasting immunity, such as adapted or accelerated schedules and the use of different adjuvants.<\/jats:p>","DOI":"10.1038\/s41598-018-28111-8","type":"journal-article","created":{"date-parts":[[2018,6,25]],"date-time":"2018-06-25T09:55:13Z","timestamp":1529920513000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":103,"title":["Age-related differences in humoral and cellular immune responses after primary immunisation: indications for stratified vaccination schedules"],"prefix":"10.1038","volume":"8","author":[{"given":"Angelika","family":"Wagner","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erika","family":"Garner-Spitzer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joanna","family":"Jasinska","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Herwig","family":"Kollaritsch","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1902-8674","authenticated-orcid":false,"given":"Karin","family":"Stiasny","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Kundi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ursula","family":"Wiedermann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2018,6,29]]},"reference":[{"key":"28111_CR1","unstructured":"United Nations, D. o. E. a. S. A., Population Division. World Population Ageing, http:\/\/www.un.org\/en\/development\/desa\/population\/theme\/ageing\/WPA2015.shtml (2015)."},{"key":"28111_CR2","doi-asserted-by":"publisher","first-page":"50","DOI":"10.1016\/j.maturitas.2015.05.004","volume":"82","author":"A Pera","year":"2015","unstructured":"Pera, A. et al. Immunosenescence: Implications for response to infection and vaccination in older people. Maturitas 82, 50\u201355, https:\/\/doi.org\/10.1016\/j.maturitas.2015.05.004 (2015).","journal-title":"Maturitas"},{"key":"28111_CR3","doi-asserted-by":"publisher","first-page":"346","DOI":"10.1016\/j.imlet.2014.06.006","volume":"162","author":"D Boraschi","year":"2014","unstructured":"Boraschi, D. & Italiani, P. Immunosenescence and vaccine failure in the elderly: strategies for improving response. Immunol Lett 162, 346\u2013353, https:\/\/doi.org\/10.1016\/j.imlet.2014.06.006 (2014).","journal-title":"Immunol Lett"},{"key":"28111_CR4","doi-asserted-by":"publisher","first-page":"230","DOI":"10.1159\/000343475","volume":"59","author":"M Prelog","year":"2013","unstructured":"Prelog, M. Differential approaches for vaccination from childhood to old age. Gerontology 59, 230\u2013239, https:\/\/doi.org\/10.1159\/000343475 (2013).","journal-title":"Gerontology"},{"issue":"Suppl 1","key":"28111_CR5","doi-asserted-by":"publisher","first-page":"S116","DOI":"10.1016\/j.jcpa.2009.10.002","volume":"142","author":"B Grubeck-Loebenstein","year":"2010","unstructured":"Grubeck-Loebenstein, B. Fading immune protection in old age: vaccination in the elderly. J Comp Pathol 142(Suppl 1), S116\u2013119, https:\/\/doi.org\/10.1016\/j.jcpa.2009.10.002 (2010).","journal-title":"J Comp Pathol"},{"key":"28111_CR6","doi-asserted-by":"publisher","first-page":"3232","DOI":"10.1016\/j.vaccine.2005.01.085","volume":"23","author":"U Hainz","year":"2005","unstructured":"Hainz, U. et al. Insufficient protection for healthy elderly adults by tetanus and TBE vaccines. Vaccine 23, 3232\u20133235, https:\/\/doi.org\/10.1016\/j.vaccine.2005.01.085 (2005).","journal-title":"Vaccine"},{"key":"28111_CR7","doi-asserted-by":"publisher","first-page":"3511","DOI":"10.1016\/j.vaccine.2010.03.024","volume":"28","author":"B Weinberger","year":"2010","unstructured":"Weinberger, B. et al. Decreased antibody titers and booster responses in tick-borne encephalitis vaccinees aged 