[Preliminary study results on the immunogenicity of a subunit herpes vaccine].
Explore the source record for details and available documents.
Animals↗
SEARCH · PubMed Health
Results for “Preclinical immunogenicity evaluation”
Explore indexed PubMed citations for clinical trials, systematic reviews and public health research. Read source abstracts and follow each citation to its original PubMed record.
Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.
Lipopeptide-based melanoma cancer vaccine induced a strong MART-27-35-cytotoxic T lymphocyte response in a preclinal study.
Identification of tumor antigens and their optimal antigenic peptides raised hopes for the development of peptide-based immunotherapeutic vaccine strategies for human melanoma, however. Synthetic peptides alone are not immunogenic enough, and adequate formulation is critical for elaboration of peptide vaccines. To improve formulation, we evaluated 2 lipopeptide constructs, both including HLA-A2-restricted MART 27-35-CD8+ T lymphocyte (CTL) epitope covalently linked to universal tetanus toxoid (TT) 830-843 helper T lymphocyte (HTL) epitope, in HLA-A2 transgenic mouse models that mimic human CTL responses in vivo. These 2 constructs only differed in the formulation of their lipid tail. We showed that lipopeptide constructs were strongly recognized, in vitro, by human MART 27-35 cytotoxic T cells derived from tumor-infiltrating lymphocytes. The transgenic Mice immunized with these 2 MART lipopeptide formulations containing covalently linked HTL-CTL epitopes induced strong MART 27-35 cytotoxic T cells. This CTL induction was critically dependent on the presence of the helper T lymphocyte epitope. These results also showed that a single palmitoyl-lysine chain is enough to assure immunogenicity of a given peptide and that the presence of a lipid tail bypass the need for adjuvant. These results support the selection of MART-lipopeptide melanoma vaccine for evaluation in a clinical trial.
Adjuvants, Immunologic↗
HIV-1 vaccine-induced immune responses which correlate with protection from SHIV infection: compiled preclinical efficacy data from trials with ten different HIV-1 vaccine candidates.
The specific immune mechanisms necessary and/or sufficient to elicit HIV-vaccine protection remain undefined. Utilising the SHIV rhesus macaque model the immunogenicity as well as the efficacy of ten different HIV-1 vaccine candidates was evaluated. Comparison of the immune responses induced, with the ability of the vaccine to protect from SHIV infection provided a means to determine which type of immune responses were necessary for protection. Vaccine candidates included VLPs, DNA, subunit protein with novel adjuvant formulations, ISCOMs and pox-virus vectors. Protection from SHIV infection was achieved in approximately half of the animals which received a primary intravenous cell-free challenge. The presence of CTL in the absence of other effector responses did not correlate with protection from this route and type of challenge. Virus neutralising antibodies (Nab) appeared to be necessary but alone were insufficient for protection. If Ag-specific IFN-gamma and/or IL-4 as well as lymphoproliferative (LP) responses were found with the lack of a detectable IL-2 response, then protection was not observed. Immunity correlated with the magnitude of Nab responses, beta-chemokines and as well as balanced, qualitative T-helper responses.
AIDS Vaccines↗
Use of cotton rats for preclinical evaluation of measles vaccines.
The continued prevalence and medical impact of measles worldwide has created interest in the development of new generations of measles vaccines. Monkeys can be used for preclinical testing of these vaccines. However, a more practical and less expensive animal model is highly desirable, particularly for initial vaccine development and evaluation. Cotton rats have been shown to support the replication of different strains of measles virus (MV), and thus may be useful for these purposes. To test this concept, the immunogenicity and protective efficacy of two standard (Moraten and trivalent measles, mumps, rubella) and four experimental (two recombinant ALVAC, one ISCOM subunit and live attenuated Edmonston-Zagreb) MV vaccines were evaluated in naïve cotton rats, and cotton rats with passively acquired MV-specific neutralizing serum antibodies. All of the test vaccines were immunogenic and protected naíve animals from pulmonary infection and viral dissemination. However, under the conditions utilized, only the Edmonston-Zagreb vaccine provided such protection to animals with significant levels of passively acquired MV-specific neutralizing antibodies. The results of these tests and the potential of using cotton rats as an animal model for preliminary testing of MV vaccines are discussed.
Animals↗
Valproic acid for the treatment of pediatric malignant glioma.
