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Results for “Preclinical immunogenicity evaluation”

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At least 127 records · Page 7Linked to original sources

PubMed2001

Global Forum on TB Vaccine Research and Development. World Health Organization, June 7-8 2001, Geneva.

The TB community now envisions a turning point in the development of improved TB vaccines for both high and low incidence countries. With a number of viable TB vaccine candidates now available for testing, the investigation of safety and immunogenicity in human clinical trials is seen as the driving force for the future development of effective vaccines for the prevention of tuberculosis.

BCG Vaccine↗

PubMedDate not supplied

Molecular bases for the construction of artificial immunogens and vaccines based on synthetic polyions.

The molecular and cellular mechanisms of action of synthetic polyions on immunogenesis are reviewed. The results of studies of principal properties of polyionic immunostimulators and of the cell responses to the action of these stimulants have been used to construct artificial antigen-polyion complexes with enhanced immunogenic properties. The immunizing properties of such macromolecular complexes, constructed with the use of bacterial or viral antigens, are analyzed.

Adjuvants, Immunologic↗

PubMed1991

Antifibrin scintigraphy in the diagnostic evaluation of acute deep venous thrombosis.

Antifibrin scintigraphy is a new and innovative approach to the diagnosis of acute deep venous thrombosis (DVT). Many antifibrin monoclonal antibodies (Mo-Abs) have been described, but only two, 59D8 and T2G1s, have undergone broad preclinical or clinical investigation. Both of these MoAbs recognize an epitope on the amino terminal end of fibrin. The epitope for 59D8 and T2G1s is available for binding only on newly formed, acute thrombi. Preclinical studies have confirmed the specificity of these MoAbs for acute DVT, and have demonstrated their ability to image experimentally induced DVT. Preliminary clinical studies in patients with signs or symptoms of DVT have evaluated indium-111 59D8 Fab and technetium-99m T2G1s Fab'. Fragments of the intact MoAbs are employed to promote faster blood clearance and to reduce immunogenicity. The initial clinical studies indicate that antifibrin scintigraphy has a diagnostic accuracy approaching 90%. Antifibrin scintigraphy has the potential for overcoming many of the deficiencies of both invasive (contrast venography) and noninvasive (Doppler/ultrasound, impedance plethysmography) methods for detecting DVT. With a single procedure, it provides an accurate and rapid evaluation of both lower extremities, both above and below the knee. Because of its unique specificity for acute DVT, it should have excellent potential for use in patients with suspected acute, recurrent DVT, a condition difficult to diagnose by all currently employed tests for DVT.

Animals↗

PubMedDate not supplied

[Characteristics of the immunological and protective effect in the simultaneous and separate use of live and killed influenza vaccines].

Simultaneous immunization with inactivated and live influenza vaccines is characterized by a more rapid and intensive formation of local protection and humoral immunity persisting for 5 months at a higher level than after separate administration of inactivated and live vaccines. The live vaccine was found to be the major factor enhancing the immune response and local protection in combined immunization. Administration as components of a live bivaccine of influenza serotype A viruses with a different degree of attenuation was not accompanied by higher reactogenicity but led to a sharp decrease of immunogenic activity that indicated incompatibility of such viruses in a bivaccine.

Adolescent↗

PubMed2006

[Immunotherapy of non-Hodgkin's lymphomas (NHL) by anti-CD22 antibody--review].

CD22 is a transmembrane sialoglycoprotein and a member of the immunoglobulin superfamily. Its expression is restricted to the B cell lineage and a vast majority of B cell NHLs. CD22 plays a key role in B cell development, survival, and function. Humanized anti-CD22 antibodies were developed to minimize the immunogenicity and to enhance effector interactions during their developments of diagnostic and immunotherapeutic agent. Preclinical test with anti-CD22 antibodies indicates that a single, conjugated or radiolabeled agent has shown preliminary antitumor activity in patients with recurrent and heavily pretreated NHL. Anti-CD22 antibodies were well tolerated, without dose-dependant toxicity. Anti-CD22 antibodies are currently being evaluated in combination with rituximab, and the early results suggest that the combination of the two antibodies are well tolerated and may result in better clinical activity than the single agent alone. Thus, anti-CD22 antibodies are theoretically good candidates alone and in combination with other drugs in the treatment of B cell malignancies. In this review, the physiologic function and characteristics of CD22 antigen as target molecule of guide therapy for NHL, the types of anti-CD22 antibodies in therapy of NHL and the combination use with other antibodies were summarized.

