Recombinant zoster vaccine is associated with a reduced risk of dementia

Domain: neuroscience
Published: 2026-02-09
Editorial outcome: major_revision

Abstract
Vaccines to prevent herpes zoster have been associated with reduced dementia risk. We conducted a retrospective matched cohort study of Kaiser Permanente Southern California members aged ≥65 years who received two doses of RZV 4 weeks–6 months apart between 01 April 2018 and 31 December 2020, with no dementia diagnoses or dementia medications prior to or within 6 months of their second RZV dose. Cox regression with inverse probability of treatment weighting was used to estimate adjusted hazard ratios (aHRs). The study included 65,800 RZV-vaccinated individuals and 263,200 unvaccinated matches. Vaccination with two doses of RZV was associated with a 51% lower risk of dementia (aHR: 0.49 [95% confidence interval (CI): 0.46–0.51]); aHRs were comparable across age, and racial and ethnic groups, but the risk reduction was stronger in females compared to males. In an evaluation of potential healthy vaccinee bias, the aHR of dementia for RZV compared to Tdap was 0.73 (95% CI: 0.67–0.79). Vaccination with two doses of RZV is associated with a statistically significant reduction in the risk of dementia in adults aged ≥65 years. After accounting for healthy vaccinee bias, RZV vaccination remains associated with a statistically significant lower risk of dementia.

Introduction
Dementia is a major public health issue worldwide and one of the major causes of disability and dependency among older people1. Dementia can be caused by various conditions that gradually destroy nerve cells and damage the brain, leading to cognitive impairment. Alzheimer’s disease is the most common form of dementia, present in an estimated 60–80% of dementia cases2. The number of people living with dementia worldwide has been increasing due to population growth and aging. In 2019, approximately 57.4 million people were living with dementia globally, and it has been estimated that this number will increase to approximately 152.8 million by 20503. In 2024, in the United States (US), approximately 6.9 million adults aged 65 years and older were living with dementia2.

A potential role of varicella-zoster virus (VZV) in the development of dementia has been considered4–9. Most people acquire VZV in childhood; the primary infection causes varicella (chickenpox), but the virus remains latent in the peripheral nervous system throughout life, and, upon reactivation, causes herpes zoster (HZ; commonly known as shingles), which manifests as a painful vesicular rash10,11. Several studies have shown an association between HZ and increased risk of dementia4,12–16. However, the exact mechanism by which viral reactivation leads to development of dementia has not been clearly demonstrated. Potential mechanisms may include neurodegeneration in the brain through neuroinflammation and/or vasculopathy, or via reactivation, possibly subclinical, of other viruses in the brain, such as herpes simplex virus-117–20.

Recent studies with a live-attenuated HZ vaccine (zoster vaccine live [ZVL; Zostavax, Merck]) provided real-world evidence that immunization to prevent HZ may offer a protective effect against dementia21–24. However, these studies mostly compared the occurrence of dementia among HZ-vaccinated versus unvaccinated individuals, a design which may not account for a “healthy vaccinee” bias25. However, a recently published natural experiment in Wales using the SAIL Databank26 compared adults who were immediately born before and after the eligibility cut-off date to receive ZVL, ensuring the greatest possible natural balance of potential confounding variables27. This study demonstrated that receiving ZVL led to a 20% relative reduction in probability of a new dementia diagnosis over a follow-up period of 7 years compared to those who did not receive ZVL27.

To date, most studies on HZ vaccination and dementia have primarily examined ZVL, which was approved by the US Food and Drug Administration (FDA) in 200628 and discontinued in the US in 202029. In 2017, the recombinant zoster vaccine (RZV; Shingrix, GSK) received FDA approval and was preferentially recommended by the Advisory Committee on Immunization Practices (ACIP) for all adults ≥50 years of age, even those who had previously received ZVL, as RZV was demonstrated to have greater efficacy and durability30–33. Given the relatively recent approval and implementation of RZV vaccination, research on the relationship between RZV vaccination and dementia risk is limited.

A recent natural experiment of dementia risk in the US compared adults who received RZV between 2017 and 2020 to those who received ZVL between 2014 and 2017, using data from the TriNetX US Collaborative Network34. In this study, RZV was associated with a 17% increase in time free from dementia diagnosis, but the study lacked validation of diagnoses and had limited information on socioeconomic factors34. Another claims-based study using data from the Optum Labs Data Warehouse examined RZV and dementia using a retrospective cohort design and found that patients who received either two doses or one dose of RZV had a statistically significant reduced risk of dementia (adjusted hazard ratio [aHR] 0.68 and 0.89, respectively) as compared to unvaccinated individuals35.

In our current study conducted at Kaiser Permanente Southern California (KPSC), we evaluated the potential association between immunization with two doses of RZV and reduction in risk of dementia in adults aged 65 years and older in the US, while addressing several limitations of previous studies. An overview of the study objectives and design can be found in Fig. 1a–c.

Results
Identification of dementia and mild cognitive impairment outcomes
To assess the quality of dementia diagnosis codes, 100 patient records with ≥1 coded dementia diagnosis (primary definition) were randomly selected for chart review of the outcome. Of the 100 cases reviewed, 94 were confirmed by chart review to have clinical documentation to support the coded diagnosis (positive predictive value [PPV]: 94.0% [95% confidence interval (CI): 87.4–97.8%]; Supplementary Table 1). Subsets of the 100 records randomly selected with the primary dementia definition also met alternative dementia definitions and were used to calculate the associated PPV. The PPV of the alternative dementia definitions were 95.9% (95% CI: 88.6–99.2%) for ≥2 dementia diagnoses, 97.0% (95% CI: 84.2–99.9%) for ≥1 dementia diagnosis with dementia medication, and 96.1% (95% CI: 88.9–99.2%) for either ≥2 dementia diagnoses or ≥1 dementia diagnosis with dementia medication (Supplementary Table 1). Of the 100 random selected records with coded mild cognitive impairment (MCI) diagnosis that were chart reviewed, 98 were confirmed (PPV: 98.0% [95% CI: 93.0–99.8%]).

