Skip to main content
SpringerLink
Log in

Adjuvants

  • Chapter
  • First Online:
Vaccination Strategies Against Highly Variable Pathogens

Part of the book series: Current Topics in Microbiology and Immunology ((CT MICROBIOLOGY,volume 428))

Abstract

Developing new vaccines against emerging pathogens or pathogens where variability of antigenic sites presents a challenge, the inclusion of stimulators of the innate immune system is critical to mature the immune response in a way that allows high avidity recognition while preserving the ability to react to drifted serovars. The innate immune system is an ancient mechanism for recognition of nonself and the first line of defense against pathogen insult. By triggering innate receptors, adjuvants can boost responses to vaccines and enhance the quality and magnitude of the resulting immune response. This chapter: (1) describes the innate immune system, (2) provides examples of how adjuvants are formulated to optimize their effectiveness, and (3) presents examples of how adjuvants can improve outcomes of immunization.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 109.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 139.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 139.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  • Alexopoulou L, Holt AC, Medzhitov R, Flavell RA (2001) Recognition of double-stranded RNA and activation of NF-kappaB by Toll-like receptor 3. Nature 413:732–738

    CAS  PubMed  Google Scholar 

  • Alexopoulou L, Thomas V, Schnare M, Lobet Y, Anguita J, Schoen RT, Medzhitov R, Fikrig E, Flavell RA (2002) Hyporesponsiveness to vaccination with Borrelia burgdorferi OspA in humans and in TLR1- and TLR2-deficient mice. Nat Med 8:878–884

    CAS  PubMed  Google Scholar 

  • Ali OA, Verbeke C, Johnson C, Sands W, Lewin SA, White D, Doherty E, Dranoff G, Mooney DJ (2014) Identification of immune factors regulating anti-tumor immunity using polymeric vaccines with multiple adjuvants. Cancer Res

    Google Scholar 

  • Anderson RC, Fox CB, Dutill TS, Shaverdian N, Evers TL, Poshusta GR, Chesko J, Coler RN, Friede M, Reed SG et al (2010) Physicochemical characterization and biological activity of synthetic TLR4 agonist formulations. Colloids Surf B: Biointerfaces 75:123–132

    Google Scholar 

  • Ansong D, Asante KP, Vekemans J, Owusu SK, Owusu R, Brobby NA, Dosoo D, Osei-Akoto A, Osei-Kwakye K, Asafo-Adjei E et al (2011) T cell responses to the RTS, S/AS01(E) and RTS, S/AS02(D) malaria candidate vaccines administered according to different schedules to Ghanaian children. PLoS ONE 6:e18891

    CAS  PubMed  PubMed Central  Google Scholar 

  • Applequist SE, Rollman E, Wareing MD, Liden M, Rozell B, Hinkula J, Ljunggren HG (2005) Activation of innate immunity, inflammation, and potentiation of DNA vaccination through mammalian expression of the TLR5 agonist flagellin. J Immunol 175:3882–3891

    CAS  PubMed  Google Scholar 

  • Baldridge JR, McGowan P, Evans JT, Cluff C, Mossman S, Johnson D, Persing D (2004) Taking a Toll on human disease: Toll-like receptor 4 agonists as vaccine adjuvants and monotherapeutic agents. Expert Opin Biol Ther 4:1129–1138

    CAS  PubMed  Google Scholar 

  • Baldwin SL, Roeffen W, Singh SK, Tiendrebeogo RW, Christiansen M, Beebe E, Carter D, Fox CB, Howard RF, Reed SG et al (2016) Synthetic TLR4 agonists enhance functional antibodies and CD4+ T-cell responses against the Plasmodium falciparum GMZ2.6C multi-stage vaccine antigen. Vaccine 34:2207–2215

    CAS  PubMed  Google Scholar 

  • Basith S, Manavalan B, Lee G, Kim SG, Choi S (2011) Toll-like receptor modulators: a patent review (2006–2010). Expert Opin Ther Pat 21:927–944

    Google Scholar 

  • Behzad H, Huckriede ALW, Haynes L, Gentleman B, Coyle K, Wilschut JC, Kollmann TR, Reed SG, McElhaney JE (2012) GLA-SE, a synthetic toll-like receptor 4 agonist, enhances T-cell responses to influenza vaccine in older adults. J Infect Dis 205:466–473

    CAS  PubMed  Google Scholar 

  • Belderbos ME, van Bleek GM, Levy O, Blanken MO, Houben ML, Schuijff L, Kimpen JL, Bont L (2009) Skewed pattern of Toll-like receptor 4-mediated cytokine production in human neonatal blood: low LPS-induced IL-12p70 and high IL-10 persist throughout the first month of life. Clin Immunol 133:228–237

    CAS  PubMed  PubMed Central  Google Scholar 

  • Beran J (2008) Safety and immunogenicity of a new hepatitis B vaccine for the protection of patients with renal insufficiency including pre-haemodialysis and haemodialysis patients. Expert Opin Biol Ther 8:235–247

    CAS  PubMed  Google Scholar 

  • Bergmann-Leitner ES, Leitner WW (2014) Adjuvants in the driver’s seat: how magnitude, type, fine specificity and longevity of immune responses are driven by distinct classes of immune potentiators. Vaccines (Basel) 2:252–296

    Google Scholar 

  • Bohnenkamp HR, Papazisis KT, Burchell JM, Taylor-Papadimitriou J (2007) Synergism of Toll-like receptor-induced interleukin-12p70 secretion by monocyte-derived dendritic cells is mediated through p38 MAPK and lowers the threshold of T-helper cell type 1 responses. Cell Immunol 247:72–84

    CAS  PubMed  Google Scholar 

  • Breckpot K, Escors D, Arce F, Lopes L, Karwacz K, Van Lint S, Keyaerts M, Collins M (2010) HIV-1 lentiviral vector immunogenicity is mediated by TLR3 and TLR7. J Virol

