scholarly journals Potent Adjuvant Activity of Cationic Liposome-DNA Complexes for Genital Herpes Vaccines

2009 ◽  
Vol 16 (5) ◽  
pp. 699-705 ◽  
Author(s):  
David I. Bernstein ◽  
Rhonda D. Cardin ◽  
Fernando J. Bravo ◽  
Jane E. Strasser ◽  
Nicholas Farley ◽  
...  
Keyword(s):  
Genital Herpes ◽  
Lipid A ◽  
Cationic Liposome ◽  
Antibody Responses ◽  
Dna Complexes ◽  
Adjuvant Activity ◽  
Monophosphoryl Lipid A ◽  
Monophosphoryl Lipid ◽  
Simplex Virus

ABSTRACT Development of a herpes simplex virus (HSV) vaccine is a priority because these infections are common. It appears that potent adjuvants will be required to augment the immune response to subunit HSV vaccines. Therefore, we evaluated cationic liposome-DNA complexes (CLDC) as an adjuvant in a mouse model of genital herpes. Using a whole-virus vaccine (HVAC), we showed that the addition of CLDC improved antibody responses compared to vaccine alone. Most important, CLDC increased survival, reduced symptoms, and decreased vaginal virus replication compared to vaccine alone or vaccine administered with monophosphoryl lipid A (MPL) plus trehalose dicorynomycolate (TDM) following intravaginal challenge of mice. When CLDC was added to an HSV gD2 vaccine, it increased the amount of gamma interferon that was produced from splenocytes stimulated with gD2 compared to the amount produced with gD2 alone or with MPL-alum. The addition of CLDC to the gD2 vaccine also improved the outcome following vaginal HSV type 2 challenge compared to vaccine alone and was equivalent to vaccination with an MPL-alum adjuvant. CLDC appears to be a potent adjuvant for HSV vaccines and should be evaluated further.

scholarly journals Adsorption of Toll-Like Receptor 4 Agonist to Alum-Based Tetanus Toxoid Vaccine Dampens Pro-T Helper 2 Activities and Enhances Antibody Responses

2015 ◽  
Vol 2015 ◽  
pp. 1-9 ◽  
Author(s):  
Juliana Bortolatto ◽  
Luciana Mirotti ◽  
Dunia Rodriguez ◽  
Eliane Gomes ◽  
Momtchilo Russo
Keyword(s):  
Tetanus Toxoid ◽  
Lipid A ◽  
Antibody Responses ◽  
Aluminum Salts ◽  
T Helper 2 ◽  
Monophosphoryl Lipid A ◽  
Tlr4 Agonist ◽  
Specific Antibody Production ◽  
Humoral Responses

Aluminum salts gels (alum) are TLR-independent adjuvants and have been used to boost antibody responses in alum-based vaccines such as diphtheria, pertussis, and tetanus toxoid (DPT) triple vaccine. However, the pro-Th2 activity of alum-based vaccine formulations has not been fully appreciated. Here we found that alum-based tetanus toxoid (TT) vaccine was biased toward a Th-2 profile as shown by TT-induced airway eosinophilic inflammation, type 2 cytokine production, and high levels of IgE anaphylactic antibodies. The adsorption into alum of prototypic TLR4 agonists such as lipopolysaccharides (LPS) derived fromEscherichia coliconsistently dampened TT-induced Th2 activities without inducing IFNγor Th1-like responses in the lung. Conversely, adsorption of monophosphoryl lipid A (MPLA) extracted fromSalmonella minnesota, which is a TIR-domain-containing adapter-inducing interferon-β- (TRIF-) biased TLR4 agonist, was less effective in decreasing Th-2 responses. Importantly, in a situation with antigenic competition (OVA plus TT), TT-specific IgG1 or IgG2a was decreased compared with TT sensitization. Notably, LPS increased the production of IgG1 and IgG2a TT-specific antibodies. In conclusion, the addition of LPS induces a more robust IgG1 and IgG2a TT-specific antibody production and concomitantly decreases Th2-cellular and humoral responses, indicating a potential use of alum/TLR-based vaccines.

