scholarly journals Combining Monophosphoryl Lipid A (MPL), CpG Oligodeoxynucleotide (ODN), and QS-21 Adjuvants Induces Strong and Persistent Functional Antibodies and T Cell Responses against Cell-Traversal Protein for Ookinetes and Sporozoites (CelTOS) ofPlasmodium falciparumin BALB/c Mice

2019 ◽  
Vol 87 (6) ◽  
Author(s):  
Sakineh Pirahmadi ◽  
Sedigheh Zakeri ◽  
Akram A. Mehrizi ◽  
Navid D. Djadid ◽  
Abbas-Ali Raz ◽  
...  
Keyword(s):  
Lipid A ◽  
Enzyme Linked Immunosorbent Assay ◽  
Vaccine Adjuvants ◽  
Content Type ◽  
Quillaja Saponaria ◽  
Monophosphoryl Lipid A ◽  
Monophosphoryl Lipid ◽  
Cpg Oligodeoxynucleotide ◽  
Membrane Feeding ◽  
Functional Antibodies

ABSTRACTPlasmodium falciparumcell-traversal protein for ookinetes and sporozoites (PfCelTOS) is an advanced vaccine candidate that has a crucial role in the traversal of the malaria parasite in both mosquito and mammalian hosts. As recombinant purified proteins are normally poor immunogens, they require to be admixed with an adjuvant(s); therefore, the objective of the present study was to evaluate the capacity of different vaccine adjuvants, monophosphoryl lipid A (MPL), CpG, andQuillaja saponariaMolina fraction 21 (QS-21), alone or in combination (MCQ [MPL/CpG/QS-21]), to enhance the immunogenicity ofEscherichia coli-expressed PfCelTOS in BALB/c mice. This goal was achieved by the assessment of anti-PfCelTOS IgG antibodies (level, titer, IgG isotype profile, avidity, and persistence) and extracellular Th1 cytokines using an enzyme-linked immunosorbent assay (ELISA) on postimmunized BALB/c mouse sera and PfCelTOS-stimulated splenocytes, respectively. Also, an assessment of the transmission-reducing activity (TRA) of anti-PfCelTOS obtained from different vaccine groups was carried out in femaleAnopheles stephensimosquitoes by using a standard membrane feeding assay (SMFA). In comparison to PfCelTOS alone, administration of PfCelTOS with three distinct potent Th1 adjuvants in vaccine mouse groups showed enhancement and improvement of PfCelTOS immunogenicity that generated more bias toward a Th1 response with significantly enhanced titers and avidity of the anti-PfCelTOS responses that could impair ookinete development inA. stephensi. However, immunization of mice with PfCelTOS with MCQ mixture adjuvants resulted in the highest levels of induction of antibody titers, avidity, and inhibitory antibodies in oocyst development (88%/26.7% reductions in intensity/prevalence) inA. stephensi. It could be suggested that adjuvant combinations with different mechanisms stimulate better functional antibody responses than adjuvants individually against challenging diseases such as malaria.

scholarly journals The Combinations Chitosan-Pam3CSK4 and Chitosan-Monophosphoryl Lipid A: Promising Immune-Enhancing Adjuvants for Anticaries Vaccine PAc

2019 ◽  
Vol 87 (12) ◽  
Author(s):  
Yongli Bi ◽  
Qingan Xu ◽  
Lingkai Su ◽  
Jiantao Xu ◽  
Zhongfang Liu ◽  
...  
Keyword(s):  
Lipid A ◽  
Vaccine Development ◽  
Protection Effect ◽  
Content Type ◽  
Monophosphoryl Lipid A ◽  
Monophosphoryl Lipid ◽  
Tooth Surfaces ◽  
Antibody Titers

ABSTRACT We previously demonstrated that recombinant protein PAc could be administered as an anticaries vaccine. However, the relatively weak immunogenicity of PAc limits its application. In the present study, we investigated the effect of two adjuvant combinations of chitosan plus Pam3CSK4 (chitosan-Pam3CSK4) and of chitosan plus monophosphoryl lipid A (chitosan-MPL) in the immune responses to the PAc protein in vivo and in vitro. PAc-chitosan-Pam3CSK4 or PAc-chitosan-MPL promoted significantly higher PAc-specific antibody titers in serum and saliva, inhibited Streptococcus mutans colonization onto the tooth surfaces, and endowed better protection effect with significantly less caries activities than PAc alone. Chitosan-Pam3CSK4 and chitosan-MPL showed no statistically significant differences. In conclusion, our study demonstrated that the chitosan-Pam3CSK4 and chitosan-MPL combinations are promising for anticaries vaccine development.

