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At least 415 records · Page 23Linked to original sources
PubMed2001

Enhancing the potency of peptide-pulsed antigen presenting cells by vector-driven hyperexpression of a triad of costimulatory molecules.

Recombinant orthopox vectors (both replication-defective fowlpox [rF], and replication competent vaccinia [rV] have been developed that simultaneously express three T-cell costimulatory molecule transgenes. The constituents of this triad of costimulatory molecules (designated TRICOM) are B7-1, ICAM-1, and LFA-3. We have previously shown that infection of murine dendritic cells (DCs) with TRICOM vectors increases their level of expression of the triad of costimulatory molecules and enhances the efficacy of DCs to activate T cells. While DCs are arguably the most potent antigen presenting cell (APC), limitations clearly exist in their use due to the level of effort and cost for their generation. The studies reported here demonstrate that a generic APC population, murine splenocytes, can be made markedly more efficient as APCs by infection with either rF-TRICOM or rV-TRICOM vectors. Infection of splenocytes with either TRICOM vector led to significant improvement of APC capabilities in terms of: (a) enhancement of mixed lymphocyte reactions; (b) a reduction in the amount of signal 1 to activate naive T cells; and (c) a reduction in the amount of APCs required to activate T cells using a constant amount of signal 1. TRICOM-enhanced T-cell activation was shown to correspond to increases in type-1 cytokines and a reduced level of apoptosis, compared with T cells activated with uninfected or control vector-infected splenocytes. In vitro and in vivo experiments compared DCs with TRICOM-infected splenocytes. Infection of splenocytes with TRICOM vectors markedly enhanced their ability to activate T cells to levels approaching that of DCs. These studies thus demonstrate for the first time that an abundant and accessible population of APCs obtainable without lengthy culture or the use of costly exogenous cytokines (in contrast to that of DCs) can be made more potent as APCs with the use of vectors that express a triad of costimulatory molecules.

Animals↗
PubMed2001

Local immune responses to influenza antigen are synergistically enhanced by the adjuvant ISCOMATRIX.

The peripheral (draining) lymph node, as the primary site of immune induction, determines the course of systemic responses to an injected antigen. Lymphatic duct cannulation procedures in sheep were used to investigate local immunoreactivity to human influenza virus antigen (Flu ag) admixed with the adjuvant ISCOMATRIX (IMX). Compared to Flu ag or IMX alone, the co-administration of Flu ag and IMX (Flu ag+IMX) synergistically enhanced a number of immunological responses (lymphocyte and blast migration from the node, antigen-specific antibody levels and IL6 output in efferent lymph, and antigen-induced proliferation in cultured efferent lymph cells). Together, these results demonstrate that IMX is an immune modulator, and that lymphatic duct cannulation procedures may be used to evaluate antigen/adjuvant combinations for vaccine development.

Adjuvants, Immunologic↗
PubMed2003

Intranasal vaccination with ISCOMATRIX adjuvanted influenza vaccine.

Mucosal delivery of inactivated vaccines that are able to elicit protective immune responses against respiratory diseases has been a long time goal of vaccinologists. Such vaccines would enable a more appropriate means of vaccination against respiratory diseases than those currently delivered by a parenteral route. The intranasal delivery of inactivated influenza vaccine plus the ISCOMATRIX (IMX) adjuvant, simply mixed together, was able to induce serum haemagglutination inhibition (HAI) titres in mice far superior to those obtained with unadjuvanted vaccine delivered subcutaneously. Furthermore, the IMX adjuvanted vaccine delivered intranasally induced mucosal IgA responses in the lung, nasal passages and large intestine, together with high levels of serum IgA. Intranasal delivery of IMX adjuvanted influenza vaccine in sheep gave antibody responses in both serum and nasal secretions that surpassed the levels obtained with unadjuvanted vaccine administered subcutaneously. These observations suggest that it may be possible to induce effective immunity to influenza in humans by intranasal vaccination with an IMX adjuvanted inactivated vaccine.

Adjuvants, Immunologic↗
PubMed1999

Evaluation of novel aggregate structures as adjuvants: composition, toxicity studies and humoral responses.