    Google Scholar 

  • Brenner S, Milstein C (1966/2006) Pillars article: origin of antibody variation. Nature 211:242–243. J Immunol 177:4237–4238

    Google Scholar 

  • Bretscher P, Wei G, Menon J, Bielefeldt-Ohmann H (1992) Establishment of stable, cell-mediated immunity that makes “susceptible” mice resistant to Leishmania major. Science 257:539–542

    CAS  PubMed  Google Scholar 

  • Bulut Y, Michelsen KS, Hayrapetian L, Naiki Y, Spallek R, Singh M, Arditi M (2005) Mycobacterium tuberculosis heat shock proteins use diverse Toll-like receptor pathways to activate pro-inflammatory signals. J Biol Chem 280:20961–20967

    CAS  PubMed  Google Scholar 

  • Campbell JD (2017) Development of the CpG adjuvant 1018: a case study. Methods Mol Biol 1494:15–27

    CAS  PubMed  Google Scholar 

  • Campbell JD, Cho Y, Foster ML, Kanzler H, Kachura MA, Lum JA, Ratcliffe MJ, Sathe A, Leishman AJ, Bahl A et al (2009) CpG-containing immunostimulatory DNA sequences elicit TNF-alpha-dependent toxicity in rodents but not in humans. J Clin Invest 119:2564–2576

    CAS  PubMed  PubMed Central  Google Scholar 

  • Capolunghi F, Rosado MM, Sinibaldi M, Aranburu A, Carsetti R (2013) Why do we need IgM memory B cells? Immunol Lett 152:114–120

    CAS  PubMed  Google Scholar 

  • Carter D, Reed SG (2010) Role of adjuvants in modeling the immune response. Curr Opin HIV AIDS 5:409–413. https://doi.org/10.1097/COH.1090b1013e32833d32832cdb

    Article  PubMed  PubMed Central  Google Scholar 

  • Carter D, Fox CB, Day TA, Guderian JA, Liang H, Rolf T, Vergara J, Sagawa ZK, Ireton G, Orr MT et al (2016) A structure-function approach to optimizing TLR4 ligands for human vaccines. Clin Trans Immunol 5:e108

    Google Scholar 

  • Cataldi A, Yevsa T, Vilte DA, Schulze K, Castro-Parodi M, Larzabal M, Ibarra C, Mercado EC, Guzman CA (2008) Efficient immune responses against Intimin and EspB of enterohaemorragic Escherichia coli after intranasal vaccination using the TLR2/6 agonist MALP-2 as adjuvant. Vaccine 26:5662–5667

    CAS  PubMed  Google Scholar 

  • Chang ZL (2010) Important aspects of Toll-like receptors, ligands and their signaling pathways. Inflamm Res

    Google Scholar 

  • Chollet JL, Jozwiakowski MJ, Phares KR, Reiter MJ, Roddy PJ, Schultz HJ, Ta QV, Tomai MA (1999) Development of a topically active imiquimod formulation. Pharm Dev Technol 4:35–43

    CAS  PubMed  Google Scholar 

  • Chuai X, Chen H, Wang W, Deng Y, Wen B, Ruan L, Tan W (2013) Poly(I:C)/alum mixed adjuvant priming enhances HBV subunit vaccine-induced immunity in mice when combined with recombinant adenoviral-based HBV vaccine boosting. PLoS ONE 8:e54126

    CAS  PubMed  PubMed Central  Google Scholar 

  • Coler RN, Bertholet S, Moutaftsi M, Guderian JA, Windish HP, Baldwin SL, Laughlin EM, Duthie MS, Fox CB, Carter D et al (2011) Development and characterization of synthetic glucopyranosyl lipid adjuvant system as a vaccine adjuvant. PLoS ONE 6:e16333

    Google Scholar 

  • Coler RN, Duthie MS, Hofmeyer KA, Guderian J, Jayashankar L, Vergara J, Rolf T, Misquith A, Laurance JD, Raman VS et al (2015) From mouse to man: safety, immunogenicity and efficacy of a candidate leishmaniasis vaccine LEISH-F3+GLA-SE. Clin Trans Immunol 4:e35

    Google Scholar 

  • Dasari P, Nicholson IC, Hodge G, Dandie GW, Zola H (2005) Expression of toll-like receptors on B lymphocytes. Cell Immunol 236:140–145

    CAS  PubMed  Google Scholar 

  • Degn SE, Thiel S (2013) Humoral pattern recognition and the complement system. Scand J Immunol 78:181–193

    CAS  PubMed  Google Scholar 

  • Desbien AL, Reed SJ, Bailor HR, Cauwelaert ND, Laurance JD, Orr MT, Fox CB, Carter D, Reed SG, Duthie MS (2015) Squalene emulsion potentiates the adjuvant activity of the TLR4 agonist, GLA, via inflammatory caspases, IL-18, and IFN-γ. Eur J Immunol 45:407–417

    Google Scholar 

  • Didierlaurent AM, Morel S, Lockman L, Giannini SL, Bisteau M, Carlsen H, Kielland A, Vosters O, Vanderheyde N, Schiavetti F 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 183:6186–6197

    CAS  PubMed  Google Scholar 

  • El Shikh ME, El Sayed RM, Wu Y, Szakal AK, Tew JG (2007) TLR4 on follicular dendritic cells: an activation pathway that promotes accessory activity. J Immunol 179:4444–4450

    PubMed  Google Scholar 

  • Excler JL, Tomaras GD, Russell ND (2013) Novel directions in HIV-1 vaccines revealed from clinical trials. Curr Opin HIV AIDS 8:421–431

