Development of a Yellow Fever Vaccine for Vulnerable Populations

为弱势群体开发黄热病疫苗

基本信息

批准号：
7648079
负责人：
Ian James Amanna
金额：
$ 29.23万
依托单位：
NAJIT TECHNOLOGIES, INC.
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-07-01 至 2011-01-14
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7648079
关键词：
Adjuvant Adult Aedes Aerosols Age-Months Age-Years Antibody Formation Attenuated Attenuated Live Virus Vaccine Attenuated Vaccines Bioterrorism Bite Cessation of life Clinical Communicable Diseases Communities Culicidae Data Development Disease Disease Outbreaks Dose Drug Formulations Elderly Encephalitis Equipment Filtration Flavivirus Generations Human Hydrogen Peroxide Immune In Vitro Inactivated Vaccines Incidence Individual Infant Infection Japanese Encephalitis Viruses Japanese encephalitis virus Life Medicine Methods Monitor Morbidity - disease rate Mus Nigeria Oral Oral Poliovirus Vaccine Paralysed Patients Phase Play Poliomyelitis Population Population Heterogeneity Price Resources Risk Role Route Scourge Seeds Smallpox Smallpox Vaccine Soldier System Technology Testing Tick-Borne Encephalitis Virus Tick-Borne Encephalitis Viruses Time Ultracentrifugation Uncertainty United States Vaccination Vaccines Viral Viral Antibodies Virus Virus Inactivation Vulnerable Populations World Health Organization Yellow Fever Yellow Fever Vaccine Yellow Fever Virus Infection Yellow fever virus age group base biodefense clinically relevant design immunogenic immunogenicity improved in vivo innovation killings mortality neurotropic new technology novel vaccines older patient pathogen protective efficacy public health relevance scale up tissue culture vaccine candidate

项目摘要

DESCRIPTION (provided by applicant): Yellow fever virus (YFV) was at one time endemic in the United States and represents an emerging/re-emerging human pathogen that causes up to 20% mortality. Although YFV is typically spread by the bite of Aedes aegypti mosquitoes, it also represents a viral encephalitide with potential for use as a bioterrorism agent because; 1) clinical isolates of YFV are available and/or easily obtained during natural outbreaks, 2) YFV grows to high titers in vitro with relatively simple equipment, and 3) YFV can cause lethal encephalitis when administered by an aerosol route. The current live attenuated YFV vaccine was developed in 1936 and following the development of a virus seed lot system, it has not been modified or otherwise improved in over 50 years. This vaccine causes 4 cases of encephalitis per million doses administered. The overall mortality rate following YFV vaccination is estimated at 1 to 2 deaths per million doses, indicating that this vaccine is as dangerous as the live smallpox vaccine, Dryvax. YFV vaccination of infants <9 months of age has been contraindicated since the 1960's due to the discovery of high rates of vaccine-associated encephalitis in this age group. More recently, YFV vaccination has been found to cause severe viscerotropic disease in a substantial number of patients >60 years of age (incidence rate is approximately 1:50,000 doses administered) and these cases result in approximately 50% mortality. This indicates that YFV vaccination is not only contraindicated in infants, but may soon be contraindicated in the elderly as well due to the increased risk of severe and life-threatening disease. Increased monitoring efforts have also documented several cases of vaccine-related fatalities in young, otherwise healthy adults with no known pre-existing immune deficiencies. To date, there is no alternative to live YFV vaccination. In this proposal, we will use a proprietary new technology to develop an inactivated vaccine formulation that can be used to immunize vulnerable populations such as infants and elderly, in addition to other healthy populations. Our preliminary studies demonstrate that this vaccine approach is feasible and highly immunogenic. In this project, we will evaluate candidate vaccine formulations, perform scale-up development, and test in vivo efficacy against lethal YFV infection. PUBLIC HEALTH RELEVANCE: In this feasibility Phase I proposal, we provide strong preliminary data demonstrating the antigenicity, immunogenicity, and protective efficacy of a proprietary new vaccine platform that can be used to develop a safer and more effective YFV vaccine.

描述（由申请人提供）：黄热病病毒（YFV）在美国一次流行，代表了一种新兴/重新出现的人类病原体，导致高达20％的死亡率。尽管YFV通常是通过埃及埃及蚊子的叮咬散布的，但它也代表了一种病毒性脑膜化，可能用作生物恐怖剂，因为1）YFV的临床分离株可用和/或在自然暴发期间很容易获得，2）YFV在用相对简单的设备的体外增长到高滴度，而3）YFV在通过气溶胶途径给药时会导致致命性脑炎。当前的现场衰减YFV疫苗是在1936年开发的，随着病毒种子批次系统的发展，在50多年来未对其进行修改或以其他方式进行改进。该疫苗会导致4例服用每百万剂量的脑炎。 YFV疫苗接种后的总死亡率估计为每百万剂量1至2次死亡，表明该疫苗与活天花疫苗Dryvax一样危险。自1960年代以来，由于发现了该年龄段的疫苗相关性脑炎的高率，因此<9个月大的婴儿的YFV疫苗接种已被禁忌。最近，已经发现YFV疫苗接种会导致大量> 60岁的患者（发病率约为1：50,000剂量）引起严重的内脏疾病，这些病例大约导致死亡率约50％。这表明，YFV疫苗不仅是禁忌的，而且由于严重和威胁生命的疾病的风险增加，在老年人中也可能很快被禁忌。监测工作的增加还记录了几例与疫苗相关的死亡案件，否则健康的成年人却没有已知的免疫缺陷。迄今为止，没有其他替代YFV疫苗接种的选择。在此提案中，我们将使用专有的新技术来开发一种灭活的疫苗配方，除其他健康人群外，还可以用于免疫弱势群体（例如婴儿和老年人）。我们的初步研究表明，这种疫苗方法是可行的且高度免疫原性的。在该项目中，我们将评估候选疫苗配方，进行扩大开发并测试针对致命YFV感染的体内功效。公共卫生相关性：在此可行性阶段提案中，我们提供了强大的初步数据，证明了专有的新疫苗平台的抗原性，免疫原性和保护性疗效，可用于开发更安全，更有效的YFV疫苗。