Insights into vaccines for elderly individuals: from the impacts of immunosenescence to delivery strategies | npj Vaccines

11 Apr 2024

Nature

Share on XTweet

Insights into vaccines for elderly individuals from the impacts of
immunosenescence to delivery strategies npj Vaccines

npj Vaccines - Insights into vaccines for elderly individuals: from the impacts of immunosenescence to delivery strategies

Li, X. et al. Inflammation and aging: signaling pathways and intervention therapies. Signal Transduct. Target Ther. 8, 239 (2023).

Article PubMed PubMed Central Google Scholar

United Nations. Department of Economic and Social Affairs, Population Division (2019). World Population Ageing 2019: Highlights (ST/ESA/SER.A/430) (2022).

Gralinski, L. E. & Menachery, V. D. Return of the Coronavirus: 2019-nCoV. Viruses 12, 135 (2020).

Article PubMed PubMed Central Google Scholar

Koff, W. C. et al. Accelerating next-generation vaccine development for global disease prevention. Science 340, 1232910 (2013).

Article PubMed PubMed Central Google Scholar

Mascola, J. R. & Fauci, A. S. Novel vaccine technologies for the 21st century. Nat. Rev. Immunol. 20, 87–88 (2020).

Article CAS PubMed Google Scholar

Hou, Y. et al. Advanced subunit vaccine delivery technologies: from vaccine cascade obstacles to design strategies. Acta Pharm. Sin. B 13, 3321–3338 (2023).

Article CAS PubMed PubMed Central Google Scholar

Cunningham, A. L., McIntyre, P., Subbarao, K., Booy, R. & Levin, M. J. Vaccines for older adults. BMJ 372, n188 (2021).

Article PubMed Google Scholar

Bell, M. R. & Kutzler, M. A. An old problem with new solutions: strategies to improve vaccine efficacy in the elderly. Adv. Drug Deliv. Rev. 183, 114175 (2022).

Article CAS PubMed Google Scholar

Osterholm, M. T. Efficacy and effectiveness of influenza vaccines: a systematic review and meta-analysis. Lancet Infect. Dis. 12, 36–44 (2012).

Article PubMed Google Scholar

Walford, R. L. The immunologic theory of aging. Gerontologist 4, 195–197 (1964).

Article CAS PubMed Google Scholar

Willyard, C. How anti-ageing drugs could boost COVID vaccines in older people. Nature 586, 352–354 (2020).

Article CAS PubMed Google Scholar

Qin, X., Jian, D. & Yi, C. Role of CD8+ T lymphocyte cells: interplay with stromal cells in tumor microenvironment. Acta Pharm. Sin. B 11, 1365–1378 (2021).

Article Google Scholar

Riese, P. et al. Distinct immunological and molecular signatures underpinning influenza vaccine responsiveness in the elderly. Nat. Commun. 13, 6894 (2022).

Article CAS PubMed PubMed Central Google Scholar

Roukens, A. H. et al. Elderly subjects have a delayed antibody response and prolonged viraemia following yellow fever vaccination: a prospective controlled cohort study. PloS One 6, e27753 (2011).

Article CAS PubMed PubMed Central Google Scholar

Schulz, A. R. et al. Low thymic activity and dendritic cell numbers are associated with the immune response to primary viral infection in elderly humans. J. Immunol. 195, 4699–4711 (2015).

Article CAS PubMed Google Scholar

Ding, Y., Li, Z., Jaklenec, A. & Hu, Q. Vaccine delivery systems toward lymph nodes. Adv. Drug Deliv. Rev. 179, 113914 (2021).

Article CAS PubMed PubMed Central Google Scholar

Lefebvre, J. S., Masters, A. R., Hopkins, J. W. & Haynes, L. Age-related impairment of humoral response to influenza is associated with changes in antigen specific T follicular helper cell responses. Sci. Rep. 6, 25051 (2016).

Article CAS PubMed PubMed Central Google Scholar

Chen, J., Deng, J. C. & Goldstein, D. R. How aging impacts vaccine efficacy: known molecular and cellular mechanisms and future directions. Trends Mol. Med. 28, 1100–1111 (2022).

Article CAS PubMed PubMed Central Google Scholar

Hadamitzky, C. et al. Age-dependent histoarchitectural changes in human lymph nodes: an underestimated process with clinical relevance? J. Anat. 216, 556–562 (2010).

Article PubMed PubMed Central Google Scholar

Agrawal, A. et al. Altered innate immune functioning of dendritic cells in elderly humans: a role of phosphoinositide 3-kinase-signaling pathway. J. Immunol. 178, 6912–6922 (2007).