    PubMed  PubMed Central  Google Scholar 

  • Foldes G, Liu A, Badiger R, Paul-Clark M, Moreno L, Lendvai Z, Wright JS, Ali NN, Harding SE, Mitchell JA (2010) Innate immunity in human embryonic stem cells: comparison with adult human endothelial cells. PLoS ONE 5:e10501

    PubMed  PubMed Central  Google Scholar 

  • Fox CB (2009) Squalene emulsions for parenteral vaccine and drug delivery. Molecules 14:3286–3312

    CAS  PubMed  PubMed Central  Google Scholar 

  • Fox CB, Anderson RC, Dutill TS, Goto Y, Reed SG, Vedvick TS (2008) Monitoring the effects of component structure and source on formulation stability and adjuvant activity of oil-in-water emulsions. Colloids Surf B Biointerfaces 65:98–105

    CAS  PubMed  Google Scholar 

  • Fox CB, Lin S, Sivananthan SJ, Dutill TS, Forseth KT, Reed SG, Vedvick TS (2010) Effects of emulsifier concentration, composition, and order of addition in squalene-phosphatidylcholine oil-in-water emulsions. Pharm Dev Technol

    Google Scholar 

  • Fox CB, Moutaftsi M, Vergara J, Desbien AL, Nana GI, Vedvick TS, Coler RN, Reed SG (2013) TLR4 ligand formulation causes distinct effects on antigen-specific cell-mediated and humoral immune responses. Vaccine 31:5848–5855

    CAS  PubMed  Google Scholar 

  • Fox CB, Sivananthan SJ, Duthie MS, Vergara J, Guderian JA, Moon E, Coblentz D, Reed SG, Carter D (2014) A nanoliposome delivery system to synergistically trigger TLR4 AND TLR7. J Nanobiotechnol 12:17

    Google Scholar 

  • Fox C, Carter D, Kramer R, Beckmann A, Reed S (2016) Current status of Toll-like receptor 4 ligand vaccine adjuvants. In: Schijns V, O’Hagan D (eds) Immunopotentiators in modern vaccines, 2nd edn. Elsevier Academic Press, pp 105–128

    Google Scholar 

  • Gallorini S, Berti F, Mancuso G, Cozzi R, Tortoli M, Volpini G, Telford JL, Beninati C, Maione D, Wack A (2009) Toll-like receptor 2 dependent immunogenicity of glycoconjugate vaccines containing chemically derived zwitterionic polysaccharides. Proc Natl Acad Sci U S A 106:17481–17486

    CAS  PubMed  PubMed Central  Google Scholar 

  • Gawchik SM, Saccar CL (2009) Pollinex Quattro Tree: allergy vaccine. Expert Opin Biol Ther 9:377–382

    CAS  PubMed  Google Scholar 

  • Ghosh TK, Mickelson DJ, Fink J, Solberg JC, Inglefield JR, Hook D, Gupta SK, Gibson S, Alkan SS (2006) Toll-like receptor (TLR) 2-9 agonists-induced cytokines and chemokines: I. Comparison with T cell receptor-induced responses. Cell Immunol 243:48–57

    CAS  PubMed  Google Scholar 

  • Gitlin AD, Shulman Z, Nussenzweig MC (2014) Clonal selection in the germinal centre by regulated proliferation and hypermutation. Nature 509:637–640

    CAS  PubMed  PubMed Central  Google Scholar 

  • Gorden KK, Qiu XX, Binsfeld CC, Vasilakos JP, Alkan SS (2006) Cutting edge: activation of murine TLR8 by a combination of imidazoquinoline immune response modifiers and polyT oligodeoxynucleotides. J Immunol 177:6584–6587

    CAS  PubMed  Google Scholar 

  • Gram GJ, Karlsson I, Agger EM, Andersen P, Fomsgaard A (2009) A novel liposome-based adjuvant CAF01 for induction of CD8(+) cytotoxic T-lymphocytes (CTL) to HIV-1 minimal CTL peptides in HLA-A*0201 transgenic mice. PLoS ONE 4:e6950

    PubMed  PubMed Central  Google Scholar 

  • Gribar SC, Richardson WM, Sodhi CP, Hackam DJ (2008) No longer an innocent bystander: epithelial toll-like receptor signaling in the development of mucosal inflammation. Mol Med 14:645–659

    CAS  PubMed  PubMed Central  Google Scholar 

  • Gupta AK, Cherman AM, Tyring SK (2004) Viral and nonviral uses of imiquimod: a review. J Cutan Med Surg 8:338–352

    PubMed  Google Scholar 

  • Guy B (2007) The perfect mix: recent progress in adjuvant research. Nat Rev Microbiol 5:505–517

    CAS  PubMed  Google Scholar 

  • Halperin SA, Van Nest G, Smith B, Abtahi S, Whiley H, Eiden JJ (2003) A phase I study of the safety and immunogenicity of recombinant hepatitis B surface antigen co-administered with an immunostimulatory phosphorothioate oligonucleotide adjuvant. Vaccine 21:2461–2467

    CAS  PubMed  Google Scholar 

  • Halperin SA, Dobson S, McNeil S, Langley JM, Smith B, McCall-Sani R, Levitt D, Nest GV, Gennevois D, Eiden JJ (2006) Comparison of the safety and immunogenicity of hepatitis B virus surface antigen co-administered with an immunostimulatory phosphorothioate oligonucleotide and a licensed hepatitis B vaccine in healthy young adults. Vaccine 24:20–26

    CAS  PubMed  Google Scholar 

  • Halperin SA, Ward B, Cooper C, Predy G, Diaz-Mitoma F, Dionne M, Embree J, McGeer A, Zickler P, Moltz K-H et al (2012) 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 30:2556–2563

    CAS  PubMed  Google Scholar 

  • Hamilton JA, Byrne R, Whitty G (2000) Particulate adjuvants can induce macrophage survival, DNA synthesis, and a synergistic proliferative response to GM-CSF and CSF-1. J Leukoc Biol 67:226–232

