The effect of herpes zoster vaccination at different stages of the disease course of dementia: Two quasi-randomized studies

Abstract

The varicella zoster virus, a neurotropic herpesvirus, has been hypothesized to play a role in the pathophysiology of dementia, such as through neuroinflammatory processes or intracerebral vasculopathy. Using unique natural experiments, our group has previously found that live-attenuated herpes zoster (HZ) vaccination reduced the incidence of new diagnoses of dementia in both Wales and Australia. To inform further research and ultimately clinical care, it is crucial to understand at which stage of the disease course of dementia the HZ vaccine has its effect. Representing the two opposing ends of the dementia disease course as it can be ascertained from electronic health record data, the aims of this study were twofold: to determine the effect of HZ vaccination on i) new diagnoses of mild cognitive impairment (MCI) among individuals without any record of cognitive impairment, and ii) deaths due to dementia among individuals living with dementia. Our approach took advantage of the fact that at the time of the start date (September 1 2013) of the HZ vaccination program in Wales, individuals who had their eightieth birthday just after this date were eligible for HZ vaccination for one year whereas those who had their eightieth birthday just before were ineligible and remained ineligible for life. This eligibility rule created comparison groups just on either side of the September 2 1933 date-of-birth eligibility threshold who differed in their age by merely a week but had a large difference in their probability of receiving HZ vaccination. The key strength of our study is that these comparison groups should be similar in their health characteristics and behaviors except for a minute difference in age. We used regression discontinuity analysis to estimate the difference in our outcomes between individuals born just on either side of the date-of-birth eligibility threshold for HZ vaccination. Our dataset consisted of detailed country-wide electronic health record data from primary care in Wales, linked to hospital records and death certificates. We restricted our dataset to individuals born between September 1 1925 and September 1 1942. Among our study cohort of 282,557 without any record of cognitive impairment at baseline, HZ vaccination eligibility and receipt reduced the incidence of a new MCI diagnosis by 1.5 (95% CI: 0.5 - 2.9, p=0.006) and 3.1 (95% CI: 1.0 - 6.2, p=0.007) percentage points over nine years, respectively. Similarly, among our study cohort of 14,350 individuals who were living with dementia at baseline, being eligible for and receiving HZ vaccination reduced deaths due to dementia by 8.5 (95% CI: 0.6 - 18.5, p=0.036) and 29.5 (95% CI: 0.6 - 62.9, p=0.046) percentage points over nine years, respectively. Except for dementia, HZ vaccination did not have an effect on any of the ten most common causes of morbidity and mortality among adults aged 70 years and older in Wales in either of our two study cohorts. The protective effects of HZ vaccination for both MCI and deaths due to dementia were larger among women than men. Our findings suggest that the live-attenuated HZ vaccine has benefits for the dementia disease process at both ends of the disease course of dementia.

Fig. 1.. The abrupt change in the probability of receiving HZ vaccination at the September 2 1933 date-of-birth eligibility threshold.^1,2,3,4

¹ “Baseline” refers to the start date of the HZ vaccination program (i.e., September 1 2013). ² Linear regression lines were drawn in the MSE-optimal bandsdwidth only. ³ Grey dots show the mean value for each 10-week increment in week of birth. ⁴ The grey shading of the dots is in proportion to the weight that observations from this 10-week increment received in the analysis. Abbreviations: HZ = herpes zoster; Coef. = coefficient; CI = confidence interval; Sept = September

Fig. 2.. The effect of HZ vaccination on new diagnoses of MCI and deaths due to dementia.1,2,3

¹ Dots show the point estimate and horizontal bars the 95% confidence interval. ² New diagnoses of MCI were analyzed among a study cohort of patients who did not have any record of cognitive impairment prior to the start date of the HZ vaccination program. ³ Deaths due to dementia were analyzed among a study cohort of patients who had received a diagnosis of dementia prior to the start date of the HZ vaccination program. Abbreviations: MCI = mild cognitive impairment; CI = confidence interval

Fig. 3.. No significant effect of being eligible for HZ vaccination on the leading causes of morbidity and mortality (other than dementia) nor on indicators of preventive health services uptake.^{1,2,3,4,5,6,7,8}

¹ Baseline refers to the start date (September 1 2013) of the HZ vaccination program. ² Dots show the point estimate and horizontal bars the 95% confidence interval. ³ Among patients without a record of cognitive impairment prior to the start date of the HZ vaccination program, the leading causes of morbidity and mortality were the ten (other than dementia) leading causes of DALYs and mortality among adults aged 70+ years in Wales as estimated by the Global Burden of Disease Project(57). ⁴ Among patients with a diagnosis of dementia made prior to the start date of the HZ vaccination program, the leading causes of mortality were the ten (other than dementia) leading causes of mortality among adults aged 70+ years in Wales as estimated by the Global Burden of Disease Project(57). ⁵ Influenza vaccination was defined as receipt of influenza vaccination at any time in the 12 months after the start date of the HZ vaccination program. ⁶ Statin and antihypertensive medication use was defined as any prescription of these medications during the 12 months after the start date of the HZ vaccination program. ⁷ Breast cancer screening was analyzed among women only. It was defined as a record of referral to, attendance at, or a report from “breast cancer screening” or mammography at any time after the start date of the HZ vaccination program. ⁸ The Read and ICD codes used to define each variable shown in this figure are provided in Supplement Materials. Abbreviations: COPD = Chronic Obstructive Pulmonary Disease; CI = Confidence Interval.

Fig. 4.. The effect of HZ vaccination on new diagnoses of MCI and deaths due to dementia, separately by gender.^1,2,3

¹ Dots show the point estimate and horizontal bars the 95% confidence interval. ² New diagnoses of MCI were analyzed among a study cohort of patients who did not have any record of cognitive impairment prior to the start date of the HZ vaccination program. ³ Deaths due to dementia were analyzed among a study cohort of patients who had received a diagnosis of dementia prior to the start date of the HZ vaccination program. Abbreviations: MCI = mild cognitive impairment; CI = confidence interval

Fig. 5.. The effect of HZ vaccination on deaths due to dementia, non-dementia deaths, and all-cause mortality.^1,2,3

¹ Dots show the point estimate and horizontal bars the 95% confidence interval. ² Deaths due to dementia were analyzed among a study cohort of patients who had received a diagnosis of dementia prior to the start date of the HZ vaccination program. ³ Non-dementia deaths were defined as deaths for which dementia was recorded as neither the underlying nor a contributing cause of death in the death certificate. Abbreviations: CI = confidence interval