We report here results of clinical trials on a birth control vaccine, consisting of a heterospecies dimer of the .3 subunit of human chorionic gonadotropin (hCG) associated noncovalently with the a subunit of ovine luteinizing hormone and coijugated to tetanus and diphtheria toxoids as carriers, that induces antibodies of high avidity (Ka 1010 M-) against hCG. Fertile women exposed to conception over 1224 cycles recorded only one pregnancy at antibody titers of >50 ng/ml (hCG bioneutralization capacity). The antibody response declines with time; fertility was regained when titers fell to <35 ng/ml. This study presents evidence of the feasibility of a vaccine for control of human fertility.A number of contraceptive methods are available; they do not, however, suit all potential users. There is need to develop additional methods, in particular those that are reversible, require only periodic intake, and do not disturb menstrual regularity or bleeding. Vaccines regulating fertility offer promising prospects to meet these specifications. The rationale for these vaccines is to induce the formation of antibodies and/or cell-mediated immunity to intercept selectively a process critical to the success of reproduction. A number of potential antigens are being investigated (1-7). Among these are hormones, which play an important role in the regulation of fertility. Human chorionic gonadotropin (hCG) is an early signal of conception and is considered essential for establishment and maintenance of early pregnancy. An advantage in choosing hCG as a target for immunocontraception is that its inactivation would not interfere with other physiological processes in the female, such as ovulation and production of sex steroid hormones.Carrier conjugation with tetanus toxoid (TT) was proposed as a strategy to overcome the immunological tolerance of a woman against hCG (8). This initial prototype vaccine (/3hCG-TT adsorbed on alum) had limitations. It induced high antibody titers in only a small percentage of women, and those with low titers were not protected from pregnancy (9). Three changes were made to enhance immunogenicity.(i) An adjuvant, the sodium phthalyl derivative of lipopolysaccharide, was included in the first injection. This nonpyrogenic adjuvant is usable in aqueous phase (10). Its use doubled, on average, anti-hCG titers and increased the frequency of high responders.(ii) The intrinsic immunogenicity of (3hCG was enhanced by associating it noncovalently with the a subunit of ovine luteinizing hormone (LH) to form a heterospecies dimer (HSD), a laboratory-made hormone that attains a conformation which recognizes receptors on target tissues (whereas isolated subunits do not) and generates a steroidogenic response even superior to that by hCG (11). HSD linked to carriers was indeed found to be more immunogenic than ,8hCG in rats and monkeys (12). Moreover, the antibodies had better capacity to neutralize the bioactivity of hCG (11,13 It was important to determine whether the antibodies induced by the HSD-and 8hC...

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IN connection with an investigation which is being made in this laboratory into the metabolism of paraffins in the higher plants it was thought that further light might be thrown on the chemistry of paraffin synthesis in the leaf if the composition of a leaf-wax known to contain large amounts of paraffin could be determined at various stages throughout the life history of the leaf. The wax of cabbage leaves (Brassica oleracea v. capitata), which was shown by Channon and Chibnall [1929] to consist chiefly of the paraffin n-nonacosane and the closely allied ketone 15-nonacosanone would have been a suitable one for such an experiment, but unfortunately the headed cabbage, which is a bud with its leaves densely compacted together and in different degrees of maturity, is unsuitable for this purpose. The Brussels sprout (B. oleracea v. gemmifera) on the contrary appeared to be quite suitable for this purpose and as the botanical difference between the two plants is a varietal one only it seemed to us probable that the leaf-waxes would be similar. Accordingly we first determined the composition of the Brussels sprout leaf-wax and having found that it consisted chiefly of n-nonacosane, 15-nonacosanone and 15-nonacosanol we investigated the change in composition throughout the life history of the leaf.In the experiments detailed below it is to be clearly understood that the term Brussels sprout leaf refers to the leaves growing on the main axis of the plant, and is in no way concerned with the bud-like shoots commonly referred to as "sprouts."Analysis of the wax. Several samples of wax ("crude hydrocarbon") had been obtained in a previous research from the mature leaves of Brussels sprout by Chibnall and Sahai [1931]. These were collected and saponified and the unsaponifiable material (22 g.) was fractionated by the phthalate method of Chibnall et al. [1931].Primary alcohols. Only a small amount of insoluble sodium salts of primary phthalates was obtained. This was thoroughly extracted with ether and then 1 The melting-points recorded in this paper were obtained by the method described by Piper et al. [1931] and are corrected.

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Signature was redacted for privacy.Signature was redacted for privacy.Signature was redacted for privacy. SUMMARY 78 BIBLIOGRAPHY 82 ACKNOWLEDGMENTS 85 APPENDIX 88 69