    CAS  PubMed  Google Scholar 

  • Hasan U, Chaffois C, Gaillard C, Saulnier V, Merck E, Tancredi S, Guiet C, Briere F, Vlach J, Lebecque S et al (2005) Human TLR10 is a functional receptor, expressed by B cells and plasmacytoid dendritic cells, which activates gene transcription through MyD88. J Immunol 174:2942–2950

    CAS  PubMed  Google Scholar 

  • Hay J, Carter D, Lieber A, Astier AL (2014) Recombinant Ad35 adenoviral proteins as potent modulators of human T cell activation. Immunology

    Google Scholar 

  • Hayashi F, Smith KD, Ozinsky A, Hawn TR, Yi EC, Goodlett DR, Eng JK, Akira S, Underhill DM, Aderem A (2001) The innate immune response to bacterial flagellin is mediated by Toll-like receptor 5. Nature 410:1099–1103

    CAS  PubMed  Google Scholar 

  • He P, Zou Y, Hu Z (2015) Advances in aluminum hydroxide-based adjuvant research and its mechanism. Hum Vaccin Immunother 11:477–488

    PubMed  PubMed Central  Google Scholar 

  • Hemmi H, Takeuchi O, Kawai T, Kaisho T, Sato S, Sanjo H, Matsumoto M, Hoshino K, Wagner H, Takeda K et al (2000) A Toll-like receptor recognizes bacterial DNA. Nature 408:740–745

    CAS  PubMed  Google Scholar 

  • Hemmi H, Kaisho T, Takeuchi O, Sato S, Sanjo H, Hoshino K, Horiuchi T, Tomizawa H, Takeda K, Akira S (2002) Small anti-viral compounds activate immune cells via the TLR7 MyD88-dependent signaling pathway. Nat Immunol 3:196–200

    CAS  PubMed  Google Scholar 

  • Hemmi H, Kaisho T, Takeda K, Akira S (2003) The roles of Toll-like receptor 9, MyD88, and DNA-dependent protein kinase catalytic subunit in the effects of two distinct CpG DNAs on dendritic cell subsets. J Immunol 170:3059–3064

    CAS  PubMed  Google Scholar 

  • Hung IFN, Zhang AJ, To KKW, Chan JFW, Li C, Zhu H-S, Li P, Li C, Chan T-C, Cheng VCC et al (2014) Immunogenicity of intradermal trivalent influenza vaccine with topical imiquimod: a double blind randomized controlled trial. Clin Infect Dis 59:1246–1255

    CAS  PubMed  Google Scholar 

  • Hung IF-N, Zhang AJ, To KK-W, Chan JF-W, Li P, Wong T-L, Zhang R, Chan T-C, Chan BC-Y, Wai HH et al (2016) Topical imiquimod before intradermal trivalent influenza vaccine for protection against heterologous non-vaccine and antigenically drifted viruses: a single-centre, double-blind, randomised, controlled phase 2b/3 trial. Lancet Infect Dis 16:209–218

    Google Scholar 

  • Imler JL, Zheng L (2004) Biology of Toll receptors: lessons from insects and mammals. J Leukoc Biol 75:18–26

    CAS  PubMed  Google Scholar 

  • Jin MS, Kim SE, Heo JY, Lee ME, Kim HM, Paik S-G, Lee H, Lee J-O (2007) Crystal structure of the TLR1-TLR2 heterodimer induced by binding of a tri-acylated lipopeptide. Cell 130:1071–1082

    Google Scholar 

  • Johnson TR, Rao S, Seder RA, Chen M, Graham BS (2009) TLR9 agonist, but not TLR7/8, functions as an adjuvant to diminish FI-RSV vaccine-enhanced disease, while either agonist used as therapy during primary RSV infection increases disease severity. Vaccine 27:3045–3052

    CAS  PubMed  PubMed Central  Google Scholar 

  • Jurk M, Heil F, Vollmer J, Schetter C, Krieg AM, Wagner H, Lipford G, Bauer S (2002) Human TLR7 or TLR8 independently confer responsiveness to the antiviral compound R-848. Nat Immunol 3:499

    CAS  PubMed  Google Scholar 

  • Kang DC, Gopalkrishnan RV, Wu Q, Jankowsky E, Pyle AM, Fisher PB (2002) mda-5: An interferon-inducible putative RNA helicase with double-stranded RNA-dependent ATPase activity and melanoma growth-suppressive properties. Proc Natl Acad Sci U S A 99:637–642

    CAS  PubMed  PubMed Central  Google Scholar 

  • Kasturi SP, Skountzou I, Albrecht RA, Koutsonanos D, Hua T, Nakaya HI, Ravindran R, Stewart S, Alam M, Kwissa M et al (2011) Programming the magnitude and persistence of antibody responses with innate immunity. Nature 470:543–547

    CAS  PubMed  PubMed Central  Google Scholar 

  • Krieg AM, Efler SM, Wittpoth M, Al Adhami MJ, Davis HL (2004) Induction of systemic TH1-like innate immunity in normal volunteers following subcutaneous but not intravenous administration of CPG 7909, a synthetic B-class CpG oligodeoxynucleotide TLR9 agonist. J Immunother 27:460–471

    CAS  PubMed  Google Scholar 

  • Kwissa M, Kasturi SP, Pulendran B (2007) The science of adjuvants. Expert Rev Vaccines 6:673–684

    CAS  PubMed  Google Scholar 

  • Leroux-Roels I, Forgus S, De Boever F, Clement F, Demoitie MA, Mettens P, Moris P, Ledent E, Leroux-Roels G, Ofori-Anyinam O (2013) Improved CD4(+) T cell responses to Mycobacterium tuberculosis in PPD-negative adults by M72/AS01 as compared to the M72/AS02 and Mtb72F/AS02 tuberculosis candidate vaccine formulations: a randomized trial. Vaccine 13:2196–2206

