{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,16]],"date-time":"2026-09-16T08:02:21Z","timestamp":1789545741714,"version":"build-2803163510"},"reference-count":119,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2023,4,22]],"date-time":"2023-04-22T00:00:00Z","timestamp":1682121600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pathophysiology"],"abstract":"<jats:p>In recent years, the elderly has become a rapidly growing proportion of the world\u2019s population as life expectancy is extending. Immunosenescence and inflammaging contribute to the increased risk of chronic non-communicable and acute infectious diseases. Frailty is highly prevalent in the elderly and is associated with an impaired immune response, a higher propensity to infection, and a lower response to vaccines. Additionally, the presence of uncontrolled comorbid diseases in the elderly also contributes to sarcopenia and frailty. Vaccine-preventable diseases that threaten the elderly include influenza, pneumococcal infection, herpes zoster, and COVID-19, which contribute to significant disability-adjusted life years lost. Previous studies had shown that conventional vaccines only yielded suboptimal protection that wanes rapidly in a shorter time. This article reviews published papers on several vaccination strategies that were developed for the elderly to solve these problems: more immunogenic vaccine formulations using larger doses of antigen, stronger vaccine adjuvants, recombinant subunit or protein conjugated vaccines, newly developed mRNA vaccines, giving booster shots, and exploring alternative routes of administration. Included also are several publications on senolytic medications under investigation to boost the immune system and vaccine response in the elderly. With all those in regard, the currently recommended vaccines for the elderly are presented.<\/jats:p>","DOI":"10.3390\/pathophysiology30020014","type":"journal-article","created":{"date-parts":[[2023,4,24]],"date-time":"2023-04-24T06:20:42Z","timestamp":1682317242000},"page":"155-173","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":37,"title":["Challenges in the Vaccination of the Elderly and Strategies for Improvement"],"prefix":"10.3390","volume":"30","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9197-3873","authenticated-orcid":false,"given":"Gatot","family":"Soegiarto","sequence":"first","affiliation":[{"name":"Allergy and Clinical Immunology Division, Department of Internal Medicine, Dr. Soetomo Academic General Hospital, Faculty of Medicine, Universitas Airlangga, Surabaya 60286, Indonesia"},{"name":"Master Program in Immunology, Postgraduate School, Universitas Airlangga, Surabaya 60286, Indonesia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dewajani","family":"Purnomosari","sequence":"additional","affiliation":[{"name":"Department of Histology and Cell Biology, Faculty of Medicine, Public Health and Nursing, Universitas Gajah Mada, Yogyakarta 55281, Indonesia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,4,22]]},"reference":[{"key":"ref_1","unstructured":"He, W., Goodkind, D., and Kowal, P. (2015). An Aging World."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"435","DOI":"10.1111\/j.1365-2567.2007.02555.x","article-title":"Immunosenescence: Emerging challenges for an ageing population","volume":"120","author":"Aw","year":"2007","journal-title":"Immunology"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"2247","DOI":"10.3389\/fimmu.2019.02247","article-title":"Immunosenescence and its hallmarks: How to oppose aging strategically? A review of potential options for therapeutic intervention","volume":"10","author":"Aiello","year":"2019","journal-title":"Front. Immunol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"S4","DOI":"10.1093\/gerona\/glu057","article-title":"Chronic inflammation (inflammaging) and its potential contribution to age-associated diseases","volume":"69","author":"Franceschi","year":"2014","journal-title":"J. Gerontol. Ser. A Biol. Sci. Med. Sci."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"576","DOI":"10.1038\/s41574-018-0059-4","article-title":"Inflammaging: A new immune\u2013metabolic viewpoint for age-related diseases","volume":"14","author":"Franceschi","year":"2018","journal-title":"Nat. Rev. Endocrinol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"147","DOI":"10.1007\/s10522-015-9615-7","article-title":"From inflamm-aging to immune-paralysis: A slippery slope during aging for immune-adaptation","volume":"17","author":"Fulop","year":"2016","journal-title":"Biogerontology"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1960","DOI":"10.3389\/fimmu.2017.01960","article-title":"Immunosenescence and inflamm-aging as two sides of the same coin: Friends or foes?","volume":"8","author":"Fulop","year":"2018","journal-title":"Front. Immunol."