Is recombinant zoster vaccine the same as shingrix

Abstract

Background

Shingrix (recombinant zoster vaccine) was licensed to prevent herpes zoster, dispensed as 2 doses given 2–6 months apart among adults aged ≥50 years. Clinical trials yielded efficacy of >90% for confirmed herpes zoster, but post-market performance has not been evaluated. Efficacy of a single dose and a delayed second dose and efficacy among persons with autoimmune or immunosuppressive conditions have not been studied. We aimed to assess post-market vaccine effectiveness of Shingrix.

Methods

We conducted a cohort study among Medicare Part D community-dwelling beneficiaries aged >65 years. Herpes zoster was identified using a medical office visit diagnosis with treatment, and postherpetic neuralgia was identified using a validated algorithm. We used inverse probability of treatment weighting to improve cohort balance and marginal structural models to estimate hazard ratios.

Results

We found a vaccine effectiveness of 70.1% (95% confidence interval [CI], 68.6–71.5) and 56.9% (95% CI, 55.0–58.8) for 2 and 1 doses, respectively. The 2-dose vaccine effectiveness was not significantly lower for beneficiaries aged >80 years, for second doses received at ≥180 days, or for individuals with autoimmune conditions. The vaccine was also effective among individuals with immunosuppressive conditions. Two-dose vaccine effectiveness against postherpetic neuralgia was 76.0% (95% CI, 68.4–81.8).

Conclusions

This large real-world observational study of the effectiveness of Shingrix demonstrates the benefit of completing the 2-dose regimen. Second doses administered beyond the recommended 6 months did not impair effectiveness. Our effectiveness estimates were lower than the clinical trials estimates, likely due to differences in outcome specificity.

(See the Major Article by Sun et al on pages 949–56 and the Editorial Commentary by Harpaz on pages 957–60.)

Shingrix, an adjuvanted recombinant zoster vaccine (RZV), was licensed in the United States in October 2017 for the prevention of herpes zoster (HZ) in adults aged ≥50 years [1–4]; it is administered intramuscularly as a series of two 0.5-mL doses 2–6 months apart [3]. Age and immunosuppression are major risk factors for HZ; the increased incidence in older individuals appears to be related to declines in varicella zoster virus immunity.

Safety, immunogenicity, and efficacy of RZV were evaluated in 2 large randomized, placebo-controlled studies [5, 6]. These clinical trials included only generally healthy, immunocompetent persons. Efficacy estimates were derived from a cohort who received 2 doses on a 0- and 2-month schedule. HZ case confirmation was primarily determined by polymerase chain reaction (PCR). In study 1, among 14 759 participants aged ≥50 years, with median follow-up of 3.1 years, vaccine efficacy against confirmed HZ was 97.2% (95% confidence interval [CI], 93.7–99.0) [3]. In study 2 (13 163 participants aged ≥70 years, median follow-up of 3.9 years), vaccine efficacy was 89.8% (95% CI, 84.2–93.7) [3]. Efficacy against HZ and postherpetic neuralgia (PHN) were evaluated in a pooled analysis using data from participants aged ≥70 years from both studies: efficacy against HZ and PHN was 91.3% (95% CI, 86.9–94.5) and 88.8% (95% CI, 68.7–97.1), respectively.

In an RZV schedule-finding study, antibody concentrations after a dose interval of 6 months were noninferior to those after a 2-month interval; responses after a 12-month interval were too varied to meet the noninferiority criteria [7]. Although the Centers for Disease Control and Prevention (CDC) clinical guidance [2] advised recipients not to restart the series if more than 6 months had elapsed since the first dose, RZV efficacy administered at intervals greater than 2 months had not been studied [7, 8].

Because post-market vaccine performance has not been investigated and to address important unanswered questions that could inform programmatic and regulatory actions relating to Shingrix vaccination, we conducted an observational study to assess: vaccine effectiveness (VE) after only 1 dose; VE when the second dose is administered >6 months after the first; VE among persons who received a prior Zostavax (zoster vaccine live [ZVL]) dose; and VE in persons with autoimmune or immunosuppressive conditions, excluded from participation in the clinical trials.

METHODS

Data Sources and Study Design

The primary data sources were Medicare claims and enrollment databases. We derived demographic and death information from the enrollment databases and information on vaccinations, health covariates, preventive services, and outcomes from Medicare Part A (inpatient), Part B (outpatient and community settings), and Part D (prescription drug) claims. Supplemental data on health-seeking attitudes and frailty conditions were captured from the Medicare Current Beneficiary Survey (MCBS; Supplement S-1) [9]. We used a prospective cohort design with a study period from 1 November 2017 to 20 October 2019 (ie, 2 years following US Food and Drug Administration [FDA] approval of RZV on 20 October 2017).

