Abstract
Lipopolysaccharide (LPS, endotoxin) is a major component of the outer membrane of gram negative bacteria. It is an activator of humoral and cellular responses in humans with potential use as adjuvant in vaccine technology. Importantly, LPS has a large capacity to induce Th1-type responses and stimulate cytotoxic T lymphocytes, which are poorly obtained by standard adjuvants but required for specific immune stimulatory therapies. In contrast, LPS possess an extreme toxicity that limit its clinical use in humans. Alteration of its chemical structure led the generation of LPS-based derivatives with reduced toxicity but retaining adjuvant properties. Monophosphoryl lipid A (MPLA) has been the most successful LPS-based adjuvant, currently incorporated in approved vaccine preparations and extensively used in vaccine trials and preclinical studies. Novel designed structures, analogous to LPS and generated by chemical synthesis, can offer lower production cost and lesser heterogenic formulations than MPLA and, in addition, be even most suitable for specific immune therapies. Thus, LPS-based structures are valuable contributions as adjuvants in human vaccinology and open new possibilities to existing demands for specific therapies.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
References
Rietschel, E.T., et al.: Bacterial endotoxins: chemical structure, biological activity and role in septicaemia. Scand. J. Infect. Dis. Suppl. 31, 8–21 (1982)
Guo, L., et al.: Lipid A acylation and bacterial resistance against vertebrate antimicrobial peptides. Cell 95, 189–198 (1998)
Gibbons, H.S., Lin, S., Cotter, R.J., Raetz, C.R.: Oxygen requirement for the biosynthesis of the S-2-hydroxymyristate moiety in Salmonella typhimurium lipid A. Function of LpxO, A new Fe2+/alpha-ketoglutarate-dependent dioxygenase homologue. J. Biol. Chem. 275, 32940–32949 (2000)
Reynolds, C.M., et al.: An outer membrane enzyme encoded by Salmonella typhimurium lpxR that removes the 3’-acyloxyacyl moiety of lipid A. J. Biol. Chem. 281, 21974–21987 (2006)
Trent, M.S., Pabich, W., Raetz, C.R., Miller, S.I.: A PhoP/PhoQ-induced Lipase (PagL) that catalyzes 3-O-deacylation of lipid A precursors in membranes of Salmonella typhimurium. J. Biol. Chem. 276, 9083–9092 (2001)
Kawai, T., Akira, S.: Toll-like receptors and their crosstalk with other innate receptors in infection and immunity. Immunity 34, 637–650 (2011)
Palsson-McDermott, E.M., O’Neill, L.A.: Signal transduction by the lipopolysaccharide receptor, Toll-like receptor-4. Immunology 113, 153–162 (2004)
Trinchieri, G., Sher, A.: Cooperation of Toll-like receptor signals in innate immune defence. Nat. Rev. Immunol. 7, 179–190 (2007)
Kawai, T., Akira, S.: TLR signaling. Cell Death Differ. 13, 816–825 (2006)
Miggin, S.M., O’Neill, L.A.: New insights into the regulation of TLR signaling. J. Leukoc. Biol. 80, 220–226 (2006)
Alexander, C., Rietschel, E.T.: Bacterial lipopolysaccharides and innate immunity. J. Endotoxin Res. 7, 167–202 (2001)
Morrison, D.C., Kline, L.F.: Activation of the classical and properdin pathways of complement by bacterial lipopolysaccharides (LPS). J. Immunol. 118, 362–368 (1977)
Cooper, N.R., Morrison, D.C.: Binding and activation of the first component of human complement by the lipid A region of lipopolysaccharides. J. Immunol. 120, 1862–1868 (1978)