},{"key":"ref_8","first-page":"84","article-title":"The role of immunosenescence in the development of age-related diseases","volume":"68","author":"Dupuis","year":"2016","journal-title":"Rev. Investig. Clin."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1016\/j.cger.2010.08.006","article-title":"The biology of aging and frailty","volume":"27","author":"Fedarko","year":"2011","journal-title":"Clin. Geriatr. Med."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"101351","DOI":"10.1016\/j.arr.2021.101351","article-title":"Fostering healthy aging: The interdependency of infections, immunity and frailty","volume":"69","author":"Vetrano","year":"2021","journal-title":"Ageing Res. Rev."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1016\/j.mib.2015.11.003","article-title":"Infection in an aging population","volume":"29","author":"Kline","year":"2016","journal-title":"Curr. Opin. Microbiol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"n188","DOI":"10.1136\/bmj.n188","article-title":"Vaccines for older adults","volume":"372","author":"Cunningham","year":"2021","journal-title":"BMJ"},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Fulop, T., Larbi, A., Pawelec, G., Cohen, A.A., Provost, G., Khalil, A., Lacombe, G., Rodrigues, S., Desroches, M., and Hirokawa, K. (2022). Immunosenescence and altered vaccine efficiency in older subjects: A myth difficult to change. Vaccines, 10.","DOI":"10.3390\/vaccines10040607"},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Aiello, A., Ligotti, M.E., Garnica, M., Accardi, G., Calabr\u00f2, A., Pojero, F., Arasanz, H., Bocanegra, A., Blanco, E., and Chocarro, L. (2022). How can we improve vaccination response in old people? Part I: Targeting immunosenescence of innate immunity cells. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23179880"},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Garnica, M., Aiello, A., Ligotti, M.E., Accardi, G., Arasanz, H., Bocanegra, A., Blanco, E., Calabr\u00f2, A., Chocarro, L., and Echaide, M. (2022). How can we improve the vaccination response in older people? Part II: Targeting immunosenescence of adaptive immunity cells. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23179797"},{"key":"ref_16","first-page":"17","article-title":"Immunosenescence: Implications for vaccination programs in the elderly","volume":"5","author":"Loukov","year":"2015","journal-title":"Vaccine Dev. Ther."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"583019","DOI":"10.3389\/fimmu.2020.583019","article-title":"Targeting inflammation and immunosenescence to improve vaccine responses in the elderly","volume":"14","author":"Pereira","year":"2020","journal-title":"Front. Immunol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1106","DOI":"10.1038\/s41564-022-01166-0","article-title":"COVID vaccination in older adults","volume":"7","author":"Religa","year":"2022","journal-title":"Nat. Microbiol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"758","DOI":"10.1093\/ageing\/afaa112","article-title":"Frailty, a multisystem ageing syndrome","volume":"49","author":"Thillainadesan","year":"2020","journal-title":"Age Ageing"},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Teissier, T., Boulanger, E., and Cox, L.S. (2022). Interconnections between inflammageing and immunosenescence during ageing. Cells, 11.","DOI":"10.3390\/cells11030359"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"769","DOI":"10.1038\/s43587-021-00114-7","article-title":"SARS-CoV-2, COVID-19 and the aging immune system","volume":"1","author":"Bartleson","year":"2021","journal-title":"Nat. Aging"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"118","DOI":"10.3389\/fmed.2019.00118","article-title":"Infections in the elderly critically-ill patients","volume":"6","author":"Esme","year":"2019","journal-title":"Front. Med."},{"key":"ref_23","unstructured":"Australian Institute of Health and Welfare (2019). The Burden of Vaccine Preventable Diseases in Australia, Australian Institute of Health and Welfare."