Article CAS PubMed Google Scholar

Yang, Y., Guo, X., Hu, B., He, P. & Feng, M. Generated SecPen_NY-ESO-1_ubiquitin-pulsed dendritic cell cancer vaccine elicits stronger and specific T cell immune responses. Acta Pharm. Sin. B 11, 476–487 (2020).

Article PubMed PubMed Central Google Scholar

Eisenbarth, S. C. Dendritic cell subsets in T cell programming: location dictates function. Nat. Rev. Immunol. 19, 89–103 (2019).

Article CAS PubMed PubMed Central Google Scholar

Heath, W. R., Kato, Y., Steiner, T. M. & Caminschi, I. Antigen presentation by dendritic cells for B cell activation. Curr. Opin. Immunol. 58, 44–52 (2019).

Article CAS PubMed Google Scholar

Wang, J., Geiger, H. & Rudolph, K. L. Immunoaging induced by hematopoietic stem cell aging. Curr. Opin. Immunol. 23, 532–536 (2011).

Article CAS PubMed Google Scholar

Panda, A. et al. Age-associated decrease in TLR function in primary human dendritic cells predicts influenza vaccine response. J. Immunol. 184, 2518–2527 (2010).

Article CAS PubMed Google Scholar

Leleux, J., Atalis, A. & Roy, K. Engineering immunity: modulating dendritic cell subsets and lymph node response to direct immune-polarization and vaccine efficacy. J. Control. Release 219, 610–621 (2015).

Article CAS PubMed PubMed Central Google Scholar

Jackaman, C. et al. Targeting macrophages rescues age-related immune deficiencies in C57BL/6J geriatric mice. Aging Cell 12, 345–357 (2013).

Article CAS PubMed Google Scholar

Prieto, L. I. et al. Senescent alveolar macrophages promote early-stage lung tumorigenesis. Cancer Cell 41, 1261–1275.e6 (2023).

Article CAS PubMed Google Scholar

Wang, J., Yang, J. & Kopecek, J. Nanomedicines in B cell-targeting therapies. Acta Biomater. 137, 1–19 (2022).

Article PubMed Google Scholar

Frasca, D. & Blomberg, B. B. Aging affects human B cell responses. J. Clin. Immunol. 31, 430–435 (2011).

Article PubMed PubMed Central Google Scholar

Pritz, T. et al. Plasma cell numbers decrease in bone marrow of old patients. Eur. J. Immunol. 45, 738–746 (2015).

Article CAS PubMed Google Scholar

Cancro, M. P. Age-associated B cells. Annu. Rev. Immunol. 38, 315–340 (2020).

Article CAS PubMed Google Scholar

Yam-Puc, J. C. et al. Age-associated B cells predict impaired humoral immunity after COVID-19 vaccination in patients receiving immune checkpoint blockade. Nat. Commun. 14, 3292 (2023).

Article CAS PubMed PubMed Central Google Scholar

Allen, C. D. et al. Germinal center dark and light zone organization is mediated by CXCR4 and CXCR5. Nat. Immunol. 5, 943–952 (2004).

Article CAS PubMed Google Scholar

Wols, H. A. et al. Migration of immature and mature B cells in the aged microenvironment. Immunology 129, 278–290 (2010).

Article PubMed Google Scholar

Frasca, D., Blomberg, B. B., Garcia, D., Keilich, S. R. & Haynes, L. Age-related factors that affect B cell responses to vaccination in mice and humans. Immunol. Rev. 296, 142–154 (2020).

Article CAS PubMed PubMed Central Google Scholar

Lefebvre, J. S. et al. The aged microenvironment contributes to the age‐related functional defects of CD4 T cells in mice. Aging Cell 11, 732–740 (2012).

Article CAS PubMed Google Scholar

Silva-Cayetano, A. et al. Spatial dysregulation of T follicular helper cells impairs vaccine responses in aging. Nat. Immunol. 24, 1124–1137 (2023).

Article CAS PubMed PubMed Central Google Scholar

Khurana, S., Frasca, D., Blomberg, B. & Golding, H. AID activity in B cells strongly correlates with polyclonal antibody affinity maturation in-vivo following pandemic 2009-H1N1 vaccination in humans. PLoS Pathog. 8, e1002920 (2012).

