3-<i>O</i>-Desacyl Monophosphoryl Lipid A Derivatives:  Synthesis and Immunostimulant Activities

Johnson, David A.; Keegan, David S.; Sowell, C. Gregory; Livesay, Mark T.; Johnson, Craig; Taubner, Lara M.; Harris, Alice C.; Myers, Kent R.; Thompson, Jennifer; Gustafson, Gary L.; Rhodes, Michael J.; Ulrich, J. Terry; Ward, Julian; Yorgensen, Yvonne M.; Cantrell, John L.; Brookshire, Valerie G.

doi:10.1021/jm990222b

Cited by 92 publications

(61 citation statements)

References 39 publications

(98 reference statements)

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“…MPL TM , also known as AS04, has recently been approved for use in Europe and is defined as 3-O-desacyl-4'-monophosphoryl lipid A, obtained by mild hydrolytic treatment and purification of Salmonella minnesota R595 LPS, and absorbed on aluminum hydroxide or aluminum phosphate. 46,47 The potent adjuvanticity and good safety profile of MPLA has spawned a large number of synthetic lipid A mimics including a new class of synthetic lipid A mimetics, the aminoalkyl glucosaminide 4-phosphates (AGPs) 48,49 such as Corixa's (now GlaxoSmithKline) Ribi 529, [50][51][52] and Eisai's E6020 (Fig. 2).…”

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confidence: 99%

Potential adjuvantic properties of innate immune stimuli

et al. 2009

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Just as the prescient comment by Gaston Ramon was relegated to the last footnote of his 1926 paper, 1 so has research on the mechanisms of action of adjuvants, until recently, languished as parenthetical annotations and addenda in the archives of immunology and vaccine development. Ramon defined immunological adjuvants as "substances used in combination with a specific antigen that produced a more robust immune response than the antigen alone." Interestingly enough, he was referring to his empirical findings that the addition of bread crumbs, tapioca, saponin and 'starch oil' to antigenic preparations greatly enhanced antibody responses to diphtheria or tetanus. 2 A year later, the adjuvanticity of aluminum salts (primarily phosphate and hydroxide) was discovered by Glenny and coworkers. 3 In the 83 years that have elapsed, the repertoire of investigational adjuvants has grown to encompass a very wide range of materials, 4 but aluminum salt-based mineral salts (generically, and incorrectly, termed "alum") have remained the only adjuvants currently approved by the FDA. Aluminum salts have enjoyed a good safety record, but they are weak adjuvants for antibody induction and induce a T helper-2 (T H 2)-skewed, rather than a T helper-1 (T H 1) response. 5,6 Furthermore, not only are aluminum salts ineffective at inducing cytotoxic T lymphocyte (CTL) or mucosal IgA antibody responses, but also have a propensity to induce IgE responses, which have been associated with allergic reactions in some subjects. 5,6 Very recent reports implicate the Nalp3 inflammasome, a component of the innate immune response, as the effector limb of alum-associated adjuvanticity. [7][8][9] In 1962, Dresser observed that injection of purified soluble proteins not only failed to stimulate an immune response, but tolerized animals unless a bacterial extract was admixed with the protein immunogen. 10 This led him to redefine adjuvanticity as "a property of a substance which can act as a physiological switch, directing at least some immunologically competent cells to respond by making antibody rather than by becoming immunologically paralyzed by the antigen," 11 confirming Johnson's earlier observations that lipopolysaccharide (LPS) from Gram-negative bacteria exerted potent adjuvant properties, 12 and perhaps paved the way for the subsequent discovery of the wide range of microorganism-derived adjuvants. 13 TLRs are pattern recognition receptors present on diverse cell types that recognize specific molecular patterns present in molecules that are broadly shared by pathogens but distinguishable from host molecules, collectively referred to as pathogen-associated molecular patterns (PAMPs). 14,15 There are 10 TLRs in the human genome;