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"17-00454","DOI":"10.2807\/1560-7917.ES.2018.23.16.17-00454","article-title":"Impact of infectious diseases on population health using incidence-based disability-adjusted life years (DALYs): Results from the Burden of Communicable Diseases in Europe Study, European Union and European Economic Area countries, 2009 to 2013","volume":"23","author":"Cassini","year":"2018","journal-title":"Eurosurveillance"},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Kwong, J.C., Ratnasingham, S., Campitelli, M.A., Daneman, N., Deeks, S.L., Manuel, D.G., Allen, V.G., Bayoumi, A.M., Fazil, A., and Fisman, D.N. (2012). The impact of infection on population health: Results of the Ontario Burden of Infectious Diseases Study. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0044103"},{"key":"ref_26","first-page":"215","article-title":"Clinical course and mortality in older patients with COVID-19: A cluster-based study in Hong Kong","volume":"28","author":"Tam","year":"2022","journal-title":"Hong Kong Med. J."},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"GBD 2019 Ageing Collaborators (2022). Global, regional, and national burden of diseases and injuries for adults 70 years and older: Systematic analysis for the Global Burden of Disease 2019 Study. BMJ, 376, e068208.","DOI":"10.1136\/bmj-2021-068208"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"398","DOI":"10.1016\/S0140-6736(20)32657-X","article-title":"Estimating the health impact of vaccination against ten pathogens in 98 low-income and middle-income countries from 2000 to 2030: A modelling study","volume":"397","author":"Li","year":"2021","journal-title":"Lancet"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"e67635","DOI":"10.7554\/eLife.67635","article-title":"Lives saved with vaccination for 10 pathogens across 112 countries in a pre-COVID-19 world","volume":"10","author":"Toor","year":"2021","journal-title":"eLife"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"e065729","DOI":"10.1136\/bmjopen-2022-065729","article-title":"Model-based estimation of burden of COVID-19 with disability-adjusted life years and value of statistical life in West Bengal, India","volume":"13","author":"John","year":"2023","journal-title":"BMJ Open"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"100145","DOI":"10.1016\/j.jvacx.2022.100145","article-title":"Incidence trend and disease burden of seven vaccine-preventable diseases in Shandong province, China, 2013\u20132017: Findings from a population-based observational study","volume":"10","author":"Li","year":"2022","journal-title":"Vaccine X"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1186\/s13690-022-00862-x","article-title":"Measuring disability-adjusted life years (DALYs) due to COVID-19 in Scotland, 2020","volume":"80","author":"Wyper","year":"2022","journal-title":"Arch. Public Health"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"e26474","DOI":"10.2196\/26474","article-title":"Impact of the COVID-19 pandemic on older adults: Rapid review","volume":"4","author":"Lebrasseur","year":"2021","journal-title":"JMIR Aging"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"113","DOI":"10.15585\/mmwr.mm7205a1","article-title":"COVID-19 mortality and progress toward vaccinating older adults\u2014World Health Organization, worldwide, 2020\u20132022","volume":"72","author":"Wong","year":"2023","journal-title":"Morb. Mortal. Wkly. Rep. MMWR"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"101271","DOI":"10.1016\/j.eclinm.2022.101271","article-title":"Non-invasive pneumococcal pneumonia due to vaccine serotypes: A systematic review and meta-analysis","volume":"44","author":"Lansbury","year":"2022","journal-title":"EClinicalMedicine"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"693","DOI":"10.1016\/S0140-6736(22)00982-5","article-title":"Influenza","volume":"400","author":"Uyeki","year":"2022","journal-title":"Lancet"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"A6","DOI":"10.1016\/j.vaccine.2020.09.048","article-title":"The disease burden of influenza beyond respiratory illness","volume":"39","author":"Macias","year":"2021","journal-title":"Vaccine"},{"key":"ref_38","unstructured":"Center for Disease Control and Prevention (CDC) (2020). Clinical Overview of Herpes Zoster (Shingles)."},{"key":"ref_39","first-page":"157","article-title":"WHO declares COVID-19 a pandemic","volume":"91","author":"Cucinotta","year":"2020","journal-title":"Acta Biomed."},{"key":"ref_40","unstructured":"World Health Organization (WHO) (2023). WHO Coronavirus (COVID-19) Dashboard, World Health Organization (WHO)."