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Zusammensetzung und Wirkmechanismen von Adjuvanzien in zugelassenen viralen Impfstoffen

  • Ralf Wagner
  • Eberhard HildtEmail author
Leitthema
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Zusammenfassung

Die Immunogenität und Wirksamkeit von Impfstoffen werden in erster Linie von den enthaltenen Antigenen bestimmt. Die induzierte Immunantwort kann jedoch durch Zugabe von Wirkverstärkern in der Impfstoffformulierung, sog. Adjuvanzien, maßgeblich beeinflusst und gesteuert werden.

Adjuvanzien sind stofflich sehr divers und durch ihren die Immunantwort verstärkenden Effekt gekennzeichnet. In diesem Beitrag werden Adjuvanzien, die Teil in der EU zugelassener Impfstoffe sind, vorgestellt und ihre immunologischen Wirkmechanismen beschrieben.

Aluminiumsalze werden bereits seit 100 Jahren als Adjuvans eingesetzt. In jüngster Zeit wurde eine ganze Reihe neuartiger Adjuvanzien entwickelt und in zugelassene Impfstoffprodukte integriert. Viele der neuen Adjuvanzien führen nicht allein zu einer Erhöhung der impfstoffinduzierten Antikörpertiter, sondern zielen auch darauf ab, die Immunantwort in eine bestimmte Richtung zu lenken und gezielt zu modulieren. Die Suche nach innovativen Wirkverstärkern wurde wesentlich vorangetrieben bei der Entwicklung pandemischer Influenzaimpfstoffe. Durch Verwendung neuartiger Öl-in-Wasser-Emulsionen (Adjuvanzien MF 59 und AS03) gelang es, Pandemieimpfstoffe zu entwickeln, die trotz deutlich verringertem Antigengehalt wirksam sind.

Die Entwicklung neuer Adjuvanzien ist ein sehr dynamischer und zentraler Aspekt des Impfstoffdesigns: Vor einigen Jahren wurden Impfstoffe gegen das HPV-induzierte humane Zervixkarzinom und Hepatitis B zugelassen, die den Toll-like-Rezeptor-4-Agonisten MPL (3-O-Desacyl-monophosphoryl Lipid A) als Adjuvansbestandteil enthalten. Jüngst wurde in Europa ein Impfstoff gegen Herpes Zoster zugelassen, der als Adjuvans eine Kombination aus MPL und dem Saponin QS21 enthält, die auch im Malaria- und im Hepatitis-B-Impfstoff des Herstellers zur Anwendung kommen.

Schlüsselwörter

Impfung Adjuvans Antigen Alum Emulsion 

Abkürzungen

AF

Adjuvant Formulation

APC

Antigen Presenting Cells

ARE

Antioxidant Response Element

AS

Adjuvant System

CCL2

CC-chemokine Ligand 2

CpG

Dinukleotid aus Cytosin und Guanin

CSF-3

Colony Stimulating Factor 3

CTL

Cytotoxic T Lymphocyte

CXCL1

Chemokine (C-X-C Motif) Ligand 1

DC

Dendritic Cell

dmLT

Mucosal Vaccine Adjuvant incl. Heat-labile Enterotoxin of Escherichia coli

ETEC

Enterotoxische Escherichia coli

HLADQB602

Major Histocompatibility Complex, Class II, DQ Beta 1

HBV

Hepatitis B Virus

HBsAg

Hepatitis B Virus Surface Antigen

HPV

Humane Papillomviren

IFN

Interferon

IL

Interleukin

lg

Immunglobulin

i.m.

intramuskulär

i.p.

intraperitoneal

LAIV

Live Attenuated Influenza Virus

LPS

Lipopolysaccharide

MHC

Major Histocompatibility Complex

MPL

3-O-Desacyl-monophosphoryl Lipid A

MyD88

Myeloid Differentiation Primary Response 88

NLRP3

NOD-like Receptor Protein 3

NET

Neutrophil Extracellular Traps

Nhp

Non-human Primates

NK

Natural Killer Cells

NKT

Natural Killer T Cells

NLRP3

Nucleotide-binding Oligomerization Domain-like(NOD)-like Receptor Protein 3

Nrf2

Nuclear Factor (Erythroid-derived 2)-like 2

QS21

Fraktion eines Extrakts aus Quillaja saponaria Molina (Seifenrindenbaum)

s.c.

