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体知之甚少，尽管如此， 出现新冠肺炎（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/1,000人年，这意味着疫苗失败在一个 人口水平。辉瑞、Moderna和Janssen的疫苗有效性试验涉及35，000至50，000人 其中没有足够的数量来研究疫苗失败，需要进行疫苗接种后监测， 在现实世界中进行的观察性队列研究。使用VHA企业数据仓库（CDW）和 新冠病毒共享数据资源，我们可以利用实时数据设计一个前瞻性的，积极的 监测系统，以务实地研究疫苗失效的流行病学。我们的首要目标是， 拟议的VAccine失败研究是为了表征疫苗接种后Covid-19的临床结果， 确定与疫苗失败相关的因素。我们的中心假设是，不利的COVID-19临床 随着时间的推移，疫苗接种后的结果将越来越常见， 与免疫反应弱或迅速下降相关的因素，以及病毒谱系积累逃逸 突变。我们建议确定一个全国纵向队列的所有退伍军人年龄>65岁谁有一个 过去2年内在VA接受过初级保健访视，并接受过至少1剂SARS-CoV-2疫苗 （N> 155万退伍军人）。我们将观察这些退伍军人长达3.5年，并确定诊断 COVID-19发病率或疫苗失败（急性SARS-CoV-2感染+至少1种症状），住院治疗，以及 mortality.我们将利用我们丰富的经验进行VA观察性队列研究， 医疗保险数据，以模仿目标试验的方法，并实现以下目标，植根于流行病学 三要素：目标1。按照疫苗类型和制造商描述和比较2019冠状病毒病临床结局， 以人群为基础的SARS-CoV-2疫苗接种退伍军人国家队列。目标2.以确定环境 与疫苗失败有关的因素。目标3：确定与疫苗失效相关的宿主因素。目的 4.确定与疫苗失败相关的因子。为了实现目标4，我们将使用病例对照 研究600名退伍军人与Covid-19，以确定与病毒变异的结果和执行密度的情况 从我们的SFVAHCS/VISN-21集水区取样对照，在那里我们可以获得库存残留物 SARS-CoV-2 PCR阳性样本。该项目具有独特的定位，可提供国家VA疫苗 利用实时证据进行规划，以快速调整其退伍军人疫苗供应（例如，疫苗助推器， 风险群体;下一代疫苗的时机），同时满足国家对疫苗接种后的迫切需求。 现实世界中的监视

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.