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Results for “Preclinical immunogenicity evaluation”

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PubMed1991

[The protective properties of the endotoxin protein].

The isolation and properties of endotoxin protein, or lipid A-associated protein (LAP), from Shigella sonnei were described earlier (Zh. mikrobiol. epidemiol. immunobiol., 1991, No. 4, pp. 11-17, and No. 7). In this report the data on its protective activity are presented. In experiments on mice one nanogram of LAP injected i. v. protected 50% of the animals against i. p. challenge with 40 LD50 of virulent S. sonnei. Guinea pigs injected s. c. with 10 micrograms of LAP were protected against local (keratoconjunctival) challenge with S. sonnei, the efficiency of immunization being 58%. LAP preparations containing no detectable amounts of O-antigen (less than 0.003%) were found to have a protective effect. Hyperimmune anti-LAP rabbit serum prevented local infection when incubated with S. sonnei challenge inoculum before injection into guinea pigs. Both active and passive protection induced by LAP was specific since no effect was observed in animals challenged with Shigella flexneri. In the homologous system the protective effect of anti-LAP serum was abolished by the addition of protein-free LPS. These results are compatible with the hypothesis that the protective activity of LAP depends on the presence of minute amounts of O-antigen whose immunogenic effect is greatly amplified by the protein component of the natural endotoxin complex.

Animals↗
PubMed2004

Preclinical evaluation of a vaccine based on conserved region of M protein that prevents group A streptococcal infection.

BACKGROUND & OBJECTIVES: Infection with group A Streptococcus (GAS) may result in a number of human diseases ranging from the relatively benign pharyngitis to the potentially life-threatening invasive diseases and post-infectious sequelae. We have previously defined a minimal B-cell epitope from the conserved region of the M-protein. Here we report on the immunogenicity, opsonic potential of the resulting sera and the level of protection induced by this peptide in comparison to a pepsin extract of the M protein. METHODS: Inbred mice were immunized with peptides derived from the M protein. Sera were collected from the immunized mice and its opsonic potential determined for M1 and M6 GAS strains. Mice were then intranasally challenged with a virulent M1 GAS strain to determine the protective efficacy of the peptides. RESULTS: The peptides induced significant antibody responses when delivered subcutaneously and immunized mice demonstrated significantly enhanced survival compared to control groups following challenge. INTERPRETATION & CONCLUSION: The data obtained in the present study indicated that the chimeric peptide J8 from the conserved region of the M protein could form the basis for an anti-streptococcal vaccine in future.

Amino Acid Sequence↗
PubMed2004

ACAM2000 clonal Vero cell culture vaccinia virus (New York City Board of Health strain)--a second-generation smallpox vaccine for biological defense.

The threat of smallpox as a biological weapon has spurred efforts to create stockpiles of vaccine for emergency preparedness. In lieu of preparing vaccine in animal skin (the original method), we cloned vaccinia virus (New York City Board of Health strain, Dryvax by plaque purification and amplified the clone in cell culture. The overarching goal was to produce a modern vaccine that was equivalent to the currently licensed Dryvax in its preclinical and clinical properties, and could thus reliably protect humans against smallpox. A variety of clones were evaluated, and many were unacceptably virulent in animal models. One clonal virus (ACAM1000) was selected and produced at clinical grade in MRC-5 human diploid cells. ACAM1000 was comparable to Dryvax in immunogenicity and protective activity but was less neurovirulent for mice and nonhuman primates. To meet requirements for large quantities of vaccine after the events of September 11th 2001, the ACAM1000 master virus seed was used to prepare vaccine (designated ACAM2000) at large scale in Vero cells under serum-free conditions. The genomes of ACAM1000 and ACAM2000 had identical nucleotide sequences, and the vaccines had comparable biological phenotypes. ACAM1000 and ACAM2000 were evaluated in three Phase 1 clinical trials. The vaccines produced major cutaneous reactions and evoked neutralizing antibody and cell-mediated immune responses in the vast majority of subjects and had a reactogenicity profile similar to that of Dryvax.