subkutan

ssRNA

Single-stranded RNA

TFH

Follicular T‑helper Cell

Th

T-helper Cell

TLR

Toll-like Receptor

TRIF

TIR (Toll/Interleukin-1 Receptor) Domain-containing Adaptor Protein Inducing Interferon Beta

Composition and mode of action of adjuvants in licensed viral vaccines

Abstract

The immunogenicity and efficacy of vaccines is largely governed by nature and the amount of antigen(s) included. Specific immune-stimulating substances, so-called adjuvants, are added to vaccine formulations to enhance and modulate the induced immune response.

Adjuvants are very different in their physicochemical nature and are primarily characterized by their immune-enhancing effects. In this report, adjuvants that are components of vaccines licensed in the EU will be presented and their mode of action will be discussed.

Aluminum salts have been used for almost a century as vaccine adjuvants. In recent years numerous novel immune-stimulating substances have been developed and integrated into licensed human vaccines. These novel adjuvants are not only intended to generally increase the vaccine-induced antibody titers, but are also aimed at modulating and triggering a specific immune response. The search for innovative adjuvants was considerably stimulated during development of pandemic influenza vaccines. By using squalene-containing oil-in-water adjuvants (namely AS03 and MF59), pandemic influenza vaccines were developed that were efficacious despite a significant reduction of the antigen content.

The development of novel adjuvants is a highly dynamic and essential area in modern vaccine design. Some years ago, vaccines for prevention of HPV-induced cervix carcinoma and hepatitis B were licensed that contained the toll-like receptor 4 agonist 3‑O-desacyl-monophosphoryl lipid A (MPL), a detoxified LPS version, as the adjuvant. Quite recently, a herpes zoster vaccine was licensed in Europe with a combination of MPL and the saponin QS21 as adjuvant. This combination of immune enhancers is also used in the formulations of the same manufacturer’s malaria and hepatitis B vaccine.

Keywords

Vaccination Adjuvants Antigen Alum Emulsion 

Notes

Danksagung

Die Autoren danken Frau Frauke Hüls für die Korrektur des Manuskripts und Frau Dr. Daniela Bender für die Erstellung der Abbildungen.

Einhaltung ethischer Richtlinien

Interessenkonflikt

R. Wagner und E. Hildt geben an, dass kein Interessenkonflikt besteht.

Dieser Beitrag beinhaltet keine von den Autoren durchgeführten Studien an Menschen oder Tieren.