Animals↗

PubMed2006

Preclinical evaluation of Hematide, a novel erythropoiesis stimulating agent, for the treatment of anemia.

OBJECTIVE: To evaluate the preclinical erythropoiesis stimulating properties of Hematide, a novel, PEGylated, synthetic peptide for the treatment of anemia associated with chronic kidney disease and cancer. METHODS: The in vitro activity of Hematide was assessed in competitive binding, proliferation, signal transduction, and apoptosis assays, and in erythroid colony-forming assays with CD34(+) cells purified from human bone marrow. Erythropoiesis and pharmacokinetics were evaluated in rat, monkey, and a rat chronic renal insufficiency (CRI) model following single administration. Erythropoiesis and immunogenicity were also evaluated following repeat administration in rats. RESULTS: Hematide binds and activates the erythropoietin receptor and causes proliferation and differentiation of erythroid progenitor cells. Sustained circulatory persistence of Hematide is observed in rats and monkeys. In a rat CRI model, Hematide exhibited twofold lower clearance than in the normal rat, with hypothesis consistent with Hematide being cleared, at least partially, via the kidney. A dose-dependent rise in hemoglobin (Hgb) and duration of response was observed following single administration in rats and monkeys. Hematide was able to alleviate anemia in an experimental CRI rodent model. Repeat intravenous (IV) and subcutaneous (SC) administration in rats yielded similar erythrogenic responses, with no anti-Hematide antibodies being detected. CONCLUSIONS: Hematide is a potent erythropoiesis stimulating agent with a prolonged half-life and slow clearance times. It is anticipated that similar prolonged clearance and activity will be observed in the clinic, potentially enabling dosing intervals of 3 to 4 weeks that may translate into improved patient convenience for the treatment of anemia.

Anemia↗

PubMed2006

Preclinical safety of recombinant human thrombin.

Recombinant human thrombin (rhThrombin) is being developed as an alternative to thrombin products purified from pooled human or bovine plasma, which are currently marketed for topical hemostasis. Preclinical studies of rhThrombin were conducted prior to its evaluation as a topical adjunct to surgical hemostasis in clinical trials. No overt clinical pathology or signs were observed in cynomolgus monkeys following implantation of a gelatin sponge containing either rhThrombin or bovine thrombin to a surgical liver wound, and similar gross and microscopic wound healing characteristics were observed over an eight-week recovery period with either compound. Repeated subcutaneous injections of rhThrombin or bovine thrombin to cynomolgus monkeys produced no treatment-related effects. Whereas no monkeys demonstrated anti-rhThrombin antibody seroconversion, specific anti-bovine antibodies were detected in all tested monkeys exposed to bovine thrombin. Addition of rhThrombin or bovine thrombin to mouse fibroblast cells resulted in expected detachment and shape change. Topical application of rhThrombin to rabbits did not cause irritation to the eye, normal skin, or abraded skin. These studies showed that topical, subcutaneous, or implanted rhThrombin was minimally immunogenic, safe, and well tolerated in nonclinical models, and supported the clinical evaluation of rhThrombin in a variety of surgical settings.

Administration, Topical↗

PubMedDate not supplied

[The immunogenicity of a cultured inactivated hepatitis A vaccine].

A trial of inactivated hepatitis A viral vaccine of heteroploid cell culture origin is described. The vaccine preparation was tested in guinea pigs and tamarins. The animals were immunized intramuscularly four or three times, respectively. The efficacy was judged by induction of anti-HAV antibody persisting for at least 12 months in guinea pigs, and development of immunity to subsequent virus challenge (monkeys only). The challenge dose of HAV was unable to produce any signs of HAV infection in the vaccinated tamarins, although the booster effect was observed in some animals. The study demonstrated that the tested batches of the vaccine were highly immunogenic.

Animals↗

PubMedDate not supplied

[Antitumor effect of a tumor-cell neuraminidase vaccine].