Article CAS PubMed PubMed Central Google Scholar

Stiasny, K., Aberle, J. H., Keller, M., Grubeck-Loebenstein, B. & Heinz, F. X. Age affects quantity but not quality of antibody responses after vaccination with an inactivated flavivirus vaccine against tick-borne encephalitis. PLoS One 7, e34145 (2012).

Article CAS PubMed PubMed Central Google Scholar

Goronzy, J. J. & Weyand, C. M. Understanding immunosenescence to improve responses to vaccines. Nat. Immunol. 14, 428–436 (2013).

Article CAS PubMed PubMed Central Google Scholar

Chen, X., Liu, Q. & Xiang, A. P. CD8+CD28- T cells: not only age-related cells but a subset of regulatory T cells. Cell Mol. Immunol. 15, 734–736 (2018).

Article CAS PubMed PubMed Central Google Scholar

Kumagai, S. et al. The PD-1 expression balance between effector and regulatory T cells predicts the clinical efficacy of PD-1 blockade therapies. Nat. Immunol. 21, 1346–1358 (2020).

Article CAS PubMed Google Scholar

Gustafson, C. E., Weyand, C. M. & Goronzy, J. J. T follicular helper cell development and functionality in immune ageing. Clin. Sci. 132, 1925–1935 (2018).

Article CAS Google Scholar

Herati, R. S. et al. Circulating CXCR5+PD-1+ response predicts influenza vaccine antibody responses in young adults but not elderly adults. J. Immunol. 193, 3528–3537 (2014).

Article CAS PubMed Google Scholar

Franceschi, C. et al. Inflamm aging: an evolutionary perspective on immunosenescence. Ann. N.Y. Acad. Sci. 908, 244–254 (2000).

Article CAS PubMed Google Scholar

Franceschi, C. et al. Inflammaging and ‘Garb-aging. Trends Endocrinol. Metab. 28, 199–212 (2017).

Article CAS PubMed Google Scholar

Gilroy, D. & De Maeyer, R. New insights into the resolution of inflammation. Semin. Immunol. 27, 161–168 (2015).

Article CAS PubMed Google Scholar

Chambers, E. S. & Akbar, A. N. Can blocking inflammation enhance immunity during aging? J. Allergy Clin. Immunol. 145, 1323–1331 (2020).

Article CAS PubMed Google Scholar

Hadrup, S. R. et al. Longitudinal studies of clonally expanded CD8 T cells reveal a repertoire shrinkage predicting mortality and an increased number of dysfunctional cytomegalovirus-specific T cells in the very elderly. J. Immunol. 176, 2645–2653 (2006).

Article CAS PubMed Google Scholar

Frasca, D., Blomberg, B. B. & Paganelli, R. Aging, obesity, and inflammatory age-related diseases. Front. Immunol. 8, 1745 (2017).

Article PubMed PubMed Central Google Scholar

Kim, K. A., Jeong, J. J., Yoo, S. Y. & Kim, D. H. Gut microbiota lipopolysaccharide accelerates inflamm-aging in mice. BMC Microbiol 16, 9 (2016).

Article PubMed PubMed Central Google Scholar

Claesson, M. J. et al. Gut microbiota composition correlates with diet and health in the elderly. Nature 488, 178–184 (2012).

Article CAS PubMed Google Scholar

De Maeyer, R. P. H. et al. Blocking elevated p38 MAPK restores efferocytosis and inflammatory resolution in the elderly. Nat. Immunol. 21, 615–625 (2020).

Article PubMed PubMed Central Google Scholar

Lasry, A. & Ben-Neriah, Y. Senescence-associated inflammatory responses: aging and cancer perspectives. Trends Immunol. 36, 217–228 (2015).

Article CAS PubMed Google Scholar

Gulen, M. F. et al. cGAS-STING drives ageing-related inflammation and neurodegeneration. Nature 620, 374–380 (2023).

Article CAS PubMed PubMed Central Google Scholar

Gritsenko, A., Green, J. P., Brough, D. & Lopez-Castejon, G. Mechanisms of NLRP3 priming in inflammaging and age-related diseases. Cytokine Growth Factor Rev. 55, 15–25 (2020).

Article CAS PubMed PubMed Central Google Scholar

Lim, S.O. et al. Deubiquitination and stabilization of PD-L1 by CSN5. Cancer Cell, 925–939 (2016).

Hamilton, J. A. G. et al. Interleukin-37 improves T-cell-mediated immunity and chimeric antigen receptor T-cell therapy in aged backgrounds. Aging Cell 20, e13309 (2021).

