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Biomedical subjects

V C Stevens

Publications and source records attributed to V C Stevens.

At least 19 recordsLinked to original sources
PubMed1992

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↗
PubMed1990

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↗
PubMed1988

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↗
PubMed1986

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↗
PubMed1986

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↗
PubMed1986

The identification of peptide sequences of human chorionic gonadotropin containing a conformational epitope.

A series of overlapping peptides were synthesized representing the entire amino acid sequence of the beta-subunit of human chorionic gonadotropin (hCG) and these were reacted with a monoclonal antibody shown to be specific for hCG. One linear peptide (residues 40-52 of the sequence) reacted significantly with the monoclonal antibody but a conjugate of this peptide to diphtheria toxoid (DT) failed to elicit significant levels of antibodies reactive to hCG in rabbits. The subsequent preparation of an extended peptide (residues 38-57) in which the two cysteines were oxidized to form a loop peptide yielded a highly immunogenic antigen when conjugated to DT. Antibody levels reactive with hCG from loop peptide immunizations of rabbits exceeded those found after immunization with a 37 residue peptide representing the carboxyl terminus of the beta-hCG subunit. The antisera did not react with pituitary glycoprotein hormones with similar sequences.

Amino Acid Sequence↗
PubMed1985

Antibody reactivity against trophoblast and trophoblast products.

Sensitive immunoassays have been applied to WHO reference bank sera from fertile and infertile women in order to assess any naturally occurring antibody reactive with isolated human placental trophoblast membranes or two separate trophoblast protein products (hCG and SP1). A very low incidence of antibody reactive with solubilised trophoblast membrane was detected, and no significant antibody to either hCG or SP1 could be detected. Infertile states represented within this serum bank appear unlikely to involve adverse immune reactions to trophoblast.

Antibodies↗
PubMed1985

Non-cross-reactive monoclonal antibodies to human chorionic gonadotropin generated after immunization with a synthetic peptide.

Noncross-reactive monoclonal antibodies specific for human chorionic gonadotropin (hCG) were obtained after pre-selection for submolecular specificity with a synthetic peptide immunogen. Mice were immunized with a synthetic peptide representing a segment unique to the beta-subunit of hCG (amino acid residues 109-145), conjugated to diphtheria toxoid. We then derived nine different hybridomas that secreted monoclonal antibodies reactive with both native hCG and isolated C-terminal peptide, after somatic cell hybridization of immune spleen cells with a nonsecretory myeloma cell line. None of the nine monoclonal antibodies, termed beta-hCG-CTPa1----a9, reacted with hLH, hFSH, or hTSH, although these pituitary hormones display extensive amino acid sequence homology with hCG. The noncross-reactive anti-beta-hCG monoclonal antibodies show apparent association constants on the order of 10(9) to 10(10) M-1. A sandwich-type enzyme-linked immunosorbent assay was set up with cut-off values of around 5 mIU/ml. These antibodies might have important implications for: a) improving the diagnosis and clinical management of pregnancy; b) monitoring the course of development of carcinomas which secrete the hormone, through in vitro assays or in vivo radioimmunodetection; c) evaluating the antibodies' therapeutic potential against such carcinomas; d) studying the biologic functions of the C-terminal segment of beta-hCG; and e) addressing the anti-fertility effect of antibodies raised against that segment.

Animals↗
PubMed1978

Immunological control of fertility: measurement of affinity of antibodies to human chorionic gonadotrophin.

Four baboons were primed with diazotized beta human chorionic gonadotrophin and boosted with diazotized C-terminal beta human chorionic gonadotrophin peptide, and the changes in antibody amount and affinity determined using a double isotope modified Farr assay, using labelled human chorionic gonadotrophin as the antigen. The degree of cross-reaction with human luteinizing hormone was also determined. Although appreciable reactivity with luteinizing hormone was observed soon after immunization, this declined rapidly during the response. At the time intervals studied, there was a progressive increase in affinity of antibodies to human chorionic gonadotrophin until day 248 after priming. At day 313, in two of the animals, there was a decrease in affinity from 1.04 X 10(11) to 6.80 X 10(10) and 1.05 X 10(11) to 4.93 X 10(10) l/mol, whereas in the other two baboons there was a further increase in antibody affinity. At corresponding time intervals, there was a steady decrease in values of total antibody binding sites. To determine the overall effect of the maturation of affinity with a decrease in antibody amount on biological efficacy, the theoretical amount of chorionic gonadotrophin that would be neutralized was calculated. We computed that in all instances, over 99% of a peak concentration of chorionic gonadotrophin that could be in circulation in a pregnant baboon would be neutralized. This was in excellent agreement with results of mating experiments in these baboons. In over forty cycles studied, none of the matings resulted in a sustained pregnancy.