Despite surgery and adjuvant cytotoxic therapy anaplastic astrocytoma, glioblastoma and diffuse intrinsic brain stem glioma continue to have dismal prognosis. Differentiation induction is a new approach taking into account that malignant glioma cells share many features with immature glial progenitor cells that are capable of terminal differentiation. The concept of differentiation therapy is currently evaluated for several pediatric malignancies with or without multimodal standard therapy. Valproic acid (VPA) is a branched chain fatty acid that is able to inhibit proliferation of neuroectodermal cells and to induce these cells along neuronal or glial lineage. Preclinical studies have shown that VPA inhibits growth of human and rodent glial tumor cells in vitro and induces a distinct mature glial phenotype. In addition, growth of human neuroblastoma cells is inhibited in vitro and in vivo and exhibits marked evidence of differentiation. Treatment of neuroblastoma and glioma cells with VPA was accompanied by changes of surface molecule expression that enhance immunogenicity and reduce their capability to metastasize. The antitumoral effects observed in preclinical studies were reached at concentrations that are readily achieved in patients treated with VPA for epilepsy. Epilepsy patients receiving VPA have significantly enhanced hemoglobin F levels, supporting the hypothesis that nontoxic levels of VPA can induce cellular differentiation. Broad clinical experience with VPA and its low toxicity encourage the evaluation of VPA in patients that have been submitted to postoperative combined chemo- and radiotherapy for pediatric malignant glioma.
Antineoplastic Agents↗
[Immunogenicity of an inactivated culture vaccine against Aujeszky's disease].
Explore the source record for details and available documents.
Animals↗
A canine conditionally replicating adenovirus for evaluating oncolytic virotherapy in a syngeneic animal model.
Oncolytic adenoviruses, which selectively replicate in and subsequently kill cancer cells, have emerged as a promising approach for treatment of tumors resistant to other modalities. Although preclinical results have been exciting, single-agent clinical efficacy has been less impressive heretofore. The immunogenicity of adenoviruses, and consequent premature abrogation of replication, may have been a partial reason. Improving the oncolytic potency of agents has been hampered by the inability to study host-vector interactions in immune-competent systems, since human serotype adenoviruses do not productively replicate in animal tissues. Therefore, approaches such as immunomodulation, which could result in sustained replication and subsequently increased oncolysis, have not been studied. Utilizing the osteocalcin promoter for restricting the replication of a canine adenovirus to dog osteosarcoma cells, we generated and tested the first nonhuman oncolytic adenovirus. This virus effectively killed canine osteosarcoma cells in vitro and yielded a therapeutic benefit in vivo. Canine osteosarcoma is the most frequent malignant disease in large dogs, with over 8000 cases in the United States annually, and there is no curative treatment. Therefore, immunomodulation for increased oncolytic potency could be studied with clinical trials in this population. This could eventually translate into human trials.
Adenoviridae↗
Development of anti-CD4 MAb hu5A8 for treatment of HIV-1 infection: preclinical assessment in non-human primates.
The anti-CD4 MAb 5A8 is a potent inhibitor of CD4-mediated infection of HIV-1. CD4 is obligatory for infection with primary HIV-1 isolates. Humanized 5A8 (hu5A8) was constructed to reduce the potential immunogenicity and enhance the in vivo half-life when used in humans. hu5A8 is a molecularly engineered human IgG4 antibody retaining the binding and functional properties of the murine version of 5A8 (mu5A8). This humanized MAb has been shown to be very effective in inhibiting HIV-1 infection of human CD4+ T cells and macrophages in vitro and to reduce viral load in rhesus monkeys chronically infected with simian immunodeficiency virus (SIV). 5A8 was evaluated in a good laboratory practice (GLP)-compliant tissue cross-reactivity study on human (three donors/37 tissues) and rhesus monkey (two donors/37 tissues) tissues. hu5A8 bound to the surface of human T cells and macrophages, but only to T cells from rhesus monkeys. The antibody did not cross react with other tissues. The highly identical staining patterns of hu5A8 in human and rhesus monkey tissues support the use of rhesus monkeys as a preclinical model for humans. In a GLP-compliant safety study in rhesus monkeys, weekly administration of hu5A8 at 5 mg/kg or 25 mg/kg for 8 weeks was shown to be safe and well tolerated in all monkeys. Although hu5A8 induced anti-hu5A8 antibody response in healthy rhesus monkeys, it was not immunogenic in chimpanzees. Together, the results from these preclinical studies support the studies of the anti-HIV-1 effect of hu5A8 in HIV-1 infected individuals.
Animals↗
[Isolation of split and whole-virion tick-borne encephalitis vaccines in an experiment and the characteristics of their immunogenic and antigenic properties].
The split preparation, obtained by the treatment of purified and concentrated tick-borne encephalitis virus with 0.5% Tween-80 and ether and inactivated with formalin at a minimal concentration of 1:10,000, did not contain the active virus. After the removal of the detergent, the preparation retained its antigenic and immunogenic properties.
Animals↗
[Immunogenic activity of vaccines against Marek's disease].
Explore the source record for details and available documents.
Animals↗
[Modifications to a method of controlling the immunogenic activity of rabies vaccines].