Literatur

  1. 1.
    Di Pasquale A, Preiss S, Tavares Da Silva F, Garçon N (2015) Vaccine adjuvants. From 1920 to 2015 and beyond. Vaccines (Basel) 3(2):320–343.  https://doi.org/10.3390/vaccines3020320 CrossRefGoogle Scholar
  2. 2.
    Asanzhanova NN, Ryskeldinova SZ, Chervyakova OV, Khairullin BM, Kasenov MM, Tabynov KK (2017) Comparison of different methods of purification and concentration in production of influenza vaccine. Bull Exp Biol Med 164(2):229–232.  https://doi.org/10.1007/s10517-017-3964-y CrossRefGoogle Scholar
  3. 3.
    Barrett PN, Terpening SJ, Snow D, Cobb RR, Kistner O (2017) Vero cell technology for rapid development of inactivated whole virus vaccines for emerging viral diseases. Expert Rev Vaccines 16(9):883–894.  https://doi.org/10.1080/14760584.2017.1357471 CrossRefGoogle Scholar
  4. 4.
    Huber VC (2014) Influenza vaccines. From whole virus preparations to recombinant protein technology. Expert Rev Vaccines 13(1):31–42.  https://doi.org/10.1586/14760584.2014.852476 CrossRefGoogle Scholar
  5. 5.
    Weinberger B (2018) Adjuvant strategies to improve vaccination of the elderly population. Curr Opin Pharmacol 41:34–41.  https://doi.org/10.1016/j.coph.2018.03.014 CrossRefGoogle Scholar
  6. 6.
    Domnich A, Arata L, Amicizia D, Puig-Barberà J, Gasparini R, Panatto D (2017) Effectiveness of MF59-adjuvanted seasonal influenza vaccine in the elderly. A systematic review and meta-analysis. Vaccine 35(4):513–520.  https://doi.org/10.1016/j.vaccine.2016.12.011 CrossRefGoogle Scholar
  7. 7.
    Jackson S, Lentino J, Kopp J et al (2018) Immunogenicity of a two-dose investigational hepatitis B vaccine, HBsAg-1018, using a toll-like receptor 9 agonist adjuvant compared with a licensed hepatitis B vaccine in adults. Vaccine 36(5):668–674.  https://doi.org/10.1016/j.vaccine.2017.12.038 CrossRefGoogle Scholar
  8. 8.
    Tregoning JS, Russell RF, Kinnear E (2018) Adjuvanted influenza vaccines. Hum Vaccin Immunother 14(3):550–564.  https://doi.org/10.1080/21645515.2017.1415684 CrossRefGoogle Scholar
  9. 9.
    Vajo Z, Balaton G, Vajo P, Kalabay L, Erdman A, Torzsa P (2017) Dose sparing and the lack of a dose-response relationship with an influenza vaccine in adult and elderly patients – a randomized, double-blind clinical trial. Br J Clin Pharmacol 83(9):1912–1920.  https://doi.org/10.1111/bcp.13289 CrossRefGoogle Scholar
  10. 10.
    Feldstein LR, Matrajt L, Elizabeth Halloran M, Keitel WA, Longini IM (2016) Extrapolating theoretical efficacy of inactivated influenza A/H5N1 virus vaccine from human immunogenicity studies. Vaccine 34(33):3796–3802.  https://doi.org/10.1016/j.vaccine.2016.05.067 CrossRefGoogle Scholar
  11. 11.
    Khurana S, Coyle EM, Manischewitz J et al (2018) AS03-adjuvanted H5N1 vaccine promotes antibody diversity and affinity maturation, NAI titers, cross-clade H5N1 neutralization, but not H1N1 cross-subtype neutralization. NPJ Vaccines 3:40.  https://doi.org/10.1038/s41541-018-0076-2 CrossRefGoogle Scholar
  12. 12.
    Khurana S, Coyle EM, Dimitrova M et al (2014) Heterologous prime-boost vaccination with MF59-adjuvanted H5 vaccines promotes antibody affinity maturation towards the hemagglutinin HA1 domain and broad H5N1 cross-clade neutralization. PLoS ONE 9(4):e95496.  https://doi.org/10.1371/journal.pone.0095496 CrossRefGoogle Scholar
  13. 13.
    Kasturi SP, Skountzou I, Albrecht RA et al (2011) Programming the magnitude and persistence of antibody responses with innate immunity. Nature 470(7335):543–547.  https://doi.org/10.1038/nature09737 CrossRefGoogle Scholar