Dementia in RZV-vaccinated versus unvaccinated individuals
There were 65,800 two-dose RZV-vaccinated, and 263,200 matched unvaccinated individuals included in the analysis examining the association between two doses of RZV and risk of dementia (Fig. 1d and Table 1). Compared to unvaccinated individuals, a higher proportion of RZV-vaccinated individuals had a recent history of HZ (≤2 years), receipt of influenza vaccines and other vaccines in the year prior to the index date (the date of receipt of the second dose of RZV; matched unvaccinated individuals were assigned the same index date), preventive care and outpatient or virtual visits in the year prior to the index date, and longer continuous KPSC membership prior to the index date (≥10 years) (absolute standard difference [ASD] >0.1 before weighting; Supplementary Table 2). Vaccinated individuals had a higher frequency of dyslipidemia diagnosis, were less likely to be smokers, had lower body mass index (BMI), and had higher neighborhood-level income and education as compared to unvaccinated individuals (ASD >0.1 before weighting). The mean follow-up time (starting 6 months after the index date) was 3.40 (standard deviation [SD]: 0.99) years for RZV-vaccinated individuals and 1.81 (SD: 1.27) years for unvaccinated individuals (Supplementary Table 2). The mean follow-up time in unvaccinated individuals was shorter, as individuals were censored if they received RZV. After weighting, all baseline characteristics were well-balanced between vaccinated and unvaccinated cohorts (Supplementary Fig. 1). After weighting, the mean age was 73.42 (SD: 6.19) years and 73.33 (SD: 6.69) years in the RZV-vaccinated and unvaccinated populations, respectively. The majority of RZV-vaccinated and unvaccinated individuals were female (57.5% vs 57.7%, respectively) and non-Hispanic White (61.1% vs 61.2%, respectively; Table 1).

Among RZV-vaccinated individuals, there were 2401 diagnosed dementia cases during follow-up with an incidence rate (IR) of 10.74 (95% CI: 10.32–11.18) per 1000 person-years (PY) compared to 10,983 diagnosed dementia cases with an IR of 23.04 (95% CI: 22.61–23.48) per 1000 PY in the unvaccinated cohort (Fig. 2, Supplementary Table 3). The cumulative incidence of dementia was significantly higher in the unvaccinated cohort (10.64%) compared to the RZV-vaccinated cohort (5.67%; Fig. 3). The overall aHR for dementia comparing RZV-vaccinated to unvaccinated individuals was 0.49 (95% CI: 0.46–0.51).

The aHRs for dementia were similar across age groups, racial and ethnic groups, history of MCI diagnosis, history of ZVL vaccination, and diagnosed dementia types (Alzheimer’s disease and vascular dementia). In females, aHR was lower than that observed in males (0.45 [95% CI: 0.42–0.48] vs 0.55 [95% CI: 0.51–0.59]; Fig. 2 and Supplementary Table 3).

To evaluate incidence of dementia in the context of diagnosed HZ, RZV-vaccinated and unvaccinated individuals were stratified in an unadjusted post-hoc analysis by HZ status. In individuals without any diagnosed HZ, the IR per 1000 PY of dementia was 10.06 (95% CI: 9.62–10.53) and 22.29 (95% CI: 21.83–22.75) in RZV-vaccinated and unvaccinated adults, respectively (Supplementary Table 4). In individuals with diagnosed HZ, whether prior to or during follow-up, the IR of dementia per 1000 PY was 14.49 (95% CI: 13.27–15.82) and 27.87 (95% CI: 26.61–29.20) in RZV-vaccinated and unvaccinated adults, respectively (Supplementary Table 4).

Dementia in RZV-vaccinated versus Tdap-vaccinated individuals
To evaluate potential healthy vaccinee bias, we compared dementia incidence in RZV-vaccinated individuals versus a separate comparator group who received tetanus, diphtheria, and acellular pertussis (Tdap) vaccine but not RZV. Tdap-vaccinated individuals were matched 1:1 to RZV-vaccinated individuals on age and index (vaccination) date in the same year or plus or minus 1 year if no matches were available in the same year. Individuals in the RZV-vaccinated cohort were permitted to also receive Tdap before or after the index date. This analysis included 65,800 two-dose RZV-vaccinated individuals (same cohort as the primary analysis) and 65,800 Tdap-vaccinated individuals (Supplementary Table 5). Compared to Tdap-vaccinated individuals, a higher proportion of RZV-vaccinated individuals were non-Hispanic White, had a history of ZVL vaccination, recent history of HZ (≤2 years), receipt of influenza vaccine and other vaccines in the year prior to the index date, preventive care in the year prior to the index date, more outpatient and virtual visits, and longer continuous KPSC membership (≥10 years; ASD >0.1 before weighting; Supplementary Table 5). Similar to the main analysis, RZV-vaccinated individuals had a higher frequency of dyslipidemia, were less likely to be smokers, had lower BMI, and had higher neighborhood-level income and education compared to Tdap-vaccinated individuals (ASD >0.1 before weighting; Supplementary Table 5). A higher proportion of Tdap-vaccinated individuals had diabetes, metabolic syndrome, a higher frailty index score, Medicaid coverage, more Emergency Department (ED) visits and hospitalizations, and earlier index dates (ASD >0.1 before weighting; Supplementary Table 5). All covariates were well-balanced after weighting (Supplementary Fig. 2). The mean follow-up time was 3.40 years (SD: 0.99) for RZV-vaccinated individuals and 2.38 years (SD: 1.27) for individuals in the Tdap comparator group. Most RZV-vaccinated individuals (98.6%) had also received Tdap by the end of follow-up. There were 2118 Tdap-vaccinated individuals (3.2%) who contributed person-time to both cohorts as they were vaccinated with RZV during follow-up (Supplementary Table 5). After weighting, the populations were similar. The mean ages were 73.34 (SD: 6.32) years and 73.23 (SD: 6.29) years in the RZV-vaccinated and Tdap-vaccinated groups, respectively. In the RZV-vaccinated group, 55.5% were female and 53.7% were non-Hispanic White, compared to 55.7% female and 53.4% non-Hispanic White in the Tdap group (Supplementary Table 6).

Among RZV-vaccinated individuals, there were 2401 dementia cases during follow-up with an IR of 10.74 (95% CI: 10.32–11.18) per 1000 PY compared to 2835 dementia cases with an IR of 18.09 (95% CI: 17.44–18.77) per 1000 PY in the Tdap-vaccinated cohort (Fig. 4 and Supplementary Table 7). The cumulative incidence of dementia was statistically significantly higher in the Tdap-vaccinated cohort (9.90%) compared to the RZV-vaccinated cohort (5.67%; Fig. 5). The aHR of dementia in RZV-vaccinated individuals compared to Tdap-vaccinated individuals was 0.73 (95% CI: 0.67–0.79; Fig. 4 and Supplementary Table 7).

