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Development of an improved, low-cost polio vaccine (Ir-IPV)

开发改进的低成本脊髓灰质炎疫苗 (Ir-IPV)

基本信息

批准号：
9255366
负责人：
GREGORY John TOBIN
金额：
$ 74.31万
依托单位：
BIOLOGICAL MIMETICS, INC.
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-05-15 至 2019-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9255366
关键词：
Animals Antigens Attenuated Bacterial Genome Biohazardous Substance Biological Preservation Capsid Proteins Chemicals Chronic Cold Chains Communities Complex Country Cryoelectron Microscopy DNA Data Dedications Deinococcus radiodurans Developing Countries Development Dose Ebola virus Ensure Epitopes Excipients Formalin Freeze Drying Future Goals Government Hand Hela Cells High Pressure Liquid Chromatography Human Human poliovirus Immune Immunity Immunization Immunize Incubated Ions Life Manganese Manufacturer Name Mass Vaccinations Measures Methods Oral Poliovirus Vaccine Pathogenicity Peptides Phase Phenotype Poliomyelitis Poliovirus Vaccines Preparation Price Procedures Process Production Proteins RNA Radiation Radiation induced damage Rattus Refrigeration Regulatory Pathway Residual state Risk Safety Scientist Serotyping Serum-Free Culture Media Shipping Site Small Business Innovation Research Grant Standardization Technology Testing Time Tissue Culture Techniques Transportation Vaccination Vaccines Vero Cells Viral Viral Genome Virus Virus Diseases Virus Shedding Wistar Rats Zika Virus bacterial resistance biosecurity cGMP production commercialization cost cost effective crosslink immunogenicity improved inorganic phosphate interest irradiation link protein milligram neutralizing antibody novel vaccines oxidative damage pathogen pathogen genome phase 1 study process optimization protein degradation radioresistant reconstitution response risk perception

项目摘要

Abstract After decades of effort, global campaigns to eradicate poliovirus are nearing completion. Eradiation of wild-type PV-2 has been certified and PV1 and PV2 may be eradicated in the next few years. Many organizations and countries have collaborated in these efforts and are to be congratulated for their dedication and persistence. The oral polio vaccine (OPV) has been the workhorse of mass vaccination efforts because of its low cost and ability to stimulate robust and durable immunity. However, OPV quickly reverts to pathogenic phenotypes in the human and vaccinees secrete wild-type virus that can infect naïve bystanders. In addition, the virus can replicate chronically in immune compromised people who can shed virus for many years. For these reasons, OPV is being replaced by the inactivated polio vaccine (IPV) which also stimulates durable immunity. Unfortunately, IPV costs considerably more than OPV per dose ($3-5 vs $0.12 on the subsidized world market). Because the WHO and most countries have plans to continue vaccination for at least 10 years after eradication, there will continue to be a market for the vaccine. Because of the high cost of the IPV, efforts are underway to derive improved and less expensive IPV vaccines. In a Phase 1 SBIR, we tested the feasibility of producing a less expensive IPV using a recently developed radiation-inactivation method. A reconstituted Mn+2-decapeptide phosphate complex (MDP) from 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. We hypothesized that the new method could increase the antigenicity per unit of starting virus because it avoids the extensive 12 - 28 day formalin incubation that damages the polio antigens by spontaneous protein degradation and cross-linking epitopes. Preservation of antigenicity would increase the number of doses that can be produced per milligram of purified virus and simplification of the inactivation process could reduce costs further. After optimizing the process for inactivating 100% of virus infectivity while protecting the protein capsid, we normalized the irradiated PV2 virus to the D antigen concentrations found in commercial vaccines. Rats immunized with irradiated PV2 developed robust neutralizing titers. A 1/32 fraction of the normal human dose of irradiated PV2 stimulated similar levels of neutralizing antibodies as a 1X dose of the commercial IPV product. We propose to extend these findings to include PV1 and PV3 and then derive a trivalent vaccine having the minimum dose of each component that stimulates equivalent neutralizing antibody levels as IPV. In addition to a reduction in cost, the novel vaccine will have two additional features: the use of attenuated Sabin strains and the development of lyophilization procedures. The transition to Sabin strains will reduce the biohazard risks currently associated with producing large quantities of pathogenic strains. This feature may allow less sophisticated companies or government labs in developing countries to manufacture their own vaccines. In addition, the use of the Sabin strains may improve acceptance of the product due to the reduced risk perception associated with low levels of residual infections virus that may not be detected in quality analysis procedures. The development of a lyophilization process would improve product stability such that the vaccine would not require refrigeration during shipping and may reduce the need for refrigerated storage. In addition, a lyophilized vaccine could be stable for many years when placed in national vaccine stockpiles. We have discussed the findings of the Phase I with several polio vaccine experts and scientists at companies that currently manufacture the vaccine. The results have been met with enthusiasm and interest for future interactions. We will keep the wider community informed of our progress during the Phase II so that we may have partnering options earlier in the development process than originally planned. The main goal of the project is to develop an improved and less expensive inactivated polio vaccine. However, the project will also advance the irradiation technology using a highly characterized virus. The same method could be applied to the rapid and efficient preparation of vaccines against newly emerging pathogens such as Ebola, Zika, and other deadly pathogens. The regulatory pathway derived from the development of a radiation-inactivated PV vaccine would be invaluable when developing vaccines against these less characterized pathogens.

摘要