带状疱疹疫苗对痴呆的影响的自然实验

美国斯坦福大学Pascal Geldsetzer小组取得一项新突破。他们开发出带状疱疹疫苗对痴呆的影响的自然实验。这一研究成果发表在2025年4月2日出版的国际学术期刊《自然》上。

在这里，课题组人员的目的是确定减毒带状疱疹疫苗接种对痴呆诊断发生的影响。为了提供与相关证据相反的因果证据，小组利用了这样一个事实，即在威尔士，带状疱疹疫苗的资格是根据个人的确切出生日期确定的。在1933年9月2日之前出生的人没有资格并且终身没有资格，而在1933年9月2日或之后出生的人至少有资格在1年内接种疫苗。使用大规模的电子健康记录数据，研究人员首先表明，接种疫苗的成年人百分比从仅仅1周大而不符合资格的患者中的0.01%增加到1周大的患者中的47.2%。

除了在接种带状疱疹疫苗的可能性上存在巨大差异之外，在1933年9月2日之前1周出生的人与在1933年9月2日之前1周出生的人在系统上不太可能存在差异。在回归不连续设计中使用这些对照组，该研究团队发现接受带状疱疹疫苗降低了在随访期间7每年减少3.5个百分点(95%置信区间(CI) = 0.6-7.1, P = 0.019)，相对减少20.0% (95% CI = 6.5-33.4)。这种保护作用在女性中比在男性中更强。该团队成功地在不同的人群(英格兰和威尔士的联合人口)中证实了他们的发现，使用不同类型的数据(死亡证明)和主题结果(以痴呆症为主要死因的死亡)与痴呆症密切相关，但较少依赖于医疗保健系统对痴呆症的及时诊断。通过一个独特的自然实验主题，本研究提供了带状疱疹疫苗预防或延缓痴呆效果的证据，与现有的相关证据相比，该证据更不容易受到混淆和偏见的影响。

据悉，嗜神经疱疹病毒主题可能与痴呆的发展有关。此外，疫苗可能具有重要的脱靶免疫效应。

附：英文原文

Title: A natural experiment on the effect of herpes zoster vaccination on dementia

Author: Eyting, Markus, Xie, Min, Michalik, Felix, He, Simon, Chung, Seunghun, Geldsetzer, Pascal

Issue&Volume: 2025-04-02

Abstract: Neurotropic herpesviruses may be implicated in the development of dementia1,2,3,4,5. Moreover, vaccines may have important off-target immunological effects6,7,8,9. Here we aim to determine the effect of live-attenuated herpes zoster vaccination on the occurrence of dementia diagnoses. To provide causal as opposed to correlational evidence, we take advantage of the fact that, in Wales, eligibility for the zoster vaccine was determined on the basis of an individual’s exact date of birth. Those born before 2 September 1933 were ineligible and remained ineligible for life, whereas those born on or after 2 September 1933 were eligible for at least 1 year to receive the vaccine. Using large-scale electronic health record data, we first show that the percentage of adults who received the vaccine increased from 0.01% among patients who were merely 1 week too old to be eligible, to 47.2% among those who were just 1week younger. Apart from this large difference in the probability of ever receiving the zoster vaccine, individuals born just 1 week before 2 September 1933 are unlikely to differ systematically from those born 1week later. Using these comparison groups in a regression discontinuity design, we show that receiving the zoster vaccine reduced the probability of a new dementia diagnosis over a follow-up period of 7years by 3.5 percentage points (95% confidence interval (CI)=0.6–7.1, P=0.019), corresponding to a 20.0% (95% CI=6.5–33.4) relative reduction. This protective effect was stronger among women than men. We successfully confirm our findings in a different population (England and Wales’s combined population), with a different type of data (death certificates) and using an outcome (deaths with dementia as primary cause) that is closely related to dementia, but less reliant on a timely diagnosis of dementia by the healthcare system10. Through the use of a unique natural experiment, this study provides evidence of a dementia-preventing or dementia-delaying effect from zoster vaccination that is less vulnerable to confounding and bias than the existing associational evidence.

DOI: 10.1038/s41586-025-08800-x