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Results for “Preclinical immunogenicity evaluation”

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At least 145 records · Page 8Linked to original sources

PubMed2006

Design and preclinical evaluation of a multigene human immunodeficiency virus type 1 subtype C DNA vaccine for clinical trial.

In this study, the design and preclinical development of a multigene human immunodeficiency virus type 1 (HIV-1) subtype C DNA vaccine are described, developed as part of the South African AIDS Vaccine Initiative (SAAVI). Genetic variation remains a major obstacle in the development of an HIV-1 vaccine and recent strategies have focused on constructing vaccines based on the subtypes dominant in the developing world, where the epidemic is most severe. The vaccine, SAAVI DNA-C, contains an equimolar mixture of two plasmids, pTHr.grttnC and pTHr.gp150CT, which express a polyprotein derived from Gag, reverse transcriptase (RT), Tat and Nef, and a truncated Env, respectively. Genes included in the vaccine were obtained from individuals within 3 months of infection and selection was based on closeness to a South African subtype C consensus sequence. All genes were codon-optimized for increased expression in humans. The genes have been modified for safety, stability and immunogenicity. Tat was inactivated through shuffling of gene fragments, whilst maintaining all potential epitopes; the active site of RT was mutated; 124 aa were removed from the cytoplasmic tail of gp160; and Nef and Gag myristylation sites were inactivated. Following vaccination of BALB/c mice, high levels of cytotoxic T lymphocytes were induced against multiple epitopes and the vaccine stimulated strong CD8+ gamma interferon responses. In addition, high titres of antibodies to gp120 were induced in guinea pigs. This vaccine is the first component of a prime-boost regimen that is scheduled for clinical trials in humans in the USA and South Africa.

AIDS Vaccines↗

PubMed1991

Preclinical and clinical studies on immunogenicity and safety of the HIV-1 p17-based synthetic peptide AIDS vaccine--HGP-30-KLH.

Immunization with a synthetic HIV-1 p17 peptide analog (HGP-30; aa 85-115 of HIV p17), coupled to a carrier protein (KLH, keyhole limpet hemocyanin) given with alum as the adjuvant induces antibodies which cross-react with both HGP-30 and HIV p17 and clones of cytotoxic and helper T-cells which recognize HGP-30 and HIV p17. Proliferation of lymphocytes in response to HGP-30 has been observed in mice, in HIV-infected individuals and in healthy HIV-seronegative volunteers vaccinated with the p17-based synthetic peptide construct. Cytotoxic T-cell responses against EBV transformed, recombinant p17 pulsed targets were observed using antigen-expanded PBLs from HGP-30-KLH immunized individuals. These results are consistent with predictions that the HGP-30 domain of HIV p17 contains both T- and B-cell epitopes that are recognized by animals and humans. In preclinical toxicology studies in animals and in initial clinical trials in humans the synthetic peptide construct (HGP-30-KLH/alum) has been shown to be safe. This paper summarizes the preclinical immunogenicity and safety data for HGP-30-KLH and presents the initial results from the first Phase 1 clinical trial.

AIDS Vaccines↗

PubMedDate not supplied

[Immunogenicity of a subunit influenza vaccine in experiments on animals].

The data on isolation of purified influenza virus glycoproteins and their reconstruction into liposomes by means of a new nonionic detergent, MESK, are presented. Sedimentational and flotational distribution of glycoprotein and liposome preparations was studied. In the presence of the detergent, the isolated glycoproteins were shown to occur mostly in a monomeric form. Removal of the detergent by dialysis resulted in formation of protein micelles, and the presence of exogenously introduced lipids in reconstruction of liposomes heterogeneous in composition. The resulting preparations had a high degree of biochemical purity and biological activity meeting the requirements for subunit vaccine properties. The immunogenic potency of a subunit influenza vaccine produced with the use of the MESK detergent was studied. The glycoproteins isolated with the use of MESK were shown to be comparable in their immunogenic potency with glycoproteins comprising viral particles. The influence of the form of glycoproteins presentation on their immunogenic potency was studied. Glycoproteins in the form of micelles and as components of liposomes were found to have a good immunogenic potency and to be able to induce protective immunity preventing experimental influenza infection in mice. Monomeric forms of glycoproteins had no such properties.