Conti, P., et al.: Activation of human natural killer cells by lipopolysaccharide and generation of interleukin-1 alpha, beta, tumour necrosis factor and interleukin-6. Effect of IL-1 receptor antagonist. Immunology 73, 450–456 (1991)
Kobayashi, M., et al.: Identification and purification of natural killer cell stimulatory factor (NKSF), a cytokine with multiple biologic effects on human lymphocytes. J. Exp. Med. 170, 827–845 (1989)
Cinel, I., Dellinger, R.P.: Advances in pathogenesis and management of sepsis. Curr. Opin. Infect. Dis. 20, 345–352 (2007)
Annane, D., Bellissant, E., Cavaillon, J.M.: Septic shock. Lancet 365(63–78) (2005)
Vincent, J.L., et al.: Sepsis in European intensive care units: results of the SOAP study. Crit. Care Med. 34, 344–353 (2006)
Martin, G.S., Mannino, D.M., Eaton, S., Moss, M.: The epidemiology of sepsis in the United States from 1979 through 2000. N. Engl. J. Med. 348, 1546–1554 (2003)
Kotani, S., Takada, H.: Structural requirements of lipid A for endotoxicity and other biological activities – an overview. Adv. Exp. Med. Biol. 256, 13–43 (1990)
Nowotny, A.: Molecular aspects of endotoxic reactions. Bacteriol. Rev. 33, 72–98 (1969)
Miller, S.I., Ernst, R.K., Bader, M.W.: LPS, TLR4 and infectious disease diversity. Nat. Rev. Microbiol. 3, 36–46 (2005)
Golenbock, D.T., Hampton, R.Y., Qureshi, N., Takayama, K., Raetz, C.R.: Lipid A-like molecules that antagonize the effects of endotoxins on human monocytes. J. Biol. Chem. 266, 19490–19498 (1991)
Kotani, S., et al.: Synthetic lipid A with endotoxic and related biological activities comparable to those of a natural lipid A from an Escherichia coli re-mutant. Infect. Immun. 49, 225–237 (1985)
Saitoh, S., et al.: Lipid A antagonist, lipid IVa, is distinct from lipid A in interaction with Toll-like receptor 4 (TLR4)-MD-2 and ligand-induced TLR4 oligomerization. Int. Immunol. 16, 961–969 (2004)
David, S., Vermeer-de Bondt, P.E., van der Maas, N.A.: Reactogenicity of infant whole cell pertussis combination vaccine compared with acellular pertussis vaccines with or without simultaneous pneumococcal vaccine in the Netherlands. Vaccine 26, 5883–5887 (2008)
Gustafsson, L., Hallander, H.O., Olin, P., Reizenstein, E., Storsaeter, J.: A controlled trial of a two-component acellular, a five-component acellular, and a whole-cell pertussis vaccine. N. Engl. J. Med. 334, 349–355 (1996)
Brewer, J.M., et al.: Aluminium hydroxide adjuvant initiates strong antigen-specific Th2 responses in the absence of IL-4- or IL-13-mediated signaling. J. Immunol. 163, 6448–6454 (1999)
Dubensky Jr., T.W., Reed, S.G.: Adjuvants for cancer vaccines. Semin. Immunol. 22, 155–161 (2010)
Soghoian, D.Z., Streeck, H.: Cytolytic CD4(+) T cells in viral immunity. Expert Rev. Vaccines 9, 1453–1463 (2010)
Ziegler, A., et al.: EpCAM, a human tumor-associated antigen promotes Th2 development and tumor immune evasion. Blood 113, 3494–3502 (2009)
Akkoc, T., Akdis, M., Akdis, C.A.: Update in the mechanisms of allergen-specific immunotheraphy. Allergy Asthma Immunol. Res. 3, 11–20 (2011)
Chen, K., Cerutti, A.: Vaccination strategies to promote mucosal antibody responses. Immunity 33, 479–491 (2010)
Lawson, L.B., Norton, E.B., Clements, J.D.: Defending the mucosa: adjuvant and carrier formulations for mucosal immunity. Curr. Opin. Immunol. 23, 414–420 (2011)