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"507","DOI":"10.1016\/S0140-6736(20)30211-7","article-title":"Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: A descriptive study","volume":"395","author":"Chen","year":"2020","journal-title":"Lancet"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"669","DOI":"10.1016\/S1473-3099(20)30243-7","article-title":"Estimates of the severity of coronavirus disease 2019: A model-based analysis","volume":"20","author":"Verity","year":"2020","journal-title":"Lancet Infect. Dis."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"100167","DOI":"10.1016\/j.lansea.2023.100167","article-title":"Clinical and treatment factors associated with the mortality of COVID-19 patients admitted to a referral hospital in Indonesia","volume":"11","author":"Hartantri","year":"2023","journal-title":"Lancet Reg. Health Southeast Asia"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"e13","DOI":"10.1093\/gerona\/glaa209","article-title":"Underlying vulnerabilities to the cytokine storm and adverse COVID-19 outcomes in the aging immune system","volume":"76","author":"Nidadavolu","year":"2021","journal-title":"J. Gerontol. A Biol. Sci. Med. Sci."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"737","DOI":"10.2147\/JIR.S276091","article-title":"Cytokine response in SARS-CoV-2 infection in the elderly","volume":"13","author":"Sherwani","year":"2020","journal-title":"J. Inflamm. Res."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"825","DOI":"10.1007\/s00011-020-01372-8","article-title":"The possible pathophysiology mechanism of cytokine storm in elderly adults with COVID-19 infection: The contribution of \u201cinflame-aging\u201d","volume":"69","author":"Meftahi","year":"2020","journal-title":"Inflamm. Res."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1186\/s12979-022-00309-5","article-title":"Aging, inflammaging and immunosenescence as risk factors of severe COVID-19","volume":"19","author":"Tizazu","year":"2022","journal-title":"Immun. Ageing"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"e00084-00018","DOI":"10.1128\/CMR.00084-18","article-title":"Factors that influence the immune response to vaccination","volume":"32","author":"Zimmermann","year":"2019","journal-title":"Clin. Microbiol. Rev."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"1078","DOI":"10.1086\/529197","article-title":"Biology of immune responses to vaccines in elderly persons","volume":"46","author":"Weinberger","year":"2008","journal-title":"Clin. Infect. Dis."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"1169","DOI":"10.1007\/s11357-011-9356-8","article-title":"Immune senescence in old and very old rhesus monkeys: Reduced antibody response to influenza vaccination","volume":"34","author":"Coe","year":"2012","journal-title":"Age"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"427","DOI":"10.1016\/S0531-5565(01)00210-8","article-title":"Role of humoral and cell-mediated immunity in protection from influenza disease after immunization of healthy elderly","volume":"37","author":"Murasko","year":"2002","journal-title":"Exp. Gerontol."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"922","DOI":"10.1111\/j.1474-9726.2011.00732.x","article-title":"Vaccination-induced changes in human B-cell repertoire and pneumococcal IgM and IgA antibody at different ages: Vaccine-induced changes in B-cell repertoire","volume":"10","author":"Ademokun","year":"2011","journal-title":"Aging Cell"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"5521","DOI":"10.1016\/j.vaccine.2008.07.071","article-title":"Pneumococcal vaccination in older adults induces antibodies with low opsonic capacity and reduced antibody potency","volume":"26","author":"Schenkein","year":"2008","journal-title":"Vaccine"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"2271","DOI":"10.1056\/NEJMoa051016","article-title":"A vaccine to prevent herpes zoster and postherpetic neuralgia in older adults","volume":"352","author":"Oxman","year":"2005","journal-title":"N. Engl. J. Med."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1186\/s12979-017-0107-2","article-title":"Vaccines for the elderly: Current use and future challenges","volume":"15","author":"Weinberger","year":"2018","journal-title":"Immun. Ageing"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"1495","DOI":"10.1080\/14760584.2016.1254044","article-title":"Fluzone\u00ae high-dose influenza vaccine","volume":"15","author":"Robertson","year":"2016","journal-title":"Expert Rev. Vaccines"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"5825","DOI":"10.1016\/j.vaccine.2019.08.016","article-title":"Safety and immunogenicity of high-dose quadrivalent influenza vaccine in adults \u226565 years of age: A phase 3 randomized clinical trial","volume":"37","author":"Chang","year":"2019","journal-title":"Vaccine"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"34","DOI":"10.1016\/j.coph.2018.03.014","article-title":"Adjuvant strategies to improve vaccination of the elderly population","volume":"41","author":"Weinberger","year":"2018","journal-title":"Curr. Opin. Pharmacol."