Article CAS PubMed PubMed Central Google Scholar

Chen, X., Baumel, M., Männel, D. N., Howard, O. M. Z. & Oppenheim, J. J. Interaction of TNF with TNF receptor type 2 promotes expansion and function of mouse CD4+CD25+ T regulatory cells. J. Immunol. 179, 154–161 (2007).

Article CAS PubMed Google Scholar

Watanabe, R., Shirai, T., Hong, N., Zhang, H. & Weyand, C. M. Pyruvate controls the checkpoint inhibitor PD-L1 and suppresses T cell immunity. J. Clin. Investig. 127, 2725–2738 (2017).

Article PubMed PubMed Central Google Scholar

Chen, J. H. et al. Prostaglandin E2 and programmed cell death 1 signaling coordinately impair CTL function and survival during chronic viral infection. Nat. Med. 21, 327–334 (2015).

Article CAS PubMed PubMed Central Google Scholar

López-Otín, C., Blasco, M. A., Partridge, L., Serrano, M. & Kroemer, G. Hallmarks of aging: an expanding universe. Cell 186, 243–278 (2023).

Article PubMed Google Scholar

Guo, J. et al. Aging and aging-related diseases: from molecular mechanisms to interventions and treatments. Signal Transduct. Target Ther. 7, 391 (2022).

Article CAS PubMed PubMed Central Google Scholar

Hansen, M., Rubinsztein, D. C. & Walker, D. W. Autophagy as a promoter of longevity: insights from model organisms. Nat. Rev. Mol. Cell Biol. 19, 579–593 (2018).

Article CAS PubMed PubMed Central Google Scholar

Zhang, H. et al. Polyamines control eIF5A hypusination, TFEB translation, and autophagy to reverse B cell senescence. Mol. Cell. 76, 110–125.e9 (2019).

Article CAS PubMed PubMed Central Google Scholar

Aman, Y. et al. Autophagy in healthy aging and disease. Nat. Aging 1, 634–650 (2021).

Article PubMed PubMed Central Google Scholar

Kim, J., Kundu, M., Viollet, B. & Guan, K. L. AMPK and mTOR regulate autophagy through direct phosphorylation of Ulk1. Nat. Cell Biol. 13, 132–141 (2011).

Article CAS PubMed PubMed Central Google Scholar

Cirone, M. Perturbation of bulk and selective macroautophagy, abnormal UPR activation and their interplay pave the way to immune dysfunction, cancerogenesis and neurodegeneration in ageing. Ageing Res. Rev. 58, 101026 (2020).

Article CAS PubMed Google Scholar

Wang, Y. et al. In situ manipulation of dendritic cells by an autophagy-regulative nanoactivator enables effective cancer immunotherapy. ACS Nano 13, 7568–7577 (2019).

Article CAS PubMed Google Scholar

Wang, S. et al. Exploration of antigen-induced CaCO3 nanoparticles for therapeutic vaccine. Small 14, e1704272 (2018).

Article PubMed Google Scholar

Hubbard, V. M. et al. Macroautophagy regulates energy metabolism during effector T cell activation. J. Immunol. 185, 7349–7357 (2010).

Article CAS PubMed Google Scholar

Fan, J., Feng, Z. & Chen, N. Spermidine as a target for cancer therapy. Pharmacol. Res. 159, 104943 (2020).

Article CAS PubMed Google Scholar

De Risi, M. et al. Mechanisms by which autophagy regulates memory capacity in ageing. Aging Cell 19, e13189 (2020).

Article PubMed PubMed Central Google Scholar

Ma, T. et al. Low-dose metformin targets the lysosomal AMPK pathway through PEN2. Nature 603, 159–165 (2022).

Article CAS PubMed PubMed Central Google Scholar

Kroemer, G. & Zitvogel, L. CD4+ T cells at the center of inflammaging. Cell Metab. 32, 4–5 (2020).

Article CAS PubMed PubMed Central Google Scholar

Chakravarti, D., LaBella, K. A. & DePinho, R. A. Telomeres: history, health, and hallmarks of aging. Cell 184, 306–322 (2021).

Article CAS PubMed PubMed Central Google Scholar

Lanna, A. et al. An intercellular transfer of telomeres rescues T cells from senescence and promotes long-term immunological memory. Nat. Cell Biol. 24, 1461–1474 (2022).

Article CAS PubMed PubMed Central Google Scholar

Gravenstein, S. et al. Comparative effectiveness of high-dose versus standard-dose influenza vaccination on numbers of US nursing home residents admitted to hospital: a cluster-randomised trial. Lancet Respir. Med. 5, 738–746 (2017).