scholarly journals Monophosphoryl Lipid A Enhances Efficacy of a Francisella tularensis LVS-Catanionic Nanoparticle Subunit Vaccine against F. tularensis Schu S4 Challenge by Augmenting both Humoral and Cellular Immunity

2017 ◽  
Vol 24 (3) ◽  
Author(s):  
Katharina Richard ◽  
Barbara J. Mann ◽  
Aiping Qin ◽  
Eileen M. Barry ◽  
Robert K. Ernst ◽  
...  
Keyword(s):  
Francisella Tularensis ◽  
Subunit Vaccine ◽  
Lipid A ◽  
Ex Vivo ◽  
The United States ◽  
Content Type ◽  
Monophosphoryl Lipid A ◽  
Monophosphoryl Lipid ◽  
Ifn Γ ◽  
Schu S4

ABSTRACT Francisella tularensis, a bacterial biothreat agent, has no approved vaccine in the United States. Previously, we showed that incorporating lysates from partially attenuated F. tularensis LVS or fully virulent F. tularensis Schu S4 strains into catanionic surfactant vesicle (V) nanoparticles (LVS-V and Schu S4-V, respectively) protected fully against F. tularensis LVS intraperitoneal (i.p.) challenge in mice. However, we achieved only partial protection against F. tularensis Schu S4 intranasal (i.n.) challenge, even when employing heterologous prime-boost immunization strategies. We now extend these findings to show that both LVS-V and Schu S4-V immunization (i.p./i.p.) elicited similarly high titers of anti-F. tularensis IgG and that the titers could be further increased by adding monophosphoryl lipid A (MPL), a nontoxic Toll-like receptor 4 (TLR4) adjuvant that is included in several U.S. FDA-approved vaccines. LVS-V+MPL immune sera also detected more F. tularensis antigens than LVS-V immune sera and, after passive transfer to naive mice, significantly delayed the time to death against F. tularensis Schu S4 subcutaneous (s.c.) but not i.n. challenge. Active immunization with LVS-V+MPL (i.p./i.p.) also increased the frequency of gamma interferon (IFN-γ)-secreting activated helper T cells, IFN-γ production, and the ability of splenocytes to control intramacrophage F. tularensis LVS replication ex vivo. Active LVS-V+MPL immunization via heterologous routes (i.p./i.n.) significantly elevated IgA and IgG levels in bronchoalveolar lavage fluid and significantly enhanced protection against i.n. F. tularensis Schu S4 challenge (to ∼60%). These data represent a significant step in the development of a subunit vaccine against the highly virulent type A strains.

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 Cell Recruitment and Cytokines in Skin Mice Sensitized with the Vaccine Adjuvants: Saponin, Incomplete Freund’s Adjuvant, and Monophosphoryl Lipid A

PLoS ONE ◽  
2012 ◽  
Vol 7 (7) ◽  
pp. e40745 ◽  
Author(s):  
Juliana Vitoriano-Souza ◽  
Nádia das Dores Moreira ◽  
Andréa Teixeira-Carvalho ◽  
Cláudia Martins Carneiro ◽  
Fernando Augusto Mathias Siqueira ◽  
...  
Keyword(s):  
Lipid A ◽  
Vaccine Adjuvants ◽  
Cell Recruitment ◽  
Monophosphoryl Lipid A ◽  
Monophosphoryl Lipid ◽  
Incomplete Freund’S Adjuvant ◽  
Freund’S Adjuvant ◽  
Freund's Adjuvant

scholarly journals Immunization with the Haemophilus ducreyi Hemoglobin Receptor HgbA with Adjuvant Monophosphoryl Lipid A Protects Swine from a Homologous but Not a Heterologous Challenge

2010 ◽  
Vol 78 (9) ◽  
pp. 3763-3772 ◽  
Author(s):  
William G. Fusco ◽  
Galyna Afonina ◽  
Igor Nepluev ◽  
Deborah M. Cholon ◽  
Neelima Choudhary ◽  
...  
Keyword(s):  
Lipid A ◽  
Haemophilus Ducreyi ◽  
Class I ◽  
Enzyme Linked Immunosorbent Assay ◽  
Whole Cells ◽  
Monophosphoryl Lipid A ◽  
Monophosphoryl Lipid ◽  
Heterologous Challenge ◽  
Hemoglobin Binding ◽  
Strict Requirement