O’Hagan, D.T.: MF59 is a safe and potent vaccine adjuvant that enhances protection against influenza virus infection. Expert Rev. Vaccines 6, 699–710 (2007)
Arenas, J.: The role of bacterial lipopolysaccharides as immune modulator in vaccine and drug development. Endocr. Metab. Immune Disord. Drug Targets 12(3), 221–235 (2012)
Baldridge, J.R., Crane, R.T.: Monophosphoryl lipid A (MPL) formulations for the next generation of vaccines. Methods 19, 103–107 (1999)
Evans, J.T., et al.: Enhancement of antigen-specific immunity via the TLR4 ligands MPL adjuvant and Ribi.529. Expert Rev. Vaccines 2, 219–229 (2003)
Ulrich, J.T., Myers, K.R.: Monophosphoryl lipid A as an adjuvant. Past experiences and new directions. Pharm. Biotechnol. 6, 495–524 (1995)
Vajdy, M., Singh, M.: The role of adjuvants in the development of mucosal vaccines. Expert Opin. Biol. Ther. 5, 953–965 (2005)
Drachenberg, K.J., Wheeler, A.W., Stuebner, P., Horak, F.: A well-tolerated grass pollen-specific allergy vaccine containing a novel adjuvant, monophosphoryl lipid A, reduces allergic symptoms after only four preseasonal injections. Allergy 56, 498–505 (2001)
Drachenberg, K.J., Heinzkill, M., Urban, E., Woroniecki, S.R.: Efficacy and tolerability of short-term specific immunotherapy with pollen allergoids adjuvanted by monophosphoryl lipid A (MPL) for children and adolescents. Allergol. Immunopathol. (Madr.) 31, 270–277 (2003)
Kundi, M.: New hepatitis B vaccine formulated with an improved adjuvant system. Expert Rev. Vaccines 6, 133–140 (2007)
Aide, P., et al.: Four year immunogenicity of the RTS, S/AS02(A) malaria vaccine in Mozambican children during a phase IIb trial. Vaccine 29, 6059–6067 (2011)
Von, E.K., et al.: The candidate tuberculosis vaccine Mtb72F/AS02A: Tolerability and immunogenicity in humans. Hum. Vaccin. 5, 475–482 (2009)
Polhemus, M.E., et al.: Evaluation of RTS, S/AS02A and RTS, S/AS01B in adults in a high malaria transmission area. PLoS One 4, e6465 (2009)
Brichard, V.G., Lejeune, D.: Cancer immunotherapy targeting tumour-specific antigens: towards a new therapy for minimal residual disease. Expert Opin. Biol. Ther. 8, 951–968 (2008)
Garcon, N., Chomez, P., Van, M.M.: GlaxoSmithKline Adjuvant Systems in vaccines: concepts, achievements and perspectives. Expert Rev. Vaccines 6, 723–739 (2007)
Fries, L.F., et al.: Liposomal malaria vaccine in humans: a safe and potent adjuvant strategy. Proc. Natl. Acad. Sci. U. S. A. 89, 358–362 (1992)
Arenas, J., et al.: Coincorporation of LpxL1 and PagL mutant lipopolysaccharides into liposomes with Neisseria meningitidis opacity protein: influence on endotoxic and adjuvant activity. Clin. Vaccine Immunol. 17, 487–495 (2010)
Vernacchio, L., et al.: Effect of monophosphoryl lipid A (MPL) on T-helper cells when administered as an adjuvant with pneumocococcal-CRM197 conjugate vaccine in healthy toddlers. Vaccine 20, 3658–3667 (2002)
Olson, K., et al.: Liposomal gD ectodomain (gD1-306) vaccine protects against HSV2 genital or rectal infection of female and male mice. Vaccine 28, 548–560 (2009)
Hall, M.A., et al.: Intranasal immunization with multivalent group A streptococcal vaccines protects mice against intranasal challenge infections. Infect. Immun. 72, 2507–2512 (2004)