Adjuvants are compounds that, when combined with an antigen, potentiate an immune response in an immunized species. There are numerous pathogens for which there are no protective vaccines and since alum is the only adjuvant licensed for use in humans, there is a clear need for more effective adjuvant preparations. In this study we describe the immunopotentiating properties of three novel molecular aggregate formulations based on tomatine (RAM1), a glycosylamide lipid (RAM2) and a fifth generation dendrimeric polymer (RAM3) respectively. These formulations were evaluated for their ability to augment antigen-specific antibody responses when administered with a soluble protein antigen. All three adjuvants were shown to be nontoxic to mice and elicited antigen-specific antibody responses. Of the three formulations, RAM1 was found to induce the highest titers of antibody; these were substantially higher than those induced by reference control adjuvants. RAM1 elicited antibodies of the IgG1 and IgG2a subclasses indicating, indirectly, that this adjuvant can stimulate Th2 and Th1 type immunity.

Adjuvants, Immunologic↗
PubMed1999

A V3 loop haptenic peptide sequence, when tandemly repeated, enhances immunogenicity by facilitating helper T-cell responses to a covalently linked carrier protein.

Subunit immunogens containing tandemly repeated copies of T- and B-cell epitopes have been shown to be more immunogenic than the respective immunogen containing only a single copy of the sequence. It has been unclear, however, whether the increased immunogenicity of a tandemly repeated B-cell epitope necessarily results from increased helper T-cell responses to intrinsic T-cell epitopes in the tandemly repeated sequences, or to neodeterminant T-cell epitopes created at the junction of adjacent repeat sequences. We examined this question by comparing the immunogenicity in mice of two immunogens containing one or eight tandemly repeated copies of an HIV-1 V3 loop haptenic sequence. Our results show that the tandemly repeated haptenic sequence potentiates the immunogenicity of the protein construct, likely through the facilitation of enhanced B-cell interaction with the tandem repeat construct and the consequent elicitation of increased carrier protein-specific helper T-cell responses.

Amino Acid Sequence↗
PubMed1993

Bovine herpesvirus-1 vaccines.

Vaccination has been important in controlling a wide variety of viral and bacterial infections of man and animals. Vaccines to herpesvirus infection of cattle are no exception. The present review describes the different types of conventional vaccines that have been used to date and furthermore describes the novel approaches which are presently being implemented to develop more effective vaccines. These include subunit vaccines as well as genetically engineered modified live deletion mutants. Both these novel vaccine approaches appear to be more efficacious than conventional vaccines. Furthermore, these vaccines provide an additional dimension for control and eradication of infection by providing an opportunity to develop companion diagnostic tests to differentiate infected animals from vaccinated animals. This review summarizes these developments as well as present knowledge regarding the important host defence mechanisms required for preventing infection and aiding recovery from infection.

Animals↗
PubMed1999

Functional definition of a B cell epitope, KGEQGEPGA, on C1q the Fc-binding subunit of the first component of complement.

A synthetic peptide representing the C1q epitope KGEQGEPGA has been shown to suppress or delay the onset of CII-induced arthritis when applied intravenously (i.v.) prior to an intradermal (i.d.) challenge, in a mouse model; the phenomenon being associated with the development of immunoglobulin (Ig)M antibodies specific for the KGEQGEPGA epitope. Here we show that this amino acid sequence provides an immunodominant B cell epitope that is recognised by autoantibodies present in the sera of patients with chronic inflammatory diseases such as systemic lupus erythematosus (SLE) and rheumatoid arthritis, two diseases associated with an immune response to C1q. The peptide's ability to produce peptide specific IgM when applied i.v. in both normal and athymic mice but not in mice exhibiting the x-linked B-cell associated Bruton's tyrosine kinase defect permits classification of the KGEQGEPGA peptide as a T-cell independent antigen type-2 (TI-2). IgM monoclonal antibodies raised against the peptide are able to functionally block activation of the complement cascade by C1q, via a mechanism that inhibits the C4 consumption. Antibodies to this immunodominant epitope may therefore modulate inflammatory processes by interfering with the activation of the classical pathway of the complement.

Agammaglobulinaemia Tyrosine Kinase↗
PubMed1998

Skin delivery of a hybrid liposome/ISCOM vaccine implicates a role for adjuvants in rapid modulation of inflammatory cells involved in innate immunity before the enhancement of adaptive immune responses.

