Nations U. World Population Prospects 2019. 2019.
UnitedNations. World population ageing: United Nations [Available from: http://www.un.org/en/development/desa/population/publications/pdf/ageing/WPA2015_Report.pdf.
Del Giudice G, Goronzy JJ, Grubeck-Loebenstein B, Lambert P-H, Mrkvan T, Stoddard JJ, et al. Fighting against a protean enemy: immunosenescence, vaccines, and healthy aging. npj Aging and Mechanisms of Disease. 2017;4(1):1.
Goodwin K, Viboud C, Simonsen L. Antibody response to influenza vaccination in the elderly: a quantitative review. Vaccine. 2006;24(8):1159–69.
Yang W, Kandula S, Huynh M, Greene SK, Van Wye G, Li W, et al. Estimating the infection-fatality risk of SARS-CoV-2 in New York City during the spring 2020 Pandemic wave: a model-based analysis. Lancet Infect Dis.
Franceschi C, Garagnani P, Vitale G, Capri M, Salvioli S. Inflammaging and ‘Garb-aging’. Trends Endocrinol Metab. 2017;28(3):199–212.
Ferrucci L, Fabbri E. Inflammageing: chronic inflammation in ageing, cardiovascular disease, and frailty. Nat Rev Cardiol. 2018;15(9):505–22.
Mannick JB, Morris M, Hockey H-UP, Roma G, Beibel M, Kulmatycki K, et al. TORC1 inhibition enhances immune function and reduces infections in the elderly. Sci Transl Med. 2018;10(449):eaaq1564.
Vukmanovic-Stejic M, Chambers ES, Suárez-Fariñas M, Sandhu D, Fuentes-Duculan J, Patel N, et al. Enhancement of cutaneous immunity during aging by blocking p38 mitogen-activated protein (MAP) kinase–induced inflammation. J Allergy Clin Immunol. 2018;142(3):844–56.
Swift ME, Burns AL, Gray KL, DiPietro LA. Age-related alterations in the inflammatory response to dermal injury. J Investig Dermatol. 2001;117(5):1027–35.
Verschoor CP, Johnstone J, Loeb M, Bramson JL, Bowdish DME. Anti-pneumococcal deficits of monocyte-derived macrophages from the advanced-age, frail elderly and related impairments in PI3K-AKT signaling. Hum Immunol. 2014;75(12):1192–6.
Mitzel DN, Lowry V, Shirali AC, Liu Y, Stout-Delgado HW. Age-enhanced endoplasmic reticulum stress contributes to increased Atg9A inhibition of STING-mediated IFN-β production during <em>Streptococcus pneumoniae</em> infection. J Immunol. 2014;192(9):4273.
Kong K-F, Wang X, Anderson JF, Fikrig E, Montgomery RR. West Nile virus attenuates activation of primary human macrophages. Viral Immunol. 2008;21(1):78–82.
Kong K-F, Delroux K, Wang X, Qian F, Arjona A, Malawista SE, et al. Dysregulation of TLR3 impairs the innate immune response to West Nile virus in the elderly. J Virol. 2008;82(15):7613–23.
Brown BN, Sicari BM, Badylak SF. Rethinking regenerative medicine: a macrophage-centered approach. Front Immunol. 2014;5:510.
Albright JM, Dunn RC, Shults JA, Boe DM, Afshar M, Kovacs EJ. Advanced age alters monocyte and macrophage responses. Antioxid Redox Signal. 2016;25(15):805–15.
Nyugen J, Agrawal S, Gollapudi S, Gupta S. Impaired functions of peripheral blood monocyte subpopulations in aged humans. J Clin Immunol. 2010;30(6):806–13.
Seidler S, Zimmermann HW, Bartneck M, Trautwein C, Tacke F. Age-dependent alterations of monocyte subsets and monocyte-related chemokine pathways in healthy adults. BMC Immunol. 2010;11(1):30.
van Duin D, Allore HG, Mohanty S, Ginter S, Newman FK, Belshe RB, et al. Prevaccine determination of the expression of costimulatory B7 molecules in activated monocytes predicts influenza vaccine responses in young and older adults. J Infect Dis. 2007;195(11):1590–7.
Molony RD, Nguyen JT, Kong Y, Montgomery RR, Shaw AC, Iwasaki A. Aging impairs both primary and secondary RIG-I signaling for interferon induction in human monocytes. Science Signaling. 2017;10(509).
Wang Q, Westra J, van der Geest KSM, Moser J, Bijzet J, Kuiper T, et al. Reduced levels of cytosolic DNA sensor AIM2 are associated with impaired cytokine responses in healthy elderly. Exp Gerontol. 2016;78:39–46.
Pillai PS, Molony RD, Martinod K, Dong H, Pang IK, Tal MC, et al. Mx1 reveals innate pathways to antiviral resistance and lethal influenza disease. Science. 2016;352(6284):463.
Metcalf TU, Wilkinson PA, Cameron MJ, Ghneim K, Chiang C, Wertheimer AM, et al. Human Monocyte Subsets Are Transcriptionally and Functionally Altered in Aging in Response to Pattern Recognition Receptor Agonists. The Journal of Immunology. 2017.
