biopreparatБИОпрепараты. Профилактика, диагностика, лечениеBiological Products. Prevention, Diagnosis, Treatment2221-996X2619-1156Scientific Centre for Expert Evaluation of Medicinal Products10.30895/2221-996X-2020-20-4-245-256biopreparat-310Research ArticleОБЗОРЫREVIEWSОбщая характеристика адъювантов и механизм их действия (часть 1)General Characteristics of Adjuvants and Their Mechanism of Action (Part 1)https://orcid.org/0000-0002-6807-508XАлпатоваН. А.AlpatovaN. A.

Алпатова Наталья Александровна, канд. биол. наук.,

Петровский б-р, д. 8, стр. 2, Москва, 127051

Natalia А. Alpatova, Cand. Sci. (Biol.),

8/2 Petrovsky Blvd, Moscow 127051

alpatova@expmed.ruhttps://orcid.org/0000-0002-9377-1378АвдееваЖ. И.AvdeevaZh. I.

Авдеева Жанна Ильдаровна, д-р мед. наук, проф.,

Петровский б-р, д. 8, стр. 2, Москва, 127051

Zhanna I. Avdeeva, Dr. Sci. (Med.), Professor,

8/2 Petrovsky Blvd, Moscow 127051

avdeeva@expmed.ruhttps://orcid.org/0000-0001-7864-8972ЛысиковаС. Л.LysikovaS. L.

Лысикова Светлана Леонидовна, канд. мед. наук.,

Петровский б-р, д. 8, стр. 2, Москва, 127051

Svetlana L. Lysikova, Cand. Sci. (Med.),

8/2 Petrovsky Blvd, Moscow 127051

lisikova@expmed.ruhttps://orcid.org/0000-0002-6966-9859ГоловинскаяО. В.GolovinskayaO. V.

Головинская Ольга Вячеславовна, канд. мед. наук.,

Петровский б-р, д. 8, стр. 2, Москва, 127051

Olga V. Golovinskaya, Cand. Sci. (Med.),

8/2 Petrovsky Blvd, Moscow 127051

golovinskaya@expmed.ruhttps://orcid.org/0000-0002-6176-5934ГайдероваЛ. А.GayderovaL. A.

Гайдерова Лидия Александровна, канд. мед. наук.,

Петровский б-р, д. 8, стр. 2, Москва, 127051

Lidia A. Gayderova, Cand. Sci. (Med.),

8/2 Petrovsky Blvd, Moscow 127051

gaiderova@exmed.ruФедеральное государственное бюджетное учреждение «Научный центр экспертизы средств медицинского применения» Министерства здравоохранения Российской ФедерацииРоссияScientific Centre for Expert Evaluation of Medicinal ProductsRussian Federation202003112020204245256Copyright © Алпатова Н.А., Авдеева Ж.И., Лысикова С.Л., Головинская О.В., Гайдерова Л.А., 20202020Алпатова Н.А., Авдеева Ж.И., Лысикова С.Л., Головинская О.В., Гайдерова Л.А.Alpatova N.A., Avdeeva Z.I., Lysikova S.L., Golovinskaya O.V., Gayderova L.A.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://www.biopreparations.ru/jour/article/view/310

Актуальной проблемой современного здравоохранения является разработка новых вакцин и совершенствование уже используемых в медицинской практике, что обусловлено снижением иммунологической активности населения, появлением новых инфекций или активацией «старых», которые ранее считались побежденными. Неотъемлемой и важной частью современных вакцин являются адъюванты, которые стимулируют развитие иммунного ответа на антиген вакцины. Однако, несмотря на многочисленные усилия по их разработке, в настоящее время в медицинской практике применяется лишь небольшое количество адъювантов. Цель работы — систематизация данных литературы по анализу механизмов действия адъювантов, особенностей их структуры, состава и стимулирующих эффектов, которые опосредуют их иммуноадъювантные свойства. Обобщены сведения об адъювантах, входящих в состав зарегистрированных вакцин, приведена их характеристика, проанализированы молекулярные механизмы действия адъювантов с целью установления взаимосвязи их структуры и проявляемой активности, что является важным для разработки более эффективных и безопасных адъювантов. Представлены сведения о перспективных разработках по совершенствованию уже используемых адъювантов с целью усиления их стимулирующего действия. Сделан вывод о том, что ключевым направлением исследований в области повышения эффективности вакцинации является изучение механизмов, способствующих развитию эффективной защиты от возбудителей инфекции, а также способов стимулирования защитных реакций организма с помощью адъювантов, в первую очередь путем воздействия на систему врожденного иммунитета.

One of priority issues of the present-day healthcare system is development of new vaccines and improvement of existing ones due to decreasing immunocompetence of the population, emergence of new infections and reemergence of old ones which were previously thought to be under control. Adjuvants have proven to be integral and important components of modern vaccines, as they enhance immune response to the vaccine antigen. However, despite a lot of effort put into their development, only a small number of adjuvants are currently used in clinical practice. The aim of the study was to systematise literature data on the adjuvants’ mechanisms of action, their specific structure, composition, and stimulation effects that mediate their immunoadjuvant properties. The paper summarises data on adjuvants used as components in licensed vaccines, describes their characteristics, analyses molecular mechanisms of their action in order to establish correlation between their structure and activity, which is important for the development of more efficacious and safe adjuvants. The paper cites advanced developments aimed at enhancing stimulation effects of existing adjuvants. It concludes by stating that the key research area aimed at improving vaccination efficacy is the study of mechanisms that contribute to the development of effective protection against infectious agents, as well as analysis of how to use adjuvants to stimulate the body’s defensive mechanisms, primarily by impacting the innate immunity.