Animals↗

PubMed2005

Safety and immunogenicity of an oral, inactivated, whole-cell vaccine for Shigella sonnei: preclinical studies and a Phase I trial.

Orally delivered, inactivated whole-cell vaccines are safe methods of inducing local and systemic immunity. To increase surface proteins associated with adherence and invasion, Shigella sonnei were grown in BHI broth containing deoxycholate. A whole-cell vaccine (SsWC) was then produced by formalin inactivation. In pre-clinical studies, the SsWC vaccine was immunogenic and protected against S. sonnei-induced keratoconjunctivitis in the guinea pig model. In a randomized, double-blind, placebo-controlled, Phase I study, 10 evaluable subjects received either three doses of SsWC on Days 0, 14, and 28 (N = 3); five doses of SsWC on Days 0, 2, 4, 6, and 28 (N = 4); or placebo (N = 3). Each dose contained 2.0 x 10(10) inactivated cells. Serum and fecal antibodies against SsWC, LPS, and IpaC were measured by ELISA. A > or = 4-fold increase in titer was considered significant. Both SsWC dosing regimens were well tolerated. No fever or severe gastrointestinal symptoms were noted by any of the vaccinated subjects. Antibody responses were similar in the two dosing groups. Serum IgG or IgA responses to SsWC were seen in six of seven vaccinees (86%), to LPS in four of seven (57%), and to IpaC in five of seven (61%). Fecal IgA responses to these three antigens developed in five of five, three of five, and three of five subjects, respectively. Among the seven vaccinees, geometric mean rises in serum IgA levels to all three immunogens were significant; IgG increases trended toward significance (paired one-tailed t-test). We conclude that SsWC was immunogenic and protective in animal studies and well tolerated and immunogenic in a Phase I trial.

Administration, Oral↗

PubMed1992

Development and phase 1 clinical testing of a conjugate vaccine against meningococcus A and C.

A conjugate vaccine against meningococcus A and C was prepared using the non-toxic mutant of diphtheria toxin CRM 197 as a carrier protein. Capsular polysaccharides of Neisseria meningitidis group A and C were hydrolysed and the resulting oligosaccharides were then coupled to CRM 197 in order to obtain conjugates with a carbohydrate content of 25-30%. The final vaccine that contained 11 micrograms of each oligosaccharide and 88 micrograms of CRM 197 was used to immunize mice and rabbits. After the preclinical studies which showed that the vaccine was safe and immunogenic in animal models, a pilot phase 1 clinical trial, blind versus placebo, was performed on adult volunteers. The difference between the incidence of adverse reactions associated with vaccine and placebo administration was not statistically significant. All the volunteers who received the vaccine had a significant increase in antibodies to group A and C meningococcal capsular polysaccharides after the first dose.

Animals↗

PubMed2003

A genome-based functional screening approach to vaccine development that combines in vitro assays and DNA immunization.

A two-step screening strategy was developed to identify strong immunogenic polypeptides with putative vaccine and/or adjuvant activity. In the first step, a mycobacterial genomic DNA library was screened in vitro to identify plasmids encoding polypeptides that stimulate splenocytes from mycobacteria-immunized mice and T cells from PPD-positive healthy donors to produce interferon-gamma. In the second step, plasmids were selected for their ability to induce protective immunity in a mouse model of tuberculosis following DNA immunization. The potential of this approach is illustrated by the identification of a panel of immunogenic polypeptides that may be used to engineer a new generation of vaccines.

Adjuvants, Immunologic↗

PubMed2004

Vaccination strategies for the treatment and prevention of cervical cancer.

