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

Abstract

Neurotropic herpesviruses may be implicated in the development of dementia^1-5. Moreover, vaccines may have important off-target immunological effects^6-9. 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 1 week 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 1 week 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 7 years 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.

Fig. 1. A large jump in zoster vaccine receipt at the date-of-birth eligibility threshold.

a–f, The date-of-birth eligibility cut-off led to a large discontinuity in zoster vaccine receipt (a), but there is baseline exchangeability across the cut-off for uptake of other preventive interventions (flu vaccine (d), pneumococcal polysaccharide vaccine (PPV) (e) and statin medications (f)) as well as past shingles (b) and dementia (c) diagnoses. The data source for this analysis was the SAIL database for Wales. All analyses were run on the same sample as those for the effect of the zoster vaccine on dementia occurrence. The exception is c, for which we did not exclude individuals with a diagnosis of dementia before the start of the zoster vaccine program. The grey dots show the mean value for each 10-week increment in week of birth. The grey shading of the dots is proportionate to the weight that observations from this 10-week increment received in the analysis.

Fig. 2. The effect of the zoster vaccine on shingles diagnoses.

a–c, Effect estimates of being eligible for (a), and having received (across different follow-up periods (b) and across different grace periods (c)), the zoster vaccine on the probability of having at least one shingles diagnosis during the follow-up period. For a, the MSE-optimal bandwidth is 145.7 weeks (95,227 adults). The grey dots show the mean value for each 10-week increment in week of birth. The grey shading of the dots is proportionate to the weight that observations from this 10-week increment received in the analysis. For b and c, the MSE-optimal bandwidth for our primary specification is 116.9 weeks (76,316 adults). The triangles (rather than points) depict our primary specification. The red (as opposed to white) fillings denote statistical significance (P < 0.05). Grace periods refer to time periods since the index date after which the follow-up time is considered to begin. The grey vertical bars show the 95% CIs around the point estimate of the regression coefficient (two-sided t tests).

Fig. 3. The effect of the zoster vaccine on new diagnoses of dementia.

a–c, Effect estimates of being eligible for (a), and having received (across different follow-up periods (b) and across different grace periods (c)), the zoster vaccine on new diagnoses of dementia. For a, the MSE-optimal bandwidth is 134.4 weeks (83,167 adults). The grey dots show the mean value for each 10-week increment in week of birth. The grey shading of the dots is proportionate to the weight that observations from this 10-week increment received in the analysis. For b and c, the MSE-optimal bandwidth for our primary specification is 90.6 weeks (56,098 adults). The triangles (rather than points) depict our primary specification. The red (as opposed to white) fillings denote statistical significance (P < 0.05). Grace periods refer to time periods since the index date after which the follow-up time is considered to begin. The grey vertical bars show the 95% CIs around the point estimate of the regression coefficient (two-sided t tests).

Fig. 4. Comparison of effect estimates between the DID-IV and regression discontinuity approach.

Comparison of absolute effect estimates of having received the zoster vaccine on new diagnoses of dementia, shingles and postherpetic neuralgia between the DID-IV and the regression discontinuity analyses. The data source for this analysis was the SAIL database for Wales. The sample size for the dementia outcome is 96,767 adults and the sample for the shingles and postherpetic neuralgia outcomes is 105,258 adults. P values were calculated using two-sided t-tests. The P value for the DID-IV effect on shingles is 0.001. The error bars depict the 95% CIs around the point estimate of the regression coefficient (two-sided t-tests).

Fig. 5. The effect of the zoster vaccine on new diagnoses of dementia, separately for women and men.

a–f, Effect estimates of being eligible for (a (women) and d (men)) and having received (b and c (women) and e and f (men); across different follow-up periods (b and e) and across different grace periods (c and f)) the zoster vaccine on new diagnoses of dementia, separately for women and men. The data source for this analysis was the SAIL database for Wales. The triangles (rather than points) depict our primary specification. Red (as opposed to white) fillings denote statistical significance (P < 0.05). Grace periods refer to time periods since the index date after which the follow-up time is considered to begin. The grey vertical bars depict the 95% CIs around the point estimate of the regression coefficient (two-sided t-test). The grey dots show the mean value for each 10-week increment in week of birth. For a, among women, the MSE-optimal bandwidth is 95.5 weeks (32,601 women). For b and c, among women, the MSE-optimal bandwidth for our primary specification is 149.1 weeks (50,816 women). For d, among men, the MSE-optimal bandwidth for our primary specification is 121.3 weeks (33,725 men). For e and f, among men, the MSE-optimal bandwidth for our primary specification is 91.8 weeks (25,563 men). The grey shading of the dots is proportionate to the weight that observations from this 10-week increment received in the analysis.