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"85ra48","DOI":"10.1126\/scitranslmed.3002336","article-title":"MF59 adjuvant enhances diversity and affinity of antibody-mediated immune response to pandemic influenza vaccines","volume":"3","author":"Khurana","year":"2011","journal-title":"Sci. Transl. Med."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1007\/978-1-0716-0872-2_4","article-title":"CpG Oligonucleotides as Vaccine Adjuvants","volume":"Volume 2197","author":"Sousa","year":"2021","journal-title":"DNA Vaccines"},{"key":"ref_61","doi-asserted-by":"crossref","unstructured":"Fan, J., Jin, S., Gilmartin, L., Toth, I., Hussein, W.M., and Stephenson, R.J. (2022). Advances in infectious disease vaccine adjuvants. Vaccines, 10.","DOI":"10.3390\/vaccines10071120"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"1370","DOI":"10.1080\/21645515.2018.1442162","article-title":"Persistence of immune response to an adjuvanted varicella-zoster virus subunit vaccine for up to year nine in older adults","volume":"14","author":"Schwarz","year":"2018","journal-title":"Hum. Vaccines Immunother."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"673","DOI":"10.4049\/jimmunol.173.1.673","article-title":"Age-associated change in the frequency of memory CD4+ T cells impairs long term CD4+ T cell responses to influenza vaccine","volume":"173","author":"Kang","year":"2004","journal-title":"J. Immunol."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"983","DOI":"10.1093\/infdis\/jiac199","article-title":"Older adults mount less durable humoral responses to two doses of COVID-19 mRNA vaccine but strong initial responses to a third dose","volume":"226","author":"Mwimanzi","year":"2022","journal-title":"J. Infect. Dis."},{"key":"ref_65","unstructured":"World Health Organization (WHO) (2022). Expert Advisory Group Recommends COVID-19 Vaccination Strategy for the Autumn Season, World Health Organization (WHO)."},{"key":"ref_66","unstructured":"United Kingdom Government (2022). A Guide to the Spring Booster for Those Aged 75 Years and Older and Older Residents in Care Homes\u2014GOV.UK.pdf."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"6808","DOI":"10.1016\/j.vaccine.2006.06.037","article-title":"Booster vaccination in the elderly: Their success depends on the vaccine type applied earlier in life as well as on pre-vaccination antibody titers","volume":"24","author":"Kaml","year":"2006","journal-title":"Vaccine"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"650","DOI":"10.1086\/590434","article-title":"Intradermal influenza vaccine administered using a new microinjection system produces superior immunogenicity in elderly adults: A randomized controlled trial","volume":"198","author":"Holland","year":"2008","journal-title":"J. Infect. Dis."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"2286","DOI":"10.1056\/NEJMoa043555","article-title":"Serum antibody responses after intradermal vaccination against influenza","volume":"351","author":"Belshe","year":"2004","journal-title":"N. Engl. J. Med."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"2295","DOI":"10.1056\/NEJMoa043540","article-title":"Dose sparing with intradermal injection of influenza vaccine","volume":"351","author":"Kenney","year":"2004","journal-title":"N. Engl. J. Med."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"584","DOI":"10.1111\/irv.12000","article-title":"Immunogenicity and adverse events: A meta-analysis of intradermal versus intramuscular influenza vaccines","volume":"7","author":"Marra","year":"2013","journal-title":"Influenza Other Respir. Viruses"},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"1069","DOI":"10.1093\/infdis\/jis402","article-title":"Direct comparison of an inactivated subvirion influenza A virus subtype H5N1 vaccine administered by the intradermal and intramuscular routes","volume":"206","author":"Patel","year":"2012","journal-title":"J. Infect. Dis."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"887729","DOI":"10.3389\/fcimb.2022.887729","article-title":"Mucosal vaccination: A promising alternative against flaviviruses","volume":"12","year":"2022","journal-title":"Front. Cell. Infect. Microbiol."