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confidence: 99%

Potential adjuvantic properties of innate immune stimuli

et al. 2009

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“…Briefly, 6-week-old pathogen-free BALB/c mice (Jackson Laboratories) were immunized with 5 g of rPppA protein at weeks 0, 2, and 4 (10 animals per group). The adjuvant used was either 0.1 g of CT-E29H, a genetically modified cholera toxin that is reduced in enzymatic activity and toxicity (38), or 10 g of RC529AF, a synthetic MPL mimetic (Corixa) (3,22,31). The immunogen was slowly instilled into the nostril of each mouse in a 10-l volume.…”

Section: Methodsmentioning

confidence: 99%

PppA, a Surface-Exposed Protein ofStreptococcus pneumoniae, Elicits Cross-Reactive Antibodies That Reduce Colonization in a Murine Intranasal Immunization and Challenge Model

Green¹,

Zhang²,

Masi³

et al. 2005

Infect Immun

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The multivalent pneumococcal conjugate vaccine is effective against both systemic disease and otitis media caused by serotypes contained in the vaccine. However, serotypes not covered by the present conjugate vaccine may still cause pneumococcal disease. To address these serotypes, and the remaining otitis media due to Streptococcus pneumoniae, efforts have been devoted to identifying protective protein antigens. Immunity to conserved surface proteins important for adhesion, nutrient acquisition, or other functions could result in a reduction of colonization and a lower disease potential. We have been searching for conserved surface-exposed proteins from S. pneumoniae that may be involved in pathogenesis to test as vaccine candidates. Here, an ϳ20-kDa protein that has significant homology to a nonheme iron-containing ferritin protein from Listeria innocua and other bactoferritins was identified as pneumococcal protective protein A (PppA). We expressed and purified recombinant PppA (rPppA) and evaluated its potential as a vaccine candidate. The antibodies elicited by purified rPppA were cross-reactive with PppA from multiple strains of S. pneumoniae and were directed against surface-exposed epitopes. Intranasal immunization of BALB/c mice with PppA protein and either a synthetic monophosphoryl lipid A analog, RC529AF, or a cholera toxin mutant, CT-E29H, used as an adjuvant reduced nasopharyngeal colonization in mice following intranasal challenge with a heterologous pneumococcal strain. PppA-specific systemic and local immunoglobulin G (IgG) and IgA antibody responses were induced. The antisera reacted with whole cells of a heterologous S. pneumoniae type 3 strain. These observations indicate that PppA may be a promising candidate for inclusion in a vaccine against pneumococcal otitis media.Infections with Streptococcus pneumoniae are a major cause of human diseases, such as otitis media, bacteremia, meningitis, and fatal pneumonia, worldwide (9). The rapid emergence of multidrug-resistant pneumococcal strains throughout the world has led to an increased emphasis on prevention of pneumococcal infections by vaccination (18). The presently available 23-valent pneumococcal capsular polysaccharide vaccine is not effective in children less than 2 years of age or immunocompromised patients, two of the major populations at risk for pneumococcal infection (14). A seven-valent pneumococcal polysaccharide-protein conjugate vaccine, recently licensed in the United States, was shown to be highly effective in infants and children against systemic pneumococcal disease caused by the vaccine serotypes and against cross-reactive capsular serotypes (36). However, parenteral immunization with the sevenvalent vaccine was only 60% effective against serotype-specific otitis media (17), demonstrating the need for additional immunization strategies (e.g., intranasal [i.n.] immunization), additional noncapsular antigens, or both. Therefore, there is an immediate need for a cost-effective vaccine to cover most or all of the disease-causin...

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“…Lipid A 1 is a potent adjuvant for both protein and carbohydrate antigens, and can lead to marked increases in both humoral and cell-mediated immunity (Azuma 1992). Although LPS as a component of whole cell vaccines against pertussis, cholera and typhoid has been used in humans for many years, its extreme toxicity precludes its use as an adjuvant in humans (Johnson, Keegan et al 1999). Attempts have been made to detoxify LPS and lipid A without affecting its adjuvanticity.…”

Section: Lipopolysaccharide Lipid a And Monophosphoryl Lipid Amentioning

confidence: 99%