вакцинаадъювантиммуногенность вакцининфекциявирусантигенантителаТ-клеткиВ-клеткииммунитетvaccineadjuvantvaccine immunogenicityinfectionvirusantigenantibodyT cellsB cellsimmunityРабота выполнена в рамках государственного задания ФГБУ «НЦЭСМП» Минздрава России № 056-00003-20-00 на проведение прикладных научных исследований (номер государственного учета НИР AAAAA18-118021590046-9).ReferencesShi S, Zhu H, Xia X, Liang Z, Ma X, Sun B. Vaccine adjuvants: understanding the structure and mechanism of adjuvanticity. Vaccine. 2019;37(24):3167–78. https://doi.org/10.1016/j.vaccine.2019.04.055Shi S, Zhu H, Xia X, Liang Z, Ma X, Sun B. Vaccine adjuvants: understanding the structure and mechanism of adjuvanticity. Vaccine. 2019;37(24):3167–78. https://doi.org/10.1016/j.vaccine.2019.04.055Медуницын НВ, Миронов АН, Мовсесянц АА. Теория и практика вакцинологии. М.: РЕМЕДИУМ; 2015.Medunitsyn NV, Mironov AN, Movsesyants AA. Theory and practice of vaccinology. Moscow: REMEDIUM; 2015 (In Russ.)Chan EH, Brewer TF, Madoff LC, Pollack MP, Sonricker AL, Keller M, et al. Global capacity for emerging infectious disease detection. Proc Natl Acad Sci USA. 2010;107(50):21701–6. https://doi.org/10.1073/pnas.1006219107Chan EH, Brewer TF, Madoff LC, Pollack MP, Sonricker AL, Keller M, et al. Global capacity for emerging infectious disease detection. Proc Natl Acad Sci USA. 2010;107(50):21701–6. https://doi.org/10.1073/pnas.1006219107WHO Ebola Response Team, Aylward B, Barboza P, Bawo L, Bertherat E, Bilivogui P, et al. Ebola virus disease in West Africa – the first 9 months of the epidemic and forward projections. N Engl J Med. 2014;371(16):1481–95. https://doi.org/10.1056/NEJMoa1411100WHO Ebola Response Team, Aylward B, Barboza P, Bawo L, Bertherat E, Bilivogui P, et al. Ebola virus disease in West Africa – the first 9 months of the epidemic and forward projections. N Engl J Med. 2014;371(16):1481–95. https://doi.org/10.1056/NEJMoa1411100Gupta T, Gupta SK. Potential adjuvants for the development of a SARS-CoV-2 vaccine based on experimental results from similar coronaviruses. Int Immunopharmacol. 2020;86:106717. https://doi.org/10.1016/j.intimp.2020.106717Gupta T, Gupta SK. Potential adjuvants for the development of a SARS-CoV-2 vaccine based on experimental results from similar coronaviruses. Int Immunopharmacol. 2020;86:106717. https://doi.org/10.1016/j.intimp.2020.106717Falsey AR, Treanor JJ, Tornieporth N, Capellan J, Gorse GJ. Randomized, double-blind controlled phase 3 trial comparing the immunogenicity of high-dose and standard-dose influenza vaccine in adults 65 years of age and older. J Infect Dis. 2009;200(2):172–80. https://doi.org/10.1086/599790Falsey AR, Treanor JJ, Tornieporth N, Capellan J, Gorse GJ. Randomized, double-blind controlled phase 3 trial comparing the immunogenicity of high-dose and standard-dose influenza vaccine in adults 65 years of age and older. J Infect Dis. 2009;200(2):172–80. https://doi.org/10.1086/599790Leroux-Roels G. Unmet needs in modern vaccinology: adjuvants to improve the immune response. Vaccine. 2010;28(Suppl 3):25–36. https://doi.org/10.1016/j.vaccine.2010.07.021Leroux-Roels G. Unmet needs in modern vaccinology: adjuvants to improve the immune response. Vaccine. 2010;28(Suppl 3):25–36. https://doi.org/10.1016/j.vaccine.2010.07.021Banzhoff A, Gasparini R, Laghi-Pasini F, Staniscia T, Durando P, Montomoli E, et al. MF59-adjuvanted H5N1 vaccine induces immunologic memory and heterotypic antibody responses in non-elderly and elderly adults. PLoS ONE. 2009;4(2):e4384. https://doi.org/10.1371/journal.pone.0004384Banzhoff A, Gasparini R, Laghi-Pasini F, Staniscia T, Durando P, Montomoli E, et al. MF59-adjuvanted H5N1 vaccine induces immunologic memory and heterotypic antibody responses in non-elderly and elderly adults. PLoS ONE. 2009;4(2):e4384. https://doi.org/10.1371/journal.pone.0004384Jackson LA, Campbell JD, Frey SE, Edwards KM, Keitel WA, Kotloff KL, et al. Effect of varying doses of a monovalent H7N9 influenza vaccine with and without AS03 and MF59 adjuvants on immune response: a randomized clinical trial. JAMA. 2015;314(3):237–46. https://doi.org/10.1001/jama.2015.7916Jackson LA, Campbell JD, Frey SE, Edwards KM, Keitel WA, Kotloff KL, et al. Effect of varying doses of a monovalent H7N9 influenza vaccine with and without AS03 and MF59 adjuvants on immune response: a randomized clinical trial. JAMA. 2015;314(3):237–46. https://doi.org/10.1001/jama.2015.7916Reed SG, Orr MT, Fox CB. Key roles of adjuvants in modern vaccines. Nat Med. 2013;19(12):1597–608. https://doi.org/10.1038/nm.3409Reed SG, Orr MT, Fox CB. Key roles of adjuvants in modern vaccines. Nat Med. 2013;19(12):1597–608. https://doi.org/10.1038/nm.3409Powell BS, Andrianov AK, Fusco PC. Polyionic vaccine adjuvants: another look at aluminum salts and polyelectrolytes. Clin Exp Vaccine Res. 2015;4(1):23–45. https://doi.org/10.7774/cevr.2015.4.1.23Powell BS, Andrianov AK, Fusco PC. Polyionic vaccine adjuvants: another look at aluminum salts and polyelectrolytes. Clin Exp Vaccine Res. 2015;4(1):23–45. https://doi.org/10.7774/cevr.2015.4.1.23Coffman RL, Sher A, Seder RA. Vaccine adjuvants: putting innate immunity to work. Immunity. 2010;33(4):492–503. https://doi.org/10.1016/j.immuni.2010.10.002Coffman RL, Sher A, Seder RA. Vaccine adjuvants: putting innate immunity to work. Immunity. 2010;33(4):492–503. https://doi.org/10.1016/j.immuni.2010.10.002Harandi AM. Systems analysis of human vaccine adjuvants. Semin Immunol. 