CFI Pathogen Inactivation Technology

CFI病原体灭活技术

• 批准号: 7830669
• 负责人: TREVOR P. CASTOR
• 金额: $ 50万
• 依托单位: APHIOS CORPORATION
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7830669
• 关键词: Acquired Immunodeficiency Syndrome; American; Animal Viruses; Antibodies; Applications Grants; Babesia; Bacteria; Biological; Bioterrorism; Blood; Blood donor screening; Chemicals; Clinical Trials; Collaborations; Community Healthcare; Conduct Clinical Trials; Cyclic GMP; Deforestation; Department of Defense; Detergents; Development; Disease; Disease Outbreaks; England; Ensure; Enzyme Immunoassay; Enzymes; Epidemic; Escherichia coli; Eukaryota; Europe; Evaluation; Excision; Exhibits; Factor VIII; Fibrinogen; Gases; Grant; HIV; Habitats; Heating; Human; Human Parvovirus B19; Individual; Infection; Infectious Agent; Influenza; Influenza A Virus, H5N1 Subtype; Institutes; International; Laboratories; Lead; Liquid substance; London; Manufacturer Name; Methods; Mexican; Modeling; Morbidity - disease rate; Mutation; National Heart, Lung, and Blood Institute; Operative Surgical Procedures; Parasites; Penetration; Pharmacologic Substance; Pharmacology; Phase; Plasma; Plasma Proteins; Plasmodium; Poliomyelitis; Process; Prokaryotic Cells; Property; Proteins; Recombinants; Recovery; Red Cross; Research; Residual state; Risk; Rupture; Saccharomyces cerevisiae; Safety; Screening procedure; Severe Acute Respiratory Syndrome; Small Business Innovation Research Grant; Smallpox; Solvents; Staging; Techniques; Technology; Testing; Therapeutic Monoclonal Antibodies; Thick; Transfusion; Transgenic Organisms; Travel; United States National Institutes of Health; Urbanization; Vaccines; Vascular blood supply; Vesicular stomatitis Indiana virus; Viral; Viral Antigens; Virus; Virus Inactivation; West Nile virus; Work; authority; base; clinical toxicology; design; design and construction; healthy volunteer; irradiation; meetings; microorganism; mortality; pandemic disease; particle; pasteurization; pathogen; pathogenic bacteria; pre-clinical; preclinical study; programs; prototype; public health relevance; research and development; response; serological marker; swine flu; ultraviolet irradiation

DESCRIPTION (provided by applicant): This project entitled "CFI Pathogen Inactivation Technology," is in response to the challenge of developing Enabling Technologies to "Ensure a safe and adequate blood supply through the development of new processing technologies" Topic 06-HL-106, p. 94 of the National Institutes of Health American Recovery and Reinvestment Act of 2009 Challenge Grant Omnibus Solicitation RFA-OD-09-003. The worldwide AIDS epidemic, the periodic emergence of Ebola and SARS, and the recent outbreaks of potentially pandemic strains of influenza such as H5N1 have highlighted a persistent concern in the healthcare community -- the need for effective pathogen inactivation and removal techniques for human blood plasma and plasma-derived products. There are also a number of emerging viruses such as West Nile and the breaking Mexican swine flu, and a number of potential bioterrorism pathogens such as smallpox