PURPOSE OF REVIEW: Immunotherapy of HPV-induced premalignant anogenital lesions and cervical cancer has made impressive progress. HPV as causative agent is targeted by prophylactic and therapeutic vaccination strategies. Preclinical and clinical studies have shown induction of natural and/or vaccine-induced immune responses. This review will summarize the status of vaccine development and clinical testing published since March 2003. RECENT FINDINGS: For prophylactic vaccines there is first clinical evidence of effectivity (ie, 100% protection from HPV infection and dysplasia by virus-like particle (VLP) vaccine-induced neutralizing antibodies). Also, therapeutic vaccines have entered clinical evaluation. While prophylactic VLP vaccines are immunogenic per se, therapeutic vaccines will need further adjuvants to guide T cell differentiation, expansion, survival, and homing to tumor sites. To enhance clinical outcome of successful T cell induction in patients, the susceptibility of the tumor cells for lysis must be addressed in the future, since tumor immune evasion is a severe problem in cervical cancer. SUMMARY: While successful prophylactic HPV vaccines have entered large clinical trials, therapeutic HPV vaccines, in spite of T cell induction, lack clinical responses due to the problem of tumor immune evasion. Adjuvants for systemic and local immune modulation will be mandatory for effective therapy.

Cancer Vaccines↗

PubMed2005

The use of animal models to guide rational vaccine design.

Although there are several varieties of animal models of tuberculosis, the mouse and the guinea pig are by far the most validated and useful. These provide information about vaccine-induced protection, immunogenicity, toxicity, and immunopathological effects. There is still much to be learned, however, in terms of rational vaccine design, especially in the context of therapeutic or anti-latent vaccine formulations and animal models of these situations.

Animals↗

PubMed1977

Pharmacological studies on an iron-poly-(sorbitol-gluconic acid) complex for parenteral treatment of iron deficiency anaemia.

Intravenous injection of the iron-poly(sorbitol-gluconic acid) complex (IPSG) to cats anaesthetized with sodium pentobarbitone caused a transient decrease in mean arterial blood pressure and a temporary increase in central venous pressure, heart rate and femoral blood flow at large doses (cumulative doses up to 744 mg/kg). Tachyphylaxis developed upon repeated administration. A temporary reduction in the magnitude of the blood pressure responses to noradrenaline and isoprenaline was obtained after large doses of IPSG. The blood pressure effects of acetylcholine, histamine and bilateral carotid occlusion were not affected. No definite effects were seen on the electrocardiograms. The transient cardiovascular effects were interpreted as being due to the presence of small amounts of ferrous iron in the preparation. IPSG did not significantly affect blood coagulation or platelet aggregation as judged from results of in vitro and in vivo experiments. Immunogenicity studies in rabbits and antibody analyses of sera from patients treated with IPSG failed to demonstrate any effect of IPSG on the immune system.

Acetylcholine↗

PubMed2006

Evaluation of the contraceptive potential of brZPCp vaccine in BALB/c mice: their safety and efficacy.

In this study we have examined the potential ability of Microtus branditi partial ZPC (brZPCp) cDNA sequence (436-1150 nt) as a target for immunocontraception. Immunogenicity studies and fertility trials were performed in BALB/c mice using recombinant construction pCR3.1-brZPC(p). ELISA outcome indicated that antibodies could be generated by immunized mice, and IgG titer was increased compared to the control. Immunohistochemistry outcome indicated that antibodies could recognize native ZP in vivo, which in turn, prevented the binding of sperm to ovulated eggs. Antibodies could also recognize recombinant protein expressed by BL21 in vitro, which was confirmed by SDS-PAGE and Western blot. Fertility rate was reduced by 45% compared to the control immunized with pCR3.1. Meanwhile, there was no incidence of significant ovarian pathology in treated mice. This experiment indicates that this vaccine can elicit the specific antibody which binds exactly to the corresponding ZPC. This construction is proved to be immunogenic, and can reduce fertility without obvious oophoritis. The result in this study suggests a potentially important method for controlling population for its safety and easy production.

