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Review 2: "Causal Evidence that Herpes Zoster Vaccination Prevents a Proportion of Dementia Cases"

Reviewers suggested further discussion of stratified analyses, vaccine record data, and follow-up period, and identified the statistical significance as lower than ideal.

Published onJun 28, 2023
Review 2: "Causal Evidence that Herpes Zoster Vaccination Prevents a Proportion of Dementia Cases"
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Causal evidence that herpes zoster vaccination prevents a proportion of dementia cases
Causal evidence that herpes zoster vaccination prevents a proportion of dementia cases

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 individual9s 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 patients9 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 vaccine9s 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.

RR:C19 Evidence Scale rating by reviewer:

  • Potentially informative. The main claims made are not strongly justified by the methods and data, but may yield some insight. The results and conclusions of the study may resemble those from the hypothetical ideal study, but there is substantial room for doubt. Decision-makers should consider this evidence only with a thorough understanding of its weaknesses, alongside other evidence and theory. Decision-makers should not consider this actionable, unless the weaknesses are clearly understood and there is other theory and evidence to further support it.


This is an elegant and robust design, in my opinion clearly superior to traditional observational studies for the purpose of detecting one difference-maker (Zostavax) among multiple confounding factors. Noticeably, the claim that Zostavax is randomly assigned to the two groups is supported by several robustness checks. For example, using a regression discontinuity approach, it is shown that none of the ten top leading causes of disability and death in Wales displayed a significant incidence jump at the Zostavax eligibility threshold (September 2, 1933). Authors also show that adjusting for variables such as hospital admissions and primary care visits during the follow-up period did not significantly change the effect sizes. Moreover, the receipt of Zostavax did not change the probability of taking up other preventive health measures, such as influenza vaccine or cancer screening. However, there are some elements which suggest that results should be taken with caution or need further enquiry.

The suspicious finding for me is that stratified analyses showed that the statistical difference in the incidence of dementia between eligible and non-eligible groups only applies to women, while there is no statistical difference for men. Although shingles is more common in women and causes of dementia may differ between sexes, this finding seems too puzzling to be given biological credibility without further enquiry. Especially because authors show that the effect size for vaccine uptake was similar between men and women, as well as the stratified effect of vaccine on shingles protection. At a closer look at Figure 2 and 4, it seems to me that the effect size in female dementia is so big that it almost exceeds the total shingles effect size. Is this a statistical artifact? Or does it suggest that the effect on dementia incidence is not due to shingle protection but by some sort of vaccine-mediated immune-modulation? It is anyway too strange to go unscrutinised.

On a similar note, authors justify their research question by quoting animal studies that point to a role of herpes chronic infections in the accumulation of amyloid protein in Alzheimer’s dementia. It seems to me however that this mechanism hardly fits with the observations of this study. As I understand, amyloid accumulation in Alzehimer’s develops over decades, and normally starts before 80 years of age. Is it plausible that protection from shingles a few years after 80 can interfere with this mechanism? It is unclear whether which phenomenon is addressed by the article, since ‘dementia’ is a broad definition that includes several diagnoses. However, as noticed also by the authors, the specific diagnosis found on the health registries lacks detail and demarcation between different types of dementia is not necessarily reliable. Also, the period of follow up (maximum 8 years) might be too short and dementia diagnoses might be delayed rather than decreased (which would still be a remarkable effect if true).

As much as I find the study rigorous, I can therefore not rule out that chance or an unnoticed systematic difference between groups might be affecting the results. For instance, it seems to me that follow-up time was different among individuals, for instance being interrupted by death (not uncommon seen the age of the cohorts). Since the control group included older adults relative to the ‘experimental’ group (date of birth +/- 104 weeks from September 2, 1933), one might think that the follow-up period differed between the two groups. I cannot find in the method an explanation of whether this was controlled for in the analysis. Since mortality rate is higher for women, women might have therefore been followed up significantly longer than males. Might this account for the fact that the effect size on men is invisible in the stratified analysis?

Although I find the experimental design potentially informative, I would nevertheless like to stress that the use of the word ‘causal’ in the title can be misleading. I understand that the authors (rightly) wish to distinguish their study design from other more traditional observational studies, however this study only suggests, without demonstrating, that Zostavax might make a difference for the statistical incidence of dementia. Moreover, I am of the opinion that a causal relationship cannot be established without evidencing the underlying biological pathways, which in this case remain to be explored.

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