Animals↗
PubMed1996

PspA, a protection-eliciting pneumococcal protein: immunogenicity of isolated native PspA in mice.

PspA is a surface exposed virulence factor of S. pneumoniae that can elicit protective immunity to pneumococcal sepsis in mice. It can be released from pneumococci by washing them with a solution containing 2% choline chloride, by growing pneumococci in media containing 1.2% choline chloride, or by growing pneumococci in media in which the choline has been replaced by ethanolamine. Our results indicate that PspA is the major protection-eliciting antigen in each of these preparations. Two injections of < or = 1 microgram of native PspA purified by use of a choline-Sepharose column are highly immunogenic in BALB/c and CBA/N mice, and even in the absence of adjuvant can elicit protection against otherwise fatal sepsis with 100 times the LD50 of S. pneumoniae. Fragments comprising the N-terminal 115 and 245 amino acids of PspA were able to elicit protection but only in the presence of complete Freund's adjuvant (CFA). In the absence of CFA the 245 amino acid fragment was less than 1/100 as immunogenic as native PspA.

Animals↗
PubMed2006

Preclinical and clinical progress of particle-mediated DNA vaccines for infectious diseases.

This review provides an overview of studies employing particle-mediated epidermal delivery (PMED) or the gene gun to administer DNA vaccines for infectious diseases in preclinical studies employing large animal models and in human clinical trials. It reviews the immunogenicity and protective efficacy of PMED DNA vaccines in nonhuman primates and swine and studies that have directly compared the effectiveness of PMED in these large animal models to existing licensed vaccines and intramuscular or intradermal delivery of DNA vaccines with a needle. Various clinical trials employing PMED have been completed and an overview of the immunogenicity, safety, and tolerability of this approach in humans is described. Finally, efforts currently in progress for commercial development of particle-mediated DNA vaccines are discussed.

Adjuvants, Immunologic↗
PubMed2005

Immunotherapy for gynaecological malignancies.

Gynaecological malignancies, excluding breast cancer, cause approximately 25,000 deaths yearly among women in the US. Therefore, novel approaches for the prevention or treatment of these diseases are urgently required. In the case of cervical cancer, human papillomavirus (HPV) xenoantigens are readily recognised by the immune system, and their targeting has shown great promise in preclinical models of therapeutic vaccination and in clinical studies of preventative vaccination. A growing body of evidence indicates that ovarian cancer is also immunogenic and can thus be targeted through immunotherapy. This review outlines the principles and problems of immunotherapy for cervical and ovarian cancer, including the authors' personal assessment.

Adoptive Transfer↗
PubMed1990

Feasibility of cellular microencapsulation technology for evaluation of anti-human immunodeficiency virus drugs in vivo.

We investigated the feasibility of micro-encapsulation technology for the evaluation of anti-human immunodeficiency virus (HIV) drugs in vivo. The ability to place human cells in microcapsules with semipermeable membranes for implantation into test animals led to the development of this assay. The anti-HIV activity assay involves microencapsulating human T-lymphoblastoid cells sensitive to the cytopathic effects of HIV; the encapsulated cells are then implanted into athymic nude mice and recovered after drug treatment in vivo. A positive antiviral effect of the test substance is indicated by growth or survival of the virus-infected cells in the microcapsules. Several HIV-sensitive cell lines of T-lymphocyte, monocyte, and nonlymphocyte origin were examined for growth in microcapsules in vitro and in vivo. Light and electron microscopic analysis of the capsules and the human cells contained therein revealed the invasion of mouse immune cells and other adverse effects that could not be overcome by any of numerous technical modifications attempted. We conclude that cellular microencapsulation technology is not feasible for in vivo drug-testing protocols because of immunogenic reactions.

Animals↗
PubMed2002

Exogenous stress proteins enhance the immunogenicity of apoptotic tumor cells and stimulate antitumor immunity.