2018;39:30–4. https://doi.org/10.1016/j.smim.2018.08.001Harandi AM. Systems analysis of human vaccine adjuvants. Semin Immunol. 2018;39:30–4. https://doi.org/10.1016/j.smim.2018.08.001Sarkar I, Garg R, van Drunen Littel-van den Hurk S. Selection of adjuvants for vaccines targeting specific pathogens. Expert Rev Vaccines. 2019;18(5):505–21. https://doi.org/10.1080/14760584.2019.1604231Sarkar I, Garg R, van Drunen Littel-van den Hurk S. Selection of adjuvants for vaccines targeting specific pathogens. Expert Rev Vaccines. 2019;18(5):505–21. https://doi.org/10.1080/14760584.2019.1604231Alving CR, Matyas GR, Torres O, Jalah R, Beck Z. Adjuvants for vaccines to drugs of abuse and addiction. Vaccine. 2014;32(42):5382–9. https://doi.org/10.1016/j.vaccine.2014.07.085Alving CR, Matyas GR, Torres O, Jalah R, Beck Z. Adjuvants for vaccines to drugs of abuse and addiction. Vaccine. 2014;32(42):5382–9. https://doi.org/10.1016/j.vaccine.2014.07.085HogenEsch H, O'Hagan DT, Fox CB. Optimizing the utilization of aluminum adjuvants in vaccines: you might just get what you want. NPJ Vaccines. 2018;3:51. https://doi.org/10.1038/s41541-018-0089-xHogenEsch H, O'Hagan DT, Fox CB. Optimizing the utilization of aluminum adjuvants in vaccines: you might just get what you want. NPJ Vaccines. 2018;3:51. https://doi.org/10.1038/s41541-018-0089-xHe P, Zou Y, Hu Z. Advances in aluminum hydroxide-based adjuvant research and its mechanism. Hum Vaccin Immunother. 2015;11(2):477–88. https://doi.org/10.1080/21645515.2014.1004026He P, Zou Y, Hu Z. Advances in aluminum hydroxide-based adjuvant research and its mechanism. Hum Vaccin Immunother. 2015;11(2):477–88. https://doi.org/10.1080/21645515.2014.1004026Trier NH, Güven E, Skogstrand K, Ciplys E, Slibinskas R, Houen G. Comparison of immunological adjuvants. APMIS. 2019;127(9):635–41. https://doi.org/10.1111/apm.12976Trier NH, Güven E, Skogstrand K, Ciplys E, Slibinskas R, Houen G. Comparison of immunological adjuvants. APMIS. 2019;127(9):635–41. https://doi.org/10.1111/apm.12976Glenny AT, Pope CG, Waddington H, Wallace U. Immunology notes. XXIII. The antigenic value of toxoid precipitated by potassium alum. J Pathol Bacteriol. 1926;29:31–40. http://dx.doi.org/10.1002/path.1700290106Glenny AT, Pope CG, Waddington H, Wallace U. Immunology notes. XXIII. The antigenic value of toxoid precipitated by potassium alum. J Pathol Bacteriol. 1926;29:31–40. http://dx.doi.org/10.1002/path.1700290106Awate S, Babiuk LA, Mutwiri G. Mechanisms of action of adjuvants. Front Immunol. 2013;4:114. https://doi.org/10.3389/fimmu.2013.00114Awate S, Babiuk LA, Mutwiri G. Mechanisms of action of adjuvants. Front Immunol. 2013;4:114. https://doi.org/10.3389/fimmu.2013.00114Aimanianda V, Haensler J, Lacroix-Desmazes S, Kaveri SV, Bayry J. Novel cellular and molecular mechanisms of induction of immune responses by aluminum adjuvants. Trends Pharmacol Sci. 2009;30(6):287–95. https://doi.org/10.1016/j.tips.2009.03.005Aimanianda V, Haensler J, Lacroix-Desmazes S, Kaveri SV, Bayry J. Novel cellular and molecular mechanisms of induction of immune responses by aluminum adjuvants. Trends Pharmacol Sci. 2009;30(6):287–95. https://doi.org/10.1016/j.tips.2009.03.005Ghimire TR, Benson RA, Garside P, Brewer JM. Alum increases antigen uptake, reduces antigen degradation and sustains antigen presentation by DCs in vitro. Immunol Lett. 2012;147(1-2):55–62. https://doi.org/10.1016/j.imlet.2012.06.002Ghimire TR, Benson RA, Garside P, Brewer JM. Alum increases antigen uptake, reduces antigen degradation and sustains antigen presentation by DCs in vitro. Immunol Lett. 2012;147(1-2):55–62. https://doi.org/10.1016/j.imlet.2012.06.002Calabro S, Tortoli M, Baudner BC, Pacitto A, Cortese M, O'Hagan DT, et al. Vaccine adjuvants alum and MF59 induce rapid recruitment of neutrophils and monocytes that participate in antigen transport to draining lymph nodes. Vaccine. 2011;29(9):1812–23. https://doi.org/10.1016/j.vaccine.2010.12.090Calabro S, Tortoli M, Baudner BC, Pacitto A, Cortese M, O'Hagan DT, et al. Vaccine adjuvants alum and MF59 induce rapid recruitment of neutrophils and monocytes that participate in antigen transport to draining lymph nodes. Vaccine. 2011;29(9):1812–23. https://doi.org/10.1016/j.vaccine.2010.12.090Lu F, Hogenеsch H. Kinetics of the inflammatory response following intramuscular injection of aluminum adjuvant. Vaccine. 2013;31(37):3979–86. https://doi.org/10.1016/j.vaccine.2013.05.107Lu F, Hogenеsch H. Kinetics of the inflammatory response following intramuscular injection of aluminum adjuvant. Vaccine. 2013;31(37):3979–86. https://doi.org/10.1016/j.vaccine.2013.05.107Apostólico JS, Lunardelli VA, Coirada FC, Boscardin SB, Rosa DS. Adjuvants: classification, modus operandi, and licensing. J Immunol Res. 2016;2016:1459394. https://doi.org/10.1155/2016/1459394Apostólico JS, Lunardelli VA, Coirada FC, Boscardin SB, Rosa DS. Adjuvants: classification, modus operandi, and licensing. J Immunol Res. 2016;2016:1459394. https://doi.org/10.1155/2016/1459394Hutchison S, Benson RA, Gibson VB, Pollock AH, Garside P, Brewer JM. Antigen depot is not required for alum adjuvanticity. FASEB J. 2012;26(3):1272–9. https://doi.org/10.1096/fj.11-184556Hutchison S, Benson RA, Gibson VB, Pollock AH, Garside P, Brewer JM. Antigen depot is not required for alum adjuvanticity. FASEB J. 2012;26(3):1272–9. https://doi.org/10.1096/fj.11-184556Hornung V, Bauernfeind F, Halle A, Samstad EO, Kono H, Rock KL, et al. Silica crystals and aluminum salts activate the NALP3 inflammasome through phagosomal destabilization. Nat Immunol. 