Negative control outcomes in RZV-vaccinated versus unvaccinated individuals
To evaluate potential residual confounding, we assessed the relationship between RZV and a composite negative control outcome (NCO) in the RZV-vaccinated and unvaccinated cohorts in a post-hoc analysis (Supplementary Table 8 and Fig. 6). Overall, there were 2171 NCO cases reported in the RZV-vaccinated cohort (IR: 9.75 [95% CI: 9.34–10.16] per 1000 PY) and 4877 in the unvaccinated cohort (IR: 10.06 [95% CI: 9.78–10.35] per 1000 PY). The overall aHR of two doses of RZV and the composite NCO was 0.94 (95% CI: 0.89–1.00; Fig. 6 and Supplementary Table 8).

E-value
The E-value for the primary analysis result was 3.50 for the point estimate and 3.33 for the upper bound of the CI.

MCI in RZV-vaccinated versus unvaccinated individuals
The analysis to evaluate the association between RZV and risk of MCI included 64,744 two-dose RZV-vaccinated and 258,199 unvaccinated individuals with no history of MCI prior to follow-up (Supplementary Table 9). The cohort used for analysis of MCI outcomes was a subset of that used in analysis of the primary dementia outcome, differing only on exclusion of individuals with MCI diagnosis prior to follow-up. As such, the baseline characteristics of the RZV-vaccinated and unvaccinated populations are similar to those reported above (Table 1 and Supplementary Tables 9–10). For the MCI analysis, the mean follow-up time was 3.41 (SD: 0.98) years for RZV-vaccinated individuals and 1.85 (SD: 1.28) years for unvaccinated individuals (Supplementary Table 9).

There were 1557 diagnosed MCI cases among RZV-vaccinated individuals (IR: 7.05 [95% CI: 6.71–7.41] per 1000 PY) compared to 3564 diagnosed MCI cases among unvaccinated individuals (IR: 7.47 [95% CI: 7.23–7.72] per 1000 PY; Fig. 7, Supplementary Table 11). The cumulative incidence of MCI was significantly higher in the unvaccinated cohort (Supplementary Fig. 3). Due to violation of the proportional hazards assumption, the analysis was stratified into <3.5 years of follow-up and ≥3.5 years of follow-up. The aHR of MCI in RZV-vaccinated individuals compared to unvaccinated individuals with follow-up of <3.5 years was 0.84 (95% CI: 0.78–0.90; Fig. 7 and Supplementary Table 11). The number of MCI cases after ≥3.5 years of follow-up was small.

There were 393 RZV-vaccinated and 909 unvaccinated individuals who were diagnosed with incident MCI and subsequently dementia during the follow-up period. The median time (interquartile range [IQR]) between MCI and dementia diagnosis was 261 (IQR: 98, 500) days and 193 (IQR: 37, 396) days in the RZV-vaccinated and unvaccinated cohorts, respectively (Supplementary Table 12).

Sensitivity analyses
In consideration of the COVID-19 pandemic and its effect on healthcare seeking behaviors, we conducted a sensitivity analysis excluding RZV-vaccinated individuals and their unvaccinated matches with an index date from 01 March 2020 through 31 December 2020. In this cohort, there were 50,542 RZV-vaccinated individuals and 202,168 unvaccinated individuals, with characteristics similar to the primary cohort (Table 1 and Supplementary Table 13). There were 2012 dementia cases (IR: 10.98 [95% CI: 10.51–11.47] per 1000 PY) in the RZV-vaccinated cohort and 9383 dementia cases (IR: 25.28 [95% CI: 24.77–25.80] per 1000 PY) in the unvaccinated cohort (Supplementary Table 14). The aHR of two doses of RZV and dementia in this alternative accrual period was 0.45 (95% CI: 0.43–0.48).

Using an alternative outcome definition for dementia (≥2 diagnoses or ≥1 diagnosis with medication; Supplementary Methods), there were 1757 dementia cases (IR: 7.84 [95% CI: 7.48–8.21] per 1000 PY) in the RZV-vaccinated cohort and 7,742 dementia cases (IR: 16.14 [95% CI: 15.79–16.51] per 1000 PY) in the unvaccinated cohort. The aHR of two doses of RZV and dementia using an alternative definition was 0.49 (95% CI: 0.46–0.52; Supplementary Table 14).

In a post-hoc sensitivity analysis in which individuals were not censored upon receipt of HZ vaccine during follow-up, there were 39,813 RZV-vaccinated individuals and 159,252 unvaccinated individuals (Supplementary Table 15), with characteristics similar to the primary cohort. There were 1540 dementia cases (IR: 10.95 [95% CI: 10.42–11.51] per 1000 PY) in the RZV-vaccinated cohort and 9834 dementia cases (IR: 20.02 [95% CI: 19.62–20.42] per 1000 PY) in the unvaccinated cohort (Supplementary Table 14). The aHR of two doses of RZV and dementia was 0.60 (95% CI: 0.56–0.63).

A final post-hoc sensitivity analysis was conducted in which the follow-up time began 1 year, instead of 6 months, after the index date. The number of dementia cases in the RZV-vaccinated cohort was 2186 (IR: 11.44 [95% CI: 10.97–11.93] per 1000 PY) compared to 7066 (IR: 19.27 [95% CI: 18.83–19.73] per 1000 PY) in the unvaccinated cohort and 2367 (IR: 18.93 [95% CI: 18.18–19.71] per 1000 PY) in the Tdap-vaccinated cohort. The aHR of two doses of RZV and dementia with follow-up starting 1 year after the index date was 0.60 (95% CI: 0.57–0.64) and 0.73 (95% CI: 0.67–0.79) compared to unvaccinated individuals and Tdap-vaccinated individuals, respectively (Supplementary Table 16). The cumulative incidence of dementia was significantly lower in the RZV-vaccinated group (5.36%) compared to the unvaccinated (9.09%; Supplementary Fig. 4) and Tdap-vaccinated (9.23%; Supplementary Fig. 5) groups.

Methods
Study setting
KPSC is a large integrated healthcare system that includes 4.9 million members with diverse sociodemographic characteristics, reflecting the Southern California population38,40. Comprehensive patient health information, including demographics, diagnoses, vaccinations, and pharmacy records of KPSC members are stored in the EHR. Demographic information, including the patient’s sex, is documented by healthcare providers during clinical encounters from available medical history and, if needed, patient self-report. KPSC is a prepaid healthcare system, and recommended vaccines, including RZV, are provided to members at no charge, incentivizing members to receive vaccines within the KPSC system. Additionally, vaccinations received outside of the health plan that are self-reported with appropriate documentation are also recorded in the EHR. The KPSC Institutional Review Board approved this study and waived the requirement for informed consent.

