Biostatistics Research Branch, National Institute of Allergy and Infectious Diseases, Bethesda MD.
Biostatistics. 2022 Apr 13;23(2):507-521. doi: 10.1093/biostatistics/kxaa037.
Determining the effect of vaccine-induced immune response on disease risk is an important goal of vaccinology. Typically, immune correlates analyses are conducted prospectively with immune response measured shortly after vaccination and subsequent disease status regressed on immune response. In outbreaks and rare disease settings, collecting samples from all vaccinees is not feasible. The test negative design is a retrospective design used to measure vaccine efficacy where symptomatic individuals who present at a clinic are assessed for relevant disease (cases) or some other disease (controls) and vaccination status ascertained. This article proposes that test negative vaccinees have immune response to vaccine assessed both for relevant (e.g., Ebola) and irrelevant (e.g., vector) proteins. If the latter immune response is unaffected by active (Ebola) infection, and is correlated with the relevant immune response, it can serve as a proxy for the immune response of interest proximal to infection. We show that logistic regression using imputed immune response as the covariate and case disease as outcome can estimate the prospective immune response slope and detail the assumptions needed for unbiased inference. The method is evaluated by simulation under various scenarios including constant and decaying immune response. A simulated dataset motivated by ring vaccination for an ongoing Ebola outbreak is analyzed.
确定疫苗诱导的免疫反应对疾病风险的影响是疫苗学的一个重要目标。通常，免疫相关性分析是前瞻性进行的，在接种疫苗后不久测量免疫反应，并将随后的疾病状态回归到免疫反应上。在暴发和罕见病情况下，从所有疫苗接种者中收集样本是不可行的。阴性测试设计是一种回顾性设计，用于测量疫苗效力，其中在诊所就诊的有症状个体被评估相关疾病（病例）或其他疾病（对照），并确定疫苗接种状态。本文提出，阴性测试疫苗接种者对疫苗有免疫反应，既针对相关（例如埃博拉）蛋白，也针对不相关（例如载体）蛋白。如果后者的免疫反应不受（埃博拉）活性感染的影响，并且与相关免疫反应相关，则可以作为感染附近感兴趣的免疫反应的替代物。我们表明，使用推断的免疫反应作为协变量，并用病例疾病作为结果的逻辑回归可以估计前瞻性免疫反应斜率，并详细说明无偏推断所需的假设。该方法在各种情况下（包括恒定和衰减的免疫反应）进行了模拟评估。分析了一个受正在进行的埃博拉暴发影响的基于环疫苗接种的模拟数据集。