There is now compelling evidence that intradermal vaccination with an efficacious adjuvanted antigen triggers a series of coordinated responses characterized initially by the rapid mobilization and recruitment of granulocytes to the lung. Activation of effector cells of the innate immune system is intended to provide surveillance and temporary protective cover at vulnerable mucosal sites while both T and B cell precursors, as well as haematopoietic progenitor cells, are undergoing dramatic reductions in numbers during the first 2-4 days post-vaccination. Some of these events recapitulate those seen after infection with a pathogen. Initial decreases in cell numbers in the thymus and bone marrow (BM) are followed by rapid increases in cellular proliferation in these organs, probably in response to peripheral signals. Vaccine-induced cell death (by apoptosis) in the thymus may provide one of many stimuli needed to up-regulate BM production of progenitor cells, and cells of the B, myeloid and monocytic lineages so that depleted peripheral compartments are replenished. Reconstitution of the latter cell population is critical in ensuring sufficient numbers of APC are generated to deal with extraneous antigen resulting from either vaccination or proliferation of a pathogen. Ultimately, these APC, as effector cells of the innate immune system, must provide pattern recognition of dangerous pathogens and serve to activate appropriate T cell responses. Vaccination not only educates both the innate and adaptive arms of the immune response but also more interestingly, appears to regulate subsequent innate immune responses following exposure to a lethal challenge dose of bacteria. Under these conditions, the rate of loss of BM precursors is greatly attenuated in mice previously vaccinated with adjuvanted antigen compared to unvaccinated controls or mice that had received only antigen. Mice intradermally vaccinated with adjuvanted antigen also displayed increased rates of granulocyte and monocyte recruitment in the lung and spleen. These events occurred very rapidly within 12-36 h of challenge and may be crucial in providing complete protection in vaccinated mice against a challenge dose that was otherwise lethal for unvaccinated controls. Therefore, an important characteristic of an efficacious intradermal vaccine may be the ability to deplete T and B precursors in the thymus and BM lymphoid compartments followed by increased rates of haematopoiesis to re-supply peripheral requirements for granulocytes/monocytes, and T and B cells. Adaptive immunity elicited by intradermal vaccination is, therefore, dependent upon prior activation of the innate immune system.

Adjuvants, Immunologic↗
PubMedDate not supplied

Using distilled water for the extraction of mucosal antibodies and the subsequent application in RSV neutralization test.

Virus neutralization (VN) is an important functional test for evaluating RSV vaccines, also encompassing in mucosal secretion of the respiratory tract considering the infection route. In our previous study, an immunoglobin extraction method described by Bergquist et al. was adopted for RSV ELISA, but it was not suitable for virus neutralization test due to the cell toxicity of the 2% saponin solution used for the antibody extraction. In order to overcome this problem, several solvents including distilled water were tested in the present study for the capacity to extract immunogloblins. Antibodies in the extracts were evaluated and compared by ELISA. Distilled water was as efficient as the 2% saponin solution for extraction of total IgA, RSV specific IgA and IgG. More importantly, the organ extracts obtained subsequently could be used for virus neutralization test without causing adverse effect on the cell culture. Therefore, distilled water was finally chosen as the solvent for immunoglobulin extraction from mucosal organs when both ELISA and virus neutralization test are required.

Animals↗
PubMed2005

Adjuvants and antibody production: dispelling the myths associated with Freund's complete and other adjuvants.

Adjuvants have been used for more than 70 yr to enhance the immune response of the host animal to an antigen. Among the mechanisms that adjuvants use to enhance the immune response are the "depot" effect, antigen presentation, antigen targeting, immune activation/modulation, and cytotoxic lymphocyte induction. The immunostimulatory properties of adjuvants result in inflammation, tissue destruction, and the potential for resulting pain and distress in the host animal. The inflammatory lesions produced by adjuvants such as Freund's complete adjuvant (FCA) have led some to conclude that pain and distress are present, even in cases where the scientific evidence fails to support this conclusion. Recommendations and regulations in the literature, based on available scientific evidence, provide guidance on total adjuvant volumes, volumes per site, routes of injection, booster injections, and adjuvants used for antibody production. Among the numerous adjuvants that are used for experimental antibody production reviewed in this article, many claim to be less inflammatory, tissue destructive, and painful than FCA while producing equal or superior antibody responses. Although no adjuvant surpasses FCA for experimental antibody production against a wide range of antigenic molecules, many produce excellent antibody responses with less inflammation and tissue destruction. Balancing the requisite degree of immuno-stimulation and the extent of inflammation, necrosis, and potential pain and distress requires consideration of the nature of the antigen, the host immune responsiveness, the adjuvant's mechanisms of action, and the desired end-product. In cases where the antigen is a weak immunogen or has a very limited availability, the type and role of adjuvant becomes a critical component in producing an acceptable immune response and humoral antibody response.