Study population
Adults aged 65 years and older at the index date (defined under “Study design”) with at least 1 year of continuous KPSC membership before the index date (allowing for a 31-day gap in membership) and until at least 6 months afterward were eligible for inclusion. Individuals were excluded if they were diagnosed with dementia (by ICD-10 [International Classification of Diseases, Tenth Revision] code; Supplementary Table 17) or were prescribed any medication to treat dementia symptoms prior to or on the index date or within 6 months following the index date (Supplementary Table 18). Additionally, individuals were excluded if they received RZV or ZVL within 6 months following the index date, received the second dose of RZV less than 4 weeks after the first dose, or died within 6 months following the index date.

Objectives
The primary objective of the study was to evaluate the association between two doses of RZV and reduction in risk of dementia in US adults aged 65 years and older (Fig. 1a). Secondary and exploratory objectives were to evaluate the association between two doses of RZV and reductions in (1) risk of dementia, by age, sex, race and ethnicity, ZVL status, and MCI status, (2) risk of dementia subtype (Alzheimer’s disease, vascular dementia), (3) risk of dementia compared to individuals who received Tdap vaccine, and (4) risk of MCI, along with time to dementia diagnosis following incident MCI diagnosis during the follow-up period.

Study design
We conducted a retrospective cohort study among KPSC members aged 65 years and older. The RZV-vaccinated group included adults who received two doses of RZV 4 weeks to 6 months apart between 01 April 2018 and 31 December 2020. Vaccinated individuals were 1:4 matched by age, sex, race, and ethnicity, and history of ZVL vaccination to unvaccinated individuals who had not received RZV as of the index date. The index date was defined as the date of the receipt of the second dose of RZV for vaccinated individuals and unvaccinated individuals were assigned the same index date as their vaccinated matches. Follow-up time began 6 months after the index date to allow time for diagnosis of dementia cases that were present prior to vaccination but had not yet been diagnosed in the medical record. Follow-up lasted until receipt of an additional dose of HZ vaccine, termination of KPSC membership (allowing for a 31-day gap in membership), occurrence of an event of interest, death, or the end of the follow-up period (31 December 2023), whichever occurred first (Fig. 1b). Unvaccinated individuals who were matched to RZV-vaccinated individuals could also contribute person-time to the RZV-vaccinated cohort if they received two doses of RZV and otherwise met eligibility criteria; their unvaccinated person-time was censored upon receipt of the first dose of RZV.

A period of 1 year before the index date was used to define most baseline variables (e.g., comorbidities and healthcare utilization; Supplementary Methods). However, for some variables (e.g., dementia history, immunosuppressive conditions identified using diagnosis codes at KPSC), all available data from October 2015 onward were used, while for other variables (i.e., MCI history, ZVL history, HZ history, length of membership, immunosuppressive conditions identified using registry data), all available data were used. The study was conducted in accordance with the International Society for Pharmacoepidemiology Guidelines for Good Pharmacoepidemiology Practices41.

Study exposure and outcomes
The exposure of interest was the receipt of two doses of RZV 4 weeks to 6 months apart (Fig. 1c). RZV doses were identified using CVX (vaccine administered) code 187: zoster vaccine recombinant. The primary outcome was all-cause dementia, defined by ≥1 ICD-10 diagnosis code for dementia (Supplementary Table 17) from hospital, outpatient (including virtual), and ED settings during the study follow-up period (Fig. 1c). Secondary outcomes included Alzheimer’s disease, vascular dementia, and MCI, defined by ≥1 ICD-10 diagnosis code (Supplementary Table 17) from hospital, outpatient (including virtual), and ED settings during the study follow-up period. Chart review was performed on a random sample of 100 records with coded dementia diagnoses and 100 records with coded MCI diagnoses, to assess whether the diagnosis codes aligned with the clinicians’ documentation in the EHR. The PPV was calculated by dividing the number of confirmed cases by the number of reviewed cases.

Statistical methods
Primary analysis. Baseline characteristics of the vaccinated and unvaccinated groups in the matched cohort were described. ASD was calculated to assess the balance of covariates, with an ASD <0.1 considered a negligible difference42.

Overall incidence rates of dementia were calculated by dividing the number of incident dementia cases by the total number of person-years; the 95% CI was calculated using SAS PROC GENMOD with a log link function assuming the incident dementia cases follow a Poisson distribution. The cumulative incidence of dementia was estimated by the Kaplan–Meier method. Vaccinated and unvaccinated cumulative incidence estimates were plotted, and the difference between two curves was tested by the log-rank test. The proportional hazards assumption was evaluated visually (Kaplan–Meier method) or by using an appropriate test (e.g., testing interactions of the exposure and survival time) if cumulative incidence curves crossed.

The incidence of dementia was compared between the vaccinated and unvaccinated groups, adjusting for potential confounders using an inverse probability of treatment weighting approach (IPTW)43. The probability of receiving two doses of RZV (i.e., propensity scores) as predicted by baseline covariates (Supplementary Table 19) was estimated using a logistic regression model (Supplementary Methods). Unadjusted and adjusted HRs and 95% CIs of dementia in the vaccinated and unvaccinated groups were estimated by two Cox proportional hazards regression models, one without IPTW and one with IPTW (SAS PROC PHREG with a WEIGHT statement in which each observation in the input dataset is weighted by the value of the weight variable). Additionally, weighted Cox regression models were adjusted for vaccinations (influenza vaccine, COVID-19 vaccine, or other vaccines) received during follow-up as time-varying covariates. Study conclusions were based on the adjusted (weighted) models (Supplementary Methods). Death was considered as a competing risk using cause-specific hazards models in which the competing events were treated as censored observations.

Secondary and exploratory analyses. Dementia incidence and aHRs in the RZV-vaccinated group and matched unvaccinated groups stratified by age (65–69 years, 70–79 years, and ≥80 years) at index date, sex, race and ethnicity, ZVL status, and baseline MCI status were calculated with 95% CIs, using a similar method as for the primary analysis. Covariate balance within subgroups was assessed using the weights from the primary analysis; imbalanced variables (ASD >0.1) were added to the adjusted models. If >20% of the variables were imbalanced, propensity scores were recalculated for the subgroup. Incidence and aHR of Alzheimer’s disease and vascular dementia were calculated similarly to the primary analysis.

