Live attenuated vaccines could have beneficial, non-specific effects of protecting against vaccine-unrelated infections, such as BCG protecting against respiratory infection. During the COVID-19 pandemic, testing of these effects against COVID-19 was of interest to the pandemic control programme. Non-specific effects occur due to the broad effects of specific live attenuated vaccines on the host immune system, relying on heterologous lymphocyte responses and induction of trained immunity. Knowledge of non-specific effects has been developed in randomised controlled trials and observational studies with children, but examining of whether the same principles apply to adults and older adults was of interest to researchers during the pandemic. In this Personal View, we aim to define a framework for the analysis of non-specific effects of live attenuated vaccines against vaccine-unrelated infections with pandemic potential using several important concepts. First, study endpoints should prioritise severity of infection and overall patient health rather than incidence of infection only (eg, although several trials found no protection of the BCG vaccine against COVID-19 infection, it is associated with lower overall mortality than placebo). Second, revaccination of an individual with the same live attenuated vaccine could be the most effective strategy against vaccine-unrelated infections. Third, coadministration of several live attenuated vaccines might enhance beneficial non-specific effects. Fourth, the sequence of vaccine administration matters; the live attenuated vaccine should be the last vaccine administered before exposure to the pandemic infection and non-live vaccines should not be administered afterwards. Fifth, live attenuated vaccines could modify the immune response to specific COVID-19 vaccines. Finally, non-specific effects of live attenuated vaccines should always be analysed with subgroup analysis by sex of individuals receiving the vaccines.

减毒活疫苗可能具有预防与疫苗无关的感染的有益的非特异性作用，例如 BCG 预防呼吸道感染。在 COVID-19 大流行期间，大流行控制计划对这些针对 COVID-19 的影响进行了测试。非特异性作用的发生是由于特异性减毒活疫苗对宿主免疫系统的广泛影响，依赖于异源淋巴细胞反应和训练免疫的诱导。在针对儿童的随机对照试验和观察性研究中，已经开发了关于非特异性效应的知识，但在大流行期间，研究人员对研究相同的原则是否适用于成人和老年人感兴趣。在这个个人观点中，我们的目标是使用几个重要概念定义一个框架，用于分析减毒活疫苗对具有大流行潜力的疫苗无关感染的非特异性影响。首先，研究终点应优先考虑感染的严重程度和患者的总体健康状况，而不仅仅是感染的发生率（例如，尽管多项试验发现 BCG 疫苗无法预防 COVID-19 感染，但与安慰剂相比总体死亡率较低）。其次，用相同的减毒活疫苗对个体进行再接种可能是对抗疫苗无关感染的最有效策略。第三，几种减毒活疫苗的共同给药可能会增强有益的非特异性作用。四、疫苗管理事项的顺序；减毒活疫苗应该是在接触大流行感染之前最后一次接种的疫苗，之后不应再接种非活疫苗。第五，减毒活疫苗可以改变对特定 COVID-19 疫苗的免疫反应。最后，减毒活疫苗的非特异性影响应始终根据接受疫苗的个体的性别进行亚组分析。