Adjuvants, Immunologic↗
PubMed1996

Influence of N-linked glycans in V4-V5 region of human immunodeficiency virus type 1 glycoprotein gp160 on induction of a virus-neutralizing humoral response.

One of the functions of N-linked glycans of viral glycoproteins is protecting otherwise accessible neutralization epitopes of the viral envelope from neutralizing antibodies. The aim of the present study was to explore the possibility to obtain a more broadly neutralizing immune response by immunizing guinea pigs with gp160 depleted of three N-linked glycans in the CD4-binding domain by site-directed mutagenesis. Mutant and wild type gp160 were formulated into immunostimulating complexes and injected s.c. into guinea pigs. Both preparations induced high serum antibody response to native gp120 and V3 peptides. Both preparations also induced antibodies that bound equally well to the V3 loop or the CD4-binding region, as determined by a competitive enzyme-linked immunosorbent assay (ELISA). The sera from animals, immunized with mutated glycoprotein, did not neutralize nonrelated HIV strains better than did sera from animals, immunized with wild type glycoprotein. Instead, a pattern of preferred homologous neutralization was observed, i.e., sera from animals, immunized with mutant gp160, neutralized mutant virus better than wild type virus, and vice versa. These data indicated that elimination of the three N-linked glycans from gp160 resulted in an altered local antigenic conformation but did not uncover hidden neutralization epitopes, broadening the immune response.

AIDS Vaccines↗
PubMed1995

Efficient replication of human immunodeficiency virus type 1 and measles virus in a human-to-mouse graft versus host disease model permits immunization research.

An acute graft versus host disease (GvHD) murine model was developed to study the pathogenic and protective mechanisms against viruses that replicate in cells of the human immune system. The model allowed efficient replication of lymphotropic, macrophage and amphitropic strains of human immunodeficiency virus type 1 (HIV-1) and measles virus (MV). Cytopathic lymphotropic strains of HIV-1 and a wild-type MV strain replicated in a 'burst'-like manner, whereas a non-cytopathic lymphotropic HIV-1 strain and all macrophage-tropic HIV-1 strains caused persistent infection of the graft. The replication kinetics of infection with these viruses were highly reproducible and were very similar to those observed in natural infection of humans. Infection with these viruses, with the exception of HIV-1SF2, led to a delay [corrected] and abrogation of the GvHD, indicating a direct immunosuppressive effect. Interestingly, infection with the lymphotropic HIV-1SF2 strain was rapidly and spontaneously abrogated. The model was also shown to be suitable for the evaluation of passive immunization strategies. Administration of a combination of antibodies against the HIV-1 V3 loop and the HIV-1 CD4 binding sites prevented subsequent infection with HIV-1IIIB. In contrast, administration of CD4 binding site specific human monoclonal antibody at a concentration that would neutralize the virus in vitro enhanced in vivo infection with HIV-1IIIB. The model also allowed evaluation of in vivo immunization studies. Immunization with a live attenuated measles vaccine resulted in protection from a wild-type MV challenge, whereas immunization with a subunit candidate vaccine appeared to give partial protection.

Animals↗
PubMed1994

Effect of adjuvant formulations on the induction of virus-neutralizing and virus-binding antibodies by chemosynthetic peptides of VP1 of foot-and-mouth-disease virus.

Synthetic peptides corresponding to the 141-160 amino acid sequence of the protein VP1 of virus type O1 Kaufbeuren (O1K) and A5 Riems (A5R) were conjugated to thyroglobulin and mixed with complete Freund's adjuvant (CFA) or incomplete Freund's adjuvant (IFA) together with Quil A. Although the peptide of A5R, together with IFA and Quil A, or with CFA, elicited a high antibody response to the virus in the ELISA, formula containing both IFA and Quil A induced only high titres of virus-neutralizing antibodies in rabbits. These adjuvant formulas did not display significant differences with regard to side effects.

