VAccine failure: natural history and determinants of post-vaccination Covid-19

随着SARS-CoV-2疫苗进入大规模分发，人们对接种疫苗的个人知之甚少 患上新冠肺炎(有症状的疾病或“疫苗失效”)，需要住院治疗，然后死亡。辉瑞-BioNtech 报告了3.8例疫苗失败病例/1000人年，这意味着疫苗失败将在 人口水平。辉瑞、莫德纳和扬森的疫苗效力试验涉及35,000至50,000人 从那里没有足够的数字来研究疫苗失败，呼吁对疫苗接种后的监测 真实世界环境中的观察性队列研究。使用VHA公司数据仓库(CDW)和 新冠肺炎共享数据资源，我们可以利用实时数据进行设计，具有前瞻性、主动性 监测系统，务实地研究疫苗失败的流行病学。我们的首要目标是 拟议的疫苗失败研究是为了表征接种新冠肺炎后的临床结果和 确定与疫苗失败相关的因素。我们的中心假设是不利的新冠肺炎临床 随着时间的推移，疫苗接种后的结果将越来越常见，原因是延迟接种，临床 与免疫反应弱或迅速下降相关的因素，以及累积逃逸的病毒谱系 突变。我们建议确定一个全国性的纵向队列，所有65岁的退伍军人都有 在过去两年内到退伍军人事务部进行初级保健访问，并至少接种一剂SARS-CoV-2疫苗 (N&GT；155万退伍军人)。我们将对这些退伍军人进行长达3.5年的观察，并确定诊断 新冠肺炎发病率或疫苗失效(急性SARS-CoV-2感染至少1个症状)、住院治疗和 死亡率。我们将利用我们丰富的经验与退伍军人事务部和 医疗保险数据效仿靶向试验方法，实现以下目标，根植于流行病学 TIAD：目标1.描述和比较不同疫苗类型和制造商的新冠肺炎临床结果 以人群为基础的全国退伍军人SARS-CoV-2疫苗接种队列。目标2.确定环境 与疫苗失败相关的因素。目的3.确定与疫苗失败相关的宿主因素。目标 4.确定与疫苗失败相关的致病因素。为了实现目标4，我们将使用病例对照 退伍军人新冠肺炎与病毒变异结局及密度关系的研究 对我们SFVAHCS/VISN-21集水区的控制进行抽样，我们可以在那里获得储存的残留物 SARS冠状病毒2型聚合酶链式反应阳性标本。该项目的独特定位是提供国家VA疫苗 具有实时证据的计划，以快速调整其针对退伍军人的疫苗交付(例如，针对At的疫苗助推器) 风险群体；下一代疫苗的时间安排)，同时满足国家对疫苗接种后的迫切需求 现实世界环境中的监控。

As SARS-CoV-2 vaccines enter mass distribution, little is known about vaccinated individuals who nonetheless develop Covid-19 (symptomatic disease or “vaccine failure”), require hospitalization, and die. Pfizer-BioNTech reported 3.8 vaccine failure cases/1,000 person-years, meaning vaccine failure will be relatively common on a population level. Pfizer, Moderna, and Janssen vaccine efficacy trials involved 35,000 to 50,000 individuals from which there are insufficient numbers to study vaccine failure, calling for post-vaccination surveillance with observational cohort studies in real-world settings. Using the VHA Corporate Data Warehouse (CDW) and the Covid-19 Shared Data Resource, we can harness real-time data to design a forward-thinking, active surveillance system to pragmatically study the epidemiology of vaccine failure. Our overarching goals in the proposed VAccine Failure study are to characterize post-vaccination Covid-19 clinical outcomes and identify factors associated with vaccine failure. Our central hypothesis is that adverse Covid-19 clinical outcomes after vaccination will be increasingly common over time, driven by delayed vaccination, clinical factors associated with weak or rapidly declining immune responses, and viral lineages accumulating escape mutations. We propose to identify a national longitudinal cohort of all Veterans age >65 years who had a primary care visit in the VA within the past 2 years and received at least 1 dose of any SARS-CoV-2 vaccine (N>1.55 million Veterans). We will observe these Veterans for up to 3.5 years and ascertain diagnoses of Covid-19 incidence or vaccine failure (acute SARS-CoV-2 infection + at least 1 symptom), hospitalization, and mortality. We will leverage our extensive experience conducting observational cohort studies with VA and Medicare data to emulate a target trial approach and achieve the following Aims, rooted in the epidemiological triad: Aim 1. To describe and compare Covid-19 clinical outcomes by vaccine type and manufacturer in a population-based national cohort of SARS-CoV-2 vaccinated Veterans. Aim 2. To determine environmental factors associated with vaccine failure. Aim 3. To determine host factors associated with vaccine failure. Aim 4. To determine agent factors associated with vaccine failure. To achieve Aim 4, we will use a case-control study of 600 Veterans with Covid-19 to identify cases with the outcome of viral variant and perform density sampling of controls from our SFVAHCS/VISN-21 catchment area, where we have access to banked remnant SARS-CoV-2 PCR-positive samples. This project is uniquely positioned to provide the National VA Vaccine Program with real-time evidence to rapidly adapt its vaccine delivery for Veterans (e.g., vaccine boosters for at- risk groups; timing of next-generation vaccines) while filling the urgent national need for post-vaccination surveillance in real-world settings.