Panda A, Qian F, Mohanty S, van Duin D, Newman FK, Zhang L, et al. Age-associated decrease in TLR function in primary human dendritic cells predicts influenza vaccine response. J Immunol. 2010;184(5):2518.
Prakash S, Agrawal S, Cao J-n, Gupta S, Agrawal a. impaired secretion of interferons by dendritic cells from aged subjects to influenza. AGE. 2013;35(5):1785–1797.
Agrawal A, Tay J, Ton S, Agrawal S, Gupta S. Increased reactivity of dendritic cells from aged subjects to self-antigen, the human DNA. J Immunol. 2009;182(2):1138.
Qian F, Wang X, Zhang L, Lin A, Zhao H, Fikrig E, et al. Impaired interferon signaling in dendritic cells from older donors infected in vitro with West Nile virus. J Infect Dis. 2011;203(10):1415–24.
Sridharan A, Esposo M, Kaushal K, Tay J, Osann K, Agrawal S, et al. Age-associated impaired plasmacytoid dendritic cell functions lead to decreased CD4 and CD8 T cell immunity. Age (Dordr). 2011;33(3):363–76.
Tseng C-TK, Perrone LA, Zhu H, Makino S, Peters CJ. Severe acute respiratory syndrome and the innate immune responses: modulation of effector cell function without productive infection. J Immunol. 2005;174(12):7977.
Zhou R, To KK-W, Wong Y-C, Liu L, Zhou B, Li X, et al. Acute SARS-CoV-2 infection impairs dendritic cell and T cell responses. Immunity. 2020;53(4):864–77.e5.
Blanco-Melo D, Nilsson-Payant BE, Liu W-C, Uhl S, Hoagland D, Møller R, et al. Imbalanced host response to SARS-CoV-2 drives development of COVID-19. Cell. 2020;181(5):1036–45.e9.
Bektas A, Schurman SH, Sen R, Ferrucci L. Human T cell immunosenescence and inflammation in aging. J Leukoc Biol. 2017;102(4):977–88.
Kyoizumi S, Kubo Y, Kajimura J, Yoshida K, Imai K, Hayashi T, et al. Age-associated changes in the differentiation potentials of human circulating hematopoietic progenitors to T- or NK-lineage cells. J Immunol. 2013;190(12):6164–72.
Palmer S, Albergante L, Blackburn CC, Newman TJ. Thymic involution and rising disease incidence with age. Proc Natl Acad Sci U S A 2018;115(8):1883–8.
Thome JJ, Grinshpun B, Kumar BV, Kubota M, Ohmura Y, Lerner H, et al. Longterm maintenance of human naive T cells through in situ homeostasis in lymphoid tissue sites. Sci Immunol. 2016;1(6).
Kilpatrick RD, Rickabaugh T, Hultin LE, Hultin P, Hausner MA, Detels R, et al. Homeostasis of the naive CD4+ T cell compartment during aging. J Immunol. 2008;180(3):1499–507.
Naylor K, Li G, Vallejo AN, Lee WW, Koetz K, Bryl E, et al. The influence of age on T cell generation and TCR diversity. J Immunol. 2005;174(11):7446–52.
Britanova OV, Putintseva EV, Shugay M, Merzlyak EM, Turchaninova MA, Staroverov DB, et al. Age-related decrease in TCR repertoire diversity measured with deep and normalized sequence profiling. J Immunol. 2014;192(6):2689–98.
Yoshida K, Cologne JB, Cordova K, Misumi M, Yamaoka M, Kyoizumi S, et al. Aging-related changes in human T-cell repertoire over 20years delineated by deep sequencing of peripheral T-cell receptors. Exp Gerontol. 2017;96:29–37.
Messaoudi I, Lemaoult J, Guevara-Patino JA, Metzner BM, Nikolich-Zugich J. Age-related CD8 T cell clonal expansions constrict CD8 T cell repertoire and have the potential to impair immune defense. J Exp Med. 2004;200(10):1347–58.
Egorov ES, Kasatskaya SA, Zubov VN, Izraelson M, Nakonechnaya TO, Staroverov DB, et al. The changing landscape of naive T cell receptor repertoire with human aging. Front Immunol. 2018;9:1618.
Zhou X, McElhaney JE. Age-related changes in memory and effector T cells responding to influenza a/H3N2 and pandemic a/H1N1 strains in humans. Vaccine. 2011;29(11):2169–77.
Haq K, Fulop T, Tedder G, Gentleman B, Garneau H, Meneilly GS, et al. Cytomegalovirus seropositivity predicts a decline in the T cell but not the antibody response to influenza in vaccinated older adults independent of type 2 diabetes status. J Gerontol A Biol Sci Med Sci. 2017;72(9):1163–70.
Song Y, Wang B, Song R, Hao Y, Wang D, Li Y, et al. T-cell immunoglobulin and ITIM domain contributes to CD8+ T-cell Immunosenescence. Aging Cell. 2018;17(2):e12716.
Bektas A, Zhang Y, Lehmann E, Wood WH, Becker KG, Madara K, et al. Age-associated changes in basal NF-κB function in human CD4<sup>+</sup> T lymphocytes via dysregulation of PI3 kinase. Aging. 2014;6(11):957–69.