    Google Scholar 

  • Leroux-Roels G, Van Belle P, Vandepapeliere P, Horsmans Y, Janssens M, Carletti I, Garcon N, Wettendorff M, Van Mechelen M (2015) Vaccine Adjuvant Systems containing monophosphoryl lipid A and QS-21 induce strong humoral and cellular immune responses against hepatitis B surface antigen which persist for at least 4 years after vaccination. Vaccine 33:1084–1091

    CAS  PubMed  Google Scholar 

  • Lewis GK, DeVico AL, Gallo RC (2014) Antibody persistence and T-cell balance: two key factors confronting HIV vaccine development. Proc Natl Acad Sci U S A 111:15614–15621

    CAS  PubMed  PubMed Central  Google Scholar 

  • Li Z, Woo CJ, Iglesias-Ussel MD, Ronai D, Scharff MD (2004) The generation of antibody diversity through somatic hypermutation and class switch recombination. Genes Dev 18:1–11

    PubMed  Google Scholar 

  • Li Y, Svehla K, Mathy NL, Voss G, Mascola JR, Wyatt R (2006) Characterization of antibody responses elicited by human immunodeficiency virus type 1 primary isolate trimeric and monomeric envelope glycoproteins in selected adjuvants. J Virol 80:1414–1426

    CAS  PubMed  PubMed Central  Google Scholar 

  • Liu L, Botos I, Wang Y, Leonard JN, Shiloach J, Segal DM, Davies DR (2008) Structural basis of toll-like receptor 3 signaling with double-stranded RNA. Science 320:379–381

    CAS  PubMed  PubMed Central  Google Scholar 

  • Liu J, Xu C, Hsu LC, Luo Y, Xiang R, Chuang TH (2010) A five-amino-acid motif in the undefined region of the TLR8 ectodomain is required for species-specific ligand recognition. Mol Immunol 47:1083–1090

    CAS  PubMed  Google Scholar 

  • Lofano G, Mancini F, Salvatore G, Cantisani R, Monaci E, Carrisi C, Tavarini S, Sammicheli C, Rossi Paccani S, Soldaini E et al (2015) Oil-in-water emulsion MF59 increases germinal center B cell differentiation and persistence in response to vaccination. J Immunol 195:1617–1627

    CAS  PubMed  Google Scholar 

  • Lousada-Dietrich S, Jogdand PS, Jepsen S, Pinto VV, Ditlev SB, Christiansen M, Larsen SO, Fox CB, Raman VS, Howard RF et al (2011) A synthetic TLR4 agonist formulated in an emulsion enhances humoral and Type 1 cellular immune responses against GMZ2—a GLURP-MSP3 fusion protein malaria vaccine candidate. Vaccine 29:3284–3292

    Google Scholar 

  • Lowes R (2017) Heplisav-B vaccine for Hep B finally wins FDA approval. Edited by Medscape

    Google Scholar 

  • Martinon F, Tschopp J (2005) NLRs join TLRs as innate sensors of pathogens. Trends Immunol 26:447–454

    CAS  PubMed  Google Scholar 

  • Martins KA, Cooper CL, Stronsky SM, Norris SL, Kwilas SA, Steffens JT, Benko JG, van Tongeren SA, Bavari S (2016) Adjuvant-enhanced CD4 T cell responses are critical to durable vaccine immunity. EBioMedicine 3:67–78

    PubMed  Google Scholar 

  • Mata-Haro V, Cekic C, Martin M, Chilton PM, Casella CR, Mitchell TC (2007) The vaccine adjuvant monophosphoryl lipid A as a TRIF-biased agonist of TLR4. Science 316:1628–1632

    CAS  PubMed  Google Scholar 

  • Matthews K, Chung NP, Klasse PJ, Moutaftsi M, Carter D, Salazar AM, Reed SG, Sanders RW, Moore JP (2013) Clinical adjuvant combinations stimulate potent B-cell responses in vitro by activating dermal dendritic cells. PLoS ONE 8:e63785

    CAS  PubMed  PubMed Central  Google Scholar 

  • McCormack PL, Wagstaff AJ (2006) Ultra-short-course seasonal allergy vaccine (Pollinex Quattro). Drugs 66:931–938

    CAS  PubMed  Google Scholar 

  • Misquith A, Fung HWM, Dowling QM, Guderian JA, Vedvick TS, Fox CB (2014) In vitro evaluation of TLR4 agonist activity: formulation effects. Colloids Surf, B 113:312–319

    CAS  Google Scholar 

  • Mosca F, Tritto E, Muzzi A, Monaci E, Bagnoli F, Iavarone C, O’Hagan D, Rappuoli R, De Gregorio E (2008) Molecular and cellular signatures of human vaccine adjuvants. Proc Natl Acad Sci U S A 105:10501–10506

    CAS  PubMed  PubMed Central  Google Scholar 

  • Mueller M, Lindner B, Kusumoto S, Fukase K, Schromm AB, Seydel U (2004) Aggregates are the biologically active units of endotoxin. J Biol Chem 279:26307–26313

    CAS  PubMed  Google Scholar 

  • Mulligan MJ, Bernstein DI, Winokur P et al (2014) Serological responses to an avian influenza a/h7n9 vaccine mixed at the point-of-use with mf59 adjuvant: a randomized clinical trial. JAMA 312:1409–1419

    CAS  PubMed  Google Scholar 

  • Nguyen M, Leuridan E, Zhang T, De Wit D, Willems F, Van Damme P, Goldman M, Goriely S (2010) Acquisition of adult-like TLR4 and TLR9 responses during the first year of life. PLoS ONE 5:e10407