Exposure and Index Date Definition

We identified RZV and ZVL vaccinations using national drug codes (NDCs) in Medicare Part D claims (Supplementary Tables 1, 2). All beneficiaries started as unvaccinated on the index date of 1 November 2017 and switched to the subsequent vaccinated cohorts (first or second dose) 30 days after the corresponding vaccination date to account for the time for a biological immune response. Additional beneficiaries cannot enter the study after the index date. Beneficiaries contributed survival time (ie, time to event) according to their status. For example, individuals who experienced an outcome prior to their first dose were censored on the outcome date and thus did not contribute any time to the first-dose population. We defined influenza vaccinees using Current Procedural Terminology/Healthcare Common Procedure Coding System codes Supplementary Table 3) [4, 10].

Study Population and Inclusion Criteria

To be included in the study, beneficiaries met the following criteria: alive and aged ≥65 years on the index date; continuously enrolled in Medicare Part D for at least 12 months prior to the index date (November 2016); continuously enrolled in Medicare Parts A and B and not Part C for at least 15 months prior to the index date (August 2016); not in a nursing home, skilled nursing facility, or hospice on the index date; and did not have a HZ diagnosis in the inpatient, institutional outpatient (OP), or professional (PB) settings in the 1 year prior to the index date. To address concerns regarding potential confounding because of differences in prevention and healthy lifestyle, we further duplicated all analyses restricted to beneficiaries who had received an influenza vaccine between the start of the 2016–2017 influenza season (7 August 2016) and the index date.

Beneficiaries were classified into an autoimmune population if they consulted for any of the selected autoimmune conditions included at least twice in the 1 year prior to the index date. We adapted our autoimmune conditions definition from Cooper et al. 2009 [11], along with supporting literature (Supplement S-1, Supplementary Table 4).

Outcome Definitions and Follow-up

Our primary outcome was community (outpatient) HZ, defined by a claim in the OP or PB setting with an International Classification of Diseases, Tenth Revision, Clinical Modification(ICD-10) diagnosis code for HZ (B020, B021, B022.x, B027-B029) in any position (Supplementary Table 5) with a claim for HZ-specific antiviral (Supplementary Table 6), identified using NDCs, within 7 days of diagnosis. As a sensitivity analysis, we used this same clinical definition without requiring a prescription for antivirals. As secondary outcomes, we evaluated community ophthalmic zoster (OZ) and PHN. We defined community OZ by a claim in the institutional OP or PB setting with an ICD-10 diagnosis code for OZ (B023.x) in any position (Supplementary Table 7), combined with a claim for a prescription for HZ-specific antivirals within 7 days of diagnosis. We defined PHN in the 90–180 days after HZ onset using a modified version of the PHN algorithms from Klompas et al and Klein [12, 13] (Supplement S-1; Supplementary Tables 8–9).

Follow-up continued until occurrence of any of the following: a subsequent claim for a third dose of RZV; death; termination of Medicare Parts A/B or D coverage or enrollment into Part C; admission to a nursing home, skilled nursing facility or hospice; occurrence of either HZ, OZ, or PHN; or end of the study period.

Covariates

We included well-studied risk factors for HZ (demographics including age, sex, and race) [2, 10, 14, 15] as well as other potential confounders including socioeconomic status, functional immunocompromising chronic conditions, frailty characteristics, health utilization, and preventive services utilization (see Supplement S-1 for a full list of covariates) [14, 15]. We determined demographic factors and socioeconomic conditions as of the index date, while the other factors were determined based on beneficiaries’ preceding 12 months of health history. Additionally, we included use of immunocompromising drugs (Supplementary Table 10) as a time-varying binary covariate, defining treatment episodes using a 30-day gap allowance. Additionally, immunocompromised and immunocompetent individuals were identified using a modified version of the algorithm developed and validated by Greenberg et al (Supplement S-1; Supplementary Table 11).

We evaluated covariate and MCBS variable balance between vaccinated and unvaccinated cohorts using the standardized mean difference over time (Supplementary Figures 1–10) [16, 17]. No imputation was performed using MCBS variables, and they were not included as covariates in any models.

Statistical Analyses

For all analyses, we used a marginal structural Cox regression model (Cox-MSM) [18, 19] to estimate the hazard ratios (HRs) for each outcome in the vaccinated cohort compared with the unvaccinated cohort. At every 30 days from study start, we applied inverse probability of treatment weighting to balance all covariates across the 3 cohorts. We used 2 time-varying treatment weights (1 each for first dose and second dose) and 1 time-varying censoring weight to calculate the final inverse probability. We derived 3 sets of propensity scores to construct weights from a Cox proportional hazard regression with RZV vaccination status as the dependent variable and the complete list of covariates as independent variables. Propensity scores thus quantified the likelihood of receiving RZV vaccination for each beneficiary based on covariates believed to be associated with the risk of HZ. A Cox proportional hazard model was then used on the weighted data to estimate HRs between the 2 cohorts of interest (1 dose vs unvaccinated or 2 dose vs unvaccinated). Vaccine effectiveness was calculated as (1 – HR) × 100%.