ABSTRACTHaemophilus ducreyi, the etiological agent of chancroid, has a strict requirement for heme, which it acquires from its only natural host, humans. Previously, we showed that a vaccine preparation containing the native hemoglobin receptor HgbA purified fromH. ducreyiclass I strain 35000HP (nHgbAI) and administered with Freund's adjuvant provided complete protection against a homologous challenge. In the current study, we investigated whether nHgbAIdispensed with monophosphoryl lipid A (MPL), an adjuvant approved for use in humans, offered protection against a challenge withH. ducreyistrain 35000HP expressing either class I or class II HgbA (35000HPhgbAIand 35000HPhgbAII, respectively). Pigs immunized with the nHgbAI/MPL vaccine were protected against a challenge from homologousH. ducreyistrain 35000HPhgbAIbut not heterologous strain 35000HPhgbAII, as evidenced by the isolation of only strain 35000HPhgbAIIfrom nHgbAI-immunized pigs. Furthermore, histological analysis of the lesions showed striking differences between mock-immunized and nHgbAI-immunized animals challenged with strains 35000HPhgbAIbut not those challenged with strain 35000HPhgbAII. Mock-immunized pigs were not protected from a challenge by either strain. The enzyme-linked immunosorbent assay (ELISA) activity of the nHgbAI/MPL antiserum was lower than the activity of antiserum from animals immunized with the nHgbAI/Freund's vaccine; however, anti-nHgbAIfrom both studies bound whole cells of 35000HPhgbAIbetter than 35000HPhgbAIIand partially blocked hemoglobin binding to nHgbAI. In conclusion, despite eliciting lower antibody ELISA activity than the nHgbAI/Freund's, the nHgbAI/MPL vaccine provided protection against a challenge with homologous but not heterologousH. ducreyi, suggesting that a bivalent HgbA vaccine may be needed.

scholarly journals Mechanisms of Monophosphoryl Lipid A Augmentation of Host Responses to Recombinant HagB from Porphyromonas gingivalis

2002 ◽  
Vol 70 (7) ◽  
pp. 3557-3565 ◽  
Author(s):  
Qiu-Bo Yang ◽  
Michael Martin ◽  
Suzanne M. Michalek ◽  
Jannet Katz
Keyword(s):  
Porphyromonas Gingivalis ◽  
Lipid A ◽  
Costimulatory Molecules ◽  
Th2 Cells ◽  
Enzyme Linked Immunosorbent Assay ◽  
Antibody Activity ◽  
Salivary Iga ◽  
Monophosphoryl Lipid A ◽  
Monophosphoryl Lipid ◽  
Control Serum

ABSTRACT Porphyromonas gingivalis, a gram-negative, black-pigmented anaerobe, is among the microorganisms implicated in the etiology of adult periodontal disease. This bacterium possesses a number of factors, including hemagglutinins, of potential importance in virulence. Our laboratory has shown the induction of protection to P. gingivalis infection after subcutaneous immunization with recombinant hemagglutinin B (rHagB). The purpose of this study was to determine if humoral antibody responses are induced after intranasal (i.n.) immunization of rHagB and if monophosphoryl lipid A (MPL), a nontoxic derivative of the lipid A region of lipopolysaccharide, acts as a mucosal adjuvant and potentiates responses to rHagB. Further, the effects of MPL on the nature of the response to HagB and on the costimulatory molecules B7-1 and B7-2 on different antigen-presenting cells (APC) were evaluated. Groups of BALB/c mice were immunized three times (2-week intervals) by the i.n. route with HagB (20 μg) alone or with MPL (25 μg). A group of nonimmunized mice served as control. Serum and saliva samples were collected prior to immunization and at approximately 2-week intervals and evaluated for serum immunoglobulin G (IgG) and IgG subclass and for salivary IgA antibody activity by enzyme-linked immunosorbent assay. Mice immunized with rHagB plus MPL had significantly higher salivary IgA (P < 0.05) and serum IgG (P < 0.05) anti-HagB responses than mice immunized with rHagB alone. The IgG1 and IgG2a subclass responses seen in mice immunized with rHagB plus MPL were significantly higher (P < 0.05) than those seen in mice immunized with rHagB only. Further, the IgG2a/IgG1 ratio in the latter group was ≈1, whereas in mice immunized with rHagB plus MPL the ratio was <1. These results provide evidence for the participation of T helper (Th) 1 and Th2 cells in responses to rHagB and that MPL potentiates a type 2 response to HagB. MPL was also shown to preferentially up-regulate B7-2 expression on B cells, whereas a preferential increase in B7-1 costimulatory molecule was seen on macrophages and dendritic cells. These results provide evidence that MPL exerts a differential regulation in the expression of costimulatory molecules on APC.