The effect of neuraminidase vaccine of CBA mouse sarcoma cells caused by simian adenovirus SA7 (C8) on growth parameters of transplanted sarcoma in a syngeneic system was studied. Inoculation of the vaccine was found to inhibit tumor growth. This effect was more marked in a group of animals given tumor cells after preliminary vaccination. There was no correlation between tumor growth parameters and cytotoxic activity of spleen cells assesses in the cytotoxicity test by 51Cr release in the groups of vaccinated and control animals. It is concluded that the treatment of tumor cells with neuraminidase increases their immunogenicity. The cytotoxic activity of spleen cells in vaccinated animals appears earlier and persists longer.

Adenoviruses, Simian↗

PubMed2003

New gene-based approaches for an AIDS vaccine.

Vaccine approaches against AIDS have focused on inducing cellular immune responses, since many studies revealed the role of T cell responses in the control of human immunodeficiency virus or simian immunodeficiency virus (SIV) infections. The experimental infection of rhesus macaques with SIV or chimeric SHIV is routinely used as a model for AIDS. In such models, DNA immunization is a tool to elicit specific T cell responses and to study their protective efficacy. DNA immunogenicity in primates depends on parameters such as level of antigen expression, choice of the antigen among SIV proteins, use of fusion proteins, route of immunization, and addition of adjuvants. Recent results suggest that priming with DNA and boosting with attenuated recombinant viral vectors, each expressing corresponding SIV antigens, leads to improved specific immunity and, in some cases, affords protection against pathogenic challenge. After preclinical evaluations, DNA has entered clinical trials for a therapeutic or prophylactic gene-based AIDS vaccine.

AIDS Vaccines↗

PubMed2001

Different hepatitis C virus nonstructural protein 3 (Ns3)-DNA-expressing vaccines induce in HLA-A2.1 transgenic mice stable cytotoxic T lymphocytes that target one major epitope.

The immunogenicity of the Hepatitis C virus (HCV) nonstructural protein 3 (NS3) was investigated using different DNA-based strategies and a preclinical mouse model transgenic for the HLA-A2.1 molecule. Plasmids expressing NS3 either as a wild-type protein, as a fusion with murine lysosome-associated-membrane protein-1 specific sequences, or under the control of the Semliki Forest virus replicase were evaluated in vitro and in vivo. All plasmids were shown to express the expected size protein. These 3 NS3-expressing vaccines induced overall comparable levels of CTLs when measured at different times postvaccination although mice injected with the NS3-LAMP expressing plasmid showed a particularly homogeneous and overall vigorous response (specific lysis ranged from 60% to 90 % for an E:T ratio of 33.3:1 with a mean CTL precursor frequency of 1:2.10(5) cells). Out of the four HLA-A2.1-restricted NS3 epitopes previously described in HCV infected patients (aa 1073-1081, aa 1406-1415; aa 1169-1177 and aa 1287-1296), the NS3-DNA generated CTLs were predominantly targeted at the aa 1073-1081 epitope. Peptide-based immunization showed that the mouse repertoire was intact for all epitopes tested except one (aa 1287-1296). In conclusion, the 3 NS3-DNA vaccines although based on different mode of action, shared a comparable efficacy at inducing CTL. Surprisingly, the breadth of such response was restricted to a single, major epitope.

3T3 Cells↗

PubMed1996

Luciferase in vivo expression technology: use of recombinant mycobacterial reporter strains to evaluate antimycobacterial activity in mice.