An analysis similar to the primary objective, using Tdap-vaccinated instead of unvaccinated individuals as a comparator, was conducted to mitigate bias due to “healthy vaccinee” effects. The Tdap vaccine was selected based on comparability to RZV in terms of indication for a similar patient population, as well as pattern of administration. The comparator group included individuals who received a dose of Tdap between 01 April 2018 and 31 December 2020, met the eligibility criteria, and did not receive a dose of RZV prior to the index date. The exposed RZV-vaccinated group remained the same as the primary analysis. Tdap recipients were matched 1:1 to RZV recipients on age and index (date of second RZV dose and Tdap vaccination date) in the same year, or ±1 year if no matches were available in the same year. In a similar approach to the main analysis, Tdap-vaccinated individuals who were matched to RZV-vaccinated individuals could also contribute person-time to the RZV-vaccinated cohort if they received two doses of RZV and otherwise met eligibility criteria; their Tdap-vaccinated person-time was censored upon receipt of the first dose of RZV. The IPTW approach was used to account for covariates, including sex, race, and ethnicity, history of ZVL, and other potential confounders.

Among individuals without MCI diagnosis prior to the start of follow-up, incidence and aHR of MCI were calculated comparing the RZV-vaccinated group with the matched unvaccinated group. Due to violation of the proportional hazards assumption (Supplementary Fig. 3), the analysis was stratified into <3.5 years of follow-up and ≥3.5 years of follow-up. In addition, among the subgroup diagnosed with MCI and then dementia during follow-up, the time from MCI diagnosis to dementia diagnosis was described, stratified by RZV vaccination status.

In an exploratory unadjusted post-hoc analysis, incidence rates of dementia by HZ status (never diagnosed with HZ vs any HZ diagnosis prior to or during follow-up) were calculated for the RZV-vaccinated group and the matched unvaccinated group.

Sensitivity analyses. Individuals who receive RZV may differ from those who do not receive the vaccine in their risk of developing dementia and/or care-seeking behaviors for dementia. To assess whether the primary analysis of dementia may have been distorted by such confounders, a similar post-hoc analysis was conducted with a composite NCO comprised of acutely painful conditions not associated with dementia but likely to require medical attention34,44. The composite NCO consisted of six conditions: acute pancreatitis, appendicitis, acute cholecystitis, adhesive capsulitis of the shoulder, trigeminal neuralgia, and wrist fractures.

To further evaluate the potential for residual confounding, the E-value was calculated post-hoc for the primary analysis45. The E-value represents the minimum strength of association an unmeasured confounder would need to have to explain away the observed exposure-outcome association. A large E-value suggests that substantial unmeasured confounding would be needed to explain away the effect estimate. PPV was evaluated, and sensitivity analysis was conducted using an alternative outcome definition for dementia, requiring ≥2 dementia diagnoses or ≥1 dementia diagnosis with prescription medication for management of dementia symptoms (Supplementary Tables 17 and 18).

Due to the effect of the COVID-19 pandemic on healthcare-seeking behaviors, a sensitivity analysis for the primary objective was also conducted, excluding vaccinated individuals and their unvaccinated matches with an index date between 01 March 2020 and 31 December 2020.

An additional post-hoc sensitivity analysis was conducted in which receipt of HZ vaccine during follow-up was removed as a censoring criterion to account for possible behavioral changes in the unvaccinated population during the follow-up period. Individuals who were unvaccinated at the start of the study continued contributing person-time to the unvaccinated cohort (disregarding subsequent receipt of HZ vaccine during follow-up) until termination of KPSC membership, dementia diagnosis, death, or the end of follow-up (31 December 2023), whichever occurred first. Thus, individuals who originally contributed person-time to both the unvaccinated and RZV-vaccinated arms (n = 25,987) were not included in the RZV-vaccinated arm for this sensitivity analysis; their unvaccinated matches (n = 103,948) were also excluded.

An additional post-hoc sensitivity analysis was conducted in which the follow-up time began 1 year after the index date, instead of 6 months, to potentially (1) reduce healthy vaccinee bias as it is expected that this effect would become less pronounced further from vaccination, (2) reduce misclassification of cases with onset of dementia preceding the index date, and (3) allow a longer period for RZV vaccination to take effect on dementia outcomes.

