Use of a baboon model for research in human contraception.
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Animals↗
Biomedical subjects
V C Stevens
Publications and source records attributed to V C Stevens.
Prevention of mammary tumors with a chimeric HER-2 B-cell epitope peptide vaccine.
Synthetic peptide vaccines targeting B-cell epitopes of the extracellular domain of the HER-2 oncoprotein were evaluated for their capacity to elicit HER-2-specific antibodies with antiproliferative activity. Several HER-2 B-cell epitopes were identified by computer-aided analysis of protein antigenicity, and selected B-cell epitopes were synthesized colinearly with a promiscuous T-helper epitope (208-302) derived from the measles virus fusion protein at either the NH2 or COOH terminus linked via a four-residue turn sequence (GPSL). In addition, one epitope sequence, 628-647, was mutated to optimize disulfide pairing to mimic the native HER-2 receptor. All of the four selected epitopes elicited high-titered antibodies in outbred rabbits with exceptionally high titers for MVF-HER-2(628-647). These antibodies were cross-reactive with the native HER-2 receptor. Antibodies elicited by MVF HER-2(628-647) inhibited proliferation of human HER-2-overexpressing breast cancer cells in vitro and caused their antibody-dependent cell-mediated cytotoxicity. Furthermore, immunization with MVF-HER-2(628-647) prevented the spontaneous development of HER-2/neu-overexpressing mammary tumors in 83% of transgenic mice. The engineered, chimeric peptide B-cell immunogen MVF-HER-2(628-647) may have applications in the prevention of HER-2-overexpressing cancers.
Amino Acid Sequence↗
The role of carboxy-terminal portion of beta subunit of human chorionic gonadotropin in human immunodeficiency virus infection.
Human chorionic gonadotropin (hCG) and the beta subunit of this dimer glycoprotein hormone (beta hCG) have been reported by us to inhibit HIV replication. In order to identify the active site responsible for the antiviral activity, twelve overlapping peptides spanning across beta hCG were examined for their effect against HIV-caused cell death. Although the NH2-terminus of beta hCG appeared to contribute to activity, the core region was biologically inert. The most potent activity was observed with the fragment representing the carboxy-terminus of beta hCG. The dose response curve to serial dilutions of the peptide, containing amino acid residues 106-145, had a bell-shaped appearance - characteristic of hCG and beta hCG. The peak of activity corresponded to 100 ng/ml - the dose at which two thirds of virus-exposed MT-4 T lymphocytes survived. None of the tested peptides were toxic to MT-4. While the mechanism of action remains unclear, the results suggest that the COOH-terminal portion, unique to beta hCG, confers anti-HIV activity.
Anti-HIV Agents↗
Effects of a beta-human chorionic gonadotropin subunit immunogen administered in aqueous solution with a novel nonionic block copolymer adjuvant in patients with advanced cancer.
The clinical and immunological effects of a vaccine consisting of CTP37, a synthetic peptide corresponding to the COOH-terminal peptide (CTP) of beta-human chorionic gonadotropin (beta-hCG) conjugated to diphtheria toxoid, combined with CRL 1005, a novel synthetic nonionic block copolymer adjuvant, were examined. Twenty-one patients with metastatic, nontrophoblastic cancers received up to four immunizations by i.m. injection of a fixed dose of CTP37 and escalating doses of CRL 1005. Doses of CRL 1005 adjuvant as high as 75 mg were administered with 1 mg of CTP37 without evidence of significant local or systemic toxicity. Immunizations resulted in the production of IgG antibody to beta-hCG. CRL 1005 doses of 3-25 mg appeared to be optimal for antibody induction. Immunizations also resulted in increases in the cellular response of peripheral blood mononuclear cells (PBMCs) to the unconjugated CTP, hCG, and diphtheria toxoid. Responding PBMCs specifically secreted the TH1-associated cytokines IFN-gamma and interleukin (IL)-2 as well as the TH2-associated IL-5 and IL-10. Increased expression of IFN gamma and IL-5 mRNAs by PBMCs 4 h after immunization was also observed. CRL 1005 administered with CTP37 in aqueous solution is well tolerated. The CTP37-CRL 1005 subunit vaccine has the capacity to stimulate potentially beneficial humoral and cellular immune responses in patients with advanced cancer.
Adjuvants, Immunologic↗
Progress in the development of human chorionic gonadotropin antifertility vaccines.