The development of new drugs and vaccines directed against Mycobacterium tuberculosis is severely impeded by the slow growth of this organism and the need to work under stringent biosafety conditions. These difficulties pose considerable obstacles when animal studies with M. tuberculosis are performed. We investigated whether a novel approach termed luciferase in vivo expression, using an enhanced luciferase-expressing mycobacterial strain, could be used to evaluate antimycobacterial activity in mice. Vectors that expressed firefly luciferase (lux gene) at high levels in the bacillus Calmette-Gu-erin (BCG) strain of Mycobacterium bovis were constructed for use in vivo. One recombinant BCG reporter strain (rBCG-lux) was selected for high-level expression of the lux gene product and for its ability to replicate in mice. Methodology to monitor in vivo growth of the rBCG-lux reporter strain in mice by direct assay of luciferase luminescence in organ homogenates was developed. The utility of this approach for assessing the in vivo efficacies of antimycobacterial compounds was evaluated. The activities of standard antimycobacterial drugs were directly apparent in mice infected with the rBCG-lux reporter strain by statistically significant reductions in spleen luminescence. In addition, antimycobacterial immunity was also evident in BCG-immunized mice, in which suppression of rBCG-lux growth in comparison with that in naive mice was clearly observed. The use of luciferase in vivo expression for the in vivo evaluation of antimycobacterial activity compared favorably with standard CFU determinations in terms of time, labor, expense, and statistical significance but permitted the evaluation of antimycobacterial drugs and immunity in mice in 7 days or less. Thus, the use of this technology can greatly accelerate the process of evaluation of antibiotics and immunogens in animal models for the slowly growing pathogenic mycobacteria.

Animals↗

PubMed2006

Intranasal immunization with a recombinant truncated FimH adhesin adjuvanted with CpG oligodeoxynucleotides protects mice against uropathogenic Escherichia coli challenge.

In this work, we assessed the efficacy of an experimental intranasal vaccine against urinary-tract infections. The vaccine contained a recombinant truncated FimH (rFimHt) adhesin plus CpG oligodeoxynucleotides. The efficacy of the vaccine was compared with that of an intramuscular vaccine that was formulated with the same immunogen plus Freund's adjuvant. Our results show that serum immunoglobulin G titers of vaccinated animals were similarly enhanced in both cases. However, the intranasal vaccine elicited higher vaginal-wash-specific immunoglobulin A titers against rFimHt than the intramuscular route. Both vaccines reduced the in vivo colonization of the bladder by uropathogenic Escherichia coli more than 100-fold in a murine cystitis model. Our results indicate that a recombinant truncated FimH adhesin plus CpG oligodeoxynucleotides is a suitable immunogenic combination that can contribute to the development of a highly efficacious urinary tract infection vaccine.

Adhesins, Escherichia coli↗

PubMedDate not supplied

[A trial of a cultured inactivated vaccine against hepatitis A on Saguinus mystax tamarins].

An experimental batch of inactivated hepatitis A vaccine was prepared using hepatitis A virus (HAV), HAS-15 strain, adapted to cell culture and purified by ultracentrifugation. The vaccine was tested in tamarins immunized intramuscularly three times one month apart. Three tamarins received a vaccine preparation containing 10 ng of immunogen each, three--100 ng each, and three animals were used as controls. The efficacy was judged by the anti-HAV antibody response in the vaccinated animals and development of immunity to subsequent virus challenge two months after the last immunization. The criteria of infection were: elevation of serum alanine aminotransferase, fecal excretion of HAV and production of specific antibody of IgM class. The immune response to 10 ng of the immunogen was lower than to 100 ng, however, both doses produced complete resistance to infection. The booster effect was observed in animals receiving 10 ng of the immunogen. The vaccine batch under study in the indicated doses was shown to have a good immunogenic potency and protective activity for tamarins.

Alanine Transaminase↗

PubMed1985

[Production of a specific gamma globulin against infectious atrophic rhinitis in swine].

A specific gamma globulin against infectious atrophic rhinitis in swine was produced following a pattern that was worked out for the hyperimmunization of serum-producing swine. Used were strains of Bordetella bronchiseptica and Mycoplasma hyorhinis isolated by the authors. The hyperimmune serum obtained was processed after Cohn's method which was improved by Ponamarova and Nechaeva. The preparation obtained was innocuous and immunogenic for both test animals and pigs. It rendered protection when applied at the rate of 0.4 cm3 per kg body mass. At 1 cm3, i/m, it was found to act therapeutically.

Animals↗

PubMed2005

Functions of the adenovirus E4 proteins and their impact on viral vectors.