Tana, W.S., Isogai, E., Oguma, K.: Induction of intestinal IgA and IgG antibodies preventing adhesion of verotoxin-producing Escherichia coli to Caco-2 cells by oral immunization with liposomes. Lett. Appl. Microbiol. 36, 135–139 (2003)
Baldridge, J.R., Yorgensen, Y., Ward, J.R., Ulrich, J.T.: Monophosphoryl lipid A enhances mucosal and systemic immunity to vaccine antigens following intranasal administration. Vaccine 18, 2416–2425 (2000)
Kidon, M.I., Shechter, E., Toubi, E.: Vaccination against human papilloma virus and cervical cancer. Harefuah 150, 33–36 (2011). 68
Labadie, J.: Postlicensure safety evaluation of human papilloma virus vaccines. Int. J. Risk Saf. Med. 23, 103–112 (2011)
Morello, C.S., Levinson, M.S., Kraynyak, K.A., Spector, D.H.: Immunization with herpes simplex virus 2 (HSV-2) genes plus inactivated HSV-2 is highly protective against acute and recurrent HSV-2 disease. J. Virol. 85, 3461–3472 (2011)
Llanos-Cuentas, A., et al.: A clinical trial to evaluate the safety and immunogenicity of the LEISH-F1 + MPL-SE vaccine when used in combination with sodium stibogluconate for the treatment of mucosal leishmaniasis. Vaccine 28, 7427–7435 (2010)
Zhu, D., Barniak, V., Zhang, Y., Green, B., Zlotnick, G.: Intranasal immunization of mice with recombinant lipidated P2086 protein reduces nasal colonization of group B Neisseria meningitidis. Vaccine 24, 5420–5425 (2006)
Green, B.A., et al.: PppA, a surface-exposed protein of Streptococcus pneumoniae, elicits cross-reactive antibodies that reduce colonization in a murine intranasal immunization and challenge model. Infect. Immun. 73, 981–989 (2005)
Egan, M.A., et al.: A comparative evaluation of nasal and parenteral vaccine adjuvants to elicit systemic and mucosal HIV-1 peptide-specific humoral immune responses in cynomolgus macaques. Vaccine 22, 3774–3788 (2004)
Mason, K.W., et al.: Reduction of nasal colonization of nontypeable Haemophilus influenzae following intranasal immunization with rLP4/rLP6/UspA2 proteins combined with aqueous formulation of RC529. Vaccine 22, 3449–3456 (2004)
Baldridge, J.R., et al.: Immunostimulatory activity of aminoalkyl glucosaminide 4-phosphates (AGPs): induction of protective innate immune responses by RC-524 and RC-529. J. Endotoxin Res. 8, 453–458 (2002)
Ishizaka, S.T., Hawkins, L.D.: E6020: a synthetic Toll-like receptor 4 agonist as a vaccine adjuvant. Expert Rev. Vaccines 6, 773–784 (2007)
Morefield, G.L., Hawkins, L.D., Ishizaka, S.T., Kissner, T.L., Ulrich, R.G.: Synthetic Toll-like receptor 4 agonist enhances vaccine efficacy in an experimental model of toxic shock syndrome. Clin. Vaccine Immunol. 14, 1499–1504 (2007)
Przetak, M., et al.: Novel synthetic LPS receptor agonists boost systemic and mucosal antibody responses in mice. Vaccine 21, 961–970 (2003)
Baudner, B.C., et al.: MF59 emulsion is an effective delivery system for a synthetic TLR4 agonist (E6020). Pharm. Res. 26, 1477–1485 (2009)
Wang, S., et al.: Effective antibody therapy induces host-protective antitumor immunity that is augmented by TLR4 agonist treatment. Cancer Immunol. Immunother. 61, 49–61 (2012)
Baldwin, S.L., et al.: Intradermal immunization improves protective efficacy of a novel TB vaccine candidate. Vaccine 27, 3063–3071 (2009)
Bertholet, S., et al.: Optimized subunit vaccine protects against experimental leishmaniasis. Vaccine 27, 7036–7045 (2009)