Animals↗
PubMed1978

Radioimmunological study of rat uterine extract.

A radioassay was used to demonstrate the high affinitiy of a crude rat uterine extract for tritiated estradiol-17B. Although no other chemical procedures were employed to further characterize the extract, it may contain the estrogen binding protein isolated by others. The isolate was antigenic in rabbits and administration of immune serum to female rats significantly lowered the in vitro retention of tritiated estradiol-17B in the rat uterus. It is thought that this immune serum could be successfully used to study the estrogen binding activity of rat uterus.

Animals↗
PubMed1977

Effect of synthetic thyrotropin-releasing hormone on ovulation in baboons.

Twice daily oral thyrotropin-releasing hormone administered to female baboons throughout the menstrual cycle had no significant influence on cycle length or upon estrogen levels but produced blunted midcycle LH peaks and luteal phase progesterone levels in three fourths of the treatment cycles. Mean plasma prolactin levels were increased approximately 2.5-fold relative to untreated, ovulatory control cycles. CB-154 alone did not alter cycle length or endocrine parameters examined (mean prolactin levels were decreased but not significantly). Cycles during which CB-154 was administered concomitantly with TRH were characterized by normal ovulation as evidenced by luteal phase progesterone levels. Since the effect on LH secretion was reversed by concomitant CB-154 administration, TRH-induced anovulation in animals given long-term treatment appeared to be mediated through physiologic mechanisms sensitive to elevated circulating prolactin levels. However, this conclusion must be considered equivocal since prolactin levels were also elevated during ovulatory cycles following long-term TRH therapy. Finally, these data do no exclude the alternative possibility that anovulation in baboons given long-term TRH treatment was a reflection of thyroid disturbance and not directly attributable to elevated prolactin.

Animals↗
PubMed1977

Disordered nocturnal prolactin regulation in women with breast cancer.

Mean 24-hr prolactin concentrations were determined in 25 female control subjects, 16 women with benign breast masses, and 23 subjects with breast cancer. This evaluation performed before breast surgery revealed significantly decreased (p less than 0.02) nocturnal (12 a.m. to 7 a.m.) prolactin concentrations in 12 postmenopausal breast cancer subjects that contrasted with significantly increased (p less than 0.05) nocturnal prolactin levels in five luteal-phase premenopausal women with breast cancers. Prolactin concentrations in patients with benign breast disease were not significantly different from control subjects. Two of the premenopausal breast cancer patients had marked preoperative elevations in their mean 24-hr prolactin levels, and they were two of the three subjects who have since expired. Nocturnal prolactin secretion was significantly decreased (p less than 0.03) in four premenopausal breast cancer patients when they were studied 1 year after surgery; however, it remained the same in the eight postmenopausal breast cancer patients similarly evaluated. Although disordered prolactin regulation has been found in these women with breast cancer, its role in the etiology and progression of human cancer is still uncertain.

Adult↗
PubMed1977

Twenty-four-hour preoperative endocrine profiles in women with benign and malignant breast disease.

Mean 24-hr growth hormone, luteinizing hormone, follicle-stimulating hormone, estradiol, and progesterone concentrations determined preoperatively in 16 women with benign breast masses and 17 patients with breast cancer were similar to those levels found in 25 age- and weight-matched control subjects. Mean 24-hr testosterone levels, however, were significantly elevated in women with breast cancer evaluated in the luteal phase of their cycles and were normal in postmenopausal breast cancer women. In addition, serum thyroid-stimulating hormone, thyroxine, cholesterol, and triglyceride levels were normal in these subjects. Plasma cortisols and urinary 17-hydroxysteroid excretion tended to be higher in both the benign and malignant breast disease group and probably reflected preoperative anxiety. Hence, we have found normal concentrations of a variety of endocrine and other biochemical agents that can stimulate breast tissue growth and/or have been previously reported to be disordered in women with breast cancer.

Adult↗
PubMed1976

Serum levels of a placental protein during gestation in the baboon.

A placental specific protein (Sp-1) isolated from human placentas was used to establish a radioimmunoassay for measurement of a baboon protein in the sera of pregnant baboons. No reaction was observed with any known pituitary or placental hormone in this assay system. Levels of Sp-1 were detected at 17 to 18 days of gestation and reached high levels by the end of the first trimester of pregnancy. A slow increase in serum levels continued thereafter until parturition. Disappearance of Sp-1 post partum was very slow and required 26 to 34 days to become undetectable in the serum. No function or role of Sp-1 in pregnancy has been suggested, but possible use of its measurement for detecting abnormal placental function deserves investigation.

Animals↗