50-90 years. Vaccine 28, 3511\u20133515, https:\/\/doi.org\/10.1016\/j.vaccine.2010.03.024 (2010).","journal-title":"Vaccine"},{"key":"28111_CR8","doi-asserted-by":"publisher","first-page":"185","DOI":"10.1038\/nri2508","volume":"9","author":"CA Siegrist","year":"2009","unstructured":"Siegrist, C. A. & Aspinall, R. B-cell responses to vaccination at the extremes of age. Nat Rev Immunol 9, 185\u2013194, https:\/\/doi.org\/10.1038\/nri2508 (2009).","journal-title":"Nat Rev Immunol"},{"key":"28111_CR9","doi-asserted-by":"publisher","first-page":"185ps188","DOI":"10.1126\/scitranslmed.3005624","volume":"5","author":"D Boraschi","year":"2013","unstructured":"Boraschi, D. et al. The gracefully aging immune system. Sci Transl Med 5, 185ps188, https:\/\/doi.org\/10.1126\/scitranslmed.3005624 (2013).","journal-title":"Sci Transl Med"},{"key":"28111_CR10","unstructured":"Austrian Ministry of Health. National Immunisation Plan 2017, http:\/\/www.bmgf.gv.at\/home\/Impfplan (2017)."},{"key":"28111_CR11","doi-asserted-by":"publisher","first-page":"239","DOI":"10.1080\/21645515.2015.1093263","volume":"12","author":"U Wiedermann","year":"2016","unstructured":"Wiedermann, U., Garner-Spitzer, E. & Wagner, A. Primary vaccine failure to routine vaccines: Why and what to do? Hum Vaccin Immunother 12, 239\u2013243, https:\/\/doi.org\/10.1080\/21645515.2015.1093263 (2016).","journal-title":"Hum Vaccin Immunother"},{"key":"28111_CR12","doi-asserted-by":"publisher","first-page":"2426","DOI":"10.4049\/jimmunol.1300293","volume":"191","author":"E Garner-Spitzer","year":"2013","unstructured":"Garner-Spitzer, E. et al. Tick-borne encephalitis (TBE) and hepatitis B nonresponders feature different immunologic mechanisms in response to TBE and influenza vaccination with involvement of regulatory T and B cells and IL-10. J Immunol 191, 2426\u20132436, https:\/\/doi.org\/10.4049\/jimmunol.1300293 (2013).","journal-title":"J Immunol"},{"key":"28111_CR13","doi-asserted-by":"publisher","first-page":"197","DOI":"10.1016\/j.vaccine.2008.10.045","volume":"27","author":"E Garner-Spitzer","year":"2009","unstructured":"Garner-Spitzer, E. et al. Correlation between humoral and cellular immune responses and the expression of the hepatitis A receptor HAVcr-1 on T cells after hepatitis A re-vaccination in high and low-responder vaccinees. Vaccine 27, 197\u2013204, https:\/\/doi.org\/10.1016\/j.vaccine.2008.10.045 (2009).","journal-title":"Vaccine"},{"key":"28111_CR14","doi-asserted-by":"publisher","first-page":"16","DOI":"10.1016\/j.clim.2016.05.007","volume":"169","author":"G Leroux-Roels","year":"2016","unstructured":"Leroux-Roels, G. et al. Impact of adjuvants on CD4(+) T cell and B cell responses to a protein antigen vaccine: Results from a phase II, randomized, multicenter trial. Clin Immunol 169, 16\u201327, https:\/\/doi.org\/10.1016\/j.clim.2016.05.007 (2016).","journal-title":"Clin Immunol"},{"key":"28111_CR15","doi-asserted-by":"publisher","first-page":"406","DOI":"10.3389\/fimmu.2012.00406","volume":"3","author":"H Hogenesch","year":"2012","unstructured":"Hogenesch, H. Mechanism of immunopotentiation and safety of aluminum adjuvants. Front Immunol 3, 406, https:\/\/doi.org\/10.3389\/fimmu.2012.00406 (2012).","journal-title":"Front Immunol"},{"key":"28111_CR16","doi-asserted-by":"publisher","first-page":"287","DOI":"10.1038\/nri2510","volume":"9","author":"P Marrack","year":"2009","unstructured":"Marrack, P., McKee, A. S. & Munks, M. W. Towards an understanding of the adjuvant action of aluminium. Nat Rev Immunol 9, 287\u2013293, https:\/\/doi.org\/10.1038\/nri2510 (2009).","journal-title":"Nat Rev Immunol"},{"key":"28111_CR17","doi-asserted-by":"publisher","first-page":"3","DOI":"10.1016\/S0065-3527(03)61001-8","volume":"61","author":"G Kuno","year":"2003","unstructured":"Kuno, G. Serodiagnosis of flaviviral infections and vaccinations in humans. Adv Virus Res 61, 3\u201365 (2003).","journal-title":"Adv Virus Res"},{"key":"28111_CR18","doi-asserted-by":"publisher","first-page":"112","DOI":"10.1016\/j.coi.2014.05.008","volume":"29","author":"D Frasca","year":"2014","unstructured":"Frasca, D. & Blomberg, B. B. B cell function and influenza vaccine responses in healthy aging and disease. Curr Opin Immunol 29, 112\u2013118, https:\/\/doi.org\/10.1016\/j.coi.2014.05.008 (2014).","journal-title":"Curr Opin Immunol"},{"key":"28111_CR19","doi-asserted-by":"publisher","first-page":"428","DOI":"10.1038\/ni.2588","volume":"14","author":"JJ Goronzy","year":"2013","unstructured":"Goronzy, J. J. & Weyand, C. M. Understanding immunosenescence to improve responses to vaccines. Nat Immunol 14, 428\u2013436, https:\/\/doi.org\/10.1038\/ni.2588 (2013).","journal-title":"Nat Immunol"},{"key":"28111_CR20","doi-asserted-by":"publisher","first-page":"61","DOI":"10.1093\/intimm\/dxt060","volume":"26","author":"JB Wing","year":"2014","unstructured":"Wing, J. B. & Sakaguchi, S. Foxp3(+) T(reg) cells in humoral immunity. Int Immunol 26, 61\u201369, https:\/\/doi.org\/10.1093\/intimm\/dxt060 (2014).","journal-title":"Int Immunol"},{"key":"28111_CR21","doi-asserted-by":"publisher","first-page":"17945","DOI":"10.1073\/pnas.1316796110","volume":"110","author":"D Sugiyama","year":"2013","unstructured":"Sugiyama, D. et al. Anti-CCR4 mAb selectively depletes effector-type FoxP3+CD4+ regulatory T cells, evoking antitumor immune responses in humans. Proc Natl Acad Sci USA 110, 17945\u201317950, https:\/\/doi.org\/10.1073\/pnas.1316796110 (2013).","journal-title":"Proc Natl Acad Sci USA"},{"key":"28111_CR22","doi-asserted-by":"publisher","first-page":"873","DOI":"10.1111\/acel.12114","volume":"12","author":"NA Duggal","year":"2013","unstructured":"Duggal, N. A., Upton, J., Phillips, A. C., Sapey, E. & Lord, J. M. An age-related numerical and functional deficit in CD19(+) CD24(hi) CD38(hi) B cells is associated with an increase in systemic autoimmunity. Aging Cell 12, 873\u2013881, https:\/\/doi.org\/10.1111\/acel.12114 (2013).","journal-title":"Aging Cell"},{"key":"28111_CR23","doi-asserted-by":"publisher","first-page":"175","DOI":"10.1016\/j.virusres.2010.09.010","volume":"157","author":"G Pawelec","year":"2011","unstructured":"Pawelec, G. & Derhovanessian, E. Role of CMV in immune senescence. Virus Res 157, 175\u2013179, https:\/\/doi.org\/10.1016\/j.virusres.2010.09.010 (2011).","journal-title":"Virus Res"},{"issue":"Suppl 2","key":"28111_CR24","doi-asserted-by":"publisher","first-page":"26","DOI":"10.1016\/S0264-410X(00)00038-4","volume":"18","author":"L Markoff","year":"2000","unstructured":"Markoff, L. Points to consider in the development of a surrogate for efficacy of novel Japanese encephalitis virus vaccines. Vaccine 18(Suppl 2), 26\u201332 (2000).","journal-title":"Vaccine"},{"key":"28111_CR25","doi-asserted-by":"publisher","first-page":"263","DOI":"10.4161\/hv.26902","volume":"10","author":"SI Yun","year":"2014","unstructured":"Yun, S. I. & Lee, Y. M. Japanese encephalitis: the virus and vaccines. Hum Vaccin Immunother 10, 263\u2013279, https:\/\/doi.org\/10.4161\/hv.26902 (2014).","journal-title":"Hum Vaccin Immunother"},{"key":"28111_CR26","doi-asserted-by":"publisher","first-page":"5925","DOI":"10.1016\/j.vaccine.2011.06.062","volume":"29","author":"Y