The recombinant shingles vaccine is associated with lower risk of dementia

Abstract

There is emerging evidence that the live herpes zoster (shingles) vaccine might protect against dementia. However, the existing data are limited and refer only to the live vaccine, which is now discontinued in the United States and many other countries in favor of a recombinant vaccine. Whether the recombinant shingles vaccine protects against dementia remains unknown. Here we used a natural experiment opportunity created by the rapid transition from the use of live to the use of recombinant vaccines to compare the risk of dementia between vaccine types. We show that the recombinant vaccine is associated with a significantly lower risk of dementia in the 6 years post-vaccination. Specifically, receiving the recombinant vaccine is associated with a 17% increase in diagnosis-free time, translating into 164 additional days lived without a diagnosis of dementia in those subsequently affected. The recombinant shingles vaccine was also associated with lower risks of dementia than were two other vaccines commonly used in older people: influenza and tetanus-diphtheria-pertussis vaccines. The effect was robust across multiple secondary analyses, and was present in both men and women but was greater in women. These findings should stimulate studies investigating the mechanisms underpinning the protection and could facilitate the design of a large-scale randomized control trial to confirm the possible additional benefit of the recombinant shingles vaccine.

Fig. 1. Association between recombinant shingles vaccine and risk of dementia within 6 years of vaccination.

a, Proportion (in %) of each vaccine being received, showing the step change that occurred in October 2017. The exposure windows used in the primary analysis are shown in gray, and the restricted exposure windows that were used in a robustness analysis are shown in dark gray. b, Curves representing the Kaplan–Meier estimates of the cumulative incidence of dementia diagnosis in the 3 months to 6 years after shingles vaccination in the primary analysis (n = 103,837 in each cohort). c, Curve representing the time-varying hazard ratio (HR) for the risk of dementia in the primary analysis (HR < 1 indicates a lower risk of dementia in those who received the vaccine after October 2017); n = 103,837 in each cohort. d, Curves representing the Kaplan–Meier estimates of the cumulative incidence for herpes zoster infection (n = 103,837 in each cohort). e,f, Curves representing the Kaplan–Meier estimates of the cumulative incidence of dementia among women (e) and men (f) (n = 54,846 in each cohort for females, and n = 43,990 for males). The RMTL ratio, the P value (obtained using the z-test defined in the SurvRM2 package in R, two-sided and not corrected for multiple comparisons) for the association and the additional time that affected people lived diagnosis-free are reported above each figure. The exact P values are 2.9 × 10⁻¹⁵ (b), 4.3 × 10⁻⁴¹ (d) and 2.3 × 10⁻¹⁵ (e). Shaded areas in b–f represent 95% CIs of the cumulative incidences (b,d–f) or the time-varying HR (c).

Extended Data Fig. 1. Kaplan-Meier curves for secondary outcomes in the 3 months-6 years after shingles vaccination in the primary analysis.

The curves represent the Kaplan-Meier estimates of the cumulative incidence of death (a) and the composite outcome of death or dementia (b). Shaded areas around curves represent 95% confidence intervals. n = 103,837 in each cohort. P-values were obtained using the z-test defined in the SurvRM2 package in R, two-sided and not corrected for multiple comparisons. The exact p-values for (B) is 3.8×10⁻⁷.

Extended Data Fig. 2. Results for the negative control outcome.

(a) Curves representing the Kaplan-Meier estimates of the cumulative incidence of the negative control outcome in the 3 months-6 years after shingles vaccination. n = 103,837 in each cohort. The p-value was obtained using the z-test defined in the SurvRM2 package in R, two-sided and not corrected for multiple comparisons. (b) Curve representing the time-varying hazard ratio for the negative control outcome (n = 103,837 in each cohort). Shaded areas in A and B represent 95% confidence intervals.

Extended Data Fig. 3. Kaplan-Meier curves showing the cumulative incidence of outcomes in the 3 months-6 years after shingles vaccination.

(a-h) Results for dementia in the different robustness analyses. In (A), the results correspond to the coarsened exact matching with pairwise alignment of follow-up horizons. (i) Results for the incidence of herpes zoster infection. The ratio of restricted mean time lost (RMTL), the p-value for the association, and the additional time lived diagnosis-free among affected people are reported above each figure. Curves in all panels represent the Kaplan-Meier estimates of the cumulative incidence of the corresponding outcome. Shaded areas in all panels represent 95% confidence intervals. See Supplementary Tables 5–9 for baseline characteristics. The number of individuals in each cohort was respectively (A) 82102, (B) 100532, (C) 110062, (D) 66998, (E) 82102, (F) 20243, (G) 54846, (H) 43990, (I) 103837. P-values were obtained using the z-test defined in the SurvRM2 package in R (except for (A) where it was obtained using bootstrap with 1000 repetitions and is reported as <0.001 because all bootstrap replicates of the ratio of RMTL were below 1), two-sided and not corrected for multiple comparisons. The exact p-values are (B) 7.5×10⁻¹⁶, (C) 1.4×10⁻¹⁴, (D) 1.5×10⁻¹⁷, (E) 1.6×10⁻¹¹, (G) 2.3×10⁻¹⁵, and (I) 4.3×10⁻⁴¹.

Extended Data Fig. 4. Kaplan-Meier curves for the comparisons between shingles vaccines and two other vaccines: influenza and Tdap.

(a-b) Comparison with the recombinant shingles vaccine. (c-d) Comparison with live shingles vaccine. The ratio of restricted mean time lost (RMTL), the number of patients in each cohort, the bootstrap p-value for the association, and the additional time lived diagnosis-free among people affected are reported above each figure. Curves in all panels represent the Kaplan-Meier estimates of the cumulative incidence of the corresponding outcome. Shaded areas in all panels represent 95% confidence intervals. Baseline characteristics for these comparisons are provided in Supplementary Tables 11–14. The number of individuals in each cohort was respectively (A) 209031, (B) 98353, (C) 41466, and (D) 64035. P-values were obtained using the z-test defined in the SurvRM2 package in R, two-sided and not corrected for multiple comparisons. The exact p-values are (A) 1.4×10⁻⁶⁷, (B) 2.6×10⁻⁵³, (C) 1.2×10⁻⁶, and (D) 2.1×10⁻⁹.

Extended Data Fig. 5. Time-varying hazard ratios (HR).

Each curve represents the value of the HR from 3 months to 6 years post-vaccination. In (A), the results correspond to the coarsened exact matching with pairwise alignment of follow-up horizons. A HR < 1 indicates the risk is lower in those vaccinated predominantly with the recombinant vaccine. The shaded areas around the curves represent 95% CI. The number of individuals in each cohort was respectively (A) 82102, (B) 100532, (C) 110062, (D) 66998, (E) 82102, (F) 20243, (G) 54846, (H) 43990, (I) 103837.