Deng Y, Jing Y, Campbell AE, Gravenstein S. Age-related impaired type 1 T cell responses to influenza: reduced activation ex vivo, decreased expansion in CTL culture in vitro, and blunted response to influenza vaccination in vivo in the elderly. J Immunol. 2004;172(6):3437–46.
Gustafson CE, Weyand CM, Goronzy JJ. T follicular helper cell development and functionality in immune ageing. Clin Sci (Lond). 2018;132(17):1925–35.
Hou PF, Zhu LJ, Chen XY, Qiu ZQ. Age-related changes in CD4+CD25+FOXP3+ regulatory T cells and their relationship with lung cancer. PLoS One. 2017;12(3):e0173048.
Trzonkowski P, Szmit E, Myśliwska J, Myśliwski A. CD4+CD25+ T regulatory cells inhibit cytotoxic activity of CTL and NK cells in humans-impact of immunosenescence. Clin Immunol. 2006;119(3):307–16.
Wagner A, Garner-Spitzer E, Jasinska J, Kollaritsch H, Stiasny K, Kundi M, et al. Age-related differences in humoral and cellular immune responses after primary immunisation: indications for stratified vaccination schedules. Sci Rep. 2018;8(1):9825.
Gibson KL, Wu YC, Barnett Y, Duggan O, Vaughan R, Kondeatis E, et al. B-cell diversity decreases in old age and is correlated with poor health status. Aging Cell. 2009;8(1):18–25.
Dunn-Walters DK, Ademokun AA. B cell repertoire and ageing. Curr Opin Immunol. 2010;22(4):514–20.
Frasca D, Landin AM, Lechner SC, Ryan JG, Schwartz R, Riley RL, et al. Aging down-regulates the transcription factor E2A, activation-induced cytidine deaminase, and Ig class switch in human B cells. J Immunol. 2008;180(8):5283–90.
Pritz T, Lair J, Ban M, Keller M, Weinberger B, Krismer M, et al. Plasma cell numbers decrease in bone marrow of old patients. Eur J Immunol. 2015;45(3):738–46.
Merani S, Pawelec G, Kuchel GA, McElhaney JE. Impact of aging and Cytomegalovirus on immunological response to influenza vaccination and infection. Front Immunol. 2017;8:784.
Frasca D, Diaz A, Romero M, Phillips M, Mendez NV, Landin AM, et al. Unique biomarkers for B-cell function predict the serum response to pandemic H1N1 influenza vaccine. Int Immunol. 2012;24(3):175–82.
Channappanavar R, Fehr AR, Zheng J, Wohlford-Lenane C, Abrahante JE, Mack M, et al. IFN-I response timing relative to virus replication determines MERS coronavirus infection outcomes. J Clin Invest. 2019;130(9):3625–39.
Züst R, Cervantes-Barragan L, Habjan M, Maier R, Neuman BW, Ziebuhr J, et al. Ribose 2′-O-methylation provides a molecular signature for the distinction of self and non-self mRNA dependent on the RNA sensor Mda5. Nat Immunol. 2011;12(2):137–43.
Sun L, Xing Y, Chen X, Zheng Y, Yang Y, Nichols DB, et al. Coronavirus papain-like proteases negatively regulate antiviral innate immune response through disruption of STING-mediated signaling. PloS one. 2012;7(2):e30802-e.
Ziegler CGK, Allon SJ, Nyquist SK, Mbano IM, Miao VN, Tzouanas CN, et al. SARS-CoV-2 receptor ACE2 is an interferon-stimulated gene in human airway epithelial cells and is detected in specific cell subsets across tissues. Cell. 2020;181(5):1016–35.e19.
Frieman M, Yount B, Heise M, Kopecky-Bromberg SA, Palese P, Baric RS. Severe acute respiratory syndrome coronavirus ORF6 antagonizes STAT1 function by sequestering nuclear import factors on the rough endoplasmic reticulum/Golgi membrane. J Virol. 2007;81(18):9812.
Cunha LL, Perazzio SF, Azzi J, Cravedi P, Riella LV. Remodeling of the immune response with aging: Immunosenescence and its potential impact on COVID-19 immune response. Front Immunol. 2020;11:1748.
Roncati L, Nasillo V, Lusenti B, Riva G. Signals of Th2 immune response from COVID-19 patients requiring intensive care. Ann Hematol. 2020;99(6):1419–20.
Grifoni A, Weiskopf D, Ramirez SI, Mateus J, Dan JM, Moderbacher CR, et al. Targets of T cell responses to SARS-CoV-2 coronavirus in humans with COVID-19 disease and unexposed individuals. Cell. 2020.
Hotez PJ, Bottazzi ME, Corry DB. The potential role of Th17 immune responses in coronavirus immunopathology and vaccine-induced immune enhancement. Microbes Infect. 2020;22(4–5):165–7.
van den Berg SPH, Wong A, Hendriks M, Jacobi RHJ, van Baarle D, van Beek J. Negative effect of age, but not of latent Cytomegalovirus infection on the antibody response to a novel influenza vaccine strain in healthy adults. Front Immunol. 2018;9:82.