that are of concern to the safety of the human plasma supply chain. In addition to viruses, bacteria and parasites such as Babesia spp. and Plasmodium spp. are major threats of spreading diseases through transfusion. The causes of the more rapid emergence and spread of these "killer" viruses and pathogens are not entirely known, but are thought to be caused by some combination of deforestation with urbanization of wild virus habitats, evolutionary mutations and rapid global travel. Annually, an estimated 3.8 million Americans are transfused with 28.2 million blood components derived from 12.8 million units of blood donated by apparently healthy volunteers. A rigorous scrutiny of blood donors and the screening of donated blood for various serological markers have significantly reduced the mortality and morbidity due to transfusion-associated infectious agents. Some enzyme immunoassays used for routine screening may detect viral antigens or antibodies, but not the infectious agents themselves. Thus, there could be an asymptomatic window period of infectivity responsible for a residual risk of post-transfusion infection. Current approaches such as pasteurization; solvent-detergent; UV irradiation; and chemical and photochemical inactivation not always effective against a wide spectrum of pathogens, are sometimes encumbered by process-specific deficiencies, and often result in denaturation of the biologics that they are designed to protect. We plan to develop a physical pathogen inactivation process for non-enveloped and enveloped viruses as well as pathogenic bacteria and parasites in human plasma and plasma protein products. The process utilizes supercritical and near-critical fluids (SuperFluids(tm) or SFS). SuperFluids(tm) are normally gases which, when compressed, exhibit enhanced solvation, penetration and expansion properties. These gases are used to permeate and inflate the virus and pathogen particles. The overfilled particles are then decompressed and, as a result of rapid phase conversion, rupture at their weakest points. Research to date indicates that the SuperFluids(tm) CFI (critical fluid inactivation) process inactivates both enveloped viruses such as MuLV, VSV, TGE, BDVD, Sindbis and HIV and nonenveloped viruses such as Polio, Adeno, Reo, Parvo and EMC while preserving biological activity of the treated product. In a research collaboration with the National Institute of Biological Standards and Control (NIBSC), London, England, we demonstrated that SuperFluids(tm) CFI can inactivate more than 4 logs of human Parvovirus B19 (one of the smallest and toughest viruses) in human plasma in a two-stage CFI unit in less than 20 seconds. We have also demonstrated that SFS can disrupt and inactivate microorganisms such as E. coli, and thick-walled prokaryotes such as B. subtilis and tough eukaryotes such as S. cerevisiae at viral inactivation SFS conditions. CFI can be used with conventional viral reduction methods such as SD and nanofiltration as an orthogonal method of pathogen clearance. Our specific plans for this challenge grant are to: (1) design and construct laboratory-scale