2008;9(8):847–56. https://doi.org/10.1038/ni.1631Hornung V, Bauernfeind F, Halle A, Samstad EO, Kono H, Rock KL, et al. Silica crystals and aluminum salts activate the NALP3 inflammasome through phagosomal destabilization. Nat Immunol. 2008;9(8):847–56. https://doi.org/10.1038/ni.1631Eisenbarth SC, Colegio OR, O'Connor W, Sutterwala FS, Flavell RA. Crucial role for the Nalp3 inflammasome in the immunostimulatory properties of aluminium adjuvants. Nature. 2008;453(7198):1122–6. https://doi.org/10.1038/nature06939Eisenbarth SC, Colegio OR, O'Connor W, Sutterwala FS, Flavell RA. Crucial role for the Nalp3 inflammasome in the immunostimulatory properties of aluminium adjuvants. Nature. 2008;453(7198):1122–6. https://doi.org/10.1038/nature06939Li H, Willingham SB, Ting JP, Re F. Cutting edge: inflammasome activation by alum and alum's adjuvant effect are mediated by NLRP3. J Immunol. 2008;181(1):17–21. https://doi.org/10.4049/jimmunol.181.1.17Li H, Willingham SB, Ting JP, Re F. Cutting edge: inflammasome activation by alum and alum's adjuvant effect are mediated by NLRP3. J Immunol. 2008;181(1):17–21. https://doi.org/10.4049/jimmunol.181.1.17Marrack P, McKee AS, Munks MW. Towards an understanding of the adjuvant action of aluminium. Nat Rev Immunol. 2009;9(4):287–93. https://doi.org/10.1038/nri2510Marrack P, McKee AS, Munks MW. Towards an understanding of the adjuvant action of aluminium. Nat Rev Immunol. 2009;9(4):287–93. https://doi.org/10.1038/nri2510Del Giudice G, Rappuoli R, Didierlaurent AM. Correlates of adjuvanticity: a review on adjuvants in licensed vaccines. Semin Immunol. 2018;39:14–21. https://doi.org/10.1016/j.smim.2018.05.001Del Giudice G, Rappuoli R, Didierlaurent AM. Correlates of adjuvanticity: a review on adjuvants in licensed vaccines. Semin Immunol. 2018;39:14–21. https://doi.org/10.1016/j.smim.2018.05.001Franchi L, Núñez G. The Nlrp3 inflammasome is critical for aluminium hydroxide-mediated IL-1beta secretion but dispensable for adjuvant activity. Eur J Immunol. 2008;38(8):2085–9. https://doi.org/10.1002/eji.200838549Franchi L, Núñez G. The Nlrp3 inflammasome is critical for aluminium hydroxide-mediated IL-1beta secretion but dispensable for adjuvant activity. Eur J Immunol. 2008;38(8):2085–9. https://doi.org/10.1002/eji.200838549McKee AS, Munks MW, MacLeod MKL, Fleenor CJ, Van Rooijen N, Kappler JW, Marrack P. Alum induces innate immune responses through macrophage and mast cell sensors, but these sensors are not required for alum to act as an adjuvant for specific immunity. J Immunol. 2009;183(7):4403–14. https://doi.org/10.4049/jimmunol.0900164McKee AS, Munks MW, MacLeod MKL, Fleenor CJ, Van Rooijen N, Kappler JW, Marrack P. Alum induces innate immune responses through macrophage and mast cell sensors, but these sensors are not required for alum to act as an adjuvant for specific immunity. J Immunol. 2009;183(7):4403–14. https://doi.org/10.4049/jimmunol.0900164Flach TL, Ng G, Hari A, Desrosiers MD, Zhang P, Ward SM, et al. Alum interaction with dendritic cell membrane lipids is essential for its adjuvanticity. Nat Med. 2011;17(4):479–87. https://doi.org/10.1038/nm.2306Flach TL, Ng G, Hari A, Desrosiers MD, Zhang P, Ward SM, et al. Alum interaction with dendritic cell membrane lipids is essential for its adjuvanticity. Nat Med. 2011;17(4):479–87. https://doi.org/10.1038/nm.2306Kool M, Soullié T, van Nimwegen M, Willart MAM, Muskens F, Jung S, et al. Alum adjuvant boosts adaptive immunity by inducing uric acid and activating inflammatory dendritic cells. J Exp Med. 2008;205(4):869–82. https://doi.org/10.1084/jem.20071087Kool M, Soullié T, van Nimwegen M, Willart MAM, Muskens F, Jung S, et al. Alum adjuvant boosts adaptive immunity by inducing uric acid and activating inflammatory dendritic cells. J Exp Med. 2008;205(4):869–82. https://doi.org/10.1084/jem.20071087Liang F, Lindgren G, Sandgren KJ, Thompson EA, Francica JR, Seubert A, et al. Vaccine priming is restricted to draining lymph nodes and controlled by adjuvant-mediated antigen uptake. Sci Transl Med. 2017;9(393):eaal2094. https://doi.org/10.1126/scitranslmed.aal2094Liang F, Lindgren G, Sandgren KJ, Thompson EA, Francica JR, Seubert A, et al. Vaccine priming is restricted to draining lymph nodes and controlled by adjuvant-mediated antigen uptake. Sci Transl Med. 2017;9(393):eaal2094. https://doi.org/10.1126/scitranslmed.aal2094Kooijman S, Brummelman J, van Els CACM, Marino F, Heck AJR, Mommen GPM, et al. Novel identified aluminum hydroxide-induced pathways prove monocyte activation and pro-inflammatory preparedness. J Proteomics. 2018;175:144–55. https://doi.org/10.1016/j.jprot.2017.12.021Kooijman S, Brummelman J, van Els CACM, Marino F, Heck AJR, Mommen GPM, et al. Novel identified aluminum hydroxide-induced pathways prove monocyte activation and pro-inflammatory preparedness. J Proteomics. 2018;175:144–55. https://doi.org/10.1016/j.jprot.2017.12.021Kooijman S, Brummelman J, van Els CACM, Marino F, Heck AJR, van Riet E, et al. Vaccine antigens modulate the innate response of monocytes to Al(OH)3. PLoS One. 2018;13(5):e0197885. https://doi.org/10.1371/journal.pone.0197885Kooijman S, Brummelman J, van Els CACM, Marino F, Heck AJR, van Riet E, et al. Vaccine antigens modulate the innate response of monocytes to Al(OH)3. PLoS One. 2018;13(5):e0197885. https://doi.org/10.1371/journal.pone.0197885HogenEsch H. Mechanisms of stimulation of the immune response by aluminium adjuvants. Vaccine. 