Nuñez IA, Carlock MA, Allen JD, Owino SO, Moehling KK, Nowalk P, et al. Impact of age and pre-existing influenza immune responses in humans receiving split inactivated influenza vaccine on the induction of the breadth of antibodies to influenza a strains. PLoS One. 2017;12(11):e0185666.
Frasca D, Diaz A, Romero M, Landin AM, Blomberg BB. Age effects on B cells and humoral immunity in humans. Ageing Res Rev. 2011;10(3):330–5.
Mohanty S, Joshi SR, Ueda I, Wilson J, Blevins TP, Siconolfi B, et al. Prolonged proinflammatory cytokine production in monocytes modulated by interleukin 10 after influenza vaccination in older adults. J Infect Dis. 2014;211(7):1174–84.
Banerjee M, Mehr R, Belelovsky A, Spencer J, Dunn-Walters DK. Age- and tissue-specific differences in human germinal center B cell selection revealed by analysis of IgVH gene hypermutation and lineage trees. Eur J Immunol. 2002;32(7):1947–57.
Frasca D, Diaz A, Romero M, Blomberg BB. The generation of memory B cells is maintained, but the antibody response is not, in the elderly after repeated influenza immunizations. Vaccine. 2016;34(25):2834–40.
Schulz AR, Mälzer JN, Domingo C, Jürchott K, Grützkau A, Babel N, et al. Low thymic activity and dendritic cell numbers are associated with the immune response to primary viral infection in elderly humans. J Immunol. 2015;195(10):4699–711.
Boyd A, Almeida JR, Darrah PA, Sauce D, Seder RA, Appay V, et al. Pathogen-specific T cell polyfunctionality is a correlate of T cell efficacy and immune protection. PLoS One. 2015;10(6):e0128714.
Goncalves Pereira MH, Figueiredo MM, Queiroz CP, Magalhaes TVB, Mafra A, Diniz LMO, et al. T-cells producing multiple combinations of IFNgamma, TNF and IL10 are associated with mild forms of dengue infection. Immunology. 2020;160(1):90–102.
van der Geest KS, Abdulahad WH, Tete SM, Lorencetti PG, Horst G, Bos NA, et al. Aging disturbs the balance between effector and regulatory CD4+ T cells. Exp Gerontol. 2014;60:190–6.
Organization WH. R&D Blueprint and COVID-19. 2020 [11/28/2020]. Available from: https://www.who.int/teams/blueprint/covid-19.
Curtis N, Sparrow A, Ghebreyesus TA, Netea MG. Considering BCG vaccination to reduce the impact of COVID-19. Lancet. 2020.
Netea MG, Joosten LA, Latz E, Mills KH, Natoli G, Stunnenberg HG, et al. Trained immunity: a program of innate immune memory in health and disease. Science. 2016;352(6284):aaf1098.
Zimmermann P, Curtis N. The influence of BCG on vaccine responses – a systematic review. Expert Rev Vaccin. 2018;17(6):547–54.
Hollm-Delgado M-G, Stuart EA, Black RE. Acute lower respiratory infection among Bacille Calmette-Guérin (BCG)–vaccinated children. Pediatrics. 2014;133(1):e73.
Pollard AJ, Finn A, Curtis N. Non-specific effects of vaccines: plausible and potentially important, but implications uncertain. Arch Dis Child. 2017;102(11):1077.
Klinman DM, Conover J, Bloom ET, Weiss W. Immunogenicity and efficacy of a DNA vaccine in aged mice. J Gerontol Series A. 1998;53A(4):B281–B6.
Baliban SM, Michael A, Shammassian B, Mudakha S, Khan AS, Cocklin S, et al. An optimized, synthetic DNA vaccine encoding the toxin a and toxin B receptor binding domains of Clostridium difficile induces protective antibody responses in vivo. Infect Immun. 2014;82(10):4080–91.
DeZure AD, Coates EE, Hu Z, Yamshchikov GV, Zephir KL, Enama ME, et al. An avian influenza H7 DNA priming vaccine is safe and immunogenic in a randomized phase I clinical trial. NPJ vaccines [Internet]. 2017 2017; 2:[15 p.]. Available from: http://europepmc.org/abstract/MED/29263871, https://doi.org/10.1038/s41541-017-0016-6, https://europepmc.org/articles/PMC5627236, https://europepmc.org/articles/PMC5627236?pdf=render, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5627236/pdf/41541_2017_Article_16.pdf.
Smith TRF, Patel A, Ramos S, Elwood D, Zhu X, Yan J, et al. Immunogenicity of a DNA vaccine candidate for COVID-19. Nat Commun. 2020;11(1):2601.
Kutzler MA, Weiner DB. DNA vaccines: ready for prime time? Nat Rev Genet. 2008;9(10):776–88.
McElhaney JE, Kuchel GA, Zhou X, Swain SL, Haynes L. T-cell immunity to influenza in older adults: a pathophysiological framework for development of more effective vaccines. Front Immunol. 2016;7:41.
Rydyznski Moderbacher C, Ramirez SI, Dan JM, Grifoni A, Hastie KM, Weiskopf D, et al. Antigen-specific adaptive immunity to SARS-CoV-2 in acute COVID-19 and associations with age and disease severity. Cell. 2020;183(4):996–1012.e19.