We have previously reported that apoptotic tumor cells can be either immunogenic or nonimmunogenic in vivo, depending on whether or not these cells are heat stressed before induction of apoptosis. Stressed apoptotic cells express heat shock proteins on their plasma membranes and dendritic cells are capable of distinguishing them from nonstressed apoptotic cells. Here we provide evidence that when purified heat shock protein 70 or chaperone-rich cell lysate (CRCL) from syngeneic normal tissue is used as an adjuvant with nonimmunogenic apoptotic tumor cells in vaccination, potent antitumor immunity can be generated. This antitumor immunity is mediated by T cells because antitumor effects are not observed in either severe combined immunodeficiency or T cell-depleted mice. We further demonstrate that vaccination of mice with apoptotic tumor cells mixed with liver-derived CRCL as adjuvant were capable of enhancing the production of T(H)1 cytokines, inducing specific cytotoxic T lymphocytes and eliciting long-lasting antitumor immunity. Stress proteins from autologous normal tissue components therefore can serve as danger signals to enhance the immunogenicity of apoptotic tumor cells and stimulate tumor-specific immunity

Adjuvants, Immunologic↗
PubMedDate not supplied

[A trial of a hepatitis A cultured inactivated vaccine on rhesus macaques].

In this work experimental model of hepatitis A virus (HAV) infection in macaques rhesus was used. In 6 seronegative monkeys immunized with the inactivated vaccine (3 injections of 0.3 micrograms of viral protein each at an interval of 1 month) pronounced antibody response was observed. The dynamics and titers of anti-HAV antibodies were similar to those in 5 rhesus macaques which received the active virus. But, in contrast to the latter, no IgM antibodies were detected in the immunized animals. Three months after the end of immunization the monkeys were resistant to challenge with a HAV strain pathogenic for humans (10(3) - 10(4) ID50). The monkeys had no morphological changes in the liver and no rise in the serum alanine-amino transferase activity, but exhibited transient excretion of the virus in feces, as well as stimulation of anti-HAV antibodies (in the absence of IgM antibodies). The vaccine under test proved to be safe, immunogenic and produced a protective effect.

Animals↗
PubMed1999

Preclinical evaluation of a synthetic Plasmodium falciparum MAP malaria vaccine in Aotus monkeys and mice.

Multiple antigen peptides (MAPs) containing epitopes of the major surface protein of the malaria sporozoite, the circumsporozoite (CS) protein, have been shown in previous studies to elicit antibody-mediated protection against sporozoite challenge in experimental murine and simian hosts. For the preparation for a phase I trial of a P. falciparum (T1B)4 MAP, which contains T and B cell epitopes from the CS repeat region, pre-clinical immunogenicity and adjuvant formulation studies were carried out in mice and Aotus monkeys. The (T1B)4 MAP was found to be immunogenic in three different species of owl monkeys, Aotus nancymae, A. vociferans and A. nigriceps. Optimal antibody responses were obtained in A. nancymae immunized s.c. with (T1B)4 MAP emulsified in Freund's, in which peak titers of over 10(6) were obtained in individual monkeys. MAP immunized A. vociferans also developed high levels of anti-sporozoite antibodies, although the kinetics and the magnitude of the response differed from A. nancymae. (T1B)4 MAP adsorbed to alum (aluminum hydroxide), a formulation that is acceptable for human use, was less immunogenic in naive A. nancymae, as well as A. nigriceps. The injection of MAPs/alum, however, significantly enhanced antibody responses in sporozoite-primed monkeys, suggesting that the administration of the MAP vaccine may be an effective means to increase the low levels of antibody present in individuals living in malaria endemic areas. The addition of a co-adjuvant QS-21, a purified saponin, significantly increased the immunogenicity of the alum-adsorbed MAP in both mice and monkeys, providing a vaccine formulation suitable for phase I trials in human volunteers.

Alum Compounds↗
PubMed1991

Development of a second generation group B meningococcal vaccine.