Peer review rounds
[{"round": 1, "reviewer_comments": {"reviewer_1": "This manuscript reports the results of a longitudinal study on recombinant zoster vaccine (RZV) and the risk of dementia among participants in the Kaiser Permanente Southern California database. Strengths of the investigation include the large sample size, the validation of outcome, the use of a vaccinated control group, and the extensive sensitivity analyses. Although the apparent protective effect may appear robust, there is a major source of potential bias that apparently has not been considered:\nA very large proportion of unvaccinated individuals are censored because they received RZV during the period of follow-up. Although this proportion is not directly reported, it can be inferred from the data provided in Extended figure 1 -- for example, between years 2 and 3 after the index date, the number at risk declines by 20% in the vaccinated and by 57% in the unvaccinated, a difference almost certainly entirely due to incident RZV vaccination. This is problematic, because it is plausible that individuals remaining at risk are more likely to have cognitive decline and be at higher risk of dementia.\nI cannot think of an easy fix of the potential bias above, but at the very least it should be acknowledged and the Authors should report the results of sensitivity analyses in which unvaccinated individuals continue to contribute to follow-up to the unvaccinated group until 31 December 2023, or until they are censored for other reasons. This would be a very conservative analyses, i.e. biased toward the null, because RZV vaccination could reduce risk of dementia in the unvaccinated group, but any remaining inverse association between RZV and dementia would be far more convincing.", "reviewer_2": "Thank you for the opportunity to review this study investigating the relationship between two doses of the recombinant Zoster Vaccine (RZV) and subsequent dementia incidence in a large sample of adults in Southern California. The study is well designed and methodologically rigorous. It will make an important contribution to the evidence base for assessing the potentially protective effects of Herpes Zoster (Shingles) vaccines against dementia - an area of substantial public health interest.\nThe study uses a retrospective matched cohort study design with inverse probability of treatment weighting to improve balance between groups. Of particular note is the extra effort to compare the RZV vaccinated group with a non-shingles vaccinated group (Tdap) and a negative control. These extra analyses help provide reassurance that the findings are unlikely to be explained purely by health vaccinee effects which have been limitations of prior studies.\nI have only minor comments for the authors to consider:\n1. It seems that one key difference between the RZV group and their matched controls was that the RZV groups must have interacted with a health service provider in the period 1 April 2018 and 31 Dec 2020, whereas the unvaccinated controls may not have had any interaction? Could this difference indicate more proactive health behavior among the RZV group? I note that the Tdap comparison does account for this but perhaps this difference could be discussed.\n2. It was not clear why there was a six-month delay included between index date and follow-up commencement – this could be explained more clearly.\n3. Page 8 – lines 202-203 – There is inconsistency with the methods section here. The results report: “There were 2,118 Tdap-vaccinated individuals (3.2%) who contributed person-time to both cohorts as they were vaccinated with RZV during follow-up” . This sounds like a control could cross over to become a case, but the methods (p18 lines 415-417) state that “Unvaccinated matches who were later vaccinated with RZV contributed person-time up until they received the first dose of RZV and were then censored.”\n4. Figure 1 – a large proportion of people (almost 25%) were excluded at the first step in the flow diagram – were these people with >6 months between RZV doses? It would be good to explain who this group is a bit further and consider whether this step could bias results in any way.\n5. Figure 2 – there are differences in the covariates included within sub-group models which seems to be based on whether the weights achieved appropriate balance within each sub-group. Wouldn’t it be more robust to recalculate the IPTW weights within each sub-group and include a consistent set of covariates?\n6. There was no detailed discussion of why the Tdap vaccine was chosen as a comparator rather than any other type of vaccine. One issue with Tdap is that because it includes the tetanus booster, it is possible that it may be prompted by a wound or injury and so may be more likely to be delivered in an ED setting than a vaccine like RZV. This means it could represent a slightly different group of people rather than just controlling for the healthy vaccinee effect."}, "author_response": "We thank the reviewers for their expertise and for taking the time to review our manuscript and to provide thoughtful comments. Please see our point-by-point responses below.\nReviewer #1 (Remarks to the Author):\nThis manuscript reports the results of a longitudinal study on recombinant zoster vaccine (RZV) and the risk of dementia among participants in the Kaiser Permanente Southern California database. Strengths of the investigation include the large sample size, the validation of outcome, the use of a vaccinated control group, and the extensive sensitivity analyses. Although the apparent protective effect may appear robust, there is a major source of potential bias that apparently has not been considered:\nA very large proportion of unvaccinated individuals are censored because they received RZV during the period of follow-up. Although this proportion is not directly reported, it can be inferred from the data provided in Extended figure 1 -- for example, between years 2 and 3 after the index date, the number at risk declines by 20% in the vaccinated and by 57% in the unvaccinated, a difference almost certainly entirely due to incident RZV vaccination. This is problematic, because it is plausible that individuals remaining at risk are more likely to have cognitive decline and be at higher risk of dementia.\nI cannot think of an easy fix of the potential bias above, but at the very least it should be acknowledged and the Authors should report the results of sensitivity analyses in which unvaccinated individuals continue to contribute to follow-up to the unvaccinated group until 31 December 2023, or until they are censored for other reasons. This would be a very conservative analyses, i.e. biased toward the null, because RZV vaccination could reduce risk of dementia in the unvaccinated group, but any remaining inverse association between RZV and dementia would be far more convincing.\nResponse: A higher censoring rate in the unvaccinated group due to subsequent RZV vaccination is expected by design; 63% of unvaccinated individuals in this study were censored due to RZV vaccination. Unvaccinated individuals who were matched to RZV-vaccinated individuals could also contribute person-time to the RZV-vaccinated cohort if they received two doses of RZV during the accrual period (01 April 2018–31 December 2020) and otherwise met eligibility criteria; their unvaccinated person-time was censored upon receipt of the first dose of RZV. Because such individuals were allowed to contribute both unvaccinated and vaccinated person-time to analyses, the vaccinated and unvaccinated groups were more comparable, which helped to mitigate healthy vaccinee bias. In addition, a 27% reduction in risk of dementia was still observed in the Tdap comparison analysis, which was included to specifically address potential healthy vaccinee bias.\nWe have concerns about the suggested sensitivity analysis, as it seems that it would introduce misclassification bias if vaccinated person-time is counted towards the unvaccinated population. Additionally, it seems that person-time (and any dementia cases occurring during it) could then be double-counted in both the vaccinated and unvaccinated groups.\nIn response to your feedback, we’ve added the following language to the limitations section in the discussion (line 360): “Fifth, the majority (63%) of unvaccinated individuals were censored due to receipt of RZV during the follow-up period. However, these individuals could subsequently contribute person-time to the RZV-vaccinated cohort if they otherwise met eligibility criteria during the accrual period which should help to mitigate healthy vaccinee bias.”\nReviewer #2 (Remarks to the Author):\nThank you for the opportunity to review this study investigating the relationship between two doses of the recombinant Zoster Vaccine (RZV) and subsequent dementia incidence in a large sample of adults in Southern California. The study is well designed and methodologically rigorous. It will make an important contribution to the evidence base for assessing the potentially protective effects of Herpes Zoster (Shingles) vaccines against dementia - an area of substantial public health interest.