After decades of effort, global campaigns to eradicate poliovirus are nearing completion. Wild-type PV- 2 and PV-3 viruses have been eradicated and India has been the latest country to certify eradication. Depending on the timing of eradication, the WHO anticipates a continued need for 200-400M doses per year for the next ten years and several countries will likely stockpile vaccine for biosecurity reasons far into the future. The oral poliovirus vaccine (OPV) stimulates robust gut immunity and has been the workhorse vaccine since its adoption in the late 1950s. Unfortunately, the attenuated viruses in OPV revert to pathogenic wild- type phenotypes and are shed in high concentrations within a week of vaccination. For this reason, vaccination with the inactivated polio vaccine (IPV) is now recommended. IPV does not provide as robust gut immunity as OPV, but it does eliminate vaccine-associated infections. However, the higher cost relative to the OPV ($3- 5/dose vs $0.12/dose) magnifies the economic burden of delivering hundreds of millions of doses. We propose to test the feasibility of producing a less expensive IPV using a recently developed radiation-inactivation method which uncouples damage to proteins and nucleic acids during exposure to ionizing radiation. A reconstituted Mn+2-decapeptide phosphate complex (Mn-Dp-Pi) of the radiation-resistant bacterium Deinococcus radiodurans protects antigenic sites in proteins from oxidative damage at radiation doses that obliterate DNA/RNA genomes of viral and bacterial pathogens. The new method should increase the antigenicity per unit of starting virus because it avoids the long (=12 days) 37C formalin incubation that damages the antigens by spontaneous non-specific protein degradation and cross-linking. Preservation of antigenicity will increase the number of doses per milligram of purified virus and simplification of the inactivation process could reduce costs further such that the cost per unit can be reduced at least 10-fold. In addition, the simpler method developed in the proposed PV studies could be directly applied to the rapid and efficient preparation of vaccines against newly emerging pathogens such as Ebola, and other deadly pathogens. The regulatory pathway derived from the development of a radiation-inactivated PV vaccine would be invaluable when developing vaccines against less characterized pathogens.
Because of safety concerns surrounding the reversion of pathogenic phenotypes with the use of the oral poliovirus vaccine (OPV), WHO and other agencies recommend that inactivated poliovirus vaccines (IPV) be used in the final stages of global eradication and for post- eradication vaccinations. IPV is produced by inactivating purified virus by prolonged incubations with formalin which reduces the immunogenicity and leads to a relatively high price of $3-5/dose compared with $0.12/dose for OPV. We propose to test a recent discovery for improving the immunogenicity of IPV while reducing the manufacturing costs at least 10-fold. Our collaborator, Dr. Michael Daly, found that a decapeptide-manganese complex protects the protein component from ionizing effects of high doses of radiation. In preliminary studies, we have found that the complex allows the capsid proteins of polio to escape damage that obliterates the RNA genome. In this application, we propose to compare irradiated polio with IPV in a quantitative rat immunogenicity study.
