scholarly journals Vaccination of Cattle with Mycobacterium bovis Culture Filtrate Proteins and Interleukin-2 for Protection against Bovine Tuberculosis

2000 ◽  
Vol 68 (10) ◽  
pp. 5809-5815 ◽  
Author(s):  
D. Neil Wedlock ◽  
Bridget Vesosky ◽  
Margot A. Skinner ◽  
Geoffrey W. de Lisle ◽  
Ian M. Orme ◽  
...  
Keyword(s):  
Immune Responses ◽  
Mycobacterium Bovis ◽  
Culture Filtrate ◽  
Lipid A ◽  
Interleukin 2 ◽  
Delayed Type Hypersensitivity ◽  
Control Group ◽  
High Dose ◽  
Monophosphoryl Lipid A ◽  
Culture Filtrate Proteins

ABSTRACT In this study vaccines prepared from culture filtrate proteins (CFP) of Mycobacterium bovis and interleukin-2 (IL-2) were tested in cattle for their capacity to stimulate immune responses and to protect against an intratracheal challenge with virulent M. bovis. Nine groups of cattle were vaccinated with combinations of different doses of CFP and bovine IL-2 mixed with a monophosphoryl lipid A (MPL) adjuvant. An additional group was vaccinated withM. bovis BCG. Immune responses in CFP–IL-2-vaccinated animals differed from those seen in BCG-vaccinated animals by inducing high antigen-specific antibody responses and low levels of gamma interferon and IL-2 released from purified protein derivative-stimulated whole-blood cultures. In a concurrent experiment, additional animals were added to the high-dose CFP–IL-2, MPL control, and BCG groups and these expanded groups of animals were challenged intratracheally with virulent M. bovis. Although the lung lesion scores were significantly lower for both the CFP–IL-2-and BCG-vaccinated groups compared to the MPL control group, the overall level of protection was greatest for the BCG-vaccinated animals. There were more animals with extrathoracic spread of disease in the CFP–IL-2 group than in the other groups. While vaccination of cattle withM. bovis CFP gave an encouraging reduction in tuberculous lesions and did not induce a delayed-type hypersensitivity response to PPD, future CFP vaccines must prevent any extrathoracic spread of disease.

scholarly journals Enhanced Protection against Bovine Tuberculosis after Coadministration of Mycobacterium bovis BCG with a Mycobacterial Protein Vaccine-Adjuvant Combination but Not after Coadministration of Adjuvant Alone

2008 ◽  
Vol 15 (5) ◽  
pp. 765-772 ◽  
Author(s):  
D. Neil Wedlock ◽  
Michel Denis ◽  
Gavin F. Painter ◽  
Gary D. Ainge ◽  
H. Martin Vordermeier ◽  
...  
Keyword(s):  
Mycobacterium Bovis ◽  
Lipid A ◽  
Protective Efficacy ◽  
Cytokine Gene Expression ◽  
Control Group ◽  
Ammonium Bromide ◽  
Protein Vaccine ◽  
Monophosphoryl Lipid A ◽  
Culture Filtrate Proteins ◽  
Mycobacterial Protein

ABSTRACT Current efforts are aimed at optimizing the protective efficacy of Mycobacterium bovis BCG by the use of vaccine combinations. We have recently demonstrated that the protection afforded by BCG alone is enhanced by vaccinating cattle with a combination of vaccines comprising BCG and a protein tuberculosis vaccine, namely, culture filtrate proteins (CFPs) from M. bovis plus an adjuvant. In the current study, three different adjuvant systems were compared. The CFP was formulated with a depot adjuvant, dimethyldioctadecyl ammonium bromide (DDA), together with one of three different immunostimulants: monophosphoryl lipid A (MPL), a synthetic mycobacterial phosphatidylinositol mannoside-2 (PIM2), and a synthetic lipopeptide (Pam3Cys-SKKKK [Pam3CSK4]). Groups of cattle (n = 10/group) were vaccinated with BCG-CFP-DDA-PIM2, BCG-CFP-DDA-MPL, or BCG-CFP-DDA-Pam3CSK4. Two additional groups (n = 10) were vaccinated with BCG alone or BCG-adjuvant (DDA-MPL), and a control group was left unvaccinated. Protection was assessed by challenging the cattle intratracheally with M. bovis. Groups of cattle vaccinated with BCG-CFP-DDA-PIM2, BCG-CFP-DDA-MPL, BCG-CFP-DDA-Pam3CSK4, and BCG alone showed significant reductions in three, three, five, and three pathological and microbiological disease parameters, respectively, compared to the results for the nonvaccinated group. Vaccination with the combination of BCG and the DDA-MPL adjuvant alone abrogated the protection conferred by BCG alone. The profiling of cytokine gene expression following vaccination, prior to challenge, did not illuminate significant differences which could explain the latter result. Vaccination of cattle with a combination of BCG and protein tuberculosis vaccine enhances protection against tuberculosis.