2002;20(Suppl 3):S34–9. https://doi.org/10.1016/S0264-410X(02)00169-XHogenEsch H. Mechanisms of stimulation of the immune response by aluminium adjuvants. Vaccine. 2002;20(Suppl 3):S34–9. https://doi.org/10.1016/S0264-410X(02)00169-XMarichal T, Ohata K, Bedoret D, Mesnil C, Sabatel C, Kobiyama K, et al. DNA released from dying host cells mediates aluminum adjuvant activity. Nat Med. 2011;17(8):996–1002. https://doi.org/10.1038/nm.2403Marichal T, Ohata K, Bedoret D, Mesnil C, Sabatel C, Kobiyama K, et al. DNA released from dying host cells mediates aluminum adjuvant activity. Nat Med. 2011;17(8):996–1002. https://doi.org/10.1038/nm.2403Mckee AS, Burchill MA, Munks MW, Jin L, Kappler JW, Friedman RS, et al. Host DNA released in response to aluminum adjuvant enhances MHC class II-mediated antigen presentation and prolongs CD4 T-cell interactions with dendritic cells. Proc Natl Acad Sci USA. 2013;110(12):Е1122–31. https://doi.org/10.1073/pnas.1300392110Mckee AS, Burchill MA, Munks MW, Jin L, Kappler JW, Friedman RS, et al. Host DNA released in response to aluminum adjuvant enhances MHC class II-mediated antigen presentation and prolongs CD4 T-cell interactions with dendritic cells. Proc Natl Acad Sci USA. 2013;110(12):Е1122–31. https://doi.org/10.1073/pnas.1300392110Stephen J, Scales HE, Benson RA, Erben D, Garside P, Brewer JM. Neutrophil swarming and extracellular trap formation play a significant role in Alum adjuvant activity. NPJ Vaccines. 2017;2:1. https://doi.org/10.1038/s41541-016-0001-5Stephen J, Scales HE, Benson RA, Erben D, Garside P, Brewer JM. Neutrophil swarming and extracellular trap formation play a significant role in Alum adjuvant activity. NPJ Vaccines. 2017;2:1. https://doi.org/10.1038/s41541-016-0001-5Mori A, Oleszycka E, Sharp FA, Coleman M, Ozasa Y, Singh M, et al. The vaccine adjuvant alum inhibits IL-12 by promoting PI3 kinase signaling while chitosan does not inhibit IL-12 and enhances Th1 and Th17 responses. Eur J Immunol. 2012;42(10):2709–19. https://doi.org/10.1002/eji.201242372Mori A, Oleszycka E, Sharp FA, Coleman M, Ozasa Y, Singh M, et al. The vaccine adjuvant alum inhibits IL-12 by promoting PI3 kinase signaling while chitosan does not inhibit IL-12 and enhances Th1 and Th17 responses. Eur J Immunol. 2012;42(10):2709–19. https://doi.org/10.1002/eji.201242372Oleszycka E, McCluskey S, Sharp FA, Muñoz-Wolf N, Hams E, Gorman AL, et al. The vaccine adjuvant alum promotes IL-10 production that suppresses Th1 responses. Eur J Immunol. 2018;48(4):705–15. https://doi.org/10.1002/eji.201747150Oleszycka E, McCluskey S, Sharp FA, Muñoz-Wolf N, Hams E, Gorman AL, et al. The vaccine adjuvant alum promotes IL-10 production that suppresses Th1 responses. Eur J Immunol. 2018;48(4):705–15. https://doi.org/10.1002/eji.201747150Didierlaurent AM, Morel S, Lockman L, Giannini SL, Bisteau M, Carlsen H, et al. AS04, an aluminum salt- and TLR4 agonist-based adjuvant system, induces a transient localized innate immune response leading to enhanced adaptive immunity. J Immunol. 2009;183(10):6186–97. https://doi.org/10.4049/jimmunol.0901474Didierlaurent AM, Morel S, Lockman L, Giannini SL, Bisteau M, Carlsen H, et al. AS04, an aluminum salt- and TLR4 agonist-based adjuvant system, induces a transient localized innate immune response leading to enhanced adaptive immunity. J Immunol. 2009;183(10):6186–97. https://doi.org/10.4049/jimmunol.0901474Ebensen T, Delandre S, Prochnow B, Guzmán CA, Schulze K. The combination vaccine adjuvant system alum/c-di-AMP results in quantitative and qualitative enhanced immune responses post immunization. Front Cell Infect Microbiol. 2019;9:31. https://doi.org/10.3389/fcimb.2019.00031Ebensen T, Delandre S, Prochnow B, Guzmán CA, Schulze K. The combination vaccine adjuvant system alum/c-di-AMP results in quantitative and qualitative enhanced immune responses post immunization. Front Cell Infect Microbiol. 2019;9:31. https://doi.org/10.3389/fcimb.2019.00031Orr MT, Khandhar AP, Seydoux E, Liang H, Gage E, Mikasa T, et al. Reprogramming the adjuvant properties of aluminum oxyhydroxide with nanoparticle technology. NPJ Vaccines. 2019;4:1. https://doi.org/10.1038/s41541-018-0094-0Orr MT, Khandhar AP, Seydoux E, Liang H, Gage E, Mikasa T, et al. Reprogramming the adjuvant properties of aluminum oxyhydroxide with nanoparticle technology. NPJ Vaccines. 2019;4:1. https://doi.org/10.1038/s41541-018-0094-0Ko EJ, Kang SM. Immunology and efficacy of MF59-adjuvanted vaccines. Hum Vaccin Immunother. 2018;14(12):3041–5. https://doi.org/10.1080/21645515.2018.1495301Ko EJ, Kang SM. Immunology and efficacy of MF59-adjuvanted vaccines. Hum Vaccin Immunother. 2018;14(12):3041–5. https://doi.org/10.1080/21645515.2018.1495301Zedda L, Forleo-Neto E, Vertruyen A, Raes M, Marchant A, Jansen W, et al. Dissecting the immune response to MF59-adjuvanted and nonadjuvanted seasonal influenza vaccines in children less than three years of age. Pediatr Infect Dis J. 2015;34(1):73–8. http://dx.doi.org/10.1097/INF.0000000000000465Zedda L, Forleo-Neto E, Vertruyen A, Raes M, Marchant A, Jansen W, et al. Dissecting the immune response to MF59-adjuvanted and nonadjuvanted seasonal influenza vaccines in children less than three years of age. Pediatr Infect Dis J. 2015;34(1):73–8. http://dx.doi.org/10.1097/INF.0000000000000465O'Hagan DT, Ott GS, Nest GV, Rappuoli R, Giudice GD. The history of MF59® adjuvant: a phoenix that arose from the ashes. Expert Rev Vaccines. 