Outer membrane protein vaccines have now been demonstrated to be effective in prevention of group B Neisseria meningitidis disease, but the extent and duration of protection needs improvement. To develop a second generation outer membrane protein vaccine we have begun studies to evaluate vaccines containing iron regulated proteins in lipopolysaccharide depleted outer membrane vesicles. Since the iron regulated proteins are critical for in vivo survival, it is our working hypothesis that antibodies to these proteins will either be bactericidal or block iron uptake. Four representative strains were selected, and preliminary studies indicate that vaccines containing the iron regulated proteins are immunogenic in mice.

Antibodies, Bacterial↗
PubMed2006

Aerosol measles vaccination in macaques: preclinical studies of immune responses and safety.

The comparative efficacy and safety of measles vaccination via the aerosol route versus subcutaneous injection has not been fully resolved. We vaccinated cynomolgus monkeys (Macaca fascicularis) with the live-attenuated Edmonston-Zagreb measles virus (MV) vaccine and compared different routes of administration in the immunocompetent and the immunocompromised host. Immunogenicity and protective efficacy of aerosol vaccination using devices similar to those previously used in humans were comparable to those in animals vaccinated by injection. No evidence for a safety hazard associated with the route of vaccination was detected. The results of this study support further clinical evaluation of aerosol vaccination for measles.

Aerosols↗
PubMed1993

[Peroral immunization--a method for enhancing the safety of the recombinant vector (the vaccinia virus)].

Oral and dermal administrations of vaccinia virus into rabbits, guinea pigs, and monkeys demonstrated a milder (without homeostasis disturbance) course of the vaccinal process with oral immunization, intensive immunity forming in minimal sensitization of the body was compared with dermal one. The results of revaccination in adults with oral smallpox vaccine and primary immunization in Ethiopia showed that oral immunization with vaccinia virus was safe, effective and lowly reactogenic. The comparative study of the preparation in remote revaccination (5 or more years later) proved its advantage over dermal vaccine. It consists in ecological safety (vaccinia virus excretion into the environment during 1 and 11 days, respectively, by 10-fold concentration reduction), reactogenicity (5 and 33% of common reactions, respectively) in the same immunogenicity.

Administration, Cutaneous↗
PubMed1993

Potency testing of bacterial vaccines for human use.

The potency tests for bacterial vaccines are quite diverse. For some products (pertussis, cholera, anthrax, typhoid and BCG vaccines) these are specified as Additional Standards in the Code of Federal Regulations. For other products (tetanus and diphtheria toxoids, plague vaccine) the testing is done according to so-called Minimum Requirements, which have less regulatory authority than Additional Standards. Still other products (e.g., polysaccharide conjugate vaccines, acellular pertussis vaccine, live oral typhoid) are tested according to individualized criteria that are contained in their specific Product License Applications. For some products there is inadequate knowledge of the pathogenic mechanisms and/or protective factors to design valid in vitro potency tests. In these cases, animal testing with subsequent serologic evaluation or challenge testing is often necessary. Examples would include vaccines such as cholera and plague vaccines. The FDA supports the elimination of animal testing when suitable alternatives are available. Thus, many of the potency tests, especially for newer products, rely on in vitro characterization. For example, the immunogenicity of conventional polysaccharide vaccines is largely proportional to their molecular weight. Potency testing therefore relies heavily on physical characterization in terms of composition, molecular weight, and quantity.

Animals↗
PubMed2005

Tuberculosis vaccine development; from mouse to man.

A tuberculosis (TB) vaccine candidate, Mtb72, was developed following an antigen discovery program involving a combination of expression cloning strategies and evaluation of human immune responses. Adjuvant selection was also performed, resulting in the prioritization of AS02A and AS01B, and an industrial process for vaccine production was developed. Safety, immunogenicity, and protection studies in mice, guinea pigs, rabbits, and monkeys supported the initiation of clinical development of Mtb72f in AS02A.

Adjuvants, Immunologic↗