Farris E, Brown DM, Ramer-Tait AE, Pannier AK. Chitosan-zein nano-in-microparticles capable of mediating in vivo transgene expression following oral delivery. J Control Release. 2017;249:150–61.
Gulla SK, Rao BR, Moku G, Jinka S, Nimmu NV, Khalid S, et al. In vivo targeting of DNA vaccines to dendritic cells using functionalized gold nanoparticles. Biomater Sci. 2019;7(3):773–88.
Lai SK, Wang YY, Hanes J. Mucus-penetrating nanoparticles for drug and gene delivery to mucosal tissues. Adv Drug Deliv Rev. 2009;61(2):158–71.
Jin P, Sha R, Zhang Y, Liu L, Bian Y, Qian J, et al. Blood circulation-prolonging peptides for engineered nanoparticles identified via phage display. Nano Lett. 2019;19(3):1467–78.
Fitzgerald JC, Gao G-P, Reyes-Sandoval A, Pavlakis GN, Xiang ZQ, Wlazlo AP, et al. A simian replication-defective adenoviral recombinant vaccine to HIV-1 gag. J Immunol. 2003;170(3):1416.
Afkhami S, Yao Y, Xing Z. Methods and clinical development of adenovirus-vectored vaccines against mucosal pathogens. Mol Ther Methods Clin Dev. 2016;3:16030.
Lee WS, Wheatley AK, Kent SJ, DeKosky BJ. Antibody-dependent enhancement and SARS-CoV-2 vaccines and therapies. Nat Microbiol. 2020;5(10):1185–91.
Smetana J, Chlibek R, Shaw J, Splino M, Prymula R. Influenza vaccination in the elderly. Human Vaccin Immunother. 2018;14(3):540–9.
Khurana S, Chearwae W, Castellino F, Manischewitz J, King LR, Honorkiewicz A, et al. Vaccines with MF59 adjuvant expand the antibody repertoire to target protective sites of pandemic avian H5N1 influenza virus. Science Translational Medicine. 2010;2(15):15ra5.
Gary E, O'Connor M, Chakhtoura M, Tardif V, Kumova OK, Malherbe DC, et al. Adenosine deaminase-1 enhances germinal center formation and functional antibody responses to HIV-1 envelope DNA and protein vaccines. Vaccine. 2020;38(22):3821–31.
Kutzler MA, Kraynyak KA, Nagle SJ, Parkinson RM, Zharikova D, Chattergoon M, et al. Plasmids encoding the mucosal chemokines CCL27 and CCL28 are effective adjuvants in eliciting antigen-specific immunity in vivo. Gene Ther. 2010;17(1):72–82.
Shedlock DJ, Tingey C, Mahadevan L, Hutnick N, Reuschel EL, Kudchodkar S, et al. Co-administration of molecular adjuvants expressing NF-kappa B subunit p65/RelA or type-1 transactivator T-bet enhance antigen specific DNA vaccine-induced immunity. Vaccines. 2014;2(2):196–215.
Sasaki S, Amara RR, Yeow W-S, Pitha PM, Robinson HL. Regulation of DNA-raised immune responses by Cotransfected interferon regulatory factors. J Virol. 2002;76(13):6652.
Castaldello A, Sgarbanti M, Marsili G, Brocca-Cofano E, Remoli AL, Caputo A, et al. Interferon regulatory factor-1 acts as a powerful adjuvant in tat DNA based vaccination. J Cell Physiol. 2010;224(3):702–9.
Luo M, Qu X, Pan R, Zhu D, Zhang Y, Wu J, et al. The virus-induced signaling adaptor molecule enhances DNA-raised immune protection against H5N1 influenza virus infection in mice. Vaccine. 2011;29(14):2561–7.
Larsen KC, Spencer AJ, Goodman AL, Gilchrist A, Furze J, Rollier CS, et al. Expression of tak1 and tram induces synergistic pro-inflammatory signalling and adjuvants DNA vaccines. Vaccine. 2009;27(41):5589–98.
de Andrés X, Reina R, Ciriza J, Crespo H, Glaria I, Ramírez H, et al. Use of B7 costimulatory molecules as adjuvants in a prime-boost vaccination against Visna/Maedi ovine lentivirus. Vaccine. 2009;27(34):4591–600.
Elizaga ML, Li SS, Kochar NK, Wilson GJ, Allen MA, Tieu HVN, et al. Safety and tolerability of HIV-1 multiantigen pDNA vaccine given with IL-12 plasmid DNA via electroporation, boosted with a recombinant vesicular stomatitis virus HIV Gag vaccine in healthy volunteers in a randomized, controlled clinical trial. PloS one. 2018;13(9):e0202753-e.
Poulin LF, Salio M, Griessinger E, Anjos-Afonso F, Craciun L, Chen J-L, et al. Characterization of human DNGR-1+ BDCA3+ leukocytes as putative equivalents of mouse CD8alpha+ dendritic cells. J Exp Med. 2010;207(6):1261–71.
Trumpfheller C, Caskey M, Nchinda G, Longhi MP, Mizenina O, Huang Y, et al. The microbial mimic poly IC induces durable and protective CD4<sup>+</sup> T cell immunity together with a dendritic cell targeted vaccine. Proc Natl Acad Sci. 2008;105(7):2574.
