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 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 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 Lipopolysaccharide directly inhibits bicarbonate absorption by the renal outer medullary collecting duct

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Shuichi Tsuruoka ◽  
Jeffrey M. Purkerson ◽  
George J. Schwartz
Keyword(s):  
Lipid A ◽  
Kinase Inhibitor ◽  
Collecting Duct ◽  
Therapeutic Interventions ◽  
E Coli ◽  
Monophosphoryl Lipid A ◽  
Tlr4 Agonist ◽  
Medullary Collecting Duct ◽  
Phosphoinositide 3 Kinase

AbstractAcidosis is associated with E. coli induced pyelonephritis but whether bacterial cell wall constituents inhibit HCO3 transport in the outer medullary collecting duct from the inner stripe (OMCDi) is not known. We examined the effect of lipopolysaccharide (LPS), on HCO3 absorption in isolated perfused rabbit OMCDi. LPS caused a ~ 40% decrease in HCO3 absorption, providing a mechanism for E. coli pyelonephritis-induced acidosis. Monophosphoryl lipid A (MPLA), a detoxified TLR4 agonist, and Wortmannin, a phosphoinositide 3-kinase inhibitor, prevented the LPS-mediated decrease, demonstrating the role of TLR4-PI3-kinase signaling and providing proof-of-concept for therapeutic interventions aimed at ameliorating OMCDi dysfunction and pyelonephritis-induced acidosis.

scholarly journals Toll-like receptor 4 agonist-based nanoparticles orchestrate protection against sepsis

2022 ◽  
Author(s):  
Yongxiang Zhao ◽  
Xinjing Lv ◽  
Jie Huang ◽  
Huiting Zhou ◽  
Hairong Wang ◽  
...  
Keyword(s):  
Lipid A ◽  
Severe Infection ◽  
Plga Nanoparticles ◽  
Great Promise ◽  
Toll Like Receptor 4 ◽  
E Coli ◽  
Monophosphoryl Lipid A ◽  
Tlr4 Agonist ◽  
Life Threatening ◽  
Plga Nanoparticle

AbstractSepsis, a life-threatening organ dysfunction induced by severe infection and uncontrolled host immune response, threatens the health of people all over the world. Herein, a type of nanoparticle formulation with simple components is synthesized by encapsulating monophosphoryl lipid A (MPLA), a TLR4 agonist, with poly(lactic-co-glycolic acid) (PLGA) nanoparticle. The obtained nanoparticles (MPLA@PLGA) could provide Escherichia coli (E. coli)-induced sepsis protection by regulating the immune system after sepsis challenge, including promoting the levels of various cytokines, boosting the percentage of natural killer cells and accelerating bacterial clearance. Notably, the survival mice pre-treated with these nanoparticles could resist repeated E. coli-induced sepsis. Our work therefore provides the great promise of MPLA@PLGA nanoparticles as a simple yet effective nano-drug for prevention and protection against E. coli-induced sepsis.

scholarly journals The TLR4 Agonist Monophosphoryl Lipid A Drives Broad Resistance to Infection via Dynamic Reprogramming of Macrophage Metabolism

2018 ◽  
Vol 200 (11) ◽  
pp. 3777-3789 ◽  
Author(s):  
Benjamin A. Fensterheim ◽  
Jamey D. Young ◽  
Liming Luan ◽  
Ruby R. Kleinbard ◽  
Cody L. Stothers ◽  
...  
Keyword(s):  
Lipid A ◽  
Monophosphoryl Lipid A ◽  
Monophosphoryl Lipid ◽  
Tlr4 Agonist ◽  
Resistance To Infection ◽  
Dynamic Reprogramming

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.

scholarly journals The Use of Translational Modelling and Simulation to Develop Immunomodulatory Therapy as an Adjunct to Antibiotic Treatment in the Context of Pneumonia

Pharmaceutics ◽  
2021 ◽  
Vol 13 (5) ◽  
pp. 601
Author(s):  
Robin Michelet ◽  
Moreno Ursino ◽  
Sandrine Boulet ◽  
Sebastian Franck ◽  
Fiordiligie Casilag ◽  
...  
Keyword(s):  
Lipid A ◽  
Bacterial Resistance ◽  
Statistical Modelling ◽  
Modelling And Simulation ◽  
Knowledge Based ◽  
Monophosphoryl Lipid A ◽  
Tlr4 Agonist ◽  
Tract Infections