    PubMed  PubMed Central  Google Scholar 

  • Nitayaphan S, Khamboonruang C, Sirisophana N, Morgan P, Chiu J, Duliege AM, Chuenchitra C, Supapongse T, Rungruengthanakit K, deSouza M et al (2000) A phase I/II trial of HIV SF2 gp120/MF59 vaccine in seronegative thais. AFRIMS-RIHES Vaccine Evaluation Group. Armed Forces Research Institute of Medical Sciences and the Research Institute for Health Sciences. Vaccine 18:1448–1455

    CAS  PubMed  Google Scholar 

  • Ohto U, Shibata T, Tanji H, Ishida H, Krayukhina E, Uchiyama S, Miyake K, Shimizu T (2015) Structural basis of CpG and inhibitory DNA recognition by Toll-like receptor 9. Nature 520:702–705

    CAS  PubMed  Google Scholar 

  • O’Neill LA, Bowie AG (2007) The family of five: TIR-domain-containing adaptors in Toll-like receptor signalling. Nat Rev Immunol 7:353–364

    PubMed  Google Scholar 

  • O’Neill LA, Bryant CE, Doyle SL (2009) Therapeutic targeting of Toll-like receptors for infectious and inflammatory diseases and cancer. Pharmacol Rev 61:177–197

    PubMed  PubMed Central  Google Scholar 

  • Orr MT, Fox CB, Baldwin SL, Sivananthan SJ, Lucas E, Lin S, Phan T, Moon JJ, Vedvick TS, Reed SG et al (2013) Adjuvant formulation structure and composition are critical for the development of an effective vaccine against tuberculosis. J Controlled Release 172:190–200

    CAS  Google Scholar 

  • Otero M, Calarota SA, Felber B, Laddy D, Pavlakis G, Boyer JD, Weiner DB (2004) Resiquimod is a modest adjuvant for HIV-1 gag-based genetic immunization in a mouse model. Vaccine 22:1782–1790

    CAS  PubMed  Google Scholar 

  • Ozinsky A, Underhill DM, Fontenot JD, Hajjar AM, Smith KD, Wilson CB, Schroeder L, Aderem A (2000) The repertoire for pattern recognition of pathogens by the innate immune system is defined by cooperation between toll-like receptors. Proc Natl Acad Sci U S A 97:13766–13771

    CAS  PubMed  PubMed Central  Google Scholar 

  • Paes W, Brown N, Brzozowski AM, Coler R, Reed S, Carter D, Bland M, Kaye PM, Lacey CJN (2016) Recombinant polymorphic membrane protein D in combination with a novel, second-generation lipid adjuvant protects against intra-vaginal Chlamydia trachomatis infection in mice. Vaccine 34:4123–4131

    CAS  PubMed  PubMed Central  Google Scholar 

  • Palm NW, Medzhitov R (2009) Pattern recognition receptors and control of adaptive immunity. Immunol Rev 227:221–233

    CAS  PubMed  Google Scholar 

  • Panda A, Qian F, Mohanty S, van Duin D, Newman FK, Zhang L, Chen S, Towle V, Belshe RB, Fikrig E et al (2010) Age-associated decrease in TLR function in primary human dendritic cells predicts influenza vaccine response. J Immunol 184:2518–2527

    CAS  PubMed  Google Scholar 

  • Park BS, Song DH, Kim HM, Choi BS, Lee H, Lee JO (2009) The structural basis of lipopolysaccharide recognition by the TLR4-MD-2 complex. Nature 458:1191–1195

    CAS  PubMed  Google Scholar 

  • Persing DH, Coler RN, Lacy MJ, Johnson DA, Baldridge JR, Hershberg RM, Reed SG (2002) Taking toll: lipid A mimetics as adjuvants and immunomodulators. Trends Microbiol 10:S32–S37

    CAS  PubMed  Google Scholar 

  • Phillipps KS, Wykes MN, Liu XQ, Brown M, Blanchfield J, Toth I (2009) A novel synthetic adjuvant enhances dendritic cell function. Immunology 128:e582–e588

    PubMed  PubMed Central  Google Scholar 

  • Pone EJ, Zhang J, Mai T, White CA, Li G, Sakakura JK, Patel PJ, Al-Qahtani A, Zan H, Xu Z et al (2012) BCR-signalling synergizes with TLR-signalling for induction of AID and immunoglobulin class-switching through the non-canonical NF-κB pathway. Nat Commun 3:767

    PubMed  Google Scholar 

  • Prajeeth CK, Jirmo AC, Krishnaswamy JK, Ebensen T, Guzman CA, Weiss S, Constabel H, Schmidt RE, Behrens GM (2010) The synthetic TLR2 agonist BPPcysMPEG leads to efficient cross-priming against co-administered and linked antigens. Eur J Immunol 40:1272–1283

    CAS  PubMed  Google Scholar 

  • Puggioni F, Durham SR, Francis JN (2005) Monophosphoryl lipid A (MPL) promotes allergen-induced immune deviation in favour of Th1 responses. Allergy 60:678–684

    CAS  PubMed  Google Scholar 

  • Rallabhandi P, Awomoyi A, Thomas KE, Phalipon A, Fujimoto Y, Fukase K, Kusumoto S, Qureshi N, Sztein MB, Vogel SN (2008) Differential activation of human TLR4 by Escherichia coli and Shigella flexneri 2a lipopolysaccharide: combined effects of lipid A acylation state and TLR4 polymorphisms on signaling. J Immunol 180:1139–1147

    CAS  PubMed  Google Scholar 

  • Raman VS, Bhatia A, Picone A, Whittle J, Bailor HR, O’Donnell J, Pattabhi S, Guderian JA, Mohamath R, Duthie MS et al (2010) Applying TLR synergy in immunotherapy: implications in cutaneous leishmaniasis. J Immunol

    Google Scholar 

  • Ray A, Cot M, Puzo G, Gilleron M, Nigou J (2013) Bacterial cell wall macroamphiphiles: pathogen-/microbe-associated molecular patterns detected by mammalian innate immune system. Biochimie 95:33–42

    CAS  PubMed  Google Scholar 

  • Reed Steven G, Fox Christopher B, Carter D (2012) Emulsion-based vaccine adjuvants. Future Medicine Ltd.