2013;12(1):13–30. https://doi.org/10.1586/erv.12.140O'Hagan DT, Ott GS, Nest GV, Rappuoli R, Giudice GD. The history of MF59® adjuvant: a phoenix that arose from the ashes. Expert Rev Vaccines. 2013;12(1):13–30. https://doi.org/10.1586/erv.12.140Seubert A, Calabro S, Santini L, Galli B, Genovese A, Valentini S, et al. Adjuvanticity of the oil-in-water emulsion MF59 is independent of Nlrp3 inflammasome but requires the adaptor protein MyD88. Proc Natl Acad Sci USA. 2011;108(27):11169–74. https://doi.org/10.1073/pnas.1107941108Seubert A, Calabro S, Santini L, Galli B, Genovese A, Valentini S, et al. Adjuvanticity of the oil-in-water emulsion MF59 is independent of Nlrp3 inflammasome but requires the adaptor protein MyD88. Proc Natl Acad Sci USA. 2011;108(27):11169–74. https://doi.org/10.1073/pnas.1107941108Vono M, Taccone M, Caccin P, Gallotta M, Donvito G, Falzoni S, et al. The adjuvant MF59 induces ATP release from muscle that potentiates response to vaccination. Proc Natl Acad Sci USA. 2013;110(52):21095–100. https://doi.org/10.1073/pnas.1319784110Vono M, Taccone M, Caccin P, Gallotta M, Donvito G, Falzoni S, et al. The adjuvant MF59 induces ATP release from muscle that potentiates response to vaccination. Proc Natl Acad Sci USA. 2013;110(52):21095–100. https://doi.org/10.1073/pnas.1319784110Mosca F, Tritto E, Muzzi A, Monaci E, Bagnoli F, Iavarone C, et al. Molecular and cellular signatures of human vaccine adjuvants. Proc Natl Acad Sci USA. 2008;105(30):10501–6. https://doi.org/10.1073/pnas.0804699105Mosca F, Tritto E, Muzzi A, Monaci E, Bagnoli F, Iavarone C, et al. Molecular and cellular signatures of human vaccine adjuvants. Proc Natl Acad Sci USA. 2008;105(30):10501–6. https://doi.org/10.1073/pnas.0804699105Seubert A, Monaci E, Pizza M, O'Hagan DT, Wack A. The adjuvants aluminum hydroxide and MF59 induce monocyte and granulocyte chemoattractants and enhance monocyte differentiation toward dendritic cells. J Immunol. 2008;180(8):5402–12. https://doi.org/10.4049/jimmunol.180.8.5402Seubert A, Monaci E, Pizza M, O'Hagan DT, Wack A. The adjuvants aluminum hydroxide and MF59 induce monocyte and granulocyte chemoattractants and enhance monocyte differentiation toward dendritic cells. J Immunol. 2008;180(8):5402–12. https://doi.org/10.4049/jimmunol.180.8.5402De Gregorio E, Caproni E, Ulmer JB. Vaccine adjuvants: mode of action. Front Immunol. 2013;4:214. https://doi.org/10.3389/fimmu.2013.00214De Gregorio E, Caproni E, Ulmer JB. Vaccine adjuvants: mode of action. Front Immunol. 2013;4:214. https://doi.org/10.3389/fimmu.2013.00214Cioncada R, Maddaluno M, Vo HTM, Woodruff M, Tavarini S, Sammicheli C, et al. Vaccine adjuvant MF59 promotes the intranodal differentiation of antigen-loaded and activated monocyte-derived dendritic cells. PLoS One. 2017;12(10):e0185843. https://doi.org/10.1371/journal.pone.0185843Cioncada R, Maddaluno M, Vo HTM, Woodruff M, Tavarini S, Sammicheli C, et al. Vaccine adjuvant MF59 promotes the intranodal differentiation of antigen-loaded and activated monocyte-derived dendritic cells. PLoS One. 2017;12(10):e0185843. https://doi.org/10.1371/journal.pone.0185843Ko EJ, Lee YT, Kim KH, Jung YJ, Lee Y, Denning TL, Kang SM. Effects of MF59 adjuvant on induction of isotype-switched IgG antibodies and protection after immunization with T-dependent influenza virus vaccine in the absence of CD4+ T cells. J Virol. 2016;90(15):6976–88. https://doi.org/10.1128/JVI.00339-16Ko EJ, Lee YT, Kim KH, Jung YJ, Lee Y, Denning TL, Kang SM. Effects of MF59 adjuvant on induction of isotype-switched IgG antibodies and protection after immunization with T-dependent influenza virus vaccine in the absence of CD4+ T cells. J Virol. 2016;90(15):6976–88. https://doi.org/10.1128/JVI.00339-16Ko EJ, Lee YT, Kim KH, Lee Y, Jung YJ, Kim MC, et al. Roles of aluminum hydroxide and monophosphoryl lipid A adjuvants in overcoming CD4+ T cell deficiency to induce isotype-switched IgG antibody responses and protection by T-dependent influenza vaccine. J Immunol. 2017;198(1):279–91. https://doi.org/10.4049/jimmunol.1600173Ko EJ, Lee YT, Kim KH, Lee Y, Jung YJ, Kim MC, et al. Roles of aluminum hydroxide and monophosphoryl lipid A adjuvants in overcoming CD4+ T cell deficiency to induce isotype-switched IgG antibody responses and protection by T-dependent influenza vaccine. J Immunol. 2017;198(1):279–91. https://doi.org/10.4049/jimmunol.1600173Pittman PR. Aluminum-containing vaccine associated adverse events. Role of route of administration and gender. Vaccine. 2002;20(Suppl 3):S48–50. https://doi.org/10.1016/s0264-410x(02)00172-xPittman PR. Aluminum-containing vaccine associated adverse events. Role of route of administration and gender. Vaccine. 2002;20(Suppl 3):S48–50. https://doi.org/10.1016/s0264-410x(02)00172-xReisinger KS, Holmes SJ, Pedotti P, Arora AK, Lattanzi M. A dose-ranging study of MF59®-adjuvanted and non-adjuvanted A/H1N1 pandemic influenza vaccine in young to middle-aged and older adult populations to assess safety, immunogenicity, and antibody persistence one year after vaccination. Hum Vaccin Immunother. 2014;10(8):2395–407. https://doi.org/10.4161/hv.29393Reisinger KS, Holmes SJ, Pedotti P, Arora AK, Lattanzi M. A dose-ranging study of MF59®-adjuvanted and non-adjuvanted A/H1N1 pandemic influenza vaccine in young to middle-aged and older adult populations to assess safety, immunogenicity, and antibody persistence one year after vaccination. Hum Vaccin Immunother. 