Prototype human chorionic gonadotropin (hCG) vaccines have demonstrated the feasibility of effectively eliciting antibodies in women and inhibiting fertility in both humans and nonhuman primates. Also, no serious side-effects due to immunization against self antigens have been revealed to date. However, the formulations so far tested in clinical trials are not suitable for widespread applications due to problems associated with complexities in production, burdensome application procedures, the need for frequent booster immunizations or cost of manufacture. Current research efforts involve the development of delivery systems to permit annual or biannual intervals between immunizations for protection from pregnancy, procedures for mucosal immunizations, methods to reduce hypersensitivity and local reactions, and procedures for reducing the cost of production. Recent progress in understanding the crystalline structure of the hCG molecule has stimulated further studies to define immunological epitope sequences that might constitute immunogens in future vaccines. The incorporation of vaccine components into biodegradable microspheres has resulted in formulations that elicit elevated antibody levels in rabbits for more than one year. Preclinical and clinical studies with such formulations are planned. Studies using totally synthetic peptide immunogens constituting hCG B-cell epitopes and "promiscuous" T-cell epitopes from bacterial or viral proteins have been shown to be equally immunogenic as conjugates of hCG peptides with macromolecular carriers. Still other peptide immunogens have been developed that can elicit antibody production without detectable proliferation of helper T cells. Some of these peptides can induce systemic immunity from oral immunization or systemic injections. Alternative vehicles for administering vaccine components with reduced local reactivity show promise for new vaccine formulations.
Animals↗
Synthetic hormone/growth factor subunit vaccine with application to antifertility and cancer.
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Animals↗
Immune recognition of genetically diverse simian T-cell lymphotropic virus type I isolates.
Nucleotide sequence analysis of selected regions of the gag, pol, env and pX genes of simian T-cell lymphotropic virus type I (STLV-I) strains indicated that African isolates were more closely related to human T-cell lymphotropic virus type I (HTLV-I) than Asian isolates. Despite these recent comparative studies on nucleotide sequence homology between HTLV-I and STLV-I isolates, only limited information is available regarding the influence of genetic differences on antigen-antibody recognition of distinct STLV-I strains. In this study, we demonstrated that sera from STLV-I-infected yellow baboons (Papio cynocephalus) reacted strongly with env gp62/68 from HTLV-I-infected cell lines MT-2 and C10/MJ. In contrast, sera from Japanese macaques (Macaca fuscata) naturally infected with Asian STLV-I had weak reactivity to env gp62/68 of these prototypic HTLV-I strains. Pst-1 restriction enzyme analysis of proviral DNA indicated that the baboon virus isolates were more closely related to HTLV-I than the Japanese isolates. These results indicate that nucleotide sequence diversity, correlates with variations in proviral restriction enzyme sites and antibody recognition of viral envelope proteins. These differences in immunoreactivity may have important implications for serologic diagnosis, as well as epidemiological and vaccine studies of STLV-I infection.
Animals↗
Sexual transmission of simian T-lymphotropic virus type I: a model of human T-lymphotropic virus type I infection.
Simian T-lymphotropic virus type-I (STLV-I) seronegative females placed together with seropositive males for breeding purposes were followed from 1984-1990 to determined seroconversion rates by enzyme immunoassay and western immunoblot analysis. Two of 26 females and 1 of 4 males previously negative for antibodies to STLV-I seroconverted during the study period. Statistical analysis of sexual encounters indicated that the probability of a seronegative female testing positive for STLV-I after a sexual encounter with a seropositive male is less than 4%. These data indicate that even though sexual contact is important in the transmission of STLV-I, it may not be an efficient mode of viral infection. These data also suggest that female-to-male transmission of STLV-I occurs, as recently reported for human T-lymphotropic virus type-I (HTLV-I) infection. These results are important because HTLV-I and STLV-I share many features in common including routes of viral transmission. In addition, the difficulty of clearly quantitating the risk of sexual transmission in humans makes the primate animal model a valuable alternative to study the human infection.
Animals↗
Vaccine delivery systems: potential methods for use in antifertility vaccines.
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Adjuvants, Immunologic↗
Future perspectives for vaccine development.
The successful development of an anti-fertility vaccine necessitates overcoming obstacles in eliciting an immune response to self species body constituents. The feasibility of accomplishing this task has been demonstrated for certain antigens described in this workshop; however, additional vaccine candidate antigens may yet be revealed from the application of recent advances in molecular biology. Improvements in vaccine design are likely to occur from discovery of more appropriate epitopes on targeting antigens, new carrier molecules for terminating immunological tolerance, expression of vaccine antigens in suitable live vectors, the co-immunization with more than one antigen, the use of safer and/or more effective adjuvants and vehicles, more efficient immunization by targeting antigens to specific lymphoid cells, and the development of superior vaccine delivery systems. Research directed to restricting the immune response to the genital tract and to intentionally reverse the effects of immunization will likely be pursued in the future. All of these areas need to be addressed if vaccines are to be developed that are not only safe and effective but also highly acceptable as birth control methods.