  14. 14.
    Goff PH, Hayashi T, Martínez-Gil L et al (2015) Synthetic toll-like receptor 4 (TLR4) and TLR7 ligands as influenza virus vaccine adjuvants induce rapid, sustained, and broadly protective responses. J Virol 89(6):3221–3235.  https://doi.org/10.1128/JVI.03337-14 CrossRefGoogle Scholar
  15. 15.
    Cimica V, Galarza JM (2017) Adjuvant formulations for virus-like particle (VLP) based vaccines. Clin Immunol 183:99–108.  https://doi.org/10.1016/j.clim.2017.08.004 CrossRefGoogle Scholar
  16. 16.
    Lodaya RN, Brito LA, Wu TYH et al (2018) Stable nanoemulsions for the delivery of small molecule immune potentiators. J Pharm Sci 107(9):2310–2314.  https://doi.org/10.1016/j.xphs.2018.05.012 CrossRefGoogle Scholar
  17. 17.
    O’Hagan DT, Fox CB (2015) New generation adjuvants – from empiricism to rational design. Vaccine 33(Suppl 2):B14–B20.  https://doi.org/10.1016/j.vaccine.2015.01.088 CrossRefGoogle Scholar
  18. 18.
    Rehli M (2002) Of mice and men. Species variations of Toll-like receptor expression. Trends Immunol 23(8):375–378CrossRefGoogle Scholar
  19. 19.
    Sun J, Li N, Oh K‑S et al (2016) Comprehensive RNAi-based screening of human and mouse TLR pathways identifies species-specific preferences in signaling protein use. Sci Signal 9(409):ra3.  https://doi.org/10.1126/scisignal.aab2191 CrossRefGoogle Scholar
  20. 20.
    Steeghs L, Keestra AM, van Mourik A et al (2008) Differential activation of human and mouse Toll-like receptor 4 by the adjuvant candidate LpxL1 of Neisseria meningitidis. Infect Immun 76(8):3801–3807.  https://doi.org/10.1128/IAI.00005-08 CrossRefGoogle Scholar
  21. 21.
    Heil F, Hemmi H, Hochrein H et al (2004) Species-specific recognition of single-stranded RNA via toll-like receptor 7 and 8. Science 303(5663):1526–1529.  https://doi.org/10.1126/science.1093620 CrossRefGoogle Scholar
  22. 22.
    Klinman DM, Currie D, Gursel I, Verthelyi D (2004) Use of CpG oligodeoxynucleotides as immune adjuvants. Immunol Rev 199:201–216.  https://doi.org/10.1111/j.0105-2896.2004.00148.x CrossRefGoogle Scholar
  23. 23.
    Wen Y, Shi Y (2016) Alum. An old dog with new tricks. Emerg Microbes Infect 5:e25.  https://doi.org/10.1038/emi.2016.40 CrossRefGoogle Scholar
  24. 24.
    Fourati S, Cristescu R, Loboda A et al (2016) Pre-vaccination inflammation and B‑cell signalling predict age-related hyporesponse to hepatitis B vaccination. Nat Commun 7:10369.  https://doi.org/10.1038/ncomms10369 CrossRefGoogle Scholar
  25. 25.
    Hutchison S, Benson RA, Gibson VB, Pollock AH, Garside P, Brewer JM (2012) Antigen depot is not required for alum adjuvanticity. FASEB J 26(3):1272–1279.  https://doi.org/10.1096/fj.11-184556 CrossRefGoogle Scholar
  26. 26.
    Mori A, Oleszycka E, Sharp FA et al (2012) 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 42(10):2709–2719.  https://doi.org/10.1002/eji.201242372 CrossRefGoogle Scholar
  27. 27.
    Bielinska AU, O’Konek JJ, Janczak KW, Baker JR (2016) Immunomodulation of TH2 biased immunity with mucosal administration of nanoemulsion adjuvant. Vaccine 34(34):4017–4024.  https://doi.org/10.1016/j.vaccine.2016.06.043 CrossRefGoogle Scholar
  28. 28.
    Didierlaurent AM, Morel S, Lockman L et al (2009) AS04, an aluminum salt- and TLR4 agonist-based adjuvant system, induces a transient localized innate immune response leading to enhanced adaptive immunity. J Immunol 183(10):6186–6197.  https://doi.org/10.4049/jimmunol.0901474 CrossRefGoogle Scholar
  29. 29.