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"313","DOI":"10.1111\/1348-0421.12775","article-title":"Human immune responses elicited by an intranasal inactivated H5 influenza vaccine","volume":"64","author":"Ainai","year":"2020","journal-title":"Microbiol. Immunol."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"190","DOI":"10.1038\/nri3386","article-title":"Circadian control of the immune system","volume":"13","author":"Scheiermann","year":"2013","journal-title":"Nat. Rev. Immunol."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"2679","DOI":"10.1016\/j.vaccine.2016.04.032","article-title":"Morning vaccination enhances antibody response over afternoon vaccination: A cluster-randomised trial","volume":"34","author":"Long","year":"2016","journal-title":"Vaccine"},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"1215","DOI":"10.1038\/s41422-021-00541-6","article-title":"Time of day influences immune response to an inactivated vaccine against SARS-CoV-2","volume":"31","author":"Zhang","year":"2021","journal-title":"Cell Res."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"268ra179","DOI":"10.1126\/scitranslmed.3009892","article-title":"mTOR inhibition improves immune function in the elderly","volume":"6","author":"Mannick","year":"2014","journal-title":"Sci. Transl. Med."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"1475","DOI":"10.1111\/ajt.16958","article-title":"mTOR inhibitors improve both humoral and cellular response to SARS-CoV-2 messenger RNA BNT16b2 vaccine in kidney transplant recipients","volume":"22","author":"Netti","year":"2022","journal-title":"Am. J. Transpl."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"110","DOI":"10.1016\/j.molcel.2019.08.005","article-title":"Polyamines control eIF5A hypusination, TFEB translation, and autophagy to reverse B cell senescence","volume":"76","author":"Zhang","year":"2019","journal-title":"Mol. Cell"},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"518","DOI":"10.1111\/joim.13141","article-title":"Senolytic drugs: From discovery to translation","volume":"288","author":"Kirkland","year":"2020","journal-title":"J. Intern. Med."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"513","DOI":"10.1016\/j.vaccine.2016.12.011","article-title":"Effectiveness of MF59-adjuvanted seasonal influenza vaccine in the elderly: A systematic review and meta-analysis","volume":"35","author":"Domnich","year":"2017","journal-title":"Vaccine"},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"635","DOI":"10.1056\/NEJMoa1315727","article-title":"Efficacy of high-dose versus standard-dose influenza vaccine in older adults","volume":"371","author":"Dunning","year":"2014","journal-title":"N. Engl. J. Med."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"379","DOI":"10.1016\/j.vaccine.2009.10.037","article-title":"Comparative immunogenicity of recombinant influenza hemagglutinin (rHA) and trivalent inactivated vaccine (TIV) among persons \u226565 years old","volume":"28","author":"Keitel","year":"2009","journal-title":"Vaccine"},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"1704","DOI":"10.1093\/cid\/ciz1034","article-title":"Comparative immunogenicity of several enhanced influenza vaccine options for older adults: A randomized, controlled trial","volume":"71","author":"Cowling","year":"2020","journal-title":"Clin. Infect. Dis."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"1170","DOI":"10.1093\/cid\/civ019","article-title":"Clinical effectiveness of split-virion versus subunit trivalent influenza vaccines in older adults","volume":"60","author":"Talbot","year":"2015","journal-title":"Clin. Infect. Dis."},{"key":"ref_87","doi-asserted-by":"crossref","unstructured":"Berild, J.D., Winje, B.A., Vestrheim, D.F., Slotved, H.-C., Valentiner-Branth, P., Roth, A., and Stors\u00e4ter, J. (2020). A systematic review of studies published between 2016 and 2019 on the effectiveness and efficacy of pneumococcal vaccination on pneumonia and invasive pneumococcal disease in an elderly population. Pathogens, 9.","DOI":"10.3390\/pathogens9040259"},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"42","DOI":"10.1016\/j.eclinm.2018.12.007","article-title":"Effectiveness of 23-valent polysaccharide pneumococcal vaccine and changes in invasive pneumococcal disease incidence from 2000 to 2017 in those aged 65 and over in England and Wales","volume":"6","author":"Djennad","year":"2018","journal-title":"EClinicalMedicine"},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1073\/pnas.1819612116","article-title":"On the mechanisms of conjugate vaccines","volume":"116","author":"Rappuoli","year":"2019","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"1015","DOI":"10.1086\/529142","article-title":"Comparison of pneumococcal conjugate polysaccharide and free polysaccharide vaccines in elderly adults: Conjugate vaccine elicits improved antibacterial immune responses and immunological memory","volume":"46","author":"Siber","year":"2008","journal-title":"Clin. Infect. Dis."