\nThe study uses a retrospective matched cohort study design with inverse probability of treatment weighting to improve balance between groups. Of particular note is the extra effort to compare the RZV vaccinated group with a non-shingles vaccinated group (Tdap) and a negative control. These extra analyses help provide reassurance that the findings are unlikely to be explained purely by health vaccinee effects which have been limitations of prior studies.\nI have only minor comments for the authors to consider:\n1. It seems that one key difference between the RZV group and their matched controls was that the RZV groups must have interacted with a health service provider in the period 1 April 2018 and 31 Dec 2020, whereas the unvaccinated controls may not have had any interaction? Could this difference indicate more proactive health behavior among the RZV group? I note that the Tdap comparison does account for this but perhaps this difference could be discussed.\nResponse: We considered healthcare utilization in the year prior to index date in our analysis to address differences in healthcare seeking behaviors in the vaccinated and unvaccinated cohorts. This included the number of outpatient [including virtual], Emergency Department, and inpatient encounters, as well as preventive care (line 427; Supplementary Methods). After weighting, healthcare utilization was similar between cohorts (ASD <0.1; Table 1). Additionally, as mentioned above, the Tdap comparator cohort would have needed to interact with a health service provider in the same period as the RZV-vaccinated group.\nThe following language is included in the limitations section in the discussion (lines 356-360): “Fourth, it is possible that there is differential misclassification of outcomes due to differences in healthcare seeking behaviors; however, healthcare utilization was included as a covariate in the analysis and reduction in dementia risk was still observed with RZV vaccination, even when compared to individuals who received Tdap vaccination during the accrual period.”\n2. It was not clear why there was a six-month delay included between index date and follow-up commencement – this could be explained more clearly.\nResponse: A 6-month period after the index date was used because dementia can develop over a long period, and lag time can be used to help exclude dementia cases that were present prior to vaccination but had not yet been diagnosed in the medical record. The 6-month period is based on other studies evaluating the association between vaccines and dementia outcomes, most of which implement some lag time between index date and dementia outcome, from 90 days to 2 years.1,2\nThe following language has been added to the methods (line 418): “Follow-up time began 6 months after the index date to allow time for diagnosis of dementia cases that were present prior to vaccination but had not yet been diagnosed in the medical record.”\n3. Page 8 – lines 202-203 – There is inconsistency with the methods section here. The results report: “There were 2,118 Tdap-vaccinated individuals (3.2%) who contributed person-time to both cohorts as they were vaccinated with RZV during follow-up”. This sounds like a control could cross over to become a case, but the methods (p18 lines 415-417) state that “Unvaccinated matches who were later vaccinated with RZV contributed person-time up until they received the first dose of RZV and were then censored.”\nResponse: As noted by the reviewer, unvaccinated individuals contributed person-time until the end of the study period or until they met censoring criteria, including RZV vaccination. However, if the previously unvaccinated individual was vaccinated with 2 RZV doses 4 weeks-6 months apart during the accrual period and met the eligibility criteria, then they also contributed person-time as an RZV-vaccinated individual.\nThe following language has been added in the methods (lines 423-426): “Unvaccinated individuals who were matched to RZV-vaccinated individuals could also contribute person-time to the RZV-vaccinated cohort if they received two doses of RZV and otherwise met eligibility criteria; their unvaccinated person-time was censored upon receipt of the first dose of RZV.”\nIn the Tdap comparison, the same RZV-vaccinated cohort was used as in the primary objective. The Tdap comparator group consisted of individuals who received Tdap during the accrual period and had no history of RZV prior to the index date. As reasoned with the unvaccinated individuals in the primary objective, if a Tdap-vaccinated comparator later received 2 doses of RZV during the accrual period and otherwise met eligibility criteria, they would contribute person-time to the RZV-vaccinated cohort as well.\nThe following language has been added to the methods (line 497): “In a similar approach to the main analysis, Tdap-vaccinated individuals who were matched to RZV-vaccinated individuals could also contribute person-time to the RZV-vaccinated cohort if they received two doses of RZV and otherwise met eligibility criteria; their Tdap-vaccinated person-time was censored upon receipt of the first dose of RZV.”\n4. Figure 1 – a large proportion of people (almost 25%) were excluded at the first step in the flow diagram – were these people with >6 months between RZV doses? It would be good to explain who this group is a bit further and consider whether this step could bias results in any way.\nResponse: Yes, this excluded any individuals who received the second dose of RZV either <4 weeks (n=523) or >6 months (n=41,599) after the first dose. The primary objective of this study was to specifically evaluate the risk of dementia in individuals who received their RZV series 4 weeks to 6 months apart, compared to unvaccinated individuals. Although RZV should be administered as 2 doses separated by 2–6 months, ACIP guidance specifies that a second dose administered <4 weeks after the first dose should be repeated, but a second dose administered ≥4 weeks after the first dose does not need to be repeated.3 Furthermore, due to variation in real-world practice, the second dose may be given earlier than 2 months after the first dose.\nWe do not anticipate bias in limiting the population to those who received the second dose within 6 months after the first dose, given that we took steps to control for confounding and healthy vaccinee effects. However, it can affect generalizability in that findings apply to those who receive the second dose within 6 months of the first dose, and this population could possibly be different from those who receive the second dose later. If we were to include individuals who received the second dose >6 months after the first dose, determining an appropriate cutoff date would be challenging, and we would still miss some individuals. We chose to evaluate the ACIP-recommended dose interval instead.\nWe have added the following language in the limitations section (line 343): “First, these results may not be generalizable to patients who receive care in different types of health systems in the US, including uninsured populations, or in other countries, or to those who received the second dose of RZV more than 6 months after the first.”\n5. Figure 2 – there are differences in the covariates included within sub-group models which seems to be based on whether the weights achieved appropriate balance within each sub-group. Wouldn’t it be more robust to recalculate the IPTW weights within each sub-group and include a consistent set of covariates?\nResponse: For each subgroup analysis, we assessed the covariate balance using the weights from the primary analysis and added imbalanced variables in the outcome models for IPTW analysis. This is a common approach when the number of subgroup analyses is moderate to large. We also followed the pre-specified analysis plan that if more than 20% of the variables were unbalanced, we would recalculate the treatment weights.\n6. There was no detailed discussion of why the Tdap vaccine was chosen as a comparator rather than any other type of vaccine. One issue with Tdap is that because it includes the tetanus booster, it is possible that it may be prompted by a wound or injury and so may be more likely to be delivered in an ED setting than a vaccine like RZV. This means it could represent a slightly different group of people rather than just controlling for the healthy vaccinee effect.\nResponse: Tdap was chosen based on similarity to RZV in terms of indication for a similar population and pattern of administration. In general, adults who have never received Tdap should receive a single dose of Tdap, and a Td/Tdap booster is recommended every 10 years, minimizing the likelihood of multiple Tdap administrations in an individual during the study period. For the Tdap-vaccinated cohort, a small portion of the population (4.7%) received their index vaccine in the ED setting.