    Ghimire TR, Benson RA, Garside P, Brewer JM (2012) Alum increases antigen uptake, reduces antigen degradation and sustains antigen presentation by DCs in vitro. Immunol Lett 147(1–2):55–62.  https://doi.org/10.1016/j.imlet.2012.06.002 CrossRefGoogle Scholar
  30. 30.
    Sollberger G, Tilley DO, Zychlinsky A (2018) Neutrophil extracellular traps. The biology of chromatin externalization. Dev Cell 44(5):542–553.  https://doi.org/10.1016/j.devcel.2018.01.019 CrossRefGoogle Scholar
  31. 31.
    Papayannopoulos V (2018) Neutrophil extracellular traps in immunity and disease. Nat Rev Immunol 18(2):134–147.  https://doi.org/10.1038/nri.2017.105 CrossRefGoogle Scholar
  32. 32.
    Riteau N, Baron L, Villeret B et al (2012) ATP release and purinergic signaling. A common pathway for particle-mediated inflammasome activation. Cell Death Dis 3:e403.  https://doi.org/10.1038/cddis.2012.144 CrossRefGoogle Scholar
  33. 33.
    Kool M, Soullié T, van Nimwegen M et al (2008) Alum adjuvant boosts adaptive immunity by inducing uric acid and activating inflammatory dendritic cells. J Exp Med 205(4):869–882.  https://doi.org/10.1084/jem.20071087 CrossRefGoogle Scholar
  34. 34.
    Harte C, Gorman AL, McCluskey S et al (2017) Alum activates the bovine NLRP3 inflammasome. Front Immunol 8:1494.  https://doi.org/10.3389/fimmu.2017.01494 CrossRefGoogle Scholar
  35. 35.
    Neumann S, Burkert K, Kemp R, Rades T, Rod Dunbar P, Hook S (2014) Activation of the NLRP3 inflammasome is not a feature of all particulate vaccine adjuvants. Immunol Cell Biol 92(6):535–542.  https://doi.org/10.1038/icb.2014.21 CrossRefGoogle Scholar
  36. 36.
    He P, Zou Y, Hu Z (2015) Advances in aluminum hydroxide-based adjuvant research and its mechanism. Hum Vaccin Immunother 11(2):477–488.  https://doi.org/10.1080/21645515.2014.1004026 CrossRefGoogle Scholar
  37. 37.
    Gavin AL, Hoebe K, Duong B et al (2006) Adjuvant-enhanced antibody responses in the absence of toll-like receptor signaling. Science 314(5807):1936–1938.  https://doi.org/10.1126/science.1135299 CrossRefGoogle Scholar
  38. 38.
    Garçon N, Wettendorff M, van Mechelen M (2011) Role of AS04 in human papillomavirus vaccine. Mode of action and clinical profile. Expert Opin Biol Ther 11(5):667–677.  https://doi.org/10.1517/14712598.2011.573624 CrossRefGoogle Scholar
  39. 39.
    Leroux-Roels G, Haelterman E, Maes C et al (2011) Randomized trial of the immunogenicity and safety of the Hepatitis B vaccine given in an accelerated schedule coadministered with the human papillomavirus type 16/18 AS04-adjuvanted cervical cancer vaccine. Clin Vaccine Immunol 18(9):1510–1518.  https://doi.org/10.1128/CVI.00539-10 CrossRefGoogle Scholar
  40. 40.
    López-Fauqued M, Zima J, Angelo M‑G, Stegmann J‑U (2017) Results on exposure during pregnancy from a pregnancy registry for AS04-HPV-16/18 vaccine. Vaccine 35(40):5325–5330.  https://doi.org/10.1016/j.vaccine.2017.08.042 CrossRefGoogle Scholar
  41. 41.
    Hogenesch H (2012) Mechanism of immunopotentiation and safety of aluminum adjuvants. Front Immunol 3:406.  https://doi.org/10.3389/fimmu.2012.00406 Google Scholar
  42. 42.
    Pittman PR (2002) Aluminum-containing vaccine associated adverse events. Role of route of administration and gender. Vaccine 20(Suppl 3):S48–S50CrossRefGoogle Scholar
  43. 43.
    Tomljenovic L, Shaw CA (2012) Mechanisms of aluminum adjuvant toxicity and autoimmunity in pediatric populations. Lupus 21(2):223–230.  https://doi.org/10.1177/0961203311430221 CrossRefGoogle Scholar
  44. 44.