2014;10(8):2395–407. https://doi.org/10.4161/hv.29393Garçon N, Vaughn DW, Didierlaurent AM. Development and evaluation of AS03, an Adjuvant System containing α-tocopherol and squalene in an oil-in-water emulsion. Expert Rev Vaccines. 2012;11(3):349–66. https://doi.org/10.1586/erv.11.192Garçon N, Vaughn DW, Didierlaurent AM. Development and evaluation of AS03, an Adjuvant System containing α-tocopherol and squalene in an oil-in-water emulsion. Expert Rev Vaccines. 2012;11(3):349–66. https://doi.org/10.1586/erv.11.192Morel S, Didierlaurent A, Bourguignon P, Delhaye S, Baras B, Jacob V, et al. Adjuvant system AS03 containing α-tocopherol modulates innate immune response and leads to improved adaptive immunity. Vaccine. 2011;29(13):2461–73. https://doi.org/10.1016/j.vaccine.2011.01.011Morel S, Didierlaurent A, Bourguignon P, Delhaye S, Baras B, Jacob V, et al. Adjuvant system AS03 containing α-tocopherol modulates innate immune response and leads to improved adaptive immunity. Vaccine. 2011;29(13):2461–73. https://doi.org/10.1016/j.vaccine.2011.01.011Givord C, Welsby I, Detienne S, Thomas S, Assabban A, Lima Silva V, et al. Activation of the endoplasmic reticulum stress sensor IRE1α by the vaccine adjuvant AS03 contributes to its immunostimulatory properties. NPJ Vaccines. 2018;3:20. https://doi.org/10.1038/s41541-018-0058-4Givord C, Welsby I, Detienne S, Thomas S, Assabban A, Lima Silva V, et al. Activation of the endoplasmic reticulum stress sensor IRE1α by the vaccine adjuvant AS03 contributes to its immunostimulatory properties. NPJ Vaccines. 2018;3:20. https://doi.org/10.1038/s41541-018-0058-4Moris P, van der Most R, Leroux-Roels I, Clement F, Dramé M, Hanon E, et al. H5N1 influenza vaccine formulated with AS03A induces strong cross-reactive and polyfunctional CD4 T-cell responses. J Clin Immunol. 2011;31(3):443–54. https://doi.org/10.1007/s10875-010-9490-6Moris P, van der Most R, Leroux-Roels I, Clement F, Dramé M, Hanon E, et al. H5N1 influenza vaccine formulated with AS03A induces strong cross-reactive and polyfunctional CD4 T-cell responses. J Clin Immunol. 2011;31(3):443–54. https://doi.org/10.1007/s10875-010-9490-6Petrovsky N, Aguilar JC. Vaccine adjuvants: current state and future trends. Immunol Cell Biol. 2004;82(5):488–96. https://doi.org/10.1111/j.0818-9641.2004.01272.xPetrovsky N, Aguilar JC. Vaccine adjuvants: current state and future trends. Immunol Cell Biol. 2004;82(5):488–96. https://doi.org/10.1111/j.0818-9641.2004.01272.xDidierlaurent AM, Morel S, Lockman L, Giannini SL, Bisteau M, Carlsen H, et al. AS04, an aluminum salt- and TLR4 agonist-based adjuvant system, induces a transient localized innate immune response leading to enhanced adaptive immunity. J Immunol. 2009;183(10):6186–97. https://doi.org/10.4049/jimmunol.0901474Didierlaurent AM, Morel S, Lockman L, Giannini SL, Bisteau M, Carlsen H, et al. AS04, an aluminum salt- and TLR4 agonist-based adjuvant system, induces a transient localized innate immune response leading to enhanced adaptive immunity. J Immunol. 2009;183(10):6186–97. https://doi.org/10.4049/jimmunol.0901474Cekic C, Casella CR, Eaves CA, Matsuzawa A, Ichijo H, Mitchell TC. Selective activation of the p38 MAPK pathway by synthetic monophosphoryl lipid A. J Biol Chem. 2009;284(46):31982–91. https://doi.org/10.1074/jbc.M109.046383Cekic C, Casella CR, Eaves CA, Matsuzawa A, Ichijo H, Mitchell TC. Selective activation of the p38 MAPK pathway by synthetic monophosphoryl lipid A. J Biol Chem. 2009;284(46):31982–91. https://doi.org/10.1074/jbc.M109.046383Coccia M, Collignon C, Hervé C, Chalon A, Welsby I, Detienne S, et al. Cellular and molecular synergy in AS01-adjuvanted vaccines results in an early IFNγ response promoting vaccine immunogenicity. NPJ Vaccines. 2017;2:25. https://doi.org/10.1038/s41541-017-0027-3Coccia M, Collignon C, Hervé C, Chalon A, Welsby I, Detienne S, et al. Cellular and molecular synergy in AS01-adjuvanted vaccines results in an early IFNγ response promoting vaccine immunogenicity. NPJ Vaccines. 2017;2:25. https://doi.org/10.1038/s41541-017-0027-3Mastelic B, Ahmed S, Egan WM, Del Giudice G, Golding H, Gust I, et al. Mode of action of adjuvants: implications for vaccine safety and design. Biologicals. 2010;38(5):594–601. https://doi.org/10.1016/j.biologicals.2010.06.002Mastelic B, Ahmed S, Egan WM, Del Giudice G, Golding H, Gust I, et al. Mode of action of adjuvants: implications for vaccine safety and design. Biologicals. 2010;38(5):594–601. https://doi.org/10.1016/j.biologicals.2010.06.002Marciani DJ. Elucidating the mechanisms of action of saponin-derived adjuvants. Trends Pharm Sci. 2018;39(6):573–85. https://doi.org/10.1016/j.tips.2018.03.005Marciani DJ. Elucidating the mechanisms of action of saponin-derived adjuvants. Trends Pharm Sci. 2018;39(6):573–85. https://doi.org/10.1016/j.tips.2018.03.005Marty-Roix R, Vladimer GI, Pouliot K, Weng D, Buglione-Corbett R, West K, et al. Identification of QS-21 as an inflammasome-activating molecular component of saponin adjuvants. J Biol Chem. 2016;291(3):1123–36. https://doi.org/10.1074/jbc.M115.683011Marty-Roix R, Vladimer GI, Pouliot K, Weng D, Buglione-Corbett R, West K, et al. Identification of QS-21 as an inflammasome-activating molecular component of saponin adjuvants. J Biol Chem. 2016;291(3):1123–36. https://doi.org/10.1074/jbc.M115.683011Lacaille-Dubois MA. Updated insights into the mechanism of action and clinical profile of the immunoadjuvant QS-21: A review. Phytomedicine. 