Animals↗
Birth control vaccines and immunological approaches to the therapy of noninfectious diseases.
Vaccination usually means the immunization of persons or animals against foreign infectious organisms for disease prevention. However, it has now been demonstrated that immunization against certain self substances to which tolerance normally exists can elicit beneficial effects to humans and other animals without inducing autoimmune disease. Clinical trials in women have been conducted with vaccines against reproductive antigens for the prevention of pregnancy and research is under way to develop more advanced formulations. Other self antigens have been described that might be used for developing methods of immunological therapy for such diseases as cancer, ulcers, and complications of diabetes. Emphasis is placed on the need for careful studies in appropriate animal models before any clinical application of such procedures is suggested.
Abortion, Habitual↗
Use of a synthetic peptide adjuvant for the immunization of baboons with denatured and deglycosylated pig zona pellucida glycoproteins.
Baboons were immunized using a synthetic peptide adjuvant with two purified pig zona pellucida glycoproteins. The major zona pellucida glycoprotein (ZPI) was purified by preparative isoelectric focusing, and the 80 K deglycosylated zona pellucida protein (ZPIII) was purified by preparative sodium dodecyl sulfate polyacrylamide gel electrophoresis. The immunogenicity as well as the antigenicity of these proteins were evaluated by characterizing antibodies using the enzyme-linked immunoassay and by immunoblotting of zona pellucida proteins separated by high-resolution two-dimensional polyacrylamide gel electrophoresis. Both groups of animals developed antibodies that recognize the major zona pellucida glycoprotein, (ZPI) and immunoblotting procedures provide evidence that two of the major porcine zona pellucida glycoprotein families (ZPI and ZPIII) contain shared antigenic determinants. The animals immunized with ZPI showed decreased levels of estrogen throughout their menstrual cycles, and two of the animals ceased ovulation. All animals in the group immunized with ZPIII had a significant reduction in the numbers of antral follicles as compared with control animals. Although ovarian cyclicity was not altered significantly within a few months after immunization, two of the five animals in this group became amenorrheic by 8 months. Histologic analysis of ovarian tissue shows that follicles were absent or frequently abnormal in animals of both groups following long-term immunization. These studies demonstrate that the synthetic adjuvant is effective in inducing antibodies (to purified zona pellucida glycoproteins) that recognize antigenic determinants to either denatured or deglycosylated zona pellucida glycoproteins, and that some of these antibodies may interfere with normal ovarian function.
Adjuvants, Immunologic↗
Phase I clinical trial of a World Health Organisation birth control vaccine.
A birth control vaccine incorporating a synthetic peptide antigen representing the aminoacid sequence 109-145 of the C-terminal region of the beta subunit of human chorionic gonadotropin (hCG-beta) was submitted to a phase 1 clinical trial. Thirty surgically sterilised female volunteers, divided into five equal groups for different vaccine doses, received two intramuscular injections six weeks apart. Over a six-month follow-up there were no important adverse reactions, and potentially contraceptive levels of antibodies to hCG developed in all subjects. In the highest vaccine dose group, the results gave promise of a contraceptive effect of six months' duration.
Adult↗
Class I-like MHC molecules expressed by baboon placental syncytiotrophoblast.
Human placental villous trophoblast is known to be unreactive with W6/32 and other monoclonal antibodies recognizing monomorphic determinants of human class I MHC heavy chains, whereas extravillous cytotrophoblast in the placental bed is W6/32-reactive by immunohistology. We have now demonstrated, in contrast, that syncytiotrophoblast is the only cellular component of baboon early placental villous tissue which is reactive with any of these antibodies. Radioimmunoprecipitation of detergent-solubilized baboon placental membrane preparations, and subsequent SDS-PAGE, has shown the W6/32-reactive component to have an m.w. of 41,000 and to be associated with beta 2-microglobulin, whereas baboon peripheral lymphocytes express 45,000 m.w. W6/32-reactive antigens comparable with the HLA-A,B,C heavy chains of human lymphocytes.
Animals↗
Effects of immunization against human choriogonadotropin on the growth of transplanted Lewis lung carcinoma and spontaneous mammary adenocarcinoma in mice.