Adjuvants, Immunologic↗
PubMed1994

Vaccine technologies: view to the future.

The development of vaccines to prevent infectious diseases has been one of the most important contributions of biomedical science. Recent advances in the basic sciences are now fueling the development of a new generation of vaccines that will be based on rational design approaches. Two factors are making this possible: an improved understanding of the microbial factors required for virulence and the nature of the immune response to infection. The status of new vaccine technologies is summarized here.

Adjuvants, Immunologic↗
PubMed2006

The combined CTA1-DD/ISCOMs vector is an effective intranasal adjuvant for boosting prior Mycobacterium bovis BCG immunity to Mycobacterium tuberculosis.

Infection with Mycobacterium tuberculosis, the causative agent of tuberculosis (TB), remains one of the leading causes of mortality worldwide. The current "gold standard" vaccine Mycobacterium bovis BCG has a limited efficacy that wanes over time. The development of a vaccine to boost BCG-induced immunity is therefore a highly active area of research. Mucosal administration of vaccines is believed to provide better protection against pathogens, such as M. tuberculosis, that invade the host via mucosal surfaces. In this study we demonstrate that an intranasal vaccine, comprising the antigenic fusion protein Ag85B-ESAT-6 and the mucosal combined adjuvant vector CTA1-DD/ISCOMs, strongly promotes a Th1-specific immune response, dominated by gamma interferon-secreting CD4-positive T cells. Mucosal administration of Ag85B-ESAT-6 mixed with CTA1-DD/ISCOMs strongly boosted prior BCG immunity, leading to a highly increased recruitment of antigen-specific cells to the site of infection. Most importantly, we observed a significantly (P < 0.001) reduced bacterial burden in the lung compared to nonboosted control animals. Thus, the results demonstrate the effectiveness of mucosal vaccination with Ag85B-ESAT-6 mixed with CTA1-DD/ISCOMs as adjuvant for stimulating TB-specific protective immunity in the lung.

Adjuvants, Immunologic↗
PubMed1993

Immune responses and resistance to Toxoplasma gondii in mice immunized with antigens of the parasite incorporated into immunostimulating complexes.

Immunostimulating complexes were prepared with antigens extracted from tachyzoites of Toxoplasma gondii and were used to immunize mice. The major antigens incorporated into the immunostimulating complexes were the P30 and P22 antigens and an antigen with an approximate molecular weight of 6,000. Other antigens of molecular weights above 30,000 were also present. High antibody titers to T. gondii antigens and a delayed-type hypersensitivity reaction were noted for the immunized mice. Challenge of these mice with tachyzoites injected interperitoneally or with oocysts administered orally resulted in a statistically significant (P < 0.001) conditional probability of survival compared with that of controls. In contrast, the differences between immunized mice and controls challenged with tissue cysts did not attain statistical significance.

Animals↗
PubMed2002

Immunization with chaperone-peptide complex induces low-avidity cytotoxic T lymphocytes providing transient protection against herpes simplex virus infection.

Heat shock proteins loaded with viral peptides were shown to induce a CD8+ T cell response and confer protective immunity against challenge with herpes simplex virus (HSV). The delivery system consisted of recombinant human hsp70 coupled to the peptide SSIEFARL, which is the immunodominant peptide epitope, recognized by HSV specific T cells in C57BL/6 mice. Immunization resulted in CD8+ T-cell responses, measured by peptide-specific tetramers and peptide-induced intracellular gamma interferon expression and cytotoxicity, similar to responses resulting from immunization with a recombinant vaccinia virus that expressed SSIEFARL as a minigene (VvgB) and UV-inactivated HSV. However, the durability of the hsp70-SSIEFARL response was less than that resulting from VvgB and HSV immunization and in addition the CD8+ T-cell responses in the memory phase were functionally less effective. Mice challenged soon after immunization showed excellent immunity, but by 90 days postimmunization this had waned to be significantly less than the level of immunity in both VvgB- and HSV-immunized mice.

Animals↗