Viral vectors based on recombinant adenoviruses (rAd) are used extensively as gene delivery systems for investigations of gene function and gene therapy applications. In both cases, the desire is for efficient expression of a transgene without substantial toxicity to the target cell. The first generation of rAd vectors were deleted of early region E1 and sometimes additionally early region E3. Evaluation of these vectors in preclinical animal models revealed transient gene expression, accompanied by cytotoxicity and immune responses. Expression of remaining viral genes, even in the absence of the E1 region, contributes to these effects and therefore it is important to have an appreciation of the functions of these viral genes. In particular, the early region E4 has been shown to affect transgene persistence, vector toxicity and immunogenicity. Proteins from the E4 genes can modulate transcription, the cell-cycle, cell signaling and DNA repair. In addition, some of these proteins also cause oncogenic transformation. Therefore interactions of these viral genes with key cell regulators should be taken into account when engineering rAd vectors. This review will summarize our knowledge of E4 functions and the implications of recent findings on the development of rAd vectors.

Adenovirus E4 Proteins↗

PubMed1999

Preclinical and phase I and II trials of rituximab.

The CD20 antigen is an attractive target for antibody-directed therapy due to its stable, high-level surface expression on normal and malignant B cells. Rituximab (Rituxan; IDEC Pharmaceuticals, San Diego, and Genentech, Inc, San Francisco, CA) is an anti-CD20 chimeric monoclonal antibody that has shown single-agent activity in phase I and II clinical trials in patients with B-cell non-Hodgkin's lymphoma. This antibody has a long serum half-life and low immunogenicity. Infusional symptoms are common with the initial infusion but rare with subsequent treatments. Temporary B-cell depletion occurs but has not been associated with immunodeficiency. The mechanism of action likely includes both immune-mediated effects and direct effects. The generally mild toxicity profile and excellent single-agent activity provide the rationale for use with or following chemotherapy. Additional studies evaluating these and other combinations are under way.

Antibodies, Monoclonal↗

PubMed2000

Preparation and preclinical evaluation of experimental group B streptococcus type III polysaccharide-cholera toxin B subunit conjugate vaccine for intranasal immunization.

Streptococcus group B (GBS) is usually carried asymptomatically in the vaginal tract of women and can be transferred to the newborn during parturition. Serum antibodies to the capsular polysaccharide (CPS) can prevent invasive diseases, whereas immunity acting at the mucosal surface may be more important to inhibit the mucosal colonization of GBS and thus the risk of infection for the newborn. We prepared different GBS type III CPS-protein conjugate vaccines and evaluated their systemic and mucosal immunogenicity in mice. GBS type III CPS was conjugated to tetanus toxoid (TT) or recombinant cholera toxin B subunit (rCTB) either directly or to rCTB indirectly via TT. The conjugation was performed by different methods: (1) CPS was coupled to TT with 1-ethyl-3 (3-dimethylaminopropyl)-carbodiimide (EDAC), using adipic acid dihydrazide (ADH) as a spacer; (2) CPS was conjugated with rCTB using reductive amination; or, (3) N-succinimidyl 3-(2-pyridyldithio) propionate (SPDP) was used to bind rCTB to the TT of the CPS-TT conjugate. Mice were immunized with these conjugates or purified CPS by subcutaneous (s.c.) and intranasal (i. n.) routes. Antibodies to GBS III in serum, lungs and vagina were measured with ELISA. All of the CPS-protein conjugates were superior to unconjugated CPS in eliciting CPS-specific immune responses in serum and mucosal tissue extracts. The conjugates, when administrated s.c., induced only IgG responses in serum, lung and vagina, while i.n. vaccination also elicited IgA responses in the lungs and vagina. The CPS-TT conjugate administrated i.n. induced a strong serum IgG, but only a weak mucosal IgA response, while the CPS-rCTB conjugate elicited high IgG as well as IgA antibodies in the lungs after i.n. immunization. GBS III CPS-TT conjugated with rCTB produced a strong systemic and local anti-CPSIII response after i.n. administration. Co-administration of CT as adjuvant enhanced the anti-CPS systemic and mucosal immune responses further after i.n. administration with the CPS conjugates. These findings indicate that: (i) i.n. immunization with GBS CPS-protein conjugates was more effective than s.c immunization for stimulating serum as well as mucosal immune responses; (ii) rCTB as a carrier protein for GBS III CPS could markedly improve the mucosal immune response; and (iii) the experimental GBS type III CPS conjugates containing rCTB should be investigated as mucosal vaccine to prevent GBS infection in humans.

Administration, Intranasal↗