Bidet K, Ho V, Chu CW, Naim ANH, Thazin K, Chan KR, et al. Mimicking immune signatures of flavivirus infection with targeted adjuvants improves dengue subunit vaccine immunogenicity. NPJ vaccines. 2019;4:27-.
Longhi MP, Trumpfheller C, Idoyaga J, Caskey M, Matos I, Kluger C, et al. Dendritic cells require a systemic type I interferon response to mature and induce CD4+ Th1 immunity with poly IC as adjuvant. J Exp Med. 2009;206(7):1589–602.
Loo Y-M, Wilkins CR, Pattabhi S, Knoll ML, Kaiser S, Mire CE, et al. RIG-ging the host innate immune response for vaccine adjuvant and antiviral therapy. J Immunol. 2016;196(1 Supplement):76.3.
Chiang C, Beljanski V, Yin K, Olagnier D, Ben Yebdri F, Steel C, et al. Sequence-specific modifications enhance the broad-spectrum antiviral response activated by RIG-I agonists. J Virol. 2015;89(15):8011–25.
Beljanski V, Chiang C, Kirchenbaum GA, Olagnier D, Bloom CE, Wong T, et al. Enhanced influenza virus-like particle vaccination with a structurally optimized RIG-I agonist as adjuvant. J Virol. 2015;89(20):10612–24.
Nanishi E, Dowling DJ, Levy O. Toward precision adjuvants: optimizing science and safety. Curr Opin Pediatr. 2020;32(1):125–38.
Mata-Haro V, Cekic C, Martin M, Chilton PM, Casella CR, Mitchell TC. The vaccine adjuvant Monophosphoryl lipid a as a TRIF-biased agonist of TLR4. Science. 2007;316(5831):1628.
Behzad H, Huckriede ALW, Haynes L, Gentleman B, Coyle K, Wilschut JC, et al. GLA-SE, a synthetic toll-like receptor 4 agonist, enhances T-cell responses to influenza vaccine in older adults. J Infect Dis. 2012;205(3):466–73.
Gorden KB, Gorski KS, Gibson SJ, Kedl RM, Kieper WC, Qiu X, et al. Synthetic TLR agonists reveal functional differences between human TLR7 and TLR8. J Immunol. 2005;174(3):1259.
Thompson EA, Ols S, Miura K, Rausch K, Narum DL, Spångberg M, et al. TLR-adjuvanted nanoparticle vaccines differentially influence the quality and longevity of responses to malaria antigen Pfs25. JCI Insight. 2018;3(10):e120692.
Baschieri S. Innovation in vaccinology: from design, through to delivery and testing: springer Netherlands; 2012.
Gao D, Liu Y, Diao Y, Gao N, Wang Z, Jiang W, et al. Synthesis and evaluation of conjugates of novel TLR7 inert ligands as self-Adjuvanting Immunopotentiators. ACS Med Chem Lett. 2015;6(3):249–53.
Huang C-H, Mendez N, Echeagaray OH, Weeks J, Wang J, Vallez CN, et al. Conjugation of a small-molecule TLR7 agonist to silica Nanoshells enhances adjuvant activity. ACS Appl Mater Interfaces. 2019;11(30):26637–47.
Campbell JD, Cho Y, Foster ML, Kanzler H, Kachura MA, Lum JA, et al. CpG-containing immunostimulatory DNA sequences elicit TNF-alpha-dependent toxicity in rodents but not in humans. J Clin Invest. 2009;119(9):2564–76.
Villani A-C, Satija R, Reynolds G, Sarkizova S, Shekhar K, Fletcher J, et al. Single-cell RNA-seq reveals new types of human blood dendritic cells, monocytes, and progenitors. Science. 2017;356(6335):eaah4573.
Hémont C, Neel A, Heslan M, Braudeau C, Josien R. Human blood mDC subsets exhibit distinct TLR repertoire and responsiveness. J Leukoc Biol. 2013;93(4):599–609.
Vollmer J, Weeratna R, Payette P, Jurk M, Schetter C, Laucht M, et al. Characterization of three CpG oligodeoxynucleotide classes with distinct immunostimulatory activities. Eur J Immunol. 2004;34(1):251–62.
Tighe H, Takabayashi K, Schwartz D, Van Nest G, Tuck S, Eiden JJ, et al. Conjugation of immunostimulatory DNA to the short ragweed allergen Amb a 1 enhances its immunogenicity and reduces its allergenicity. J Allergy Clin Immunol. 2000;106(1):124–34.
Brahmakshatriya V, Kuang Y, Devarajan P, Xia J, Zhang W, Vong AM, et al. IL-6 production by TLR-activated APC broadly enhances aged cognate CD4 helper and B cell antibody responses in vivo. J Immunol. 2017;198(7):2819–33.
Halperin SA, Ward B, Cooper C, Predy G, Diaz-Mitoma F, Dionne M, et al. Comparison of safety and immunogenicity of two doses of investigational hepatitis B virus surface antigen co-administered with an immunostimulatory phosphorothioate oligodeoxyribonucleotide and three doses of a licensed hepatitis B vaccine in healthy adults 18–55 years of age. Vaccine. 2012;30(15):2556–63.