    Google Scholar 

  • Rosewich M, Lee D, Zielen S (2013) Pollinex Quattro: an innovative four injections immunotherapy in allergic rhinitis. Hum Vaccin Immunother 9:1523–1531

    CAS  PubMed  Google Scholar 

  • Ruwona TB, Xu H, Li X, Taylor AN, Shi YC, Cui Z (2016) Toward understanding the mechanism underlying the strong adjuvant activity of aluminum salt nanoparticles. Vaccine 34:3059–3067

    CAS  PubMed  PubMed Central  Google Scholar 

  • Santini-Oliveira M, Coler RN, Parra J, Veloso V, Jayashankar L, Pinto PM, Ciol MA, Bergquist R, Reed SG, Tendler M (2016) Schistosomiasis vaccine candidate Sm14/GLA-SE: Phase 1 safety and immunogenicity clinical trial in healthy, male adults. Vaccine 34:586–594

    CAS  PubMed  Google Scholar 

  • Schwarz TF (2009) Clinical update of the AS04-Adjuvanted human Papillomavirus-16/18 cervical cancer vaccine, cervarix®. Adv Ther 26:983–998

    PubMed  Google Scholar 

  • Seubert A, Monaci E, Pizza M, O’Hagan DT, Wack A (2008) The adjuvants aluminum hydroxide and MF59 induce monocyte and granulocyte chemoattractants and enhance monocyte differentiation toward dendritic cells. J Immunol 180:5402–5412

    CAS  PubMed  Google Scholar 

  • Seydel U, Oikawa M, Fukase K, Kusumoto S, Brandenburg K (2000) Intrinsic conformation of lipid A is responsible for agonistic and antagonistic activity. Eur J Biochem 267:3032–3039

    CAS  PubMed  Google Scholar 

  • Shukla NM, Malladi SS, Mutz CA, Balakrishna R, David SA (2010) Structure-activity relationships in human toll-like receptor 7-active imidazoquinoline analogues. J Med Chem 53:4450–4465

    CAS  PubMed  PubMed Central  Google Scholar 

  • Sigal LH, Zahradnik JM, Lavin P, Patella SJ, Bryant G, Haselby R, Hilton E, Kunkel M, Adler-Klein D, Doherty T et al (1998) A vaccine consisting of recombinant Borrelia burgdorferi outer-surface protein A to prevent lyme disease. Recombinant outer-surface protein A lyme disease vaccine study consortium. N Engl J Med 339:216–222

    CAS  PubMed  Google Scholar 

  • Singh M, Khong H, Dai Z, Huang XF, Wargo JA, Cooper ZA, Vasilakos JP, Hwu P, Overwijk WW (2014) Effective innate and adaptive antimelanoma immunity through localized TLR7/8 activation. J Immunol 193:4722–4731

    CAS  PubMed  Google Scholar 

  • Smirnov D, Schmidt JJ, Capecchi JT, Wightman PD (2011) Vaccine adjuvant activity of 3M-052: an imidazoquinoline designed for local activity without systemic cytokine induction. Vaccine 29:5434–5442

    CAS  PubMed  Google Scholar 

  • Smith KJ, Hamza S, Skelton H (2003) The imidazoquinolines and their place in the therapy of cutaneous disease. Expert Opin Pharmacother 4:1105–1119

    CAS  PubMed  Google Scholar 

  • Sogaard OS, Lohse N, Harboe ZB, Offersen R, Bukh AR, Davis HL, Schonheyder HC, Ostergaard L (2010) Improving the immunogenicity of pneumococcal conjugate vaccine in HIV-infected adults with a toll-like receptor 9 agonist adjuvant: a randomized, controlled trial. Clin Infect Dis 51:42–50

    PubMed  Google Scholar 

  • Song L, Liu G, Umlauf S, Liu X, Li H, Tian H, Reiserova L, Hou F, Bell R, Tussey L (2014) A rationally designed form of the TLR5 agonist, flagellin, supports superior immunogenicity of Influenza B globular head vaccines. Vaccine 32:4317–4323

    CAS  PubMed  Google Scholar 

  • Spreafico R, Ricciardi-Castagnoli P, Mortellaro A (2010) The controversial relationship between NLRP3, alum, danger signals and the next-generation adjuvants. Eur J Immunol 40:638–642

    CAS  PubMed  Google Scholar 

  • Steers NJ, Peachman KK, McClain S, Alving CR, Rao M (2009) Liposome-encapsulated HIV-1 Gag p24 containing lipid A induces effector CD4+ T-cells, memory CD8+ T-cells, and pro-inflammatory cytokines. Vaccine 27:6939–6949

    CAS  PubMed  Google Scholar 

  • Surquin M, Tielemans C, Nortier J, Jadoul M, Peeters P, Ryba M, Roznovsky L, Doman J, Barthelemy X, Crasta PD et al (2011) Anti-HBs antibody persistence following primary vaccination with an investigational AS02(v)-adjuvanted hepatitis B vaccine in patients with renal insufficiency. Hum vaccines 7:913–918

    CAS  Google Scholar 

  • Takeuchi O, Kawai T, Muhlradt PF, Morr M, Radolf JD, Zychlinsky A, Takeda K, Akira S (2001) Discrimination of bacterial lipoproteins by Toll-like receptor 6. Int Immunol 13:933–940