prototypes to conduct evaluation and trade-off studies that will lead to the selection of a commercial-scale SFS-CFI design to achieve > 6 logs of inactivation levels of nonenveloped and enveloped viruses with >90% retention of protein (e.g., Factor VIII) integrity; (2) test prototypical and emerging viruses and bacteria in human plasma in extant SFS-CFI units and in laboratory-scale prototypes in order to establish universal operation conditions as well as the universality of the SFS-CFI process for enveloped and nonenveloped viruses and pathogenic bacteria; (3) evaluate the potential of applying SFS-CFI enabling technology to human plasma proteins such as fibrinogen and other components; and (4) evaluate compatibility of SFS-CFI with other enabling pathogen inactivation/ reduction technologies such as nanofiltration to define orthogonal effective approaches to meet manufacturers' specifications and FDA requirements. Subsequently, with a pharmaceutical/biologics partner such as Baxter International and/or an institutional partner such as the American Red Cross, DOD or NHLBI, we plan to conduct pre-clinical studies, file an IND with the FDA and conduct clinical trials on CFI-treated plasma. A generally-applicable physical technology for inactivating viruses and emerging pathogens with high retention of biological activity will help ensure a blood supply that is safe from emerging and unknown pathogens as well as bioterrorism threats. In addition to human plasma and human plasma proteins, the developed technology will also be applicable to recombinant therapeutics, monoclonal antibodies, transgenics and vaccines. PUBLIC HEALTH RELEVANCE: There are a number of emerging viruses such as West Nile, Ebola, SARS, potential pandemic strains of influenza (H5N1), the breaking Mexican swine flu, bacteria, parasites and a number of potential bioterrorism pathogens such as smallpox that are of concern to the safety of the human plasma supply. Current approaches are not always effective against a wide spectrum of human and animal viruses, are sometimes encumbered by process-specific deficiencies, and often result in denaturation of the biologicals that they are designed to protect. CFI pathogen inactivation technology gives pathogens the "bends," inactivating them without damaging proteins and enzymes in medically important transfusion fluids such as human plasma. This purely physical technique does not involve the use of heat, chemicals and/or irradiation, each of which has significant drawbacks in the viral inactivation of human plasma. As such, while CFI is capable of inactivating wide classes of viruses, bacteria and parasites, CFI has negligible negative impact on biological integrity and potency of the treated fluids. We plan to develop this technology as an orthogonal virus inactivation technology to techniques such as solvent-detergent (SD) that is not effective against non-enveloped viruses and passive virus removal techniques such as nanofiltration which does not render viruses inactive. This orthogonal approach is consistent with the regulatory authorities in Europe and the US that