Marshall JD, Higgins D, Abbate C, Yee P, Teshima G, Ott G, et al. Polymyxin B enhances ISS-mediated immune responses across multiple species. Cell Immunol. 2004;229(2):93–105.
Jennings GT, Bachmann MF. Immunodrugs: therapeutic VLP-based vaccines for chronic diseases. Annu Rev Pharmacol Toxicol. 2009;49(1):303–26.
Li N, Zhang L, Zheng B, Li W, Liu J, Zhang H, et al. RSV recombinant candidate vaccine G1F/M2 with CpG as an adjuvant prevents vaccine-associated lung inflammation, which may be associated with the appropriate types of immune memory in spleens and lungs. Human Vaccin Immunother. 2019;15(11):2684–94.
Asanuma H, Zamri NB, Sekine S, Fukuyama Y, Tokuhara D, Gilbert RS, et al. A novel combined adjuvant for nasal delivery elicits mucosal immunity to influenza in aging. Vaccine. 2012;30(4):803–12.
Ma Z, Damania B. The cGAS-STING defense pathway and its counteraction by viruses. Cell Host Microbe. 2016;19(2):150–8.
Marinho FV, Benmerzoug S, Oliveira SC, Ryffel B, Quesniaux VFJ. The emerging roles of STING in bacterial infections. Trends Microbiol. 2017;25(11):906–18.
Carroll EC, Jin L, Mori A, Muñoz-Wolf N, Oleszycka E, Moran HBT, et al. The vaccine adjuvant chitosan promotes cellular immunity via DNA sensor cGAS-STING-dependent induction of type I interferons. Immunity. 2016;44(3):597–608.
Alsharifi M, Lobigs M, Regner M, Lee E, Koskinen A, Müllbacher A. Type I interferons trigger systemic, partial lymphocyte activation in response to viral infection. J Immunol. 2005;175(7):4635.
Van Dis E, Sogi KM, Rae CS, Sivick KE, Surh NH, Leong ML, et al. STING-activating adjuvants elicit a Th17 immune response and protect against mycobacterium tuberculosis infection. Cell Rep. 2018;23(5):1435–47.
Sanchez Alberti A, Bivona AE, Cerny N, Schulze K, Weißmann S, Ebensen T, et al. Engineered trivalent immunogen adjuvanted with a STING agonist confers protection against Trypanosoma cruzi infection. NPJ vaccines. 2017;2:9-.
Madhun AS, Haaheim LR, Nøstbakken JK, Ebensen T, Chichester J, Yusibov V, et al. Intranasal c-di-GMP-adjuvanted plant-derived H5 influenza vaccine induces multifunctional Th1 CD4+ cells and strong mucosal and systemic antibody responses in mice. Vaccine. 2011;29(31):4973–82.
Lee MJ, Jo H, Shin SH, Kim S-M, Kim B, Shim HS, et al. Mincle and STING-stimulating adjuvants elicit robust cellular immunity and drive long-lasting memory responses in a foot-and-mouth disease vaccine. Front Immunol. 2019;10:2509.
Blaauboer SM, Mansouri S, Tucker HR, Wang HL, Gabrielle VD, Jin L. The mucosal adjuvant cyclic di-GMP enhances antigen uptake and selectively activates pinocytosis-efficient cells in vivo. eLife. 2015;4:e06670.
Vajo Z, Wood J, Kosa L, Szilvasy I, Paragh G, Pauliny Z, et al. A single-dose influenza a (H5N1) vaccine safe and immunogenic in adult and elderly patients: an approach to pandemic vaccine development. J Virol. 2010;84(3):1237–42.
Hotez PJ, Corry DB, Strych U, Bottazzi ME. COVID-19 vaccines: neutralizing antibodies and the alum advantage. Nat Rev Immunol. 2020:1–2.
Gao Q, Bao L, Mao H, Wang L, Xu K, Yang M, et al. Rapid development of an inactivated vaccine candidate for SARS-CoV-2. Science. 2020.
Morgan EL, Thoman ML, Sanderson SD, Phillips JA. A novel adjuvant for vaccine development in the aged. Vaccine. 2010;28(52):8275–9.
Tsai TF. Fluad®-MF59®-Adjuvanted Influenza Vaccine in Older Adults. Infect Chemother. 2013;45(2):159–74.
O'Hagan DT, Rappuoli R, De Gregorio E, Tsai T, Del Giudice G. MF59 adjuvant: the best insurance against influenza strain diversity. Expert Rev Vaccin. 2011;10(4):447–62.
Singh M, Ugozzoli M, Kazzaz J, Chesko J, Soenawan E, Mannucci D, et al. A preliminary evaluation of alternative adjuvants to alum using a range of established and new generation vaccine antigens. Vaccine. 2006;24(10):1680–6.
Domnich A, Arata L, Amicizia D, Puig-Barberà J, Gasparini R, Panatto D. Effectiveness of MF59-adjuvanted seasonal influenza vaccine in the elderly: a systematic review and meta-analysis. Vaccine. 2017;35(4):513–20.
Garçon N, Di Pasquale A. From discovery to licensure, the adjuvant system story. Hum Vaccin Immunother. 2017;13(1):19–33.
