Development of a New Low-Cost Poliovirus Vaccine (Ir-IPV): Feasibility study with PV-2

 描述(申请人提供)：经过几十年的努力，全球根除脊髓灰质炎病毒的运动接近完成。野生型PV-2和PV-3病毒已被根除，印度是最新一个获得根除证书的国家。根据根除时间的不同，世卫组织预计未来10年每年仍需要2亿至4亿剂疫苗，几个国家可能会出于生物安全原因在很久以后储存疫苗。口服脊髓灰质炎病毒疫苗(OPV)刺激强大的肠道免疫，自20世纪50年代末采用以来一直是主力疫苗。不幸的是，口服脊髓灰质炎疫苗中的减毒病毒恢复到致病的野生型表型，并在接种疫苗后一周内高浓度脱落。为此，现在建议接种灭活脊髓灰质炎疫苗。IPV不像OPV那样提供强大的肠道免疫力，但它确实消除了疫苗相关感染。然而，与口服脊髓灰质炎疫苗相比，较高的成本(3-5美元/剂对0.12美元/剂)放大了提供数亿剂的经济负担。我们建议使用最近开发的辐射灭活方法来测试生产成本较低的IPV的可行性，该方法在暴露于电离辐射期间解除对蛋白质和核酸的损害。抗辐射细菌耐辐射球菌重组的Mn+2-十肽磷酸盐复合体(Mn-DP-PI)保护蛋白质中的抗原部位免受辐射剂量的氧化损伤，这种损伤会破坏病毒和细菌病原体的DNA/RNA基因组。这种新方法应该会提高每单位起始病毒的抗原性，因为它避免了长时间(=12天)的37°C福尔马林孵化，因为福尔马林孵育会通过自发的非特异性蛋白质降解和交联来破坏抗原。保存抗原性将增加每毫克纯化病毒的剂量，简化灭活过程可以进一步降低成本，使单位成本至少降低10倍。此外，在拟议的光伏研究中开发的更简单的方法可以直接应用于快速有效地制备针对埃博拉等新出现的病原体和其他致命病原体的疫苗。在开发针对特征较少的病原体的疫苗时，开发辐射灭活的光伏疫苗所产生的调控途径将是无价的。

 DESCRIPTION (provided by applicant): 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) 37°C 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.