Idiotype Vaccination in Human Myeloma: Generation of Tumor-Specific Immune Responses After High-Dose Chemotherapy

Blood ◽  
1999 ◽  
Vol 94 (2) ◽  
pp. 673-683 ◽  
Author(s):  
Massimo Massaia ◽  
Paolo Borrione ◽  
Silvano Battaglio ◽  
Sara Mariani ◽  
Eloise Beggiato ◽  
...  
Keyword(s):  
Immune Responses ◽  
Residual Disease ◽  
Interleukin 2 ◽  
Keyhole Limpet Hemocyanin ◽  
High Dose Chemotherapy ◽  
Outpatient Setting ◽  
Delayed Type Hypersensitivity ◽  
High Dose ◽  
Gm Csf ◽  
Macrophage Colony

Abstract Igs contain unique portions, collectively termed idiotypes (Id), that can be recognized by the immune system. Id expressed by tumor cells in B-cell malignancies can be regarded as tumor-specific antigens and a target for vaccine immunotherapy. We have started a vaccination trial in multiple myeloma (MM) using Id-specific proteins conjugated to keyhole limpet hemocyanin (KLH) as immunogens and low doses of subcutaneous granulocyte-macrophage colony-stimulating factor (GM-CSF) or interleukin-2 (IL-2) as immunoadjuvants. Twelve patients who had previously been treated with high-dose chemotherapy followed by peripheral blood progenitor cell (PBPC) transplantation entered this study from August 1995 to January 1998. All patients were in first remission at the time of vaccination. They received subcutaneous injections of Id vaccines and immunoadjuvants in an outpatient setting. The generation of Id-specific T-cell proliferative responses was documented in 2 patients, whereas a positive Id-specific delayed-type hypersensitivity (DTH) reaction was observed in 8 of the 10 patients studied. DTH specificity was confirmed in 1 patient by investigating the reactivity to synthetic peptides derived from the VDJ sequence of the tumor-specific Ig heavy chain. None of the patients generated soluble immune responses to Id, whereas the generation of soluble and cellular immune responses to KLH was observed in 100% and 80%, respectively. Eleven patients completed the treatment, whereas 1 patient failed to finish owing to progression of disease. Freedom from disease progression (FFDP), measured from the date of first Id/KLH injection to the date of first treatment after vaccination or last follow-up, ranged from 9 to 36 months. These data indicate that the immune competence status of MM patients is still susceptible to specific immunization after high-dose chemotherapy and PBPC transplantation. It remains to be determined whether generation of Id-specific immune responses can reduce the relapse rate of patients with minimal residual disease.

Idiotype Vaccination in Human Myeloma: Generation of Tumor-Specific Immune Responses After High-Dose Chemotherapy

Blood ◽  
1999 ◽  
Vol 94 (2) ◽  
pp. 673-683 ◽  
Author(s):  
Massimo Massaia ◽  
Paolo Borrione ◽  
Silvano Battaglio ◽  
Sara Mariani ◽  
Eloise Beggiato ◽  
...  
Keyword(s):  
Immune Responses ◽  
Residual Disease ◽  
Interleukin 2 ◽  
Keyhole Limpet Hemocyanin ◽  
High Dose Chemotherapy ◽  
Outpatient Setting ◽  
Delayed Type Hypersensitivity ◽  
High Dose ◽  
Gm Csf ◽  
Macrophage Colony

Igs contain unique portions, collectively termed idiotypes (Id), that can be recognized by the immune system. Id expressed by tumor cells in B-cell malignancies can be regarded as tumor-specific antigens and a target for vaccine immunotherapy. We have started a vaccination trial in multiple myeloma (MM) using Id-specific proteins conjugated to keyhole limpet hemocyanin (KLH) as immunogens and low doses of subcutaneous granulocyte-macrophage colony-stimulating factor (GM-CSF) or interleukin-2 (IL-2) as immunoadjuvants. Twelve patients who had previously been treated with high-dose chemotherapy followed by peripheral blood progenitor cell (PBPC) transplantation entered this study from August 1995 to January 1998. All patients were in first remission at the time of vaccination. They received subcutaneous injections of Id vaccines and immunoadjuvants in an outpatient setting. The generation of Id-specific T-cell proliferative responses was documented in 2 patients, whereas a positive Id-specific delayed-type hypersensitivity (DTH) reaction was observed in 8 of the 10 patients studied. DTH specificity was confirmed in 1 patient by investigating the reactivity to synthetic peptides derived from the VDJ sequence of the tumor-specific Ig heavy chain. None of the patients generated soluble immune responses to Id, whereas the generation of soluble and cellular immune responses to KLH was observed in 100% and 80%, respectively. Eleven patients completed the treatment, whereas 1 patient failed to finish owing to progression of disease. Freedom from disease progression (FFDP), measured from the date of first Id/KLH injection to the date of first treatment after vaccination or last follow-up, ranged from 9 to 36 months. These data indicate that the immune competence status of MM patients is still susceptible to specific immunization after high-dose chemotherapy and PBPC transplantation. It remains to be determined whether generation of Id-specific immune responses can reduce the relapse rate of patients with minimal residual disease.