Thanh Le T, Andreadakis Z, Kumar A, Gomez Roman R, Tollefsen S, Saville M, et al. The COVID-19 vaccine development landscape. Nat Rev Drug Discov 2020;19(5):305–306.
Baras B, Stittelaar KJ, Kuiken T, Jacob V, Bernhard R, Giannini S, et al. Longevity of the protective immune response induced after vaccination with one or two doses of AS03A-adjuvanted split H5N1 vaccine in ferrets. Vaccine. 2011;29(11):2092–9.
Baras B, Stittelaar KJ, Simon JH, Thoolen RJ, Mossman SP, Pistoor FH, et al. Cross-protection against lethal H5N1 challenge in ferrets with an adjuvanted pandemic influenza vaccine. PLoS One. 2008;3(1):e1401.
Leroux-Roels G. Prepandemic H5N1 influenza vaccine adjuvanted with AS03: a review of the pre-clinical and clinical data. Expert Opin Biol Ther. 2009;9(8):1057–71.
Langley JM, Risi G, Caldwell M, Gilderman L, Berwald B, Fogarty C, et al. Dose-sparing H5N1 a/Indonesia/05/2005 pre-pandemic influenza vaccine in adults and elderly adults: a phase III, placebo-controlled, randomized study. J Infect Dis. 2011;203(12):1729–38.
den Brok MH, Büll C, Wassink M, de Graaf AM, Wagenaars JA, Minderman M, et al. Saponin-based adjuvants induce cross-presentation in dendritic cells by intracellular lipid body formation. Nat Commun. 2016;7:13324.
Morein B, Sundquist B, Höglund S, Dalsgaard K, Osterhaus A. Iscom, a novel structure for antigenic presentation of membrane proteins from enveloped viruses. Nature. 1984;308(5958):457–60.
NovaVax. NovaVax initiates phase1/2 clinical trial of COVID-19 vaccine. 2020. p. https://ir.novavax.com/news-releases/news-release-details/novavax-initiates-phase-12-clinical-trial-covid-9-vaccine.
Technologies A. Adjuvance technologies announces NIH funding for COVID-19 vaccine research. 2020. p. http://adjuvancetechnologies.com/2020/05/19/adjuvance-technologies-announces-nih-funding-for-covid-19-vaccine-research/.
Lal H, Cunningham AL, Godeaux O, Chlibek R, Diez-Domingo J, Hwang S-J, et al. Efficacy of an adjuvanted herpes zoster subunit vaccine in older adults. N Engl J Med. 2015;372(22):2087–96.
Goff PH, Hayashi T, Martínez-Gil L, Corr M, Crain B, Yao S, et al. Synthetic toll-like receptor 4 (TLR4) and TLR7 ligands as influenza virus vaccine adjuvants induce rapid, sustained, and broadly protective responses. J Virol. 2015;89(6):3221.
Nouri-Shirazi M, Tamjidi S, Nourishirazi E, Guinet E. TLR8 combined withTLR3 or TLR4 agonists enhances DC-NK driven effector Tc1 cells. Immunol Lett. 2018;193:58–66.
Didierlaurent AM, Laupèze B, Di Pasquale A, Hergli N, Collignon C, Garçon N. Adjuvant system AS01: helping to overcome the challenges of modern vaccines. Expert Rev Vaccin. 2017;16(1):55–63.
van Haren SD, Dowling DJ, Foppen W, Christensen D, Andersen P, Reed SG, et al. Age-specific adjuvant synergy: dual TLR7/8 and Mincle activation of human newborn dendritic cells enables Th1 polarization. J Immunol. 2016;197(11):4413.
Tseng C-T, Sbrana E, Iwata-Yoshikawa N, Newman PC, Garron T, Atmar RL, et al. Immunization with SARS coronavirus vaccines leads to pulmonary immunopathology on challenge with the SARS virus. PLoS One. 2012;7(4):e35421.
Czub M, Weingartl H, Czub S, He R, Cao J. Evaluation of modified vaccinia virus Ankara based recombinant SARS vaccine in ferrets. Vaccine. 2005;23(17):2273–9.
Yang Z-y, Kong W-p, Huang Y, Roberts A, Murphy BR, Subbarao K, et al. A DNA vaccine induces SARS coronavirus neutralization and protective immunity in mice. Nature. 2004;428(6982):561–4.
Ruan S. Likelihood of survival of coronavirus disease 2019. Lancet Infect Dis.
Jackson LA, Anderson EJ, Rouphael NG, Roberts PC, Makhene M, Coler RN, et al. An mRNA vaccine against SARS-CoV-2 - preliminary report. N Engl J Med. 2020;383(20):1920–31.
NIH. Promising interim results from clinical trial of NIH-Moderna COVID-19 vaccine 2020 [Available from: https://www.nih.gov/news-events/news-releases/promising-interim-results-clinical-trial-nih-moderna-covid-19-vaccine.
Pfizer. Pfizer and BioNTech conclude phase 3 study of COVID-19 vaccine candidate, meeting all primary efficacy endpoints 2020 [Available from: https://www.businesswire.com/news/home/20201118005595/en/.
Team H-CSP, Consortium H-I. Multicohort analysis reveals baseline transcriptional predictors of influenza vaccination responses. Science immunology. 2017;2(14):eaal4656.