Article PubMed Google Scholar

Couch, R. B. et al. Safety and immunogenicity of a high dosage trivalent influenza vaccine among elderly subjects. Vaccine 25, 7656–7663 (2007).

Article CAS PubMed PubMed Central Google Scholar

Wilkinson, K. et al. Efficacy and safety of high-dose influenza vaccine in elderly adults: a systematic review and meta-analysis. Vaccine 35, 2775–2780 (2017).

Article CAS PubMed Google Scholar

Goronzy, J. J., Fang, F., Cavanagh, M. M., Qi, Q. & Weyand, C. M. Naive T cell maintenance and function in human aging. J. Immunol. 194, 4073–4080 (2015).

Article CAS PubMed Google Scholar

Sun, Y. et al. Metal-organic framework nanocarriers for drug delivery in biomedical applications. Nanomicro Lett. 12, 103 (2020).

CAS PubMed PubMed Central Google Scholar

Hong, X. et al. The pore size of mesoporous silica nanoparticles regulates their antigen delivery efficiency. Sci. Adv. 6, eaaz4462 (2020).

Article CAS PubMed PubMed Central Google Scholar

Xia, Y. et al. Exploiting the pliability and lateral mobility of Pickering emulsion for enhanced vaccination. Nat. Mater. 17, 187–194 (2018).

Article CAS PubMed Google Scholar

Liu, K. et al. A novel multifunctional vaccine platform with dendritic cell-targeting and pH-responsive for cancer immunotherapy: antigen-directed biomimetic fabrication of a cabbage-like mannatide-zinc-antigen hybrid microparticles. Chem. Eng. J. 426, 130867 (2021).

Article CAS Google Scholar

Zhao, J. et al. A minimalist binary vaccine carrier for personalized postoperative cancer vaccine therapy. Adv. Mater. 34, e2109254 (2022).

Article PubMed Google Scholar

Pereira, B., Xu, X. N. & Akbar, A. N. Targeting inflammation and immunosenescence to improve vaccine responses in the rlderly. Front. Immunol. 11, 583019 (2020).

Article CAS PubMed PubMed Central Google Scholar

Lauer, K. B., Borrow, R. & Blancharda, T. J. Multivalent and multipathogen viral vector vaccines. Clin. Vaccin. Immunol. 24, e00298–16 (2017).

Article CAS Google Scholar

Lewnard, J. A. et al. Effectiveness of 13-Valent pneumococcal conjugate vaccine against medically attended lower respiratory tract infection and pneumonia among older adults. Clin. Infect. Dis. 75, 832–841 (2022).

Article CAS PubMed Google Scholar

Lawrence, H. et al. Effectiveness of the 23-valent pneumococcal polysaccharide vaccine against vaccine serotype pneumococcal pneumonia in adults: a case-control test-negative design study. PLoS Med. 17, e1003326 (2020).

Article CAS PubMed PubMed Central Google Scholar

Hernandez-Davies, J. E. et al. Administration of multivalent influenza virus recombinant hemagglutinin vaccine in combination-adjuvant elicits broad reactivity beyond the vaccine components. Front. Immunol. 12, 692151 (2021).

Article CAS PubMed PubMed Central Google Scholar

Reed, S. G., Orr, M. T. & Fox, C. B. Key roles of adjuvants in modern vaccines. Nat. Med. 19, 1597–1608 (2013).

Article CAS PubMed Google Scholar

Pulendran, B., Arunachalam, P. S. & O’Hagan, D. T. Emerging concepts in the science of vaccine adjuvants. Nat. Rev. Drug Discov. 20, 454–475 (2021).

Article CAS PubMed PubMed Central Google Scholar

Peletta, A., Lemoine, C., Courant, T., Collin, N. & Borchard, G. Meeting vaccine formulation challenges in an emergency setting: towards the development of accessible vaccines. Pharmacol. Res. 189, 106699 (2023).

Article CAS PubMed Google Scholar

Nanishi, E. et al. Precision vaccine adjuvants for older adults: a scoping review. Clin. Infect. Dis. 75, S72–S80 (2022).

Article PubMed Google Scholar

Ciabattini, A. et al. Vaccination in the elderly: the challenge of immune changes with aging. Semin. Immunol. 40, 83–94 (2018).

Article PubMed Google Scholar

Nicolay, U., Heijnen, E., Nacci, P., Patriarca, P. A. & Leav, B. Immunogenicity of aIIV3, MF59-adjuvanted seasonal trivalent influenza vaccine, in older adults ≥65 years of age: meta-analysis of cumulative clinical experience. Int. J. Infect. Dis. 85S, S1–S9 (2019).