scholarly journals Vaccination Route as a Determinant of Protective Antibody Responses against Herpes Simplex Virus

Vaccines ◽  
2020 ◽  
Vol 8 (2) ◽  
pp. 277
Author(s):  
Clare Burn Aschner ◽  
Carl Pierce ◽  
David M. Knipe ◽  
Betsy C. Herold
Keyword(s):  
Herpes Simplex ◽  
Neutralizing Antibodies ◽  
Lipid A ◽  
Low Dose ◽  
High Titer ◽  
Antibody Responses ◽  
Protein Vaccine ◽  
Herpes Simplex Viruses ◽  
Monophosphoryl Lipid A ◽  
Simplex Virus

Herpes simplex viruses (HSV) are significant global health problems associated with mucosal and neurologic disease. Prior experimental vaccines primarily elicited neutralizing antibodies targeting glycoprotein D (gD), but those that advanced to clinical efficacy trials have failed. Preclinical studies with an HSV-2 strain deleted in gD (ΔgD-2) administered subcutaneously demonstrated that it elicited a high titer, weakly neutralizing antibodies that activated Fcγ receptors to mediate antibody-dependent cellular cytotoxicity (ADCC), and completely protected mice against lethal disease and latency following vaginal or skin challenge with HSV-1 or HSV-2. Vaccine efficacy, however, may be impacted by dose and route of immunization. Thus, the current studies were designed to compare immunogenicity and efficacy following different routes of vaccination with escalating doses of ΔgD-2. We compared ΔgD-2 with two other candidates: recombinant gD protein combined with aluminum hydroxide and monophosphoryl lipid A adjuvants and a replication-defective virus deleted in two proteins involved in viral replication, dl5-29. Compared to the subcutaneous route, intramuscular and/or intradermal immunization resulted in increased total HSV antibody responses for all three vaccines and boosted the ADCC, but not the neutralizing response to ΔgD and dl5-29. The adjuvanted gD protein vaccine provided only partial protection and failed to elicit ADCC independent of route of administration. In contrast, the increased ADCC following intramuscular or intradermal administration of ΔgD-2 or dl5-29 translated into significantly increased protection. The ΔgD-2 vaccine provided 100% protection at doses as low as 5 × 104 pfu when administered intramuscularly or intradermally, but not subcutaneously. However, administration of a combination of low dose subcutaneous ΔgD-2 and adjuvanted gD protein resulted in greater protection than low dose ΔgD-2 alone indicating that gD neutralizing antibodies may contribute to protection. Taken together, these results demonstrate that ADCC provides a more predictive correlate of protection against HSV challenge in mice and support intramuscular or intradermal routes of vaccination.

scholarly journals STAT4 is required for the generation of Th1 and Th2, but not Th17 immune responses during monophosphoryl lipid A adjuvant activity

2018 ◽  
Vol 30 (8) ◽  
pp. 385-385
Author(s):  
Sanjay Varikuti ◽  
Steve Oghumu ◽  
Gayathri Natarajan ◽  
Jennifer Kimble ◽  
Rachel H Sperling ◽  
...  
Keyword(s):  
Immune Responses ◽  
Lipid A ◽  
Adjuvant Activity ◽  
Monophosphoryl Lipid A ◽  
Monophosphoryl Lipid ◽  
Th1 And Th2

scholarly journals STAT4 is required for the generation of Th1 and Th2, but not Th17 immune responses during monophosphoryl lipid A adjuvant activity

2016 ◽  
Vol 28 (11) ◽  
pp. 565-570 ◽  
Author(s):  
Sanjay Varikuti ◽  
Steve Oghumu ◽  
Gayathri Natarajan ◽  
Jennifer Kimble ◽  
Rachel H. Sperling ◽  
...  
Keyword(s):  
Immune Responses ◽  
Lipid A ◽  
Adjuvant Activity ◽  
Monophosphoryl Lipid A ◽  
Monophosphoryl Lipid ◽  
Th1 And Th2

scholarly journals Adjuvant Activity of Monophosphoryl Lipid A for Nasal and Oral Immunization with Soluble or Liposome-Associated Antigen

