Selection of antigens for use in a virus-vectored immunocontraceptive vaccine: PH-20 as a case study

Abstract

The European wild rabbit (Oryctolagus cuniculus) has become the major agricultural and environmental pest species in Australia. Current methods of rabbit control are lethal procedures which are increasingly questioned for their overall efficiency, applicability, specificity, cost and humaneness. New initiatives are required. One such initiative is virus-vectored immunocontraception. In this approach, the lagomorph-specific myxoma virus will be genetically engineered to include genes encoding components of rabbit gametes which can induce an immune response that causes infertility. Central to such a strategy is the ability to identify antigens capable of inducing an immunocontraceptive response. A strategy for identifying such antigens has been described previously. A case study of one sperm antigen, PH-20, is reported here. The issues involved in developing this antigen to the stage where it could be considered as a candidate for insertion into a recombinant myxoma virus with the ultimate goal of testing for immunocontraceptive efficacy are discussed. Techniques for inserting genes into myxoma virus have been described previously. The knowledge gained from research with this particular antigen are broadly applicable to other antigens used for both immunocontraceptive vaccines in general and, specifically, for virus-vectored immunocontraception.

Clinical Immunogenicity of rHuPH20, a Hyaluronidase Enabling Subcutaneous Drug Administration

“…These observations serve to alleviate potential concerns raised by the apparent binding (although not neutralization) of a treatment-induced antibody to an endogenous protein involved in aspects of reproduction and are further supported by published reports in which several attempts were made to immunize males with PH20 as an immunocontraceptive approach in animal models. These studies involved rabbits ( 45 , 46 ), mice ( 47 ), and guinea pigs ( 48 ), and only the latter experienced infertility following PH20 immunization with a crude testicular extract that resulted in autoimmune orchitis ( 49 ). Furthermore, sperm from mice lacking PH20 were able to fertilize eggs, albeit in a somewhat delayed manner ( 50 ).…”

Identification of a novel GPI‐anchored CRISP glycoprotein, MAK248, located on the posterior head and equatorial segment of cynomolgus macaque sperm

“…PH-20 is another well characterized GPI-anchored sperm surface protein and has been the focus of a number of immunocontraception studies (Primakoff et al, 1988a,b;Holland et al, 1997;Deng et al, 2002). Although PH-20 comprises a significant proportion of the GPI-anchored glycoproteins released after sperm are treated with PI-PLC, it did not stimulate a recognizable immune response, regardless of the adjuvant used.…”

Rat Sperm 2B1 Glycoprotein (PH20) Contains a C-Terminal Sequence Motif for Attachment of a Glycosyl Phosphatidylinositol Anchor. Effects of Endoproteolytic Cleavage on Hyaluronidase Activity1

“…Unfortunately, the efficacy of PH20 has not been confirmed in other species. Immunization of female rabbits with homologous recombinant PH20 had no significant effect on their fertility despite high titers of circulating antibodies [46]. We have also investigated the effects of immunizing male and female rats with bacterially expressed fragments of 2B1 representing nucleotides 436-879, 898-1375, and 1376-1863 [11].…”