    Shoenfeld Y, Agmon-Levin N (2011) ’ASIA‘ – autoimmune/inflammatory syndrome induced by adjuvants. J Autoimmun 36(1):4–8.  https://doi.org/10.1016/j.jaut.2010.07.003 CrossRefGoogle Scholar
  45. 45.
    Lindblad EB (2004) Aluminium compounds for use in vaccines. Immunol Cell Biol 82(5):497–505.  https://doi.org/10.1111/j.0818-9641.2004.01286.x CrossRefGoogle Scholar
  46. 46.
    Masson J‑D, Crépeaux G, Authier F‑J, Exley C, Gherardi RK (2018) Critical analysis of reference studies on the toxicokinetics of aluminum-based adjuvants. J Inorg Biochem 181:87–95.  https://doi.org/10.1016/j.jinorgbio.2017.12.015 CrossRefGoogle Scholar
  47. 47.
    Mitkus RJ, King DB, Hess MA, Forshee RA, Walderhaug MO (2011) Updated aluminum pharmacokinetics following infant exposures through diet and vaccination. Vaccine 29(51):9538–9543.  https://doi.org/10.1016/j.vaccine.2011.09.124 CrossRefGoogle Scholar
  48. 48.
    Mold M, Shardlow E, Exley C (2016) Insight into the cellular fate and toxicity of aluminium adjuvants used in clinically approved human vaccinations. Sci Rep 6:31578.  https://doi.org/10.1038/srep31578 CrossRefGoogle Scholar
  49. 49.
    Weisser K, Göen T, Oduro JD, Wangorsch G, Hanschmann K‑MO, Keller-Stanislawski B (2018) Aluminium toxicokinetics after intramuscular, subcutaneous, and intravenous injection of Al citrate solution in rats. Arch Toxicol.  https://doi.org/10.1007/s00204-018-2323-8 Google Scholar
  50. 50.
    Podda A (2001) The adjuvanted influenza vaccines with novel adjuvants. Experience with the MF59-adjuvanted vaccine. Vaccine 19(17–19):2673–2680CrossRefGoogle Scholar
  51. 51.
    Wilkins AL, Kazmin D, Napolitani G et al (2017) AS03- and MF59-adjuvanted influenza vaccines in children. Front Immunol 8:1760.  https://doi.org/10.3389/fimmu.2017.01760 CrossRefGoogle Scholar
  52. 52.
    Cioncada R, Maddaluno M, Vo HTM et al (2017) Vaccine adjuvant MF59 promotes the intranodal differentiation of antigen-loaded and activated monocyte-derived dendritic cells. PLoS ONE 12(10):e185843.  https://doi.org/10.1371/journal.pone.0185843 CrossRefGoogle Scholar
  53. 53.
    Morel S, Didierlaurent A, Bourguignon P et al (2011) Adjuvant system AS03 containing α‑tocopherol modulates innate immune response and leads to improved adaptive immunity. Vaccine 29(13):2461–2473.  https://doi.org/10.1016/j.vaccine.2011.01.011 CrossRefGoogle Scholar
  54. 54.
    Liang F, Lindgren G, Sandgren KJ et al (2017) Vaccine priming is restricted to draining lymph nodes and controlled by adjuvant-mediated antigen uptake. Sci Transl Med.  https://doi.org/10.1126/scitranslmed.aal2094 Google Scholar
  55. 55.
    Galson JD, Trück J, Kelly DF, van der Most R (2016) Investigating the effect of AS03 adjuvant on the plasma cell repertoire following pH1N1 influenza vaccination. Sci Rep.  https://doi.org/10.1038/srep37229 Google Scholar
  56. 56.
    Sarkanen TO, Alakuijala APE, Dauvilliers YA, Partinen MM (2018) Incidence of narcolepsy after H1N1 influenza and vaccinations. Systematic review and meta-analysis. Sleep Med Rev 38:177–186.  https://doi.org/10.1016/j.smrv.2017.06.006 CrossRefGoogle Scholar
  57. 57.
    Eurosurveillance Editorial Team (2011) Swedish Medical Products Agency publishes report from a case inventory study on Pandemrix vaccination and development of narcolepsy with cataplexy. Euro Surveill.  https://doi.org/10.2807/ese.16.26.19904-en Google Scholar
  58. 58.
    Sarkanen T, Alakuijala A, Julkunen I, Partinen M (2018) Narcolepsy associated with Pandemrix vaccine. Curr Neurol Neurosci Rep 18(7):43.  https://doi.org/10.1007/s11910-018-0851-5 CrossRefGoogle Scholar