Van Gessel","year":"2011","unstructured":"Van Gessel, Y. et al. Correlation of protection against Japanese encephalitis virus and JE vaccine (IXIARO((R))) induced neutralizing antibody titers. Vaccine 29, 5925\u20135931, https:\/\/doi.org\/10.1016\/j.vaccine.2011.06.062 (2011).","journal-title":"Vaccine"},{"key":"28111_CR27","doi-asserted-by":"publisher","first-page":"1847","DOI":"10.1016\/S0140-6736(07)61780-2","volume":"370","author":"E Tauber","year":"2007","unstructured":"Tauber, E. et al. Safety and immunogenicity of a Vero-cell-derived, inactivated Japanese encephalitis vaccine: a non-inferiority, phase III, randomised controlled trial. Lancet 370, 1847\u20131853, https:\/\/doi.org\/10.1016\/S0140-6736(07)61780-2 (2007).","journal-title":"Lancet"},{"key":"28111_CR28","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/S0749-3797(98)00003-8","volume":"15","author":"F Averhoff","year":"1998","unstructured":"Averhoff, F. et al. Immunogenicity of hepatitis B Vaccines. Implications for persons at occupational risk of hepatitis B virus infection. Am J Prev Med 15, 1\u20138 (1998).","journal-title":"Am J Prev Med"},{"key":"28111_CR29","doi-asserted-by":"publisher","first-page":"197","DOI":"10.1080\/003655499750006272","volume":"31","author":"K Cardell","year":"1999","unstructured":"Cardell, K., Fryden, A. & Normann, B. Intradermal hepatitis B vaccination in health care workers. Response rate and experiences from vaccination in clinical practise. Scand J Infect Dis 31, 197\u2013200 (1999).","journal-title":"Scand J Infect Dis"},{"key":"28111_CR30","doi-asserted-by":"publisher","first-page":"689","DOI":"10.1016\/j.exger.2009.09.003","volume":"44","author":"U Karrer","year":"2009","unstructured":"Karrer, U., Mekker, A., Wanke, K., Tchang, V. & Haeberli, L. Cytomegalovirus and immune senescence: culprit or innocent bystander? Exp Gerontol 44, 689\u2013694, https:\/\/doi.org\/10.1016\/j.exger.2009.09.003 (2009).","journal-title":"Exp Gerontol"},{"key":"28111_CR31","doi-asserted-by":"publisher","first-page":"202","DOI":"10.1002\/rmv.655","volume":"20","author":"MJ Cannon","year":"2010","unstructured":"Cannon, M. J., Schmid, D. S. & Hyde, T. B. Review of cytomegalovirus seroprevalence and demographic characteristics associated with infection. Rev Med Virol 20, 202\u2013213, https:\/\/doi.org\/10.1002\/rmv.655 (2010).","journal-title":"Rev Med Virol"},{"key":"28111_CR32","doi-asserted-by":"publisher","first-page":"685","DOI":"10.1016\/j.vaccine.2012.11.041","volume":"31","author":"E Derhovanessian","year":"2013","unstructured":"Derhovanessian, E. et al. Cytomegalovirus-associated accumulation of late-differentiated CD4 T-cells correlates with poor humoral response to influenza vaccination. Vaccine 31, 685\u2013690, https:\/\/doi.org\/10.1016\/j.vaccine.2012.11.041 (2013).","journal-title":"Vaccine"},{"key":"28111_CR33","doi-asserted-by":"publisher","first-page":"4869","DOI":"10.1016\/j.vaccine.2011.03.086","volume":"29","author":"WP den Elzen","year":"2011","unstructured":"den Elzen, W. P. et al. Cytomegalovirus infection and responsiveness to influenza vaccination in elderly residents of long-term care facilities. Vaccine 29, 4869\u20134874, https:\/\/doi.org\/10.1016\/j.vaccine.2011.03.086 (2011).","journal-title":"Vaccine"},{"key":"28111_CR34","doi-asserted-by":"publisher","first-page":"1433","DOI":"10.1016\/j.vaccine.2015.01.071","volume":"33","author":"D Frasca","year":"2015","unstructured":"Frasca, D., Diaz, A., Romero, M., Landin, A. M. & Blomberg, B. B. Cytomegalovirus (CMV) seropositivity decreases B cell responses