INFLUENCE OF AUTOIMMUNE OVARIAN DISEASE PATHOGENESIS ON ZP3 CONTRACEPTIVE VACCINE DESIGN

Zona pellucida (ZP) glycoproteins possess sperm receptor-binding activ ities. Antibodies against ZP can block sperm-egg interaction and there by prevent fertilization. The feasibility of developing a safe contrac eptive vaccine based on the ZP has been hampered by the finding that a ctive immunization with autologous or heterologous ZP proteins results in infertility that is associated with ovarian dysfunction. A mouse m odel was used to investigate mechanisms of the ovarian pathology that is induced by active immunization with a 13mer peptide derived from mo use ZP3 (mZP3(330-342)). This peptide includes one native B-cell epito pe and two nested T-cell epitopes. Ovarian pathology could be transfer red into naive recipients by CD4(+) T cells, but not by antibodies, fr om immunized mice, suggesting the importance of T cells in the mechani sm of ovarian pathogenesis. Moreover, immune responses, as well as dis ease induction, were restricted to H-2(ak,u,s,axb) haplotypes. On the basis of this mouse model, a strategy to generate a contraceptive anti -ZP antibody response without a pathogenic T-cell response, irrespecti ve of H-2 haplotype, is described. The B-cell epitope was modified by amino acid substitution to eliminate the overlapping oophoritogenic T- cell epitope, and was linked to a promiscuous foreign T-cell epitope, bovine RNase(94-104) The resultant chimaeric peptide (CP2) induced ant i-ZP antibodies in 100% of the eight strains of inbred mice with diffe rent H-2 haplotypes without significant disease induction. An antifert ility trial in B6AF1 female mice immunized with CP2 showed that the an ti-ZP antibody was associated with a reduction in fertility. This infe rtility was reversed with a decline in anti-ZP antibody titre. Prelimi nary data show that this strategy of vaccine design may also be applie d to primates.