Review 1: "Causal Evidence that Herpes Zoster Vaccination Prevents a Proportion of Dementia Cases"

Michael Anderson

doi:doi:10.1162/2e3983f5.5075b345

Causal evidence that herpes zoster vaccination prevents a proportion of dementia cases

by Markus Eyting, Min Xie, Simon Heß, Simon Heß, and Pascal Geldsetzer

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Published on May 25, 2023
www.medrxiv.org

Description

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:

Reliable. The main study claims are generally justified by its methods and data. The results and conclusions are likely to be similar to the hypothetical ideal study. There are some minor caveats or limitations, but they would/do not change the major claims of the study. The study provides sufficient strength of evidence on its own that its main claims should be considered actionable, with some room for future revision.

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Review:

This manuscript estimates the effects of a herpes zoster (i.e. shingles) vaccination, Zostavax, on future dementia diagnoses. To measure these effects it exploits a natural experiment in which Zostavax was offered to individuals in Wales born on or after September 2, 1933. This eligibility criteria allows estimation of a regression discontinuity design (RDD) with week of birth as the running variable; effectively, the RDD compares individuals born in the months after September 2, 1933 — the RDD “threshold” — with those born in the months before September 2, 1933. Since these two groups of individuals are plausibly similar in all ways except exposure to Zostavax, it approximates a randomized encouragement design. The manuscript finds that being born after September 1, 1933 is associated with a nearly 50 percentage point increase in Zostavax receipt, a 1 percentage point (20 percent) decrease in shingles incidence, and a 1.3 percentage point (8 percent) decrease in dementia diagnoses over a seven-year followup period.

The strengths of the study are its RDD research design and its large-scale dataset. Due to their transparency, within economics RDDs are often considered to be the most credible research design after randomized controlled trials. A downside to RDDs is that they generally require prodigious amounts of data. Since the analysis focuses on the data near the RDD threshold (at least if correctly executed), most observations contribute little or nothing to the estimates. Furthermore, most RDDs, including this one, are “fuzzy” in nature (i.e. the treatment probability changes by less than 100 percentage points at the threshold), which further reduces statistical power. Fortunately the study has rich data on approximately 280,000 adults, of whom approximately 30,000 were born within one year of the relevant cutoff date.

The manuscript convincingly establishes a “first stage” effect of eligibility on vaccination and reproduces the clinical trial effects of Zostavax on shingles using the RDD. The plotted age profile of dementia diagnosis rates shows visible evidence of a break at the relevant threshold (September 1933 birthdate). The results also pass the standard RDD robustness and falsification tests: bandwidth sensitivity; functional form choices; continuity of covariates at the threshold; and continuity of density at the threshold. Overall the manuscript makes a compelling case that Zostavax reduces dementia diagnoses.

The results are provocative and, if correct, have profound implications for public health. While previous observational studies have suggested linkages between herpesviruses and Alzheimer’s Disease, this is, to my knowledge, the first robust quasi-experimental evidence on this subject. My main concern is that the statistical significance of the main result (p = 0.022) is not as strong as one might like to see for a novel result. Consider the result from a Bayesian perspective. For a (one-sided) test using the standard normal distribution, the observed β̂ corresponding to p = 0.022 is approximately 7.6 times more likely under the alternate hypothesis that β = β̂ than it is under the null. If the null and alternate are believed equally likely ex ante, this suggests an 88% chance that the alternate is correct. But if, for example, we believe the null is seven times more likely than the alternate ex ante — as we might for a novel result — then the chance that the alternate is correct drops to approximately 50%. The sharp visual result for females, accompanied by a p-value of 0.001, provides reassurance, but ideally the result will replicate in a different context as well.

Other limitations are more modest and could be easily addressed. There is little discussion of the vaccination record data, and the authors do not mention whether individuals may receive Zostavax through channels that do not appear in their health records (fortunately this would not affect the ITT estimates). My personal preference is to omit the regression lines in the RDD figures, so that readers may judge the evidence from the bin scatterplots themselves. Finally, most of the health service utilization controls utilized in a robustness check are potentially endogenous and would better appear as outcomes in supplementary RDD analyses.

In conclusion, this study presents convincing evidence that Zostavax has effectiveness against dementia. Given that the net benefits of herpes zoster vaccines are generally believed to be positive, the result is certainly strong enough to support additional encouragement of herpes zoster vaccine take-up. Furthermore, its provocative nature should encourage additional research into the linkages between herpesviruses and dementia.

Review 1: "Causal Evidence that Herpes Zoster Vaccination Prevents a Proportion of Dementia Cases"

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