  59. 59.
    Masoudi S, Ploen D, Kunz K, Hildt E (2014) The adjuvant component α‑tocopherol triggers via modulation of Nrf2 the expression and turnover of hypocretin in vitro and its implication to the development of narcolepsy. Vaccine 32(25):2980–2988.  https://doi.org/10.1016/j.vaccine.2014.03.085 CrossRefGoogle Scholar
  60. 60.
    Latorre D, Kallweit U, Armentani E et al (2018) T cells in patients with narcolepsy target self-antigens of hypocretin neurons. Nature 562(7725):63–68.  https://doi.org/10.1038/s41586-018-0540-1 CrossRefGoogle Scholar
  61. 61.
    Marty-Roix R, Vladimer GI, Pouliot K et al (2016) Identification of QS-21 as an inflammasome-activating molecular component of saponin adjuvants. J Biol Chem 291(3):1123–1136.  https://doi.org/10.1074/jbc.M115.683011 CrossRefGoogle Scholar
  62. 62.
    Welsby I, Detienne S, N’Kuli F et al (2016) Lysosome-dependent activation of human dendritic cells by the vaccine adjuvant QS-21. Front Immunol 7:663.  https://doi.org/10.3389/fimmu.2016.00663 Google Scholar
  63. 63.
    Whitmire JK, Tan JT, Whitton JL (2005) Interferon-gamma acts directly on CD8+ T cells to increase their abundance during virus infection. J Exp Med 201(7):1053–1059.  https://doi.org/10.1084/jem.20041463 CrossRefGoogle Scholar
  64. 64.
    Cummings JF, Spring MD, Schwenk RJ et al (2010) Recombinant liver stage antigen-1 (LSA-1) formulated with AS01 or AS02 is safe, elicits high titer antibody and induces IFN-gamma/IL-2 CD4+ T cells but does not protect against experimental plasmodium falciparum infection. Vaccine 28(31):5135–5144.  https://doi.org/10.1016/j.vaccine.2009.08.046 CrossRefGoogle Scholar
  65. 65.
    Frasca L, Nasso M, Spensieri F et al (2008) IFN-arms human dendritic cells to perform multiple effector functions. J Immunol 180(3):1471–1481.  https://doi.org/10.4049/jimmunol.180.3.1471 CrossRefGoogle Scholar
  66. 66.
    Coccia M, Collignon C, Hervé C et al (2017) Cellular and molecular synergy in AS01-adjuvanted vaccines results in an early IFNγ response promoting vaccine immunogenicity. NPJ Vaccines 2:25.  https://doi.org/10.1038/s41541-017-0027-3 CrossRefGoogle Scholar
  67. 67.
    Lau Y‑F, Santos C, Torres-Vélez FJ, Subbarao K (2011) The magnitude of local immunity in the lungs of mice induced by live attenuated influenza vaccines is determined by local viral replication and induction of cytokines. J Virol 85(1):76–85.  https://doi.org/10.1128/JVI.01564-10 CrossRefGoogle Scholar
  68. 68.
    Jegaskanda S, Mason RD, Andrews SF et al (2018) Intranasal live influenza vaccine priming elicits localized B cell responses in mediastinal lymph nodes. J Virol.  https://doi.org/10.1128/JVI.01970-17 Google Scholar
  69. 69.
    Pantazi E, Marks E, Stolarczyk E, Lycke N, Noelle RJ, Elgueta R (2015) Cutting edge. Retinoic acid signaling in B cells is essential for oral immunization and microflora composition. J Immunol 195(4):1368–1371.  https://doi.org/10.4049/jimmunol.1500989 CrossRefGoogle Scholar
  70. 70.
    Raphael I, Nalawade S, Eagar TN, Forsthuber TG (2015) T cell subsets and their signature cytokines in autoimmune and inflammatory diseases. Cytokine 74(1):5–17.  https://doi.org/10.1016/j.cyto.2014.09.011 CrossRefGoogle Scholar

Copyright information

© Springer-Verlag GmbH Deutschland, ein Teil von Springer Nature 2019

Authors and Affiliations

  1. 1.Paul-Ehrlich-InstitutBundesinstitut für Impfstoffe und biomedizinische Arzneimittel, Abteilung VirologieLangenDeutschland

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