\nWe considered the pneumococcal vaccine as a potential comparator; however, we ultimately decided against it due to its age- and risk-based recommendations, and individuals could have received multiple pneumococcal vaccine doses of various formulations during the study period. To the former point, pneumococcal vaccine is recommended for adults <65 years with certain underlying medical conditions or other risk factors and is recommended for all adults ≥65 years.4 In addition, recommendations for pneumococcal vaccination in adults changed during the study period.\nThe following language has been added to the methods (line 490): “The Tdap vaccine was selected based on comparability to RZV in terms of indication for a similar patient population, as well as pattern of administration.”\nREFERENCES\n1. Wiemken, T.L., Salas, J., Morley, J.E., Hoft, D.F., Jacobs, C. & Scherrer, J.F. Comparison of rates of dementia among older adult recipients of two, one, or no vaccinations. J Am Geriatr Soc 70, 1157-1168 (2022).\n2. Douros, A., Ante, Z., Suissa, S. & Brassard, P. Common Vaccines and the Risk of Incident Dementia: A Population-based Cohort Study. J Infect Dis 227, 1227-1236 (2023).\n3. Dooling, K.L., et al. Recommendations of the Advisory Committee on Immunization Practices for Use of Herpes Zoster Vaccines. MMWR Morb Mortal Wkly Rep 67, 103-108 (2018).\n4. Kobayashi, M., et al. Pneumococcal Vaccine for Adults Aged >/=19 Years: Recommendations of the Advisory Committee on Immunization Practices, United States, 2023. MMWR Recomm Rep 72, 1-39 (2023)."}, {"round": 2, "reviewer_comments": {"reviewer_1": "The Authors in the original manuscript addressed confounding by using inverse probability of treatment weighting (IPTW) that effectively made the group of vaccinate and unvaccinated individuals comparable at baseline. However, this comparability does not apply to the pre- and post-vaccination person-time in those individuals who were unvaccinated at baseline. Conceivably, this group is heterogeneous with respect to several potential confounders, and those who decided to get the zoster vaccine are likely to have a lower dementia risk than those who did not.\nI still believe that ignoring this source of potential bias is not acceptable.\nAllowing non-vaccinated individuals to contribute person-time to the vaccination group would be equivalent to emulating a trial in which individuals randomized to placebo are analyzed as part of the group randomized to active treatment once they get the vaccine. The fact that this was \"by design\", as stated by the authors, does not make the individuals who got the vaccine during the follow-up comparable to those who did not. The analysis that I suggested is to keep unvaccinated individuals in the unvaccinated group until the end of the follow-up, whether or not they received the vaccine -- i.e. these individuals should not contribute person-time to the vaccinated group. This analyses would emulate an intention to treat analyses in the hypothetical trial. The large proportion of individuals who \"broke protocol\" by choosing vaccination will attenuate any effect of the vaccine, but there will be no bias due to lack of comparability between vaccinated and non-vaccinated individuals.", "reviewer_2": "Thank you for the opportunity to re-review this paper. The authors have addressed the previous comments comprehensively and clarified aspects of the design that were raised by both reviewers. I have the following remaining comments:\n1. It is very clear now from the authors’ responses that the control group could contribute person time to the vaccinated group if they were censored due to a treatment switch (ie they later were vaccinated). What is still not clear is how the IPTW weighting accounted for this treatment switch? It appears that the matching and weighting process occurred based on the original inclusion criteria, but if a large proportion of participants were able to swap groups, then do the two groups remain balanced over time?\n2. If this issue has not currently been addressed, it would be possible to undertake an “intention-to-treat” sensitivity analysis that censors cases when they switch treatment and this might provide an important conservative bound for the findings. It would also be possible to incorporate censoring weights into the study design which may also address this problem."}, "author_response": "We thank the reviewers for their expertise and for taking the time to review our manuscript and to provide thoughtful comments. Please see our point-by-point responses below.\nREVIEWER COMMENTS\nReviewer #1 (Remarks to the Author):\nThe Authors in the original manuscript addressed confounding by using inverse probability of treatment weighting (IPTW) that effectively made the group of vaccinate and unvaccinated individuals comparable at baseline. However, this comparability does not apply to the pre- and post-vaccination person-time in those individuals who were unvaccinated at baseline. Conceivably, this group is heterogeneous with respect to several potential confounders, and those who decided to get the zoster vaccine are likely to have a lower dementia risk than those who did not.\nI still believe that ignoring this source of potential bias is not acceptable.\nAllowing non-vaccinated individuals to contribute person-time to the vaccination group would be equivalent to emulating a trial in which individuals randomized to placebo are analyzed as part of the group randomized to active treatment once they get the vaccine. The fact that this was \"by design\", as stated by the authors, does not make the individuals who got the vaccine during the follow-up comparable to those who did not. The analysis that I suggested is to keep unvaccinated individuals in the unvaccinated group until the end of the follow-up, whether or not they received the vaccine -- i.e. these individuals should not contribute person-time to the vaccinated group. This analyses would emulate an intention to treat analyses in the hypothetical trial. The large proportion of individuals who \"broke protocol\" by choosing vaccination will attenuate any effect of the vaccine, but there will be no bias due to lack of comparability between vaccinated and non-vaccinated individuals.\nResponse: We have added the suggested sensitivity analysis. We observed a 40% (95% CI: 37%-44%) reduction in risk of dementia with this approach, which included vaccinated person-time in the “unvaccinated” cohort. As expected, the hazard ratio moved closer to the null, but vaccination with two doses of RZV was still associated with a significant reduction in risk of dementia diagnosis.\nThe following language has been added in the results (line 273): “In a post-hoc sensitivity analysis in which individuals were not censored upon receipt of HZ vaccine during follow-up, there were 39,813 RZV-vaccinated individuals and 159,252 unvaccinated individuals (Supplementary Table 15), with characteristics similar to the primary cohort. There were 1,540 dementia cases (IR: 10.95 [95% CI: 10.42–11.51] per 1,000 PY) in the RZV-vaccinated cohort and 9,834 dementia cases (IR: 20.02 [95% CI: 19.62–20.42] per 1,000 PY) in the unvaccinated cohort (Supplementary Table 14). The aHR of two doses of RZV and dementia was 0.60 (95% CI: 0.56–0.63).”\nAdditional information is presented in the methods (line 544) and discussion (line 331).\nReviewer #2 (Remarks to the Author):\nThank you for the opportunity to re-review this paper. The authors have addressed the previous comments comprehensively and clarified aspects of the design that were raised by both reviewers. I have the following remaining comments:\n1. It is very clear now from the authors’ responses that the control group could contribute person time to the vaccinated group if they were censored due to a treatment switch (ie they later were vaccinated). What is still not clear is how the IPTW weighting accounted for this treatment switch? It appears that the matching and weighting process occurred based on the original inclusion criteria, but if a large proportion of participants were able to swap groups, then do the two groups remain balanced over time?\nResponse: We thank the reviewer for highlighting this point as it is a valid concern in this study design. We assessed covariate balance during the follow-up period and found that most covariates remained balanced. A few showed slight imbalances, with ASDs between 0.1 and 0.2. However, the hazard ratio estimates remained similar after adjusting for these covariates (data not shown).\n2. If this issue has not currently been addressed, it would be possible to undertake an “intention-to-treat” sensitivity analysis that censors cases when they switch treatment and this might provide an important conservative bound for the findings. It would also be possible to incorporate censoring weights into the study design which may also address this problem.\nResponse: We have included the suggested sensitivity analysis, with an observed 40% reduction in risk of dementia associated with 2 doses of RZV. Changes are detailed in the response to Reviewer 1 above."}, {"round": 3, "reviewer_comments": {"reviewer_2": "No further comments. The additional sensitivity test appears to address the previous concerns regarding potential group imbalances and increases the robustness of the conclusions."}, "author_response": ""}]

Decision letter