2000 ◽  
Vol 68 (10) ◽  
pp. 5509-5516 ◽  
Author(s):  
Noel K. Childers ◽  
Keri L. Miller ◽  
Giang Tong ◽  
Juan Carlos Llarena ◽  
Terrance Greenway ◽  
...  
Keyword(s):  
Lipid A ◽  
Immunoglobulin A ◽  
Oral Immunization ◽  
Enzyme Linked Immunosorbent Assay ◽  
Antibody Activity ◽  
Soluble Antigen ◽  
Adjuvant Activity ◽  
Anamnestic Response ◽  
Monophosphoryl Lipid A ◽  
Monophosphoryl Lipid

ABSTRACT The effectiveness of monophosphoryl lipid A (MPL) as a mucosal adjuvant was investigated following oral or intranasal (i.n.) administration of an aqueous adjuvant formulation of MPL (MPL-AF) added to soluble antigen or liposomal antigen or incorporated into liposomal antigen membranes. Groups of BALB/c female mice were immunized with 50 to 100 μg of free or liposomal Streptococcus mutans crude glucosyltransferase (C-GTF) with or without MPL-AF added to the vaccine or incorporated into the liposomal membrane. Plasma, saliva, vaginal wash, and fecal extract samples were collected biweekly following immunization and assessed for antigen-specific antibody activity by enzyme-linked immunosorbent assay (ELISA). Mice immunized by the i.n. route had higher levels of salivary, plasma, and vaginal immunoglobulin A (IgA) anti-C-GTF responses and higher levels of plasma IgG anti-C-GTF than the orally immunized groups. A second administration of the vaccine 14 weeks after the initial immunization resulted in an anamnestic response to C-GTF resulting in 10- and 100-fold increases in saliva and plasma IgA and plasma IgG, respectively (in the i.n. immunized groups). Mice receiving a second i.n. immunization with liposomal antigen and MPL-AF had higher salivary IgA anti-C-GTF responses than mice immunized with antigen plus MPL-AF or liposomal antigen (P < 0.05). Plasma IgG anti-C-GTF activity was highest in mice immunized by the i.n. route with antigen formulations containing MPL-AF (P < 0.05). These results demonstrate the effectiveness of MPL-AF as an adjuvant for potentiating mucosal and systemic immune responses to liposomal C-GTF following i.n. immunization.

scholarly journals The Immunogenicity of Capsid-Like Particle Vaccines in Combination with Different Adjuvants Using Different Routes of Administration

Vaccines ◽  
2021 ◽  
Vol 9 (2) ◽  
pp. 131
Author(s):  
Christoph M. Janitzek ◽  
Philip H. R. Carlsen ◽  
Susan Thrane ◽  
Vijansh M. Khanna ◽  
Virginie Jakob ◽  
...  
Keyword(s):  
Aluminum Hydroxide ◽  
Lipid A ◽  
Antibody Responses ◽  
Bacterial Protein ◽  
Adjuvant Effect ◽  
Water Emulsion ◽  
Routes Of Administration ◽  
Monophosphoryl Lipid A ◽  
Monophosphoryl Lipid ◽  
Vaccine Antigens