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"1114","DOI":"10.1056\/NEJMoa1408544","article-title":"Polysaccharide conjugate vaccine against pneumococcal pneumonia in adults","volume":"372","author":"Bonten","year":"2015","journal-title":"N. Engl. J. Med."},{"key":"ref_92","unstructured":"Centers for Disease Control and Prevention (CDC) (2022). Pneumococcal Vaccination: Who and When to Vaccinate."},{"key":"ref_93","doi-asserted-by":"crossref","unstructured":"Kudlay, D., and Svistunov, A. (2022). COVID-19 vaccines: An overview of different platforms. Bioengineering, 9.","DOI":"10.3390\/bioengineering9020072"},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"561","DOI":"10.1038\/s41586-020-2294-9","article-title":"Rapid reconstruction of SARS-CoV-2 using a synthetic genomics platform","volume":"582","author":"Labroussaa","year":"2020","journal-title":"Nature"},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"4046","DOI":"10.1016\/j.vaccine.2022.05.059","article-title":"Hypertension is associated with antibody response and breakthrough infection in health care workers following vaccination with inactivated SARS-CoV-2","volume":"40","author":"Soegiarto","year":"2022","journal-title":"Vaccine"},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"e84","DOI":"10.1056\/NEJMoa2114583","article-title":"Waning immune humoral response to BNT162b2 COVID-19 vaccine over 6 months","volume":"385","author":"Levin","year":"2021","journal-title":"N. Engl. J. Med."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"924","DOI":"10.1016\/S0140-6736(22)00152-0","article-title":"Duration of effectiveness of vaccines against SARS-CoV-2 infection and COVID-19 disease: Results of a systematic review and meta-regression","volume":"399","author":"Feikin","year":"2022","journal-title":"Lancet"},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"409","DOI":"10.1038\/s41579-021-00573-0","article-title":"SARS-CoV-2 variants, spike mutations and immune escape","volume":"19","author":"Harvey","year":"2021","journal-title":"Nat. Rev. Microbiol."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"e126","DOI":"10.1002\/mco2.126","article-title":"SARS-CoV-2 Omicron variant: Immune escape and vaccine development","volume":"3","author":"Ao","year":"2022","journal-title":"MedComm"},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"1205","DOI":"10.1038\/s41591-021-01377-8","article-title":"Neutralizing antibody levels are highly predictive of immune protection from symptomatic SARS-CoV-2 infection","volume":"27","author":"Khoury","year":"2021","journal-title":"Nat. Med."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"1255","DOI":"10.1016\/S2213-2600(21)00357-X","article-title":"Safety, reactogenicity, and immunogenicity of homologous and heterologous prime-boost immunisation with ChAdOx1 nCoV-19 and BNT162b2: A prospective cohort study","volume":"9","author":"Hillus","year":"2021","journal-title":"Lancet Respir. Med."},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1038\/s41541-021-00394-5","article-title":"Strong immunogenicity of heterologous prime-boost immunizations with the experimental vaccine GRAd-COV2 and BNT162b2 or ChAdOx1-nCOV19","volume":"6","author":"Agrati","year":"2021","journal-title":"NPJ Vaccines"},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"951","DOI":"10.1056\/NEJMoa2116747","article-title":"for the SWITCH Research Group. Immunogenicity and reactogenicity of vaccine boosters after Ad26.COV2.S priming","volume":"386","author":"Sablerolles","year":"2022","journal-title":"N. Engl. J. Med."},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"104","DOI":"10.1038\/s41541-021-00369-6","article-title":"Distinguishing features of current COVID-19 vaccines: Knowns and unknowns of antigen presentation and modes of action","volume":"6","author":"Heinz","year":"2021","journal-title":"NPJ Vaccines"},{"key":"ref_105","doi-asserted-by":"crossref","unstructured":"Zhang, L., Jiang, L., Tian, T., Li, W., Pan, Y., and Wang, Y. (2023). Efficacy and safety of COVID-19 vaccination in older adults: A systematic review and meta-analysis. Vaccines, 11.","DOI":"10.3390\/vaccines11010033"},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"82","DOI":"10.1186\/s12929-022-00853-8","article-title":"COVID-19 vaccine update: Vaccine effectiveness, SARS-CoV-2 variants, boosters, adverse effects, and immune correlates of protection","volume":"29","author":"Chi","year":"2022","journal-title":"J Biomed. Sci."