2019;60:152905. https://doi.org/10.1016/j.phymed.2019.152905Lacaille-Dubois MA. Updated insights into the mechanism of action and clinical profile of the immunoadjuvant QS-21: A review. Phytomedicine. 2019;60:152905. https://doi.org/10.1016/j.phymed.2019.152905Didierlaurent 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 Vaccines. 2017;16(1):55–63. https://doi.org/10.1080/14760584.2016.1213632Didierlaurent 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 Vaccines. 2017;16(1):55–63. https://doi.org/10.1080/14760584.2016.1213632Garçon N, Chomez P, Van Mechelen M. GlaxoSmithKline adjuvant systems in vaccines: concepts, achievements and perspectives. Expert Rev Vaccines. 2007;6(5):723–39. https://doi.org/10.1586/14760584.6.5.723Garçon N, Chomez P, Van Mechelen M. GlaxoSmithKline adjuvant systems in vaccines: concepts, achievements and perspectives. Expert Rev Vaccines. 2007;6(5):723–39. https://doi.org/10.1586/14760584.6.5.723Laurens MB. RTS,S/AS01 vaccine (Mosquirix™): an overview. Hum Vaccin Immunother. 2020;16(3):480–9. https://doi.org/10.1080/21645515.2019.1669415Laurens MB. RTS,S/AS01 vaccine (Mosquirix™): an overview. Hum Vaccin Immunother. 2020;16(3):480–9. https://doi.org/10.1080/21645515.2019.1669415Leroux-Roels I, Leroux-Roels G, Clement F, Vandepapelière P, Vassilev V, Ledent E, Heineman TC. A phase 1/2 clinical trial evaluating safety and immunogenicity of a varicella zoster glycoprotein E subunit vaccine candidate in young and older adults. J Infect Dis. 2012;206(8):1280–90. https://doi.org/10.1093/infdis/jis497Leroux-Roels I, Leroux-Roels G, Clement F, Vandepapelière P, Vassilev V, Ledent E, Heineman TC. A phase 1/2 clinical trial evaluating safety and immunogenicity of a varicella zoster glycoprotein E subunit vaccine candidate in young and older adults. J Infect Dis. 2012;206(8):1280–90. https://doi.org/10.1093/infdis/jis497Van der Meeren O, Hatherill M, Nduba V, Wilkinson RJ, Muyoyeta M, Van Brakel E, et al. Phase 2b controlled trial of M72/AS01E vaccine to prevent tuberculosis. N Engl J Med. 2018;379(13):1621–34. https://doi.org/10.1056/NEJMoa1803484Van der Meeren O, Hatherill M, Nduba V, Wilkinson RJ, Muyoyeta M, Van Brakel E, et al. Phase 2b controlled trial of M72/AS01E vaccine to prevent tuberculosis. N Engl J Med. 2018;379(13):1621–34. https://doi.org/10.1056/NEJMoa1803484Burny W, Callegaro A, Bechtold V, Clement F, Delhaye S, Fissette L, et al. Different adjuvants induce common innate pathways that are associated with enhanced adaptive responses against a model antigen in humans. Front Immunol. 2017;8:943. https://doi.org/10.3389/fimmu.2017.00943Burny W, Callegaro A, Bechtold V, Clement F, Delhaye S, Fissette L, et al. Different adjuvants induce common innate pathways that are associated with enhanced adaptive responses against a model antigen in humans. Front Immunol. 2017;8:943. https://doi.org/10.3389/fimmu.2017.00943Giannini SL, Hanon E, Moris P, Van Mechelen M, Morel S, Dessy F, et al. Enhanced humoral and memory B cellular immunity using HPV16/18 L1 VLP vaccine formulated with the MPL/aluminium salt combination (AS04) compared to aluminium salt only. Vaccine. 2006;24(33-34):5937–49. https://doi.org/10.1016/j.vaccine.2006.06.005Giannini SL, Hanon E, Moris P, Van Mechelen M, Morel S, Dessy F, et al. Enhanced humoral and memory B cellular immunity using HPV16/18 L1 VLP vaccine formulated with the MPL/aluminium salt combination (AS04) compared to aluminium salt only. Vaccine. 2006;24(33-34):5937–49. https://doi.org/10.1016/j.vaccine.2006.06.005Keam SJ, Harper DM. Human papillomavirus types 16 and 18 vaccine (recombinant, AS04 adjuvanted adsorbed) [Cervarix™]. Drugs. 2008;68(3):359–72. https://doi.org/10.2165/00003495-200868030-00007Keam SJ, Harper DM. Human papillomavirus types 16 and 18 vaccine (recombinant, AS04 adjuvanted adsorbed) [Cervarix™]. Drugs. 2008;68(3):359–72. https://doi.org/10.2165/00003495-200868030-00007Toussi DN, Massari P. Immune adjuvant effect of molecularly-defined toll-like receptor ligands. Vaccines (Basel). 2014;2(2):323–53. https://doi.org/10.3390/vaccines2020323Toussi DN, Massari P. Immune adjuvant effect of molecularly-defined toll-like receptor ligands. Vaccines (Basel). 2014;2(2):323–53. https://doi.org/10.3390/vaccines2020323Garçon N, Morel S, Didierlaurent A, Descamps D, Wettendorff M, Van Mechelen M. Development of an AS04-adjuvanted HPV vaccine with the adjuvant system approach. BioDrugs. 2011;25(4):217–26. https://doi.org/10.2165/11591760-000000000-00000Garçon N, Morel S, Didierlaurent A, Descamps D, Wettendorff M, Van Mechelen M. Development of an AS04-adjuvanted HPV vaccine with the adjuvant system approach. BioDrugs. 2011;25(4):217–26. https://doi.org/10.2165/11591760-000000000-00000Fabrizi F, Tarantino A, Castelnovo C, Martín P, Messa P. Recombinant Hepatitis B vaccine adjuvanted with as04 in dialysis patients: a prospective cohort study. Kidney Blood Press Res. 2015;40(6):584–92. https://doi.org/10.1159/000368534Fabrizi F, Tarantino A, Castelnovo C, Martín P, Messa P. Recombinant Hepatitis B vaccine adjuvanted with as04 in dialysis patients: a prospective cohort study. Kidney Blood Press Res. 2015;40(6):584–92. https://doi.org/10.1159/000368534

The authors declare that there are no conflicts of interest present.