scholarly journals TRAF6-IRF5 kinetics, TRIF, and biophysical factors drive synergistic innate responses to particle-mediated MPLA-CpG co-presentation

2021 ◽  
Vol 7 (3) ◽  
pp. eabd4235
Author(s):  
P. Pradhan ◽  
R. Toy ◽  
N. Jhita ◽  
A. Atalis ◽  
B. Pandey ◽  
...  
Keyword(s):  
Immune Responses ◽  
Molecular Mechanisms ◽  
Lipid A ◽  
Critical Role ◽  
Mouse Bone Marrow ◽  
Biophysical Properties ◽  
Gm Csf ◽  
Monophosphoryl Lipid A ◽  
Integrated Response ◽  
Particulate Carriers

Innate immune responses to pathogens are driven by co-presentation of multiple pathogen-associated molecular patterns (PAMPs). Combinations of PAMPs can trigger synergistic immune responses, but the underlying molecular mechanisms of synergy are poorly understood. Here, we used synthetic particulate carriers co-loaded with monophosphoryl lipid A (MPLA) and CpG as pathogen-like particles (PLPs) to dissect the signaling pathways responsible for dual adjuvant immune responses. PLP-based co-delivery of MPLA and CpG to GM-CSF–driven mouse bone marrow–derived antigen-presenting cells (BM-APCs) elicited synergistic interferon-β (IFN-β) and interleukin-12p70 (IL-12p70) responses, which were strongly influenced by the biophysical properties of PLPs. Mechanistically, we found that MyD88 and interferon regulatory factor 5 (IRF5) were necessary for IFN-β and IL-12p70 production, while TRIF signaling was required for the synergistic response. Both the kinetics and magnitude of downstream TRAF6 and IRF5 signaling drove the synergy. These results identify the key mechanisms of synergistic Toll-like receptor 4 (TLR4)–TLR9 co-signaling in mouse BM-APCs and underscore the critical role of signaling kinetics and biophysical properties on the integrated response to combination adjuvants.

Monophosphoryl lipid A: an effective adjuvant for potentiating mucosal immune responses

1999 ◽  
Vol 5 (3) ◽  
pp. 181-182 ◽  
Author(s):  
Suzanne M. Michalek ◽  
Noel K. Childers ◽  
Terry Greenway ◽  
George Hajishengallis ◽  
J. Terry Ulrich
Keyword(s):  
Immune Responses ◽  
Lipid A ◽  
Monophosphoryl Lipid A ◽  
Monophosphoryl Lipid ◽  
Mucosal Immune Responses

scholarly journals Induction of Protective Antiplague Immune Responses by Self-Adjuvanting Bionanoparticles Derived from Engineered Yersinia pestis

2020 ◽  
Vol 88 (5) ◽  
Author(s):  
Xiuran Wang ◽  
Amit K. Singh ◽  
Xiangmin Zhang ◽  
Wei Sun
Keyword(s):  
Immune Responses ◽  
Yersinia Pestis ◽  
Rational Design ◽  
Lipid A ◽  
Vaccine Development ◽  
Lethal Dose ◽  
Outer Membrane Vesicles ◽  
Vector System ◽  
Content Type ◽  
Monophosphoryl Lipid A

ABSTRACT A Yersinia pestis mutant synthesizing an adjuvant form of lipid A (monophosphoryl lipid A, MPLA) displayed increased biogenesis of bacterial outer membrane vesicles (OMVs). To enhance the immunogenicity of the OMVs, we constructed an Asd-based balanced-lethal host-vector system that oversynthesized the LcrV antigen of Y. pestis, raised the amounts of LcrV enclosed in OMVs by the type II secretion system, and eliminated harmful factors like plasminogen activator (Pla) and murine toxin from the OMVs. Vaccination with OMVs containing MPLA and increased amounts of LcrV with diminished toxicity afforded complete protection in mice against subcutaneous challenge with 8 × 105 CFU (80,000 50% lethal dose [LD50]) and intranasal challenge with 5 × 103 CFU (50 LD50) of virulent Y. pestis. This protection was significantly superior to that resulting from vaccination with LcrV/alhydrogel or rF1-V/alhydrogel. At week 4 postimmunization, the OMV-immunized mice showed more robust titers of antibodies against LcrV, Y. pestis whole-cell lysate (YPL), and F1 antigen and more balanced IgG1:IgG2a/IgG2b-derived Th1 and Th2 responses than LcrV-immunized mice. Moreover, potent adaptive and innate immune responses were stimulated in the OMV-immunized mice. Our findings demonstrate that self-adjuvanting Y. pestis OMVs provide a novel plague vaccine candidate and that the rational design of OMVs could serve as a robust approach for vaccine development.