Capsid-like particle (CLP) displays can be used to enhance the immunogenicity of vaccine antigens, but a better understanding of how CLP vaccines are best formulated and delivered is needed. This study compared the humoral immune responses in mice elicited against two different vaccine antigens (a bacterial protein and a viral peptide) delivered on an AP205 CLP platform using six different adjuvant formulations. In comparison to antibody responses obtained after immunization with the unadjuvanted CLP vaccine, three of the adjuvant systems (neutral liposomes/monophosphoryl lipid A/quillaja saponaria 21, squalene-in-water emulsion, and monophosphoryl lipid A) caused significantly increased antibody levels, whereas formulation with the three other adjuvants (aluminum hydroxide, cationic liposomes, and cationic microparticles) resulted in similar or even decreased antibody responses. When delivering the soluble bacterial protein in a squalene-in-water emulsion, 4-log lower IgG levels were obtained compared to when the protein was delivered on CLPs without the adjuvant. The AP205 CLP platform promoted induction of both IgG1 and IgG2 subclasses, which could be skewed towards a higher production of IgG1 (aluminum hydroxide). Compared to other routes, intramuscular administration elicited the highest IgG levels. These results indicate that the effect of the external adjuvant does not always synergize with the adjuvant effect of the CLP display, which underscores the need for empirical testing of different extrinsic adjuvants.

Monophosphoryl lipid A analogues with varying 3-O-substitution: synthesis and potent adjuvant activity

2007 ◽  
Vol 342 (6) ◽  
pp. 784-796 ◽  
Author(s):  
Zi-Hua Jiang ◽  
Wladyslaw A. Budzynski ◽  
Dongxu Qiu ◽  
Damayanthi Yalamati ◽  
R. Rao Koganty
Keyword(s):  
Lipid A ◽  
Adjuvant Activity ◽  
Monophosphoryl Lipid A ◽  
Monophosphoryl Lipid

scholarly journals Role of Innate Immune Factors in the Adjuvant Activity of Monophosphoryl Lipid A

2003 ◽  
Vol 71 (5) ◽  
pp. 2498-2507 ◽  
Author(s):  
Michael Martin ◽  
Suzanne M. Michalek ◽  
Jannet Katz
Keyword(s):  
Map Kinases ◽  
Cell Activation ◽  
Lipid A ◽  
Mononuclear Cells ◽  
Human Peripheral Blood ◽  
Human Monocytes ◽  
Adjuvant Activity ◽  
Peripheral Blood Mononuclear ◽  
Monophosphoryl Lipid A ◽  
Monophosphoryl Lipid

ABSTRACT Monophosphoryl lipid A (MPL) is a nontoxic derivative of lipopolysaccharide (LPS) that exhibits adjuvant properties similar to those of the parent LPS molecule. However, the mechanism by which MPL initiates its immunostimulatory properties remains unclear. Due to the involvement of Toll-like receptors in recognizing and transducing intracellular signals in response to LPS, the aim of the present study was to determine the ability of MPL to utilize the Toll-like receptor 2 (TLR2) and TLR4. We provide evidence that MPL differentially utilizes TLR2 and TLR4 for the induction of tumor necrosis factor alpha, interleukin 10 (IL-10), and IL-12 by purified human monocytes as well as by human peripheral blood mononuclear cells. Assessment of NF-κB activity demonstrated that MPL utilized TLR2 and especially TLR4 for the activation of NF-κB p65 by human monocytes. In addition, stimulation of human monocytes by MPL led to an up-regulation of the costimulatory molecules CD80 and CD86, an effect that could be reduced by pretreatment of cells with a monoclonal antibody to TLR2 or TLR4. Analysis of MPL-induced activation of the extracellular signal-regulated kinase (ERK) and p38 mitogen-activated protein (MAP) kinases revealed that MPL utilized both TLR2 and TLR4 for the phosphorylation of ERK1/2, while TLR4 was the predominant receptor involved in the ability of MPL to phosphorylate p38. Moreover, using selective inhibitors for MAP kinase kinase (PD98059) and p38 (SB203580), we show that ERK1/2 exhibited differential effects on production of TNF-α and IL-12 p40 by human monocytes, whereas MPL-induced activation of p38 appeared to be predominantly involved in production of IL-10 and IL-12 p40 by MPL-stimulated monocytes. Taken together, these findings aid in understanding the cellular mechanisms by which MPL induces host cell activation and subsequent adjuvant properties.

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