To determine the immunogenic potency of different rabies vaccines, they were tested in the modified test, originally developed by the National Institutes of Health (USA). In this modification the mice used in the test were challenged with strains Vnukovo-32 and Moskva instead of strain CVS, and the vaccine was introduced not in two injections, but in a single injection. The study revealed that the use of test strain Vnukovo-32, homologous to the production vaccine strain, enhanced the absolute potency of vaccines but produced no effect on the relative potency when used with the similarly prepared reference agents. A single injection of the vaccine in the test for immunogenic potency was found to produce no changes in the results of tests for relative immunogenic potency. However, this modification needs further more extensive trials and discussion.
Animals↗
Regulation and review of DNA vaccine products.
Research efforts to develop DNA vaccine products have progressed to the clinical evaluation of several vaccine candidates. These clinical trials are assessing safety and immunogenicity and whether different routes and schedules of administration can improve immune responses. Vaccine candidates under study include those for hepatitis B, HSV-2, HIV-1, influenza, and malaria. Unique safety concerns include the potential for genomic integration, biodistribution, tolerance and auto-immunity. CBER has issued a Points to Consider (PTC) document outlining regulatory policy, recommendations for the development of consistent manufacturing processes, and the design of preclinical studies to establish the safety of DNA vaccine products. This presentation will provide an overview of DNA vaccine products currently under clinical evaluation and the regulatory policy that has guided their development.
Animals↗
Preclinical evaluation of Seprafilm bioresorbable membrane.
OBJECTIVE: To characterize Seprafilm bioresorbable membrane and assess its efficacy and safety in reducing adhesions. DESIGN: In vitro and animal studies designed to provide precise control of tissue trauma and closely approximate clinically relevant conditions in abdominal surgery. SETTING: Experimental laboratories, USA. SUBJECTS: Experimental animals, principally rats and rabbits. INTERVENTIONS: The rat cecal abrasion or sidewall injury model evaluated the efficacy of seprafilm in the presence of blood and irrigation solutions, in multiple layers, under ischemic conditions, and in adhesion reformation. A rabbit anastomosis model tested the effect of the membrane on wound healing, and a series of challenge tests determined its toxicology, immunogenicity, and biocompatibility. MAIN OUTCOME MEASURES: Incidence and severity of adhesions; mutagenicity; pyrogenicity; irritation effects; systemic toxicity. RESULTS: Seprafilm significantly reduced the number of cecal adhesions (p < 0.001) and the number of animals with severe adhesions (p < 0.001) when compared with nontreated controls, even in the presence of bleeding. The membrane also significantly decreased the number of animals with any adhesions (p < 0.001). Seprafilm maintains efficacy when used with excess irrigation solutions, when layered, and under ischemic conditions. Among rats tested for adhesion reformation, the treated group had a significantly larger proportion of adhesion-free animals than the untreated group, 72% versus 28%, (p = 0.007). Seprafilm did not impair wound healing in anastomosis and is nontoxic, nonmutagenic, nonimmunogenic, nonpyrogenic, nonirritating, and biocompatible. CONCLUSION: Preclinical studies have shown that Seprafilm is safe and effective in reducing postsurgical adhesions. Seprafilm meets the requirements of an ideal barrier and can be a useful adjuvant in abdominal and pelvic surgery.
Abdomen↗
Biological principles and clinical development of prostate cancer gene therapy.
Several clinical trials of prostate cancer gene therapy are underway. The therapeutic genes being evaluated by these and other, forthcoming, trials include immunogenes, cell death-inducing genes, antioncogenes, and tumor suppressor genes. Constraints of current gene transfer vectors limit, to local-regional targeting, those gene therapy strategies that do not rely on an intervening immune response. Preclinical models predict modest, if any, therapeutic effects with current forms of prostate cancer gene therapy. Using biological surrogate endpoints and applying further preclinical advances will allow clinical prostate cancer gene therapy to attain its full potential.
Adenoviridae↗
Immunogenicity of biopharmaceuticals in laboratory animals.
The potential immunogenicity of new protein therapeutics raises concerns about the possibility of inducing untoward immune reactions in humans. It is generally assumed that all animals will make antibody to human proteins and therefore, there is sentiment among some scientists that this makes the issue of immunogenicity as a safety concern irrelevant. However, recent clinical trials with some proteins have detected the presence of autoantibodies that have resulted in clinical sequelae. These reactions were also observed in preclinical animal studies. In fact, non-human primate and transgenic mouse models can be useful for predicting the relative immunogenicity of human proteins. In addition, the characterization of the immunogenicity of biotechnology molecules provides a practical basis for determining the significance of antibody formation in preclinical safety studies.
Animals↗
Safety assessment of biotechnology-derived pharmaceuticals: ICH and beyond.