Article PubMed Google Scholar

Isakova Sivak, I. & Rudenko, L. Cross-protective potential of a MF59-adjuvanted quadrivalent influenza vaccine in older adults. Lancet Infect. Dis. 21, 900–901 (2021).

Article PubMed Google Scholar

Morel, S. et al. Adjuvant System AS03 containing α-tocopherol modulates innate immune response and leads to improved adaptive immunity. Vaccine 29, 2461–2473 (2011).

Article CAS PubMed Google Scholar

Yam, K. K. et al. AS03-adjuvanted, very-low-dose influenza vaccines induce distinctive immune responses compared to unadjuvanted high-dose vaccines in BALB/c mice. Front. Immunol. 6, 207 (2015).

Article PubMed PubMed Central Google Scholar

Dendouga, N., Fochesato, M., Lockman, L., Mossman, S. & Giannini, S. L. Cell-mediated immune responses to a varicella-zoster virus glycoprotein E vaccine using both a TLR agonist and QS21 in mice. Vaccine 30, 3126–3135 (2012).

Article CAS PubMed Google Scholar

Nam, H. J. et al. An adjuvanted zoster vaccine elicits potent cellular immune responses in mice without QS21. NPJ Vaccines 7, 45 (2022).

Article CAS PubMed PubMed Central Google Scholar

Lal, H. et al. Efficacy of an adjuvanted herpes zoster subunit vaccine in older adults. N. Engl. J. Med. 372, 2087–2096 (2015).

Article PubMed Google Scholar

Renshaw, M. et al. Cutting Edge: impaired toll-like receptor expression and function in aging. J. Immunol. 169, 4697–4701 (2002).

Article CAS PubMed Google Scholar

Metcalf, T. U. et al. Global analyses revealed age-related alterations in innate immune responses after stimulation of pathogen recognition receptors. Aging Cell 14, 421–432 (2015).

Article CAS PubMed PubMed Central Google Scholar

Janssen, J. M., Jackson, S., Heyward, W. L. & Janssen, R. S. Immunogenicity of an investigational hepatitis B vaccine with a toll-like receptor 9 agonist adjuvant (HBsAg-1018) compared with a licensed hepatitis B vaccine in subpopulations of healthy adults 18-70 years of age. Vaccine 33, 3614–3618 (2015).

Article CAS PubMed Google Scholar

Lim, J. S. et al. Flagellin-dependent TLR5/caveolin-1 as a promising immune activator in immunosenescence. Aging Cell 14, 907–915 (2015).

Article CAS PubMed PubMed Central Google Scholar

Denton, A. E. et al. Targeting TLR4 during vaccination boosts MAdCAM-1+lymphoid stromal cell activation and promotes the aged germinal center response. Sci. Immunol. 7, eabk0018 (2022).

Article CAS PubMed PubMed Central Google Scholar

Zareian, N. et al. Triggering of toll-like receptors in old individuals. Relevance for vaccination. Curr. Pharm. Des. 25, 4163–4167 (2019).

Article CAS PubMed Google Scholar

Wu, T. Y. et al. Rational design of small molecules as vaccine adjuvants. Sci. Transl. Med. 6, 263ra160 (2014).

Article PubMed Google Scholar

Ross, K. A. et al. Novel nanoadjuvants balance immune activation with modest inflammation: implications for older adult vaccines. Immun. Ageing 20, 28 (2023).

Article CAS PubMed PubMed Central Google Scholar

Ananya, A. et al. Just right” combinations of adjuvants with nanoscale carriers activate aged dendritic cells without overt inflammation. Immun. Ageing 20, 10 (2023).

Article CAS PubMed PubMed Central Google Scholar

Nanishi, E., Borriello, F., O’Meara, T. R., Mcgrath, M. E. & Dowling, D. J. An aluminum hydroxide:CpG adjuvant enhances protection elicited by a SARS-CoV-2 receptor-binding domain vaccine in aged mice. Sci. Transl. Med. 14, eabj5305 (2021).

Article Google Scholar

Lanna, A. et al. A sestrin-dependent Erk-Jnk-p38 MAPK activation complex inhibits immunity during aging. Nat. Immunol. 18, 354–363 (2017).

Article CAS PubMed PubMed Central Google Scholar

Kennedy, R. B. et al. Immunosenescence-related transcriptomic and immunologic changes in older individuals following influenza vaccination. Front. Immunol. 7, 450 (2016).