Coler, R.N., et al.: A synthetic adjuvant to enhance and expand immune responses to influenza vaccines. PLoS One 5, e13677 (2010)
Xiao, L., et al.: A TLR4 agonist synergizes with dendritic cell-directed lentiviral vectors for inducing antigen-specific immune responses. Vaccine 30, 2570–2581 (2012)
Pantel, A., et al.: A new synthetic TLR4 agonist, GLA, allows dendritic cells targeted with antigen to elicit Th1 T-cell immunity in vivo. Eur. J. Immunol. 42, 101–109 (2012)
Cong, H., et al.: Toxoplasma gondii HLA-B*0702-restricted GRA7(20-28) peptide with adjuvants and a universal helper T cell epitope elicits CD8(+) T cells producing interferon-gamma and reduces parasite burden in HLA-B*0702 mice. Hum. Immunol. 73, 1–10 (2012)
Baldwin, S.L., et al.: The importance of adjuvant formulation in the development of a tuberculosis vaccine. J. Immunol. 188, 2189–2197 (2012)
Windish, H.P., et al.: Protection of mice from Mycobacterium tuberculosis by ID87/GLA-SE, a novel tuberculosis subunit vaccine candidate. Vaccine 29, 7842–7848 (2011)
Ueda, H., Yamazaki, M.: Induction of tumor necrosis factor in a murine tumor by systemic administration of a novel synthetic lipid A analogue, ONO-4007. J. Immunother. 20, 65–69 (1997)
Matsumoto, N., Aze, Y., Akimoto, A., Fujita, T.: Restoration of immune responses in tumor-bearing mice by ONO-4007, an antitumor lipid A derivative. Immunopharmacology 36, 69–78 (1997)
Kuramitsu, Y., et al.: A new synthetic lipid A analog, ONO-4007, stimulates the production of tumor necrosis factor-alpha in tumor tissues, resulting in the rejection of transplanted rat hepatoma cells. Anticancer Drugs 8, 500–508 (1997)
Matsumoto, N., Oida, H., Aze, Y., Akimoto, A., Fujita, T.: Intratumoral tumor necrosis factor induction and tumor growth suppression by ONO-4007, a low-toxicity lipid A analog. Anticancer Res. 18, 4283–4289 (1998)
Inagawa, H., et al.: Mechanisms by which chemotherapeutic agents augment the antitumor effects of tumor necrosis factor: involvement of the pattern shift of cytokines from Th2 to Th1 in tumor lesions. Anticancer Res. 18, 3957–3964 (1998)
Matsumoto, N., Aze, Y., Akimoto, A., Fujita, T.: ONO-4007, an antitumor lipid A analog, induces tumor necrosis factor-alpha production by human monocytes only under primed state: different effects of ONO-4007 and lipopolysaccharide on cytokine production. J. Pharmacol. Exp. Ther. 284, 189–195 (1998)
Khan, M.A., et al.: Inhibition of intracellular proliferation of Leishmania parasites in vitro and suppression of skin lesion development in BALB/c mice by a novel lipid A analog (ONO-4007). Am. J. Trop. Med. Hyg. 67, 184–190 (2002)
Iio, J., et al.: Lipid A analogue, ONO-4007, inhibits IgE response and antigen-induced eosinophilic recruitment into airways in BALB/c mice. Int. Arch. Allergy Immunol. 127, 217–225 (2002)
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2014 Springer International Publishing Switzerland
About this chapter
Cite this chapter
Arenas, J. (2014). Bacterial Lipopolysaccharide as Adjuvants. In: Giese, M. (eds) Molecular Vaccines. Springer, Cham. https://doi.org/10.1007/978-3-319-00978-0_7
Download citation
DOI: https://doi.org/10.1007/978-3-319-00978-0_7
Published:
Publisher Name: Springer, Cham
Print ISBN: 978-3-319-00977-3
Online ISBN: 978-3-319-00978-0
eBook Packages: Biomedical and Life SciencesBiomedical and Life Sciences (R0)