Many scientific discussions, especially in the past 8 yr, have focused on definition of criteria for the optimal assessment of the preclinical toxicity of pharmaceuticals. With the current overlap of responsibility among centers within the Food and Drug Administration (FDA), uniformity of testing standards, when appropriate, would be desirable. These discussions have extended beyond the boundaries of the FDA and have culminated in the acceptance of formalized, internationally recognized guidances. The work of the International Committee on Harmonisation (ICH) and the initiatives developed by the FDA are important because they (a) represent a consensus scientific opinion, (b) promote consistency, (c) improve the quality of the studies performed, (d) assist the public sector in determining what may be generally acceptable to prepare product development plans, and (e) provide guidance for the sponsors in the design of preclinical toxicity studies. Disadvantages associated with such initiatives include (a) the establishment of a historical database that is difficult to relinquish, (b) the promotion of a check-the-box approach, i.e., a tendancy to perform only the minimum evaluation required by the guidelines, (c) the creation of a disincentive for industry to develop and validate new models, and (d) the creation of state-of-the-art guidances that may not allow for appropriate evaluation of novel therapies. The introduction of biotechnology-derived pharmaceuticals for clinical use has often required the application of unique approaches to assessing their safety in preclinical studies. There is much diversity among these products, which include the gene and cellular therapies, monoclonal antibodies, human-derived recombinant regulatory proteins, blood products, and vaccines. For many of the biological therapies, there will be unique product issues that may require specific modifications to protocol design and may raise additional safety concerns (e.g., immunogenicity). Guidances concerning the design of preclinical studies for such therapies are generally based on the clinical indication. Risk versus benefit decisions are made with an understanding of the nature of the patient population, the severity of disease, and the availability of alternative therapies. Key components of protocol design for preclinical studies addressing the risks of these agents include (a) a safe starting dose in humans, (b) identification of potential target organs, (c) identification of clinical parameters that should be monitored in humans, and (d) identification of at-risk populations. One of the distinct aspects of the safety evaluation of biotechnology-derived pharmaceuticals is the use of relevant and often nontraditional species and the use of animal models of disease in preclinical safety evaluation. Extensive contributions were made by the Center for Biologics Evaluation and Research to the ICH document on the safety of biotherapeutics, which is intended to provide worldwide guidance for a framework approach to the design and review of preclinical programs. Rational, scientifically sound study design and early identification of the potential safety concerns that may be anticipated in the clinical trial can result in preclinical data that facilitate use of these novel therapies for use in humans without duplication of effort or the unnecessary use of animals.
Animals↗
Advances in vaccine adjuvants.
Currently, aluminum salts and MF59 are the only vaccine adjuvants approved for human use. With the development of new-generation vaccines (including recombinant subunit and mucosal vaccines) that are less immunogenic, the search for more potent vaccine adjuvants has intensified. Of the novel compounds recently evaluated in human trials, immunostimulatory molecules such as the lipopolysaccharide derived MPL and the saponin derivative QS21 appear most promising, although doubts have been raised as to their safety in humans. Preclinical work with particulate adjuvants, such as the MF59 microemulsion and lipid-particle immune-stimulating complexes (Iscoms), suggest that these molecules are also potent elicitors of humoral and cellular immune responses. In addition, preclinical data on CpG oligonucleotides appear to be encouraging, particularly with respect to their ability to selectively manipulate immune responses. While all these adjuvants show promise, further work is needed to better define the mechanisms of adjuvant action. Ultimately, the development of more potent adjuvants may allow vaccines to be used as therapeutic, rather than prophylactic, agents.
Adjuvants, Immunologic↗
Recent advances in immunological adjuvants: the development of particulate antigen delivery systems.
New generation vaccines, including those based on recombinant proteins, are safer than traditional vaccines, but are less immunogenic. Therefore, there is an urgent need for the development of new and improved vaccine adjuvants. A number of potent immunostimulatory molecules obtained from bacterial cells or plants have been extensively evaluated as adjuvants. However, a number of these molecules have displayed significant toxicity, both in preclinical animal models and in human clinical trials. An alternative approach to the development of novel adjuvants involves the preparation of particulate antigen delivery systems of similar dimensions to natural pathogens. In the absence of additional immunostimulatory molecules, emulsion droplets and microparticles have been shown to be potent adjuvants for the induction of both humoral and cell-mediated immune responses following systemic administration. Moreover, particulate delivery systems have been shown to display an acceptable toxicity profile in a number of clinical trials. Particulate antigen delivery systems also have the potential to function as potent adjuvants following administration by mucosal routes, including oral and intranasal. An alternative approach to the mucosal delivery of vaccines involves the use of genetically detoxified mutant toxins, e.g., LT-K63, as mucosal adjuvants. The use of novel adjuvants and antigen delivery systems is likely to extend the use of vaccines into the area of therapeutics, involving the eradication of infectious diseases and cancers, or the amelioration of autoimmune disorders.
Journal Article↗