Animals↗

PubMedDate not supplied

[Evaluation of the stability of pertussis vaccine OCO-3 standard].

The evaluation of the immunogenic activity and residual toxicity of the National Standard of pertussis vaccine (OCO-3) was carried out. As shown by observations lasting for a period of 25 years, the preparation possesses stable immunogenicity and its toxicity remained unchanged, which makes it possible to use OCO-3 for the routine control of the pertussis component of commercial lots of adsorbed DPT vaccine.

Animals↗

PubMedDate not supplied

SPR for molecular interaction analysis: a review of emerging application areas.

PubMed searches identified four emerging application areas for surface plasmon resonance systems. Food analysis, proteomics, immunogenicity and drug discovery. These application areas are reviewed. In connection with the review of drug discovery applications a case study is presented. This study demonstrates the value of combining results from drug-target and ADME predictive assays for compound selection.

Antigens↗

PubMed2005

Umbilical cord blood-derived stem cells and brain repair.

Human umbilical cord blood (HUCB) is now considered a valuable source for stem cell-based therapies. HUCB cells are enriched for stem cells that have the potential to initiate and maintain tissue repair. This potential is especially attractive in neural diseases for which no current cure is available. Furthermore, HUCB cells are easily available and less immunogenic compared to other sources for stem cell therapy such as bone marrow. Accordingly, the number of cord blood transplants has doubled in the last year alone, especially in the pediatric population. The therapeutic potential of HUCB cells may be attributed to inherent ability of stem cell populations to replace damaged tissues. Alternatively, various cell types within the graft may promote neural repair by delivering neural protection and secretion of neurotrophic factors. In this review, we evaluate the preclinical studies in which HUCB was applied for treatment of neurodegenerative diseases and for traumatic and ischemic brain damage. We discuss how transplantation of HUCB cells affects these disorders and we present recent clinical studies with promising outcome.

Animals↗

PubMed1998

A phased approach to clinical testing: criteria for progressing from Phase I to Phase II to Phase III studies.

The overall intent of clinical testing is to establish, in a series of phased studies, the clinical tolerance and acceptable "safety" of the candidate vaccine, as well as the type, level and persistence of the immune response after its inoculation, to a representative target population, according to a convenient administration schedule. The final stages involve the direct or indirect demonstration of protective efficacy, if possible in the population(s) for which the vaccine is intended. In addition, consistency of production must be demonstrated. At all these stages, the amount of prior information from preclinical and other studies affects and informs the objectives and design of subsequent studies. Progression from one testing phase to the next is dependent upon attaining the pre-set objectives of each series of studies. The precise objectives to be met will be decided on a case-by-case basis. The earliest assessments in humans (Phase I) involve evaluation of short-term clinical tolerance as measured by local and general reactogenicity, and gross assessments of immunogenicity, in a small number of highly selected individuals in an idealised situation. The selection of "optimal" dose and schedule are the result of further dose-ranging investigations (Phase II), involving more volunteers, with longer, more detailed follow-up assessments. It is at this stage that the accumulated evidence on its immunogenicity profile should be sufficient to assess whether or not the vaccine is worthy of further development. The next level of investigation (Phase III) aims to measure with greater precision the vaccine protective efficacy in the intended target population(s) by comparison of infection and/or disease attack rates in vaccine and placebo recipients. In consistency studies different production lots, manufactured at commercial scale, are tested to demonstrate consistency of manufacture. Additional bridging studies to establish similarity of lots at different production scales, or studies of the duration of the immunity conferred, are conducted in parallel with the progression of the studies in the different phases mentioned above. These latter types of studies are usually carried out concurrently with Phase III studies. This progression continues into the post-marketing period (Phase IV) with surveillance of long term efficacy and observational studies of possible rare adverse events to establish "safety" with more confidence. This paper examines, in general, the aims and designs of studies in each phase as an introduction to the more specific publications that follow.