},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"673","DOI":"10.1177\/1060028018758431","article-title":"Shingrix: The new adjuvanted recombinant herpes zoster vaccine","volume":"52","author":"James","year":"2018","journal-title":"Ann. Pharmacother."},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"152905","DOI":"10.1016\/j.phymed.2019.152905","article-title":"Updated insights into the mechanism of action and clinical profile of the immunoadjuvant QS-21: A review","volume":"60","year":"2019","journal-title":"Phytomedicine"},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"2087","DOI":"10.1056\/NEJMoa1501184","article-title":"Efficacy of an adjuvanted herpes zoster subunit vaccine in older adults","volume":"372","author":"Lal","year":"2015","journal-title":"N. Engl. J. Med."},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"1019","DOI":"10.1056\/NEJMoa1603800","article-title":"Efficacy of the herpes zoster subunit vaccine in adults 70 years of age or older","volume":"375","author":"Cunningham","year":"2016","journal-title":"N. Engl. J. Med."},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"1750","DOI":"10.1093\/infdis\/jiy095","article-title":"Immune responses to a recombinant glycoprotein E herpes zoster vaccine in adults aged 50 years or older","volume":"217","author":"Cunningham","year":"2018","journal-title":"J. Infect. Dis."},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"k4029","DOI":"10.1136\/bmj.k4029","article-title":"Efficacy, effectiveness, and safety of herpes zoster vaccines in adults aged 50 and older: Systematic review and network meta-analysis","volume":"363","author":"Tricco","year":"2018","journal-title":"BMJ"},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"1279","DOI":"10.1093\/infdis\/jiu606","article-title":"Safety and immunogenicity of an adjuvanted herpes zoster subunit candidate vaccine in HIV-infected adults: A phase 1\/2a randomized, placebo-controlled study","volume":"211","author":"Berkowitz","year":"2015","journal-title":"J. Infect. Dis."},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"2474","DOI":"10.1016\/j.bbmt.2019.07.036","article-title":"Recombinant zoster vaccine significantly reduces the impact on quality of life caused by herpes zoster in adult autologous hematopoietic stem cell transplant recipients: A randomized placebo-controlled trial (ZOE-HSCT)","volume":"25","author":"Curran","year":"2019","journal-title":"Biol. Blood Marrow Transpl."},{"key":"ref_115","doi-asserted-by":"crossref","unstructured":"Weinberger, B., Schirmer, M., Matteucci Gothe, R., Siebert, U., Fuchs, D., and Grubeck-Loebenstein, B. (2013). Recall responses to tetanus and diphtheria vaccination are frequently insufficient in elderly persons. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0082967"},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"660","DOI":"10.7326\/0003-4819-136-9-200205070-00008","article-title":"Serologic immunity to diphtheria and tetanus in the United States","volume":"136","author":"McQuillan","year":"2002","journal-title":"Ann. Intern. Med."},{"key":"ref_117","unstructured":"Centers for Disease Control and Prevention (CDC) (2022). Diphtheria, Tetanus, and Pertussis Vaccine Recommendations."},{"key":"ref_118","doi-asserted-by":"crossref","first-page":"325","DOI":"10.1007\/s40259-022-00531-z","article-title":"Dengue vaccines: An update","volume":"36","author":"Salazar","year":"2022","journal-title":"BioDrugs"},{"key":"ref_119","doi-asserted-by":"crossref","first-page":"S48","DOI":"10.1038\/d41586-022-04343-7","article-title":"The slow roll-out of the world\u2019s first malaria vaccine","volume":"612","author":"Willyard","year":"2022","journal-title":"Nature"}],"container-title":["Pathophysiology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1873-149X\/30\/2\/14\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T19:21:25Z","timestamp":1760124085000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1873-149X\/30\/2\/14"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,4,22]]},"references-count":119,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2023,6]]}},"alternative-id":["pathophysiology30020014"],"URL":"https:\/\/doi.org\/10.3390\/pathophysiology30020014","relation":{},"ISSN":["1873-149X"],"issn-type":[{"value":"1873-149X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,4,22]]}}}