    CAS  PubMed  Google Scholar 

  • Tanji H, Ohto U, Shibata T, Taoka M, Yamauchi Y, Isobe T, Miyake K, Shimizu T (2015) Toll-like receptor 8 senses degradation products of single-stranded RNA. Nat Struct Mol Biol 22:109–115

    CAS  PubMed  Google Scholar 

  • Thoma-Uszynski S, Stenger S, Takeuchi O, Ochoa MT, Engele M, Sieling PA, Barnes PF, Rollinghoff M, Bolcskei PL, Wagner M et al (2001) Induction of direct antimicrobial activity through mammalian toll-like receptors. Science 291:1544–1547

    CAS  PubMed  Google Scholar 

  • Tighe H, Takabayashi K, Schwartz D, Marsden R, Beck L, Corbeil J, Richman DD, Eiden JJ Jr, Spiegelberg HL, Raz E (2000) Conjugation of protein to immunostimulatory DNA results in a rapid, long-lasting and potent induction of cell-mediated and humoral immunity. Eur J Immunol 30:1939–1947

    CAS  PubMed  Google Scholar 

  • van Duin D, Shaw AC (2007) Toll-like receptors in older adults. J Am Geriatr Soc 55:1438–1444

    PubMed  Google Scholar 

  • van Duin D, Mohanty S, Thomas V, Ginter S, Montgomery RR, Fikrig E, Allore HG, Medzhitov R, Shaw AC (2007) Age-associated defect in human TLR-1/2 function. J Immunol 178:970–975

    PubMed  Google Scholar 

  • Van Hoeven N, Fox CB, Granger B, Evers T, Joshi SW, Nana GI, Evans SC, Lin S, Liang H, Liang L et al (2017) A formulated TLR7/8 agonist is a flexible, highly potent and effective adjuvant for pandemic influenza vaccines. Sci Rep 7:46426

    PubMed  PubMed Central  Google Scholar 

  • Vandepapeliere P, Horsmans Y, Moris P, Van Mechelen M, Janssens M, Koutsoukos M, Van Belle P, Clement F, Hanon E, Wettendorff M et al (2008) Vaccine adjuvant systems containing monophosphoryl lipid A and QS21 induce strong and persistent humoral and T cell responses against hepatitis B surface antigen in healthy adult volunteers. Vaccine 26:1375–1386

    CAS  PubMed  Google Scholar 

  • Vono M, Taccone M, Caccin P, Gallotta M, Donvito G, Falzoni S, Palmieri E, Pallaoro M, Rappuoli R, Di Virgilio F et al (2013) The adjuvant MF59 induces ATP release from muscle that potentiates response to vaccination. Proc Natl Acad Sci 110:21095–21100

    CAS  PubMed  PubMed Central  Google Scholar 

  • Wen Y, Shi Y (2016) Alum: an old dog with new tricks. Emerg Microbes Infect 5:e25

    CAS  PubMed  PubMed Central  Google Scholar 

  • Wiley SR, Raman VS, Desbien A, Bailor HR, Bhardwaj R, Shakri AR, Reed SG, Chitnis CE, Carter D (2011) Targeting TLRs expands the antibody repertoire in response to a malaria vaccine. Sci Transl Med 3:93ra69

    Google Scholar 

  • Yoon S-i, Kurnasov O, Natarajan V, Hong M, Gudkov AV, Osterman AL, Wilson IA (2012) Structural basis of TLR5-flagellin recognition and signaling. Science 335:859–864

    CAS  PubMed  PubMed Central  Google Scholar 

  • Zhang X, Mosser DM (2008) Macrophage activation by endogenous danger signals. J Pathol 214:161–178

    CAS  PubMed  PubMed Central  Google Scholar 

  • Zhao BG, Vasilakos JP, Tross D, Smirnov D, Klinman DM (2014) Combination therapy targeting toll like receptors 7, 8 and 9 eliminates large established tumors. J Immunother Cancer 2:12

    CAS  PubMed  PubMed Central  Google Scholar 

  • Zucchini N, Bessou G, Traub S, Robbins SH, Uematsu S, Akira S, Alexopoulou L, Dalod M (2008) Cutting edge: overlapping functions of TLR7 and TLR9 for innate defense against a herpesvirus infection. J Immunol 180:5799–5803

    CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. PAI Life Sciences Inc., 1616 Eastlake Ave E, Suite 550, Seattle, WA, 98102, USA

    Darrick Carter

  2. Adjuvant Technologies, IDRI, 1616 Eastlake Avenue E., Suite 400, Seattle, WA, 98102, USA

    Darrick Carter, Malcolm S. Duthie & Steven G. Reed

  3. Global Health, University of Washington, 1616 Eastlake Ave E, Suite 400, Seattle, WA, 98102, USA

    Darrick Carter, Malcolm S. Duthie & Steven G. Reed

Authors
  1. Darrick Carter
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Malcolm S. Duthie
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Steven G. Reed
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Darrick Carter .

Editor information

Editors and Affiliations

  1. Dept. of Immunology & Microbiology, The Scripps Research Institute, La Jolla, CA, USA

    Lars Hangartner

  2. Dept. of Immunology & Microbiology, The Scripps Research Institute, La Jolla, CA, USA

    Dennis R. Burton

Rights and permissions

Reprints and permissions

Copyright information

© 2018 Springer International Publishing AG, part of Springer Nature

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

Carter, D., Duthie, M.S., Reed, S.G. (2018). Adjuvants. In: Hangartner, L., Burton, D. (eds) Vaccination Strategies Against Highly Variable Pathogens. Current Topics in Microbiology and Immunology, vol 428. Springer, Cham. https://doi.org/10.1007/82_2018_112

Download citation

Publish with us

Policies and ethics

Search

Navigation