to the influenza vaccine. Vaccine 33, 1433\u20131439, https:\/\/doi.org\/10.1016\/j.vaccine.2015.01.071 (2015).","journal-title":"Vaccine"},{"key":"28111_CR35","doi-asserted-by":"publisher","first-page":"281ra243","DOI":"10.1126\/scitranslmed.aaa2293","volume":"7","author":"D Furman","year":"2015","unstructured":"Furman, D. et al. Cytomegalovirus infection enhances the immune response to influenza. Sci Transl Med 7, 281ra243, https:\/\/doi.org\/10.1126\/scitranslmed.aaa2293 (2015).","journal-title":"Sci Transl Med"},{"key":"28111_CR36","doi-asserted-by":"publisher","first-page":"1557","DOI":"10.1002\/jmv.23642","volume":"85","author":"A Wald","year":"2013","unstructured":"Wald, A., Selke, S., Magaret, A. & Boeckh, M. Impact of human cytomegalovirus (CMV) infection on immune response to pandemic 2009 H1N1 influenza vaccine in healthy adults. J Med Virol 85, 1557\u20131560, https:\/\/doi.org\/10.1002\/jmv.23642 (2013).","journal-title":"J Med Virol"},{"key":"28111_CR37","doi-asserted-by":"publisher","first-page":"206","DOI":"10.15252\/embr.201745302","volume":"19","author":"FA Rey","year":"2018","unstructured":"Rey, F. A., Stiasny, K., Vaney, M. C., Dellarole, M. & Heinz, F. X. The bright and the dark side of human antibody responses to flaviviruses: lessons for vaccine design. EMBO Rep 19, 206\u2013224, https:\/\/doi.org\/10.15252\/embr.201745302 (2018).","journal-title":"EMBO Rep"},{"key":"28111_CR38","doi-asserted-by":"publisher","first-page":"2821","DOI":"10.1099\/vir.0.031641-0","volume":"92","author":"KL Mansfield","year":"2011","unstructured":"Mansfield, K. L. et al. Flavivirus-induced antibody cross-reactivity. J Gen Virol 92, 2821\u20132829, https:\/\/doi.org\/10.1099\/vir.0.031641-0 (2011).","journal-title":"J Gen Virol"},{"key":"28111_CR39","doi-asserted-by":"publisher","first-page":"6151","DOI":"10.1016\/j.vaccine.2008.08.056","volume":"26","author":"E Schuller","year":"2008","unstructured":"Schuller, E. et al. Effect of pre-existing anti-tick-borne encephalitis virus immunity on neutralising antibody response to the Vero cell-derived, inactivated Japanese encephalitis virus vaccine candidate IC51. Vaccine 26, 6151\u20136156, https:\/\/doi.org\/10.1016\/j.vaccine.2008.08.056 (2008).","journal-title":"Vaccine"},{"key":"28111_CR40","doi-asserted-by":"publisher","first-page":"847","DOI":"10.1016\/j.immuni.2012.02.012","volume":"36","author":"A Ballesteros-Tato","year":"2012","unstructured":"Ballesteros-Tato, A. et al. Interleukin-2 inhibits germinal center formation by limiting T follicular helper cell differentiation. Immunity 36, 847\u2013856, https:\/\/doi.org\/10.1016\/j.immuni.2012.02.012 (2012).","journal-title":"Immunity"},{"key":"28111_CR41","doi-asserted-by":"publisher","first-page":"283","DOI":"10.1038\/nri3823","volume":"15","author":"D Klatzmann","year":"2015","unstructured":"Klatzmann, D. & Abbas, A. K. The promise of low-dose interleukin-2 therapy for autoimmune and inflammatory diseases. Nat Rev Immunol 15, 283\u2013294, https:\/\/doi.org\/10.1038\/nri3823 (2015).","journal-title":"Nat Rev Immunol"},{"key":"28111_CR42","doi-asserted-by":"publisher","first-page":"1789","DOI":"10.1002\/eji.201243152","volume":"43","author":"M Larena","year":"2013","unstructured":"Larena, M., Regner, M. & Lobigs, M. Cytolytic effector pathways and IFN-gamma help protect against Japanese encephalitis. Eur J Immunol 43, 1789\u20131798, https:\/\/doi.org\/10.1002\/eji.201243152 (2013).","journal-title":"Eur J Immunol"},{"key":"28111_CR43","doi-asserted-by":"publisher","first-page":"880","DOI":"10.1086\/381768","volume":"189","author":"P