Clinical Trials as Topic↗

PubMed1997

Preclinical evaluation of group B Neisseria meningitidis and Escherichia coli K92 capsular polysaccharide-protein conjugate vaccines in juvenile rhesus monkeys.

We reported the first use of group B meningococcal conjugate vaccines in a nonhuman primate model (S. J. N. Devi, C. E. Frasch, W. Zollinger, and P. J. Snoy, p. 427-429, in J. S. Evans, S. E. Yost, M. C. J. Maiden, and I. M. Feavers, ed., Proceedings of the Ninth International Pathogenic Neisseria Conference, 1994). Three different group B Neisseria meningitidis capsular polysaccharide (B PS)-protein conjugate vaccines and an Escherichia coli K92 capsular polysaccharide-tetanus toxoid (K92-TT) conjugate vaccine are here evaluated for safety and relative immunogenicities in juvenile rhesus monkeys with or without adjuvants. Monkeys were immunized intramuscularly with either B PS-cross-reactive material 197 conjugate, B PS-outer membrane vesicle (B-OMV) conjugate, or N-propionylated B PS-outer membrane protein 3 (N-pr. B-OMP3) conjugate vaccine with or without adjuvants at weeks 0, 6, and 14. A control group of monkeys received one injection of the purified B PS alone, and another group received three injections of B PS noncovalently complexed with OMV. Antibody responses as measured by enzyme-linked immunosorbent assay varied among individual monkeys. All vaccines except B PS and the K92-TT conjugate elicited a twofold or greater increase in total B PS antibodies after one immunization. All vaccines, including the K92-TT conjugate, elicited a rise in geometric mean B PS antibody levels of ninefold or more over the preimmune levels following the third immunization. Antibodies elicited by N-pr. B-OMP3 and B-OMV conjugates were directed to the N-propionylated or to the spacer-containing B PS antigens as well as to the native B PS complexed with methylated human serum albumin. None of the vaccines caused discernible safety-related symptoms.

Animals↗

PubMed2004

Safety and efficacy of chimeric yellow Fever-dengue virus tetravalent vaccine formulations in nonhuman primates.

To construct chimeric YF/DEN viruses (ChimeriVax-DEN), the premembrane (prM) and envelope (E) genes of yellow fever (YF) 17D virus were replaced with those of each wild-type (WT) dengue (DEN) virus representing serotypes 1 to 4. ChimeriVax-DEN1-4 vaccine viruses were prepared by electroporation of Vero cells with RNA transcripts prepared from viral cDNA (F. Guirakhoo, J. Arroyo, K. V. Pugachev, C. Miller, Z.-X. Zhang, R. Weltzin, K. Georgakopoulos, J. Catalan, S. Ocran, K. Soike, M. Ratteree, and T. P. Monath, J. Virol. 75:7290-7304, 2001; F. Guirakhoo, K. Pugachev, J. Arroyo, C. Miller, Z.-X. Zhang, R. Weltzin, K. Georgakopoulos, J. Catalan, S. Ocran, K. Draper, and T. P. Monath, Virology 298:146-159, 2002). Progeny viruses were subjected to three rounds of plaque purifications to produce the Pre-Master Seed viruses at passage 7 (P7). Three further passages were carried out using U.S. current Good Manufacturing Practices (cGMP) to produce the Vaccine Lot (P10) viruses. Preclinical studies demonstrated that the vaccine candidates are replication competent and genetically stable and do not become more neurovirulent upon 20 passages in Vero cells. The safety of a tetravalent vaccine was determined and compared to that of YF-VAX in a formal monkey neurovirulence test. Brain lesions produced by the tetravalent ChimeriVax-DEN vaccine were significantly less severe than those observed with YF-VAX. The immunogenicity and protective efficacy of four different tetravalent formulations were evaluated in cynomolgus monkeys following a single-dose subcutaneous vaccination followed by a virulent virus challenge 6 months later. All monkeys developed low levels of viremia postimmunization, and all the monkeys that had received equal concentrations of either a high-dose (5,5,5,5) or a low-dose (3,3,3,3) formulation seroconverted against all four DEN virus serotypes. Twenty-two (92%) of 24 monkeys were protected as determined by lack of viremia post-challenge. This report is the first to demonstrate the safety of a recombinant DEN virus tetravalent vaccine in a formal neurovirulence test, as well as its protective efficacy in a monkey challenge model.