The treatment of respiratory tract infections is threatened by the emergence of bacterial resistance. Immunomodulatory drugs, which enhance airway innate immune defenses, may improve therapeutic outcome. In this concept paper, we aim to highlight the utility of pharmacometrics and Bayesian inference in the development of immunomodulatory therapeutic agents as an adjunct to antibiotics in the context of pneumonia. For this, two case studies of translational modelling and simulation frameworks are introduced for these types of drugs up to clinical use. First, we evaluate the pharmacokinetic/pharmacodynamic relationship of an experimental combination of amoxicillin and a TLR4 agonist, monophosphoryl lipid A, by developing a pharmacometric model accounting for interaction and potential translation to humans. Capitalizing on this knowledge and associating clinical trial extrapolation and statistical modelling approaches, we then investigate the TLR5 agonist flagellin. The resulting workflow combines expert and prior knowledge on the compound with the in vitro and in vivo data generated during exploratory studies in order to construct high-dimensional models considering the pharmacokinetics and pharmacodynamics of the compound. This workflow can be used to refine preclinical experiments, estimate the best doses for human studies, and create an adaptive knowledge-based design for the next phases of clinical development.

scholarly journals Adjuvantation of an Influenza Hemagglutinin Antigen with TLR4 and NOD2 Agonists Encapsulated in Poly(D,L-Lactide-Co-Glycolide) Nanoparticles Enhances Immunogenicity and Protection against Lethal Influenza Virus Infection in Mice

Vaccines ◽  
2020 ◽  
Vol 8 (3) ◽  
pp. 519
Author(s):  
Amir Tukhvatulin ◽  
Alina Dzharullaeva ◽  
Alina Erokhova ◽  
Anastasia Zemskaya ◽  
Maxim Balyasin ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Lipid A ◽  
Influenza Virus Infection ◽  
Muramyl Dipeptide ◽  
Plga Nanoparticles ◽  
Influenza Hemagglutinin ◽  
Monophosphoryl Lipid A ◽  
Tlr4 Agonist

Along with their excellent safety profiles, subunit vaccines are typically characterized by much weaker immunogenicity and protection efficacy compared to whole-pathogen vaccines. Here, we present an approach aimed at bridging this disadvantage that is based on synergistic collaboration between pattern-recognition receptors (PRRs) belonging to different families. We prepared a model subunit vaccine formulation using an influenza hemagglutinin antigen incorporated into poly-(D,L-lactic-co-glycolic acid) (PLGA) nanoparticles adjuvanted with monophosphoryl lipid A (TLR4 agonist) and muramyl dipeptide (NOD2 agonist). The efficacy studies were conducted in comparison to control vaccine formulations containing individual PRR agonists. We show that the complex adjuvant based on TLR4 and NOD2 agonists potentiates proinflammatory cell responses (measured by activity of transcription factors and cytokine production both in vitro and in vivo) and enhances the phagocytosis of vaccine particles up to comparable levels of influenza virus uptake. Finally, mice immunized with vaccine nanoparticles containing both PRR agonists exhibited enhanced humoral (IgG, hemagglutination-inhibition antibody titers) and cellular (percentage of proliferating CD4+ T-cells, production of IFNɣ) immunity, leading to increased resistance to lethal influenza challenge. These results support the idea that complex adjuvants stimulating different PRRs may present a better alternative to individual PAMP-based adjuvants and could further narrow the gap between the efficacy of subunit versus whole-pathogen vaccines.

scholarly journals TLR4 Agonist Combined with Trivalent Protein JointS of Streptococcus suis Provides Immunological Protection in Animals

Vaccines ◽  
2021 ◽  
Vol 9 (2) ◽  
pp. 184
Author(s):  
Zhaofei Wang ◽  
Mengting Guo ◽  
Licheng Kong ◽  
Ya Gao ◽  
Jingjiao Ma ◽  
...  
Keyword(s):  
Lipid A ◽  
High Titer ◽  
Streptococcus Suis ◽  
Innate Immune ◽  
Monophosphoryl Lipid A ◽  
Tlr4 Agonist ◽  
Associated Proteins ◽  
Immunological Protection ◽  
Immune Efficacy ◽  
Suis Serotype

Streptococcus suis (S. suis) serotype 2 (SS2) is the causative agent of swine streptococcosis and can cause severe diseases in both pigs and humans. Although the traditional inactive vaccine can protect pigs from SS2 infection, novel vaccine candidates are needed to overcome its shortcomings. Three infection-associated proteins in S. suis—muramidase-released protein (MRP), glyceraldehyde-3-phosphate dehydrogenase (GAPDH), and DLD, a novel putative dihydrolipoamide dehydrogenase—have been previously identified by immunoproteomic assays. In this study, the effective immune protection of the recombinant trivalent protein GAPDH-MRP-DLD (JointS) against SS2, SS7, and SS9 was determined in zebrafish. To improve the immune efficacy of JointS, monophosphoryl lipid A (MPLA) as a TLR4 agonist adjuvant, which induces a strong innate immune response in the immune cells of mice and pigs, was combined with JointS to immunize the mice. The results showed that immunized mice could induce the production of a high titer of anti-S. suis antibodies; as a result, 100% of mice survived after SS2 infection. Furthermore, JointS provides good protection against virulent SS2 strain infections in piglets. Given the above, there is potential to develop JointS as a novel subunit vaccine for piglets to prevent infection by SS2 and other S. suis serotypes.

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