require a minimum of two pathogen inactivation technologies, which work by different mechanisms of action. The potential impact of a generally-applicable physical technology for inactivating viruses and emerging pathogens with high retention of biological activity will be very significant. Such a technology, especially when used with conventional virus inactivation or removal methods such as SD or nanofiltration, will help ensure a blood supply that is safe from emerging and unknown pathogens and bioterrorism threats. In addition to human plasma and human plasma proteins such as fibrinogen, the developed technology will also be applicable to recombinant therapeutics, monoclonal antibodies, transgenics and vaccines.

描述（由申请人提供）：该项目标题为“ CFI病原体灭活技术”，这是针对开发使技术来开发“通过开发新处理技术确保安全有足够的血液供应”主题06-HL-106的挑战。 2009年美国国立卫生研究院的回收与再投资法案第94号挑战授予综合征集RFA-OD-09-003。全球流行病，埃博拉病毒和SAR的周期性出现以及最近可能出现的流感流感菌株（如H5N1）的爆发强调了医疗保健社区中的持续关注 - 需要有效的病原体灭活和消除人血浆血浆和血浆血浆和血浆质量的产品。还有许多新兴病毒，例如西尼罗河和破裂的墨西哥猪流感，以及许多潜在的生物恐怖病原体（例如天花），这些病原体引起了人类血浆供应链安全的关注。除病毒外，细菌和寄生虫（例如贝贝斯属）。和疟原虫属。是通过输血传播疾病的主要威胁。这些“杀手”病毒和病原体的出现更快出现和传播的原因尚不完全清楚，但被认为是由于森林砍伐与野生病毒栖息地，进化突变和快速全球旅行的某种结合而引起的。估计，估计有380万美国人被输出，有2820万血成分，这些血液成分来自1.280万单位的血液，这些血液显然是健康的志愿者。严格对献血者的审查以及各种血清学标记的捐赠血液的筛查显着降低了由于输血相关的传染剂而引起的死亡率和发病率。一些用于常规筛查的酶免疫测定可能检测病毒抗原或抗体，但不能检测到感染剂本身。因此，可能有一个无症状的感染性窗户期间，导致转移后感染的残留风险。当前的巴氏灭菌方法；溶剂少；紫外线照射；化学和光化学灭活并不总是针对广泛的病原体有效，有时会因过程特异性缺陷而抑制，并且通常会导致其设计为保护的生物制剂的变性。我们计划为人血浆和血浆蛋白产物中的致病性病毒以及致病性细菌和寄生虫开发一种物理病原体灭活过程。该过程利用超临界和近临界流体（超氟（TM）或SFS）。超氟（TM）通常是气体，当压缩时，它会表现出增强的溶剂化，穿透性和膨胀特性。这些气体用于渗透和充气病毒和病原体颗粒。然后对过度填充的颗粒进行解压缩，并且由于快速相位转换而在其最弱点处破裂。迄今为止的研究表明，超级流体（TM）CFI（临界流体失活）过程使两种包围病毒（例如MULV，VSV，TGE，BDVD，SINDBIS，SINDBIS和HIV）以及未发育的病毒（例如Polio，Polio，Adeno，Reo，Reo，Parvo，Parvo和Emc）养育生物学的生产产品。在与英国伦敦国家生物学标准与控制研究所（NIBSC）的研究合作中，我们证明了超过4个以上的人类小palvovovirus b19（在较小的CFI单位中，人类质量质量之一）可以使超过4个以上的人类palvovovirus b19日志。我们还证明，SFS可以破坏和灭活微生物，例如大肠杆菌，以及在病毒灭活sfs条件下酿酒酵母和坚韧的真核生物（例如酿酒酵母）等坚硬的真核生物。 CFI可以与常规病毒还原方法（例如SD和纳米过滤）一起用作病原体清除率的正交方法。我们针对这项挑战赠款的具体计划是：（1）设计和构建实验室规模的原型，以进行评估和权衡研究，这将导致选择商业规模的SFS-CFI设计，以实现> 6个未发育和包裹病毒的灭活水平的日志，并具有> 90％的蛋白质保留（例如，viii viii viii Intemptions）> 90％的保留; （2）在现有的SFS-CFI单元和实验室规模的原型中，在人血浆中测试原型和新兴病毒和细菌，以建立通用的操作条件以及 SFS-CFI过程的普遍性，用于包裹和非发育的病毒和致病性细菌； （3）评估将SFS-CFI促进技术应用于人血浆蛋白（例如纤维蛋白原和其他成分）的潜力； （4）评估SFS-CFI与其他使病原体失活/还原技术（例如纳米过滤）的兼容性，以定义正交有效的方法，以满足制造商的规格和FDA要求。随后，我们计划与Baxter International和/或机构合作伙伴（例如American Red Cross，DoD或NHLBI）这样的制药/生物制作合作伙伴，我们计划进行临床前研究，并向FDA提交IND并对CFI-PREATEAD的等离子体进行临床试验。一项通常可灭活病毒和新兴病原体具有高度保留生物活性的病原体的物理技术，将有助于确保避免新兴和未知病原体以及生物恐怖主义威胁的血液供应。除了人血浆和人血浆蛋白外，开发的技术还适用于重组疗法，单克隆抗体，转基因和疫苗。 公共卫生相关性：有许多新兴病毒，例如西尼罗河，埃博拉病毒，SARS，潜在的流感流行菌株（H5N1），墨西哥猪的破裂流感，细菌，寄生虫和许多潜在的生物恐怖病原体（如天花），例如天花，这与人类质量供应的安全有关。当前的方法并不总是有效地针对各种各样的人类和动物病毒，有时会因过程特异性缺陷而抑制，并且通常会导致其旨在保护的生物学变性。 CFI病原体灭活技术为病原体提供了“弯曲”，使它们失活而不会在医学上重要的输血液（如人血浆）中损害蛋白质和酶。这种纯粹的物理技术不涉及使用热，化学物质和/或辐照，每种技术都在人血浆的病毒灭活中存在明显的缺点。因此，尽管CFI能够使广泛的病毒，细菌和寄生虫失活，但CFI对处理的液体的生物完整性和效力具有可忽略的负面影响。我们计划将这项技术作为正交病毒灭活技术开发到诸如溶剂含量（SD）之类的技术，这些技术对非发育的病毒和被动病毒去除技术（例如纳米过滤）无效，这些技术不会使病毒不活跃。这种正交方法与欧洲和美国的监管机构一致，这些机构至少需要两种病原体灭活技术，这些技术通过不同的作用机理起作用。普遍适用的物理技术对灭活病毒和新兴病原体的潜在影响将非常重要。这样的技术，尤其是在与常规病毒灭活或去除方法（如SD或纳米过滤）一起使用时，将有助于确保避免新兴和未知病原体和生物恐怖主义威胁的血液供应。除了人血浆和人血浆蛋白（例如纤维蛋白原）外，开发的技术还适用于重组疗法，单克隆抗体，转基因和疫苗。