Article PubMed PubMed Central Google Scholar

Mannick, J. B. et al. mTOR inhibition improves immune function in the elderly. Sci. Transl. Med. 6, 268ra179 (2014).

Article PubMed Google Scholar

Song, S., Lam, E. W. F., Tchkonia, T., Kirkland, J. L. & Sun, Y. Senescent cells: emerging targets for human aging and age-related diseases. Trends Biochem. Sci. 45, 578–592 (2020).

Article CAS PubMed PubMed Central Google Scholar

Wissler Gerdes, E. O., Misra, A., Netto, J. M. E., Tchkonia, T. & Kirkland, J. L. Strategies for late phase preclinical and early clinical trials of senolytics. Mech. Ageing Dev. 200, 111591 (2021).

Article CAS PubMed Google Scholar

Kirkland, J. L. & Tchkonia, T. Senolytic drugs: from discovery to translation. J. Intern. Med. 288, 518–536 (2020).

Article CAS PubMed PubMed Central Google Scholar

Zhang, Q., Li, S., Chen, F., Zeng, R. & Tong, R. Targeted delivery strategy: a beneficial partner for emerging senotherapy. Biomed. Pharmacother. 155, 113737 (2022).

Article CAS PubMed Google Scholar

Chen, S. et al. Metformin in aging and aging-related diseases: clinical applications and relevant mechanisms. Theranostics 12, 2722–2740 (2022).

Article CAS PubMed PubMed Central Google Scholar

Bharath, L. P. et al. Metformin enhances autophagy and normalizes mitochondrial function to alleviate aging-associated inflammation. Cell Metab. 32, 44–55.e6 (2020).

Article CAS PubMed PubMed Central Google Scholar

Hung, I. F. et al. Immunogenicity of intradermal trivalent influenza vaccine with topical imiquimod: a double blind randomized controlled trial. Clin. Infect. Dis. 59, 1246–1255 (2014).

Article CAS PubMed Google Scholar

Pettersen, F. O. et al. An exploratory trial of cyclooxygenase type 2 inhibitor in HIV-1 infection: downregulated immune activation and improved T cell-dependent vaccine responses. J. Virol. 85, 6557–6566 (2011).

Article CAS PubMed PubMed Central Google Scholar

Madeo, F., Eisenberg, T., Pietrocola, F. & Kroemer, G. Spermidine in health and disease. Science 359, eaan2788 (2018).

Article PubMed Google Scholar

Nakamura, A. et al. Symbiotic polyamine metabolism regulates epithelial proliferation and macrophage differentiation in the colon. Nat. Commun. 12, 2105 (2021).

Article CAS PubMed PubMed Central Google Scholar

Aggarwal, V. et al. Molecular mechanisms of action of epigallocatechin gallate in cancer: recent trends and advancement. Semin. Cancer Biol. 80, 256–275 (2022).

Article CAS PubMed Google Scholar

Yuan, H. et al. The phytochemical epigallocatechin gallate prolongs the lifespan by improving lipid metabolism, reducing inflammation and oxidative stress in high-fat diet-fed obese rats. Aging Cell 19, e13199 (2020).

Article CAS PubMed PubMed Central Google Scholar

Tavenier, J. et al. Alterations of monocyte NF-kappaB p65/RelA signaling in a cohort of older medical patients, age-matched controls, and healthy young adults. Immun. Ageing 17, 25 (2020).

Article CAS PubMed PubMed Central Google Scholar

Cheong, Y. et al. Epigallocatechin-3-Gallate as a novel vaccine adjuvant. Front. Immunol. 12, 769088 (2021).

Article CAS PubMed PubMed Central Google Scholar

Herati, R. S. et al. Vaccine-induced ICOS+CD38+ circulating Tfh are sensitive biosensors of age-related changes in inflammatory pathways. Cell Rep. Med. 2, 100262 (2021).

Article PubMed PubMed Central Google Scholar

Carrasco, E. et al. The role of T cells in age-related diseases. Nat. Rev. Immunol. 22, 97–111 (2022).

Article CAS PubMed Google Scholar

Heitmann, J. S. et al. A COVID-19 peptide vaccine for the induction of SARS-CoV-2 T cell immunity. Nature 601, 617–622 (2022).

Article CAS PubMed Google Scholar

Hu, Y. et al. Synergistic tumor immunological strategy by combining tumor nanovaccine with gene-mediated extracellular matrix scavenger. Biomaterials 252, 120114 (2020).

