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Genetic imprints of therapeutic Ad26/MVA mosaic vaccine in rebound HIV-1 genome from acutely treated individuals

治疗性 Ad26/MVA 嵌合疫苗在急性治疗个体反弹的 HIV-1 基因组中的遗传印记

基本信息

批准号：
10175390
负责人：
Hongshuo Song
金额：
$ 20.96万
依托单位：
UNIVERSITY OF MARYLAND BALTIMORE
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-07-08 至 2022-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10175390
关键词：
Acute Adherence Antibody Response Antigens Attention Cells Clinical Development Disease remission Double-Blind Method Drug resistance Epitopes Exhibits Future Genetic Genetic Determinism Genetic study Genome Genomic Imprinting Goals HIV HIV Genome HIV Infections HIV vaccine HIV-1 Human Immune Immune response Individual Infection Interruption Knowledge Life Modeling Mosaicism Mutation Nature Outcome Participant Pattern Phase Placebos Population Probability RNA-Directed DNA Polymerase Randomized Regimen Sampling Therapeutic Time Translating Vaccination Vaccine Antigen Vaccine Therapy Vaccines Vial device Viral Viral Genome Viral Load result Virus antiretroviral therapy arm cost fitness immunogenicity improved in vivo nonhuman primate novel sequencing technology placebo controlled study pressure public health priorities response safety study side effect social stigma therapeutic vaccine transmission process vaccine efficacy vaccine trial viral rebound virology virus genetics

项目摘要

Summary Due to the persistent reservoir established soon after HIV-1 transmission, life-long ART is required to maintain viral load suppression in HIV-1 infected individuals. Development of strategies able to induce long-term, ART-free remission is a high public health priority. One important strategy is therapeutic HIV vaccine. Although to date, majority of therapeutic vaccines failed to show clinical benefit, some showed evidence of vaccine efficacy as a delayed time to rebound or decreased viral load set point. This provides the hope to achieve a long-term remission if optimized vaccine strategies can be developed. The proposed study leverages a highly unique opportunity to employ novel sequencing technologies to understand viral evolutionary patterns in response to therapeutic vaccination in a promising Ad26.Mos/MVA.Mos vaccine regimen amongst acutely treated individuals who underwent analytical treatment interruption (ATI) in the RV405 study. This will be the first HIV-1 genetic study in the setting of a randomized, placebo- controlled therapeutic vaccine trial. Preliminary analysis showed successfully elicited immune responses in all RV405 vaccine recipients and a slightly delayed time to viral load rebound in the vaccine arm. Our central hypothesis is that the immune responses elicited by Ad26/MVA vaccination will exert selection pressures on the replicating viruses during rebound, which will leave “genetic imprints” in the rebound viral genomes. Both the genetic background of the T/F virus and its evolutionary trajectory in response to vaccine-induced immune pressures will correlate with the vaccine outcomes. We propose the following specific aims: Aim 1: To compare the genetic compositions of pre-ART and rebound viral populations and to identify vaccine-related genetic imprints in rebound viral genomes. Aim 2: To identify viral genetic correlates of the vaccine outcomes in both the T/F and rebound viral genomes. Our long-term goal is to translate knowledge of HIV vulnerabilities into optimizing future vaccine strategies towards the goal of HIV remission and eradication.

总结由于HIV-1传播后不久就建立了持久的储存库，是维持HIV-1感染者病毒载量抑制所必需的。发展因此，制定能够诱导长期、无抗逆转录病毒疗法缓解的战略是一项高度优先的公共卫生工作。一个重要的战略是治疗性艾滋病毒疫苗。尽管到目前为止，大多数治疗性疫苗未能显示临床益处，一些疫苗显示出疫苗的证据有效性作为延迟的反弹时间或降低的病毒载量设定点。这提供了以下如果能够开发出优化的疫苗策略，希望能够实现长期缓解。这项拟议的研究利用了一个非常独特的机会，技术来了解病毒的进化模式，在有希望的Ad26.Mos/MVA.Mos疫苗方案中，在RV 405中接受分析性治疗中断（ATI）的治疗个体 study.这将是第一个在随机、安慰剂背景下进行的HIV-1遗传研究，对照治疗性疫苗试验初步分析显示成功地引出了所有RV 405疫苗接种者的免疫应答和病毒感染时间的略微延迟我们的中心假设是，由Ad 26/MVA疫苗接种引起的免疫应答将对复制病毒施加选择压力在反弹期间，这将在反弹病毒基因组中留下“遗传印记”。两 T/F病毒的遗传背景及其响应于疫苗诱导的免疫压力将与疫苗结果相关。我们提出以下具体目标：目的1：比较ART前和反弹病毒群体的遗传组成并鉴定反弹病毒基因组中与疫苗相关的遗传印记。目的2：确定T/F和T/F中疫苗结果的病毒遗传相关性，病毒基因组反弹我们的长期目标是将艾滋病毒脆弱性的知识转化为优化未来疫苗战略，以实现缓解和根除艾滋病毒的目标。