Kumar","year":"2004","unstructured":"Kumar, P. et al. Impaired T helper 1 function of nonstructural protein 3-specific T cells in Japanese patients with encephalitis with neurological sequelae. J Infect Dis 189, 880\u2013891, https:\/\/doi.org\/10.1086\/381768 (2004).","journal-title":"J Infect Dis"},{"key":"28111_CR44","doi-asserted-by":"publisher","first-page":"34","DOI":"10.1016\/j.coph.2018.03.014","volume":"41","author":"B Weinberger","year":"2018","unstructured":"Weinberger, B. Adjuvant strategies to improve vaccination of the elderly population. Curr Opin Pharmacol 41, 34\u201341, https:\/\/doi.org\/10.1016\/j.coph.2018.03.014 (2018).","journal-title":"Curr Opin Pharmacol"},{"key":"28111_CR45","doi-asserted-by":"publisher","first-page":"2087","DOI":"10.1056\/NEJMoa1501184","volume":"372","author":"H Lal","year":"2015","unstructured":"Lal, H. et al. Efficacy of an adjuvanted herpes zoster subunit vaccine in older adults. N Engl J Med 372, 2087\u20132096, https:\/\/doi.org\/10.1056\/NEJMoa1501184 (2015).","journal-title":"N Engl J Med"},{"key":"28111_CR46","doi-asserted-by":"publisher","first-page":"1331","DOI":"10.1084\/jem.20151517","volume":"213","author":"L Turtle","year":"2016","unstructured":"Turtle, L. et al. Human T cell responses to Japanese encephalitis virus in health and disease. J Exp Med 213, 1331\u20131352, https:\/\/doi.org\/10.1084\/jem.20151517 (2016).","journal-title":"J Exp Med"},{"key":"28111_CR47","doi-asserted-by":"publisher","DOI":"10.1038\/srep19953","volume":"6","author":"J Li","year":"2016","unstructured":"Li, J. et al. Cross-protection induced by Japanese encephalitis vaccines against different genotypes of Dengue viruses in mice. Sci Rep 6, 19953, https:\/\/doi.org\/10.1038\/srep19953 (2016).","journal-title":"Sci Rep"},{"key":"28111_CR48","doi-asserted-by":"publisher","first-page":"5363","DOI":"10.4049\/jimmunol.1203267","volume":"190","author":"SJ Griffiths","year":"2013","unstructured":"Griffiths, S. J. et al. Age-associated increase of low-avidity cytomegalovirus-specific CD8+ T cells that re-express CD45RA. J Immunol 190, 5363\u20135372, https:\/\/doi.org\/10.4049\/jimmunol.1203267 (2013).","journal-title":"J Immunol"},{"key":"28111_CR49","doi-asserted-by":"publisher","first-page":"260","DOI":"10.1111\/j.1751-7915.2011.00299.x","volume":"5","author":"L Berod","year":"2012","unstructured":"Berod, L., Puttur, F., Huehn, J. & Sparwasser, T. Tregs in infection and vaccinology: heroes or traitors? Microb Biotechnol 5, 260\u2013269, https:\/\/doi.org\/10.1111\/j.1751-7915.2011.00299.x (2012).","journal-title":"Microb Biotechnol"},{"key":"28111_CR50","doi-asserted-by":"publisher","first-page":"265","DOI":"10.1016\/j.clim.2007.11.010","volume":"127","author":"Z Yang","year":"2008","unstructured":"Yang, Z. et al. Increased CD4+CD25+FoxP3+ regulatory T cells in the blood of nonresponders after standard hepatitis B surface antigen vaccine immunization. Clin Immunol 127, 265\u2013266, https:\/\/doi.org\/10.1016\/j.clim.2007.11.010 (2008).","journal-title":"Clin Immunol"},{"key":"28111_CR51","doi-asserted-by":"publisher","first-page":"673","DOI":"10.1007\/s10549-009-0666-9","volume":"119","author":"U Wiedermann","year":"2010","unstructured":"Wiedermann, U. et al. A virosomal formulated Her-2\/neu multi-peptide vaccine induces Her-2\/neu-specific immune responses in patients with metastatic breast cancer: a phase I study. Breast Cancer Res Treat 119, 673\u2013683 (2010).","journal-title":"Breast Cancer Res Treat"},{"key":"28111_CR52","doi-asserted-by":"publisher","unstructured":"Brezar, V. et al. T-Regulatory Cells