Article CAS PubMed Google Scholar

Mittelbrunn, M. & Kroemer, G. Hallmarks of T cell aging. Nat. Immunol. 22, 687–698 (2021).

Article CAS PubMed Google Scholar

Fear, V. S. et al. Tumour draining lymph node-generated CD8 T cells play a role in controlling lung metastases after a primary tumour is removed but not when adjuvant immunotherapy is used. Cancer Immunol. Immunother. 70, 3259 (2021).

Article PubMed PubMed Central Google Scholar

Liu, X., Hoft, D. F. & Peng, G. Senescent T cells within suppressive tumor microenvironments: emerging target for tumor immunotherapy. J. Clin. Investig. 130, 1073–1083 (2020).

Article CAS PubMed PubMed Central Google Scholar

Liu, C. et al. A nanovaccine for antigen self-presentation and immunosuppression reversal as a personalized cancer immunotherapy strategy. Nat. Nanotechnol. 17, 531–540 (2022).

Article CAS PubMed Google Scholar

Antonangeli, F., Zingoni, A., Soriani, A. & Santoni, A. Senescent cells: living or dying is a matter of NK cells. J. Leukoc. Biol. 105, 1275–1283 (2019).

Article CAS PubMed Google Scholar

Chaudhary, N., Weissman, D. & Whitehead, K. A. mRNA vaccines for infectious diseases: principles, delivery and clinical translation. Nat. Rev. Drug Discov. 20, 817–838 (2021).

Article CAS PubMed PubMed Central Google Scholar

Newman, J. et al. Neutralizing antibody activity against 21 SARS-CoV-2 variants in older adults vaccinated with BNT162b2. Nat. Microbiol. 7, 1180–1188 (2022).

Article CAS PubMed PubMed Central Google Scholar

Parry, H. et al. Extended interval BNT162b2 vaccination enhances peak antibody generation. NPJ Vaccines 7, 14 (2022).

Article CAS PubMed PubMed Central Google Scholar

Thompson, W. W. et al. Mortality associated with influenza and respiratory syncytial virus in the United States. JAMA 289, 179–186 (2003).

Article PubMed Google Scholar

Di Pasquale, A., Preiss, S., Tavares Da Silva, F. & Garcon, N. Vaccine adjuvants: from 1920 to 2015 and beyond. Vaccines 3, 320–343 (2015).

Article PubMed PubMed Central Google Scholar

Tsang, P. et al. Immunogenicity and safety of Fluzone® intradermal and high-dose influenza vaccines in older adults ≥65 years of age: a randomized, controlled, phase II trial. Vaccine 32, 2507–2517 (2014).

Article CAS PubMed Google Scholar

Muszkat, M. et al. Local and systemic immune response in nursing-home elderly following intranasal or intramuscular immunization with inactivated influenza vaccine. Vaccine 21, 1180–1186 (2003).

Article CAS PubMed Google Scholar

Mosafer, J., Sabbaghi, A. H., Badiee, A., Dehghan, S. & Tafaghodi, M. Preparation, characterization and in vivo evaluation of alginate-coated chitosan and trimethylchitosan nanoparticles loaded with PR8 influenza virus for nasal immunization. Asian J. Pharm. Sci. 14, 216–221 (2019).

Article PubMed Google Scholar

Andrew, M. K. et al. The importance of frailty in the assessment of influenza vaccine effectiveness against influenza-related hospitalization in elderly people. J. Infect. Dis. 216, 405–414 (2017).

Article PubMed PubMed Central Google Scholar

Huang, C. Q., Vishwanath, S., Carnell, G. W., Chan, A. C. Y. & Heeney, J. L. Immune imprinting and next-generation coronavirus vaccines. Nat. Microbiol. 8, 1971–1985 (2023).

Article CAS PubMed Google Scholar

Jirru, E. et al. Impact of influenza on pneumococcal vaccine effectiveness during Streptococcus pneumoniae infection in aged murine lung. Vaccines 8, 298 (2020).

Article CAS PubMed PubMed Central Google Scholar

Wang, J. et al. Broadly reactive IgG responses to heterologous H5 prime-boost influenza vaccination are shaped by antigenic relatedness to priming strains. mBio 12, e0044921 (2021).

Article PubMed Google Scholar

Kim, J. H., Davis, W. G., Sambhara, S. & Jacob, J. Strategies to alleviate original antigenic sin responses to influenza viruses. Proc. Natl Acad. Sci. USA 109, 13751–13756 (2012).

Article CAS PubMed PubMed Central Google Scholar