scholarly journals Comparative Analysis of Bacillus subtilis Spores and Monophosphoryl Lipid A as Adjuvants of Protein-Based Mycobacterium tuberculosis-Based Vaccines: Partial Requirement for Interleukin-17A for Induction of Protective Immunity

2014 ◽  
Vol 21 (4) ◽  
pp. 501-508 ◽  
Author(s):  
Sandra C. Esparza-Gonzalez ◽  
Amber R. Troy ◽  
Angelo A. Izzo
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Bacillus Subtilis ◽  
T Cell Activation ◽  
Protective Immunity ◽  
Cell Activation ◽  
Lipid A ◽  
Content Type ◽  
Monophosphoryl Lipid A ◽  
Monophosphoryl Lipid ◽  
Interleukin 17A

ABSTRACTThe development of adjuvants for vaccines has become an important area of research as the number of protein-based vaccines against infectious pathogens increases. Currently, there are a number of adjuvant-basedMycobacterium tuberculosisvaccines in clinical trials that have shown efficacy in animal models. Despite these novel adjuvants, there is still a need to design new and more versatile adjuvants that have minimal adverse side effects but produce robust long-lasting adaptive immune responses. To this end, we hypothesized thatBacillus subtilisspores may provide the appropriate innate signals that are required to generate such vaccine-mediated responses, which would be sufficient to reduce the mycobacterial burden after infection withM. tuberculosis. In addition, we compared the response generated byB. subtilisspores to that generated by monophosphoryl lipid A (MPL), which has been used extensively to test tuberculosis vaccines. The well-characterized, 6-kDa early secretory antigenic target ofM. tuberculosis(ESAT-6; Rv3875) was used as a test antigen to determine the T cell activation potential of each adjuvant. Inoculated into mice,B. subtilisspores induced a strong proinflammatory response and Th1 immunity, similar to MPL; however, unlike MPL formulated with dimethyldioctadecylammonium (DDA) bromide, it failed to induce significant levels of interleukin-17A (IL-17A) and was unable to significantly reduce the mycobacterial burden after pulmonary infection withM. tuberculosis. Further analysis of the activity of MPL-DDA suggested that IL-17A was required for protective immunity. Taken together, the data emphasize the requirement for a network of cytokines that are essential for protective immunity.

scholarly journals Vaccine adjuvants aluminum and monophosphoryl lipid A provide distinct signals to generate protective cytotoxic memory CD8 T cells

2011 ◽  
Vol 108 (19) ◽  
pp. 7914-7919 ◽  
Author(s):  
M. K. L. MacLeod ◽  
A. S. McKee ◽  
A. David ◽  
J. Wang ◽  
R. Mason ◽  
...  
Keyword(s):  
T Cells ◽  
Cd8 T Cells ◽  
Lipid A ◽  
Vaccine Adjuvants ◽  
Memory Cd8 T Cells ◽  
Monophosphoryl Lipid A ◽  
Monophosphoryl Lipid

Enhanced endogenous antioxidant activity and inhibition of cerebral vasospasm in rabbits by pretreatment with a nontoxic endotoxin analog, monophosphoryl lipid A

1998 ◽  
Vol 88 (6) ◽  
pp. 1082-1087 ◽  
Author(s):  
Tomikatsu Toyoda ◽  
Aij-Lie Kwan ◽  
Murad Bavbek ◽  
Neal F. Kassell ◽  
John E. Wanebo ◽  
...  
Keyword(s):  
Antioxidant Activity ◽  
Protective Effect ◽  
Cerebral Vasospasm ◽  
Lipid A ◽  
Sod Activity ◽  
Content Type ◽  
Monophosphoryl Lipid A ◽  
Monophosphoryl Lipid ◽  
Basilar Arteries ◽  
Fine Print