and Vaccination \u201cPay Attention and Do Not Neglect Them\u201d: Lessons from HIV and Cancer Vaccine Trials. Vaccines (Basel) 4, https:\/\/doi.org\/10.3390\/vaccines4030030 (2016).","DOI":"10.3390\/vaccines4030030"},{"key":"28111_CR53","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.coi.2013.12.005","volume":"27","author":"H Nishikawa","year":"2014","unstructured":"Nishikawa, H. & Sakaguchi, S. Regulatory T cells in cancer immunotherapy. Curr Opin Immunol 27, 1\u20137, https:\/\/doi.org\/10.1016\/j.coi.2013.12.005 (2014).","journal-title":"Curr Opin Immunol"},{"key":"28111_CR54","doi-asserted-by":"publisher","first-page":"1382","DOI":"10.1093\/infdis\/jit576","volume":"209","author":"N Terrazzini","year":"2014","unstructured":"Terrazzini, N. et al. A novel cytomegalovirus-induced regulatory-type T-cell subset increases in size during older life and links virus-specific immunity to vascular pathology. J Infect Dis 209, 1382\u20131392, https:\/\/doi.org\/10.1093\/infdis\/jit576 (2014).","journal-title":"J Infect Dis"},{"key":"28111_CR55","doi-asserted-by":"publisher","first-page":"607","DOI":"10.1016\/j.immuni.2015.04.005","volume":"42","author":"EC Rosser","year":"2015","unstructured":"Rosser, E. C. & Mauri, C. Regulatory B cells: origin, phenotype, and function. Immunity 42, 607\u2013612, https:\/\/doi.org\/10.1016\/j.immuni.2015.04.005 (2015).","journal-title":"Immunity"},{"key":"28111_CR56","doi-asserted-by":"publisher","first-page":"7021","DOI":"10.1016\/j.vaccine.2009.09.069","volume":"27","author":"K Stiasny","year":"2009","unstructured":"Stiasny, K., Holzmann, H. & Heinz, F. X. Characteristics of antibody responses in tick-borne encephalitis vaccination breakthroughs. Vaccine 27, 7021\u20137026, https:\/\/doi.org\/10.1016\/j.vaccine.2009.09.069 (2009).","journal-title":"Vaccine"},{"key":"28111_CR57","doi-asserted-by":"publisher","unstructured":"Eder, S. et al. Long term immunity following a booster dose of the inactivated Japanese Encephalitis vaccine IXIARO((R)), IC51. Vaccine 29, 2607\u20132612, https:\/\/doi.org\/10.1016\/j.vaccine.01.058 (2011).","DOI":"10.1016\/j.vaccine.01.058"}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-018-28111-8.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-018-28111-8","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-018-28111-8.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,12,21]],"date-time":"2022-12-21T06:47:27Z","timestamp":1671605247000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-018-28111-8"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2018,6,29]]},"references-count":57,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2018,12]]}},"alternative-id":["28111"],"URL":"https:\/\/doi.org\/10.1038\/s41598-018-28111-8","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2018,6,29]]},"assertion":[{"value":"31 August 2017","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"8 June 2018","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"29 June 2018","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"UW declares that she and HK have been commissioned as expert witnesses by the Austrian government. We received financial support by Novartis (at this time holding the market\/sales authorization of Ixiaro\u00ae in Austria) to purchase the vaccine for this study. For antigen restimulation, the JEV antigen was kindly provided by Dr Klade, formerly of Intercell and now Valneva and the TBE antigen strain Neud\u00f6rfl was provided by Baxter now Pfizer.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing Interests"}}],"article-number":"9825"}}