Causal evidence that herpes zoster vaccination prevents a proportion of dementia cases.
Causal evidence that herpes zoster vaccination prevents a proportion of dementia cases.
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因果证据表明带状疱疹疫苗接种可预防部分痴呆病例。
DOI：
10.1101/2023.05.23.23290253
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发表时间：
2023
期刊：
影响因子：
--
通讯作者：
Geldsetzer,Pascal
中科院分区：
文献类型：
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作者：
Eyting,Markus;Xie,Min;Heß,Simon;Geldsetzer,Pascal
痴呆症的根本原因在很大程度上仍然不清楚，医学界缺乏高度有效的预防和治疗痴呆症的药物，尽管对它们的开发进行了大量投资。越来越多的人对感染因子是否在痴呆症的发展中发挥作用的问题感兴趣，其中疱疹病毒引起了特别的关注。为了提供因果关系，而不仅仅是相关的证据，我们利用了这样一个事实，即在威尔士，带状疱疹疫苗（Zostavax）预防带状疱疹的资格是根据个人的确切出生日期确定的。1933年9月2日之前出生的人不符合条件，并且终身不符合条件，而1933年9月2日或之后出生的人有资格接种疫苗。通过使用全国范围内所有接种疫苗的数据，初级和二级保健接触，死亡证明以及患者的出生日期（以周为单位），我们首先表明，接受疫苗的成年人比例从仅一周大的患者中的0.01%增加到47.2%。除了接种带状疱疹疫苗的概率有很大的差异之外，没有合理的理由说明为什么1933年9月2日之前一周出生的人和之后一周出生的人会有系统性的差异。我们通过显示没有系统性差异（例如，在已有的条件或其他预防性干预措施的吸收）之间的成年人之间的出生日期的资格截止，并没有其他干预措施，使用完全相同的出生日期的资格截止作为带状疱疹疫苗计划。这种独特的自然随机化，因此，允许强大的因果关系，而不是相关性，效果估计。我们首先从临床试验中复制了疫苗已知的减少带状疱疹发生的效果。然后，我们表明，在7年的随访期内，接种带状疱疹疫苗使新痴呆症诊断的概率降低了3.5个百分点（95% CI：0.6 - 7.1，p=0.019），相当于痴呆症发生率相对降低了19.9%。除了预防带状疱疹和痴呆症，带状疱疹疫苗对任何其他常见的发病和死亡原因没有影响。在探索性分析中，我们发现痴呆症疫苗的保护作用在女性中远远强于男性。需要随机试验来确定带状疱疹疫苗预防或延迟痴呆的最佳人群和时间间隔，以及当使用更精确的认知测量时量化因果效应的大小。我们的研究结果强烈表明水痘带状疱疹病毒在痴呆的病因学中的重要作用。
The root causes of dementia are still largely unclear, and the medical community lacks highly effective preventive and therapeutic pharmaceutical agents for dementia despite large investments into their development. There is growing interest in the question if infectious agents play a role in the development of dementia, with herpesviruses attracting particular attention. To provide causal as opposed to merely correlational evidence on this question, we take advantage of the fact that in Wales eligibility for the herpes zoster vaccine (Zostavax) for shingles prevention was determined based on an individual’s exact date of birth. Those born before September 2 1933 were ineligible and remained ineligible for life, while those born on or after September 2 1933 were eligible to receive the vaccine. By using country-wide data on all vaccinations received, primary and secondary care encounters, death certificates, and patients’ date of birth in weeks, we first show that the percentage of adults who received the vaccine increased from 0.01% among patients who were merely one week too old to be eligible, to 47.2% among those who were just one week younger. Apart from this large difference in the probability of ever receiving the herpes zoster vaccine, there is no plausible reason why those born just one week prior to September 2 1933 should differ systematically from those born one week later. We demonstrate this empirically by showing that there were no systematic differences (e.g., in pre-existing conditions or uptake of other preventive interventions) between adults across the date-of-birth eligibility cutoff, and that there were no other interventions that used the exact same date-of-birth eligibility cutoff as was used for the herpes zoster vaccine program. This unique natural randomization, thus, allows for robust causal, rather than correlational, effect estimation. We first replicate the vaccine’s known effect from clinical trials of reducing the occurrence of shingles. We then show that receiving the herpes zoster vaccine reduced the probability of a new dementia diagnosis over a follow-up period of seven years by 3.5 percentage points (95% CI: 0.6 – 7.1, p=0.019), corresponding to a 19.9% relative reduction in the occurrence of dementia. Besides preventing shingles and dementia, the herpes zoster vaccine had no effects on any other common causes of morbidity and mortality. In exploratory analyses, we find that the protective effects from the vaccine for dementia are far stronger among women than men. Randomized trials are needed to determine the optimal population groups and time interval for administration of the herpes zoster vaccine to prevent or delay dementia, as well as to quantify the magnitude of the causal effect when more precise measures of cognition are used. Our findings strongly suggest an important role of the varicella zoster virus in the etiology of dementia.