Hematological and clinical chemistry measurements are an integral part of vaccine safety monitoring. While adopting a conservative approach is important to exclude potential risks for patients, the rationale and methodology underlying the assessment of given adverse events have to be well grounded to avoid raising unfounded concerns. Using asymptomatic transient neutropenia as an example, this paper aims to address the complexity of interpreting abnormal hematological values in vaccine clinical trials and to evaluate the validity of using neutrophil count cut-off points to assess neutropenia in the context of safety monitoring. The validity of the neutrophil count cut-off point methodology was assessed in terms of content validity (i.e., the extent to which a single neutrophil count below the cut-off point corresponds to a clinically significant adverse event), criterion validity (i.e., the extent to which a neutrophil count below a given cut-off point correlates with another manifestation of neutropenia, namely bacteremia), and construct validity (i.e., the exactness of the assumption that a neutrophil count below a given cut-off point corresponds to a reactogenic event caused by the vaccination). We argue that, because of within-individual physiological fluctuations, variations according to population demographics, and poor predictive potential with regard to neutropenia-associated infection, the application of the cut-off point methodology to neutropenia safety monitoring presents major limitations. Based on this assessment, we conclude that hematological laboratory values must be evaluated on a case-by-case basis by investigators to determine their clinical significance.

血液学和临床化学测量是疫苗安全监测的一个组成部分。虽然采取保守的方法对于排除患者的潜在风险很重要，但评估特定不良事件的基本原理和方法必须有充分的基础，以避免引起毫无根据的担忧。本文以无症状短暂性中性粒细胞减少症为例，旨在解决在疫苗临床试验中解释异常血液学值的复杂性，并评估在安全监测背景下使用中性粒细胞计数截止点评估中性粒细胞减少症的有效性。中性粒细胞计数截止点方法的有效性根据内容有效性（即，低于临界点的单个中性粒细胞计数对应于临床显着不良事件的程度），标准有效性（即低于给定临界点的中性粒细胞计数与中性粒细胞减少症的另一种表现相关的程度，即菌血症）和结构有效性（即假设中性粒细胞计数低于给定截止点对应于疫苗接种引起的反应原事件的准确性）。我们认为，由于个体内部的生理波动、人口统计数据的变化以及对中性粒细胞减少症相关感染的预测潜力较差，将截止点方法应用于中性粒细胞减少症安全监测存在重大限制。基于这个评估，