Animals↗

PubMed2006

Oxygen therapeutics: oxygen delivery without blood.

Nearly 14 million units of packed red blood cells are transfused in the United States each year. According to the U.S. Department of Health and Human Services, in 1999, 6% of hospitals reported a shortage of blood, resulting in the cancellation or postponement of surgical procedures. The many limitations and risks of transfusions of packed red blood cells in critically ill patients have facilitated interest in developing alternative agents for oxygen delivery. Over the past few decades, safe and effective substitutes have been in development. However, no currently approved agent provides both oxygen transport and volume in place of packed red blood cells. Oxygen therapeutic products have several advantages compared with packed red blood cells, including a prolonged shelf-life, lack of a cross-matching requirement, and minimal infectious risks or concerns about immunogenicity. Hemoglobin-based oxygen carriers and perfluorocarbons are being developed. Two products are undergoing clinical trials. Polyheme is undergoing a phase III study in trauma patients, and Hemopure is being evaluated in a phase II study in patients undergoing cardiopulmonary bypass surgery. A third product (Hemolink) was being evaluated in a phase III study in patients undergoing coronary artery bypass grafting surgery; however, the trial was suspended. In addition, several other hemoglobin-based oxygen carriers are in the preclinical stages. Oxygen therapeutics have several potential clinical applications in the management of perioperative blood loss, trauma, acute normovolemic hemodilution, traumatic brain injury, and blood requirements in patients who refuse or have contraindications to transfusions of red blood cells.

Blood Substitutes↗

PubMedDate not supplied

Cytotoxic effects of dacarbazine in patients with acute myelogenous leukemia: a pilot study.

BACKGROUND AND METHODS: Preclinical studies performed in our laboratory showed that mouse leukemias become highly immunogenic following in vivo treatment with Decarbazine. This observation led to a successful immunochemotherapy protocol in mice using Dacarbazine plus cytoreductive chemotherapy. Therefore an in vivo and in vitro pilot study was conducted in patients (pts) with resistant or relapsed acute myelogenous leukemia (AML). The DNA-repair enzyme O6-alkylguanine-DNA-alkyl-transferase (OGAT) and the in vitro chemosensitivity to Temozolomide, a Dacarbazine derivative, were evaluated in leukemic blasts. RESULTS: Nine pts received Dacarbazine (0.4-0.8 g/sqm/day) on days 0, 1 and 2. On day 7, noticeable blast reduction occurred in 4 pts: pt 1 was in partial remission on day 21, pt 6 still showed bone marrow leukemia, pt 8 died of sepsis on day 8, pt 9 is still in aplasia on day 25. Low OGAT levels and consistent sensitivity to Temozolomide in vitro were found in the blasts of pts responsive to Dacarbazine. Subsequently, pts 1-7 underwent Ara-C (1g/sqm/day) plus Mitoxantrone (6mg/sqm/day) treatment for 6 days. Four pts entered complete remission after 27-45 days of aplasia. Failures were due to hypoplastic death, absolute drug resistance, or hypoplasia followed by blast cell regrowth. CONCLUSIONS: These data point out that Dacarbazine can induce a marked reduction of blast cells as well as severe myelotoxicity in leukemic patients.

Antiemetics↗