We studied the effects of preimmunization with a synthetic carboxy-terminal peptide of the beta-subunit of human choriogonadotropin (hCG) conjugated to diphtheria toxoid on the growth of two tumor models, the transplantable Lewis lung carcinoma in C57BL/6J mice and the spontaneous mammary carcinoma in C3H/OuJ mice. Immunization with the conjugate prior to Lewis lung tumor implantation significantly (P less than 0.05) retarded the growth of tumors as measured by tumor weight 18 days following transplantation. The weights of Lewis lung tumors in animals preimmunized with the hCG immunogen were inversely correlated (r = 0.61) with the levels of circulating antibodies against human chorionic gonadotropin, whereas no statistical correlation was found between tumor weights and the levels of antibodies reactive to diphtheria toxoid. The number of conjugate-treated C3H/OuJ mice that developed mammary tumors was significantly (P less than 0.05) reduced compared to their vehicle-treated cohorts. Pretreatment with the synthetic muramyl dipeptide analog utilized as an adjuvant with both immunogens did not show any effect on the tumor growth in either tumor system.
Adenocarcinoma↗
Use of synthetic peptides as immunogens for developing a vaccine against human chorionic gonadotropin.
Human chorionic gonadotropin (hCG) is a glycoprotein hormone produced by the placental trophoblast soon after conception and is essential for successful gestation in women. A vaccine against this hormone has been developed for the purposes of birth control and the treatment of hormone-related diseases. Synthetic peptides representing the native primary structure of the hCG beta subunit have been coupled to protein carriers to produce immunogens. Several peptides, representing varying lengths from the C-terminus of the beta subunit, were synthesized and their ability to elicit antibodies reactive to hCG and able to neutralize hCG activity in vivo was tested. A peptide representing the 37 amino acids of the C-terminal end of the beta subunit was selected as the vaccine antigen and diphtheria toxoid was selected as the carrier for the first prototype vaccine. Procedures for coupling a specified number of peptide molecules to each carrier molecule in a reproducible fashion were developed. The immunogen is mixed with an adjuvant compound and the mixture administered in an oil-in-water emulsion. Significant levels of antibodies to hCG have been elicited in several species and a marked reduction in the fertility of immunized baboons has been observed. Extensive evaluations of vaccine safety have been conducted and Phase I clinical trials have been proposed to test its utility for human birth control. Possible applications of the hCG vaccine to health problems other than birth control are being considered.
Adjuvants, Immunologic↗
Humoral response of normal and athymic (nude) mice to human choriogonadotropin immunogens.
The production of antibodies against human choriogonadotropin (hCG) was studied in normal and athymic (nu/nu) mice of two strains (C57/BL and Balb/c), injected with native (whole) hCG or an immunogen consisting of a synthetic hCG beta COOH-terminal peptide, residues 109-145, conjugated to diphtheria toxoid and mixed with a synthetic muramyl dipeptide analog (nor-MDP) as adjuvant. Both the short-term effect of native hCG dissolved in saline and injected IM (primary response), and the long-term effect of the native hCG and of the hCG immunogen dissolved in saline, emulsified in squalene-Arlacel A, and injected SC as a depot injection (secondary or memory response), were considered. The results obtained indicate that native hCG may be classified as a T-cell independent antigen in the sense that it can elicit low levels of IgM antibodies on a short term basis in athymic mice that have either no or very low T-cell levels. In long-term studies using hCG and the hCG immunogen no antibodies could be detected in athymic mice 14 days after a booster inoculation given 28 days after primary immunization, a regimen that produced high levels of antibodies in normal mice. Because of their inability to sustain humoral responses to native hCG as well as to other hCG immunogens, athymic mice seem well suited for in vivo studies of some of the biological effects of hCG.
Animals↗
Antibodies to bacterial vaccines demonstrating specificity for human choriogonadotropin (hCG) and immunochemical detection of hCG-like factor in subcellular bacterial fractions.
Investigations were done to determine whether vaccines prepared with chemically killed Staphylococcus haemolyticus RU1 and Streptococcus bovis AV46 (bacteria that have been demonstrated to express human choriogonadotropin [hCG]-like material on their surface) elicited antibodies in rabbits with specificity for hCG determinants. In addition, the anatomical locus of the hCG-like factor was determined by separation of bacterial subcellular fractions. The results demonstrated that these bacterial vaccines elicited antibodies immunologically similar to those antibodies produced in response to the whole human trophoblastic hormone, a similarity extending even to cross-reactivity with human luteinizing hormone. The bacterial hCG-like material appeared to be localized in the membranes of the cell wall, and most was present in the soluble membranous and cytoplasmic constituents. Its expression in bacteria was a strain characteristic and not a species characteristic.
Animals↗