Object. Monophosphoryl lipid A (MPL) and diphosphoryl lipid (DPL) are derivatives of the lipopolysaccharide (endotoxin) of Salmonella minnesota strain R595. Monophosphoryl lipid A is relatively nontoxic and can stimulate the natural defense or immune system. Diphosphoryl lipid is relatively toxic; however, at higher concentrations, it can also stimulate an immune response. The purpose of the present study was to determine the effects of these endotoxin analogs on cerebral vasospasm after the onset of subarachnoid hemorrhage (SAH) in rabbits. Methods. Intrathecal administration of MPL or DPL (5 µg/kg) was performed immediately before and 24 hours after induction of SAH in New Zealand White rabbits. Forty-eight hours after induction of SAH, the animals were killed by perfusion fixation for morphometric analyses of vessels or perfused with saline and assayed for superoxide dismutase (SOD) activity. Additional rabbits were administered MPL or DPL and killed 24 hours later for assessment of SOD activity; no SAH was induced in these animals. Experimental SAH elicited spasm of the basilar arteries in each group. Vasospasm was markedly attenuated in animals treated with MPL (p < 0.01 compared with vehicle-treated animals), but not in animals treated with DPL. A substantial reduction in SOD activity in the basilar artery accompanied the vasospasm; this loss of activity was significantly blocked by treatment with MPL, but not DPL. In animals that were not subjected to experimental SAH, MPL elicited a significant increase in SOD activity over basal levels, whereas DPL was ineffective. Conclusions. These data provide evidence of a marked protective effect of the endotoxin analog MPL against vasospasm. Although the mechanism(s) responsible for the protective effect of MPL remains to be verified, an enhancement of basal antioxidant activity and an inhibition of SAH-induced loss of this activity are attractive candidates. An MPL-based therapy could represent a useful addition to current therapies for SAH-induced cerebral injury.

scholarly journals Enhanced Immunogenicity and Protective Efficacy of aCampylobacter jejuniConjugate Vaccine Coadministered with Liposomes Containing Monophosphoryl Lipid A and QS-21

mSphere ◽  
2019 ◽  
Vol 4 (3) ◽  
Author(s):  
Amritha Ramakrishnan ◽  
Nina M. Schumack ◽  
Christina L. Gariepy ◽  
Heather Eggleston ◽  
Gladys Nunez ◽  
...  
Keyword(s):  
Campylobacter Jejuni ◽  
Conjugate Vaccine ◽  
Aluminum Hydroxide ◽  
Nonhuman Primates ◽  
Lipid A ◽  
Diarrheal Disease ◽  
Protective Efficacy ◽  
Content Type ◽  
Monophosphoryl Lipid A ◽  
Monophosphoryl Lipid

ABSTRACTCampylobacter jejuniis among the most common causes of diarrheal disease worldwide and efforts to develop protective measures against the pathogen are ongoing. One of the few defined virulence factors targeted for vaccine development is the capsule polysaccharide (CPS). We have developed a capsule conjugate vaccine againstC. jejunistrain 81-176 (CPS-CRM) that is immunogenic in mice and nonhuman primates (NHPs) but only moderately immunogenic in humans when delivered alone or with aluminum hydroxide. To enhance immunogenicity, two novel liposome-based adjuvant systems, the Army Liposome Formulation (ALF), containing synthetic monophosphoryl lipid A, and ALF plus QS-21 (ALFQ), were evaluated with CPS-CRM in this study. In mice, ALF and ALFQ induced similar amounts of CPS-specific IgG that was significantly higher than levels induced by CPS-CRM alone. Qualitative differences in antibody responses were observed where CPS-CRM alone induced Th2-biased IgG1, whereas ALF and ALFQ enhanced Th1-mediated anti-CPS IgG2b and IgG2c and generated functional bactericidal antibody titers. CPS-CRM + ALFQ was superior to vaccine alone or CPS-CRM + ALF in augmenting antigen-specific Th1, Th2, and Th17 cytokine responses and a significantly higher proportion of CD4+IFN-γ+IL-2+TNF-α+and CD4+IL-4+IL-10+T cells. ALFQ also significantly enhanced anti-CPS responses in NHPs when delivered with CPS-CRM compared to alum- or ALF-adjuvanted groups and showed the highest protective efficacy against diarrhea following orogastric challenge withC. jejuni. This study provides evidence that the ALF adjuvants may provide enhanced immunogenicity of this and other novelC. jejunicapsule conjugate vaccines in humans.IMPORTANCECampylobacter jejuniis a leading cause of diarrheal disease worldwide, and currently no preventative interventions are available.C. jejuniis an invasive mucosal pathogen that has a variety of polysaccharide structures on its surface, including a capsule. In phase 1 studies, aC. jejunicapsule conjugate vaccine was safe but poorly immunogenic when delivered alone or with aluminum hydroxide. Here, we report enhanced immunogenicity of the conjugate vaccine delivered with liposome adjuvants containing monophosphoryl lipid A without or with QS-21, known as ALF and ALFQ, respectively, in preclinical studies. Both liposome adjuvants significantly enhanced immunity in mice and nonhuman primates and improved protective efficacy of the vaccine compared to alum in a nonhuman primateC. jejunidiarrhea model, providing promising evidence that these potent adjuvant formulations may enhance immunogenicity in upcoming human studies with thisC. jejuniconjugate and other malaria and HIV vaccine platforms.

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