scholarly journals Chemical and Immunological Characteristics of Aluminum-Based, Oil-Water Emulsion, and Bacterial-Origin Adjuvants

2019 ◽  
Vol 2019 ◽  
pp. 1-9 ◽  
Author(s):  
Susana Martiñón ◽  
Angel Cisneros ◽  
Sergio Villicaña ◽  
Ricardo Hernández-Miramontes ◽  
Edgar Mixcoha ◽  
...  
Keyword(s):  
Immune Response ◽  
Immune Responses ◽  
Lipid A ◽  
Humoral Response ◽  
Main Concern ◽  
Protein Antigens ◽  
Water Emulsion ◽  
Bacterial Origin ◽  
Monophosphoryl Lipid A ◽  
Oil Water

Adjuvants are a diverse family of substances whose main objective is to increase the strength, quality, and duration of the immune response caused by vaccines. The most commonly used adjuvants are aluminum-based, oil-water emulsion, and bacterial-origin adjuvants. In this paper, we will discuss how the election of adjuvants is important for the adjuvant-mediated induction of immunity for different types of vaccines. Aluminum-based adjuvants are the most commonly used, the safest, and have the best efficacy, due to the triggering of a strong humoral response, albeit generating a weak induction of cell-mediated immune response. Freund’s adjuvant is the most widely used oil-water emulsion adjuvant in animal trials; it stimulates inflammation and causes aggregation and precipitation of soluble protein antigens that facilitate the uptake by antigen-presenting cells (APCs). Adjuvants of bacterial origin, such as flagellin,E. colimembranes, and monophosphoryl lipid A (MLA), are known to potentiate immune responses, but their safety and risks are the main concern of their clinical use. This minireview summarizes the mechanisms that classic and novel adjuvants produce to stimulate immune responses.

scholarly journals A Potent Adjuvant Monophosphoryl Lipid A Triggers Various Immune Responses, but Not Secretion of IL-1β or Activation of Caspase-1

2006 ◽  
Vol 176 (2) ◽  
pp. 1203-1208 ◽  
Author(s):  
Kazuo Okemoto ◽  
Kiyoshi Kawasaki ◽  
Kentaro Hanada ◽  
Masami Miura ◽  
Masahiro Nishijima
Keyword(s):  
Immune Responses ◽  
Lipid A ◽  
Caspase 1 ◽  
Monophosphoryl Lipid A ◽  
Monophosphoryl Lipid

scholarly journals Oral Vaccination with Subunit Vaccines Protects Animals against Aerosol Infection with Mycobacterium tuberculosis

2002 ◽  
Vol 70 (6) ◽  
pp. 3111-3121 ◽  
Author(s):  
T. Mark Doherty ◽  
Anja Weinrich Olsen ◽  
Laurens van Pinxteren ◽  
Peter Andersen
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Immune Responses ◽  
Lipid A ◽  
Vaccination Strategy ◽  
Oral Immunization ◽  
Subunit Vaccines ◽  
Monophosphoryl Lipid A ◽  
Subcutaneous Immunization ◽  
Aerosol Infection

ABSTRACT Immunity against Mycobacterium tuberculosis depends largely on activation of cell-mediated responses, and gamma interferon has been shown to play a crucial role in this process in both humans and animal models. Since the lung is normally the organ in which infection is initiated and is the major site of pathology, immune responses in the lung play a significant role in restricting initial infection with M. tuberculosis. The aim of the present study was to stimulate efficient immunity in the lung by targeting the gut mucosa. Detoxified monophosphoryl lipid A (MPL) has been shown to be a relatively nontoxic adjuvant which efficiently promotes the induction of type 1 responses when it is given by the traditional subcutaneous route. We have therefore compared subcutaneous immunization of mice to oral immunization by using a model subunit vaccine carrying two immunodominant proteins from M. tuberculosis, in combination with MPL-based adjuvants. While less effective when used to prime a response, a heterologous priming and boosting vaccination strategy employing oral boosting induced significant systemic type 1 responses which equaled and surpassed those attained by subcutaneous immunization protocols. Moreover, the increased immune responses observed correlated with the induction of substantial protection against subsequent aerosol infection with virulent M. tuberculosis at levels comparable to, or better than, those obtained by multiple subcutaneous vaccinations. These results demonstrate that booster vaccinations via mucosal surfaces, by combining efficient subunit vaccines with the potent adjuvant MPL, may be an effective method of addressing some of the shortcomings of current vaccination strategies.

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