Primary Analyses

The primary analyses evaluated RZV VE in preventing the outcome of interest as well as the RZV VE and effect modification by both age group and timing of the second dose.

For all analysis models, we ran stratified Cox-MSM by immunocompromised status to allow for different baseline hazards between the immunocompromised and the immunocompetent populations. We compared the 1-dose and 2-dose vaccine cohorts to the unvaccinated cohort to evaluate vaccine effectiveness. We also performed 2 primary effect modification analyses, 1 of which assessed the effect of age and another that evaluated the effect of timing of the second vaccination dose.

Secondary Analyses

Our secondary analyses included the evaluation of RZV VE and effect modification by immunocompromised status, by ZVL vaccination status within the prior 5 years, and within individuals with selected autoimmune conditions. We further conducted an analysis to assess the effectiveness of 1 dose of the vaccine over time by comparing effectiveness within 180 days since first vaccination and beyond 180 days since first vaccination. For more details on the secondary and sensitivity analyses, see Supplement S-1.

RESULTS

In the Medicare population, 15 589 546 beneficiaries eligible for RZV vaccination at the start of the study period ultimately contributed 25 026 129 person-years to the unvaccinated cohort (Table 1). Of these beneficiaries, 258 293 met the HZ case definition while in the unvaccinated cohort (Tables 1–2). There were 2152 HZ cases in the 1-dose cohort (478 532 person-years) and 1880 HZ cases in the 2-dose cohort (608 928 person-years). We found that for every 1000 person-years, there were 10.32 HZ cases among unvaccinated beneficiaries, while there were 4.50 HZ and 3.09 HZ cases among 1-dose and 2-dose vaccinees, respectively (Table 2). Among Medicare beneficiaries who received their first dose of RZV, 78% received their second dose by 6 months and 86% by 12 months (Figure 1).

Table 1.

Primary Analysis Vaccine Effectiveness Summary, Herpes Zoster Outcome for the General Medicare Population

HZ Outcome (Per 1000 Person-Years)Vaccine EffectivenessCharacteristicBeneficiariesNo. of HZ OutcomesPerson-Time (1000 Person-Years)Rate95% CI%95% CI

Overall unvaccinated (Ref)	15 589 546	258 293	25 026	10.32	(10.28–10.36)	...	...
Overall 1 dose	1 498 275	2152	479	4.50	(4.31–4.69)	56.9	(55.0%–58.8%)
Overall 2 doses	1 006 446	1880	609	3.09	(2.95–3.23)	70.1	(68.6%–71.5%)
Age, y
65–79
Unvaccinated (Ref)	11 486 608	191 424	18 962	10.10	(10.05–10.14)	...	...
One dose	1 222 612	1654	386	4.29	(4.08–4.49)	58.6	(56.5%–60.7%)
Two doses	821 731	1473	495	2.98	(2.82–3.13)	70.6	(68.9%–72.1%)
80 +
Unvaccinated (Ref)	4 102 938	66 869	6064	11.03	(10.94–11.11)	...	...
One dose	275 663	498	93	5.38	(4.91–5.85)	50.9	(46.2%–55.1%)
Two doses	184 715	407	114	3.57	(3.22–3.91)	68.5	(65.1%–71.6%)
Timing of second dose, d
≤180	912 258	1746	564	3.09	(2.95–3.24)	70.0	(68.4%–71.5%)
>180	94 188	134	44	3.01	(2.50–3.52)	71.7	(66.1%–76.3%)
Time since first dose, da
≤180	…	…	…	…	…	59.5	(57.4%–61.4%)
>180	…	…	…	…	…	43.5	(37.9%–48.7%)
Zoster vaccine live status within 5 y
No
Unvaccinated (Ref)	13 514 350	229 674	21 667	10.60	(10.56–10.64)	...	...
One dose	1 228 423	1790	392	4.56	(4.35–4.77)	57.6	(55.4%–59.6%)
Two doses	831 079	1558	507	3.07	(2.92–3.23)	71.1	(69.5%–72.6%)
Yes
Unvaccinated (Ref)	2 075 196	28 619	3359	8.52	(8.42–8.62)	...	...
One dose	269 852	362	86	4.20	(3.76–4.63)	51.0	(45.4%–56.0%)
Two doses	175 367	322	102	3.15	(2.81–3.50)	63.0	(58.3%–67.2%)
Immunocompromised status
No
Unvaccinated (Ref)	14 842 892	239 789	23 947	10.01	(9.97–10.05)	...	...
One dose	1 437 675	1947	459	4.24	(4.06–4.43)	58.4	(56.4%–60.3%)
Two doses	966 004	1737	584	2.97	(2.83–3.11)	70.5	(69.0%–72.0%)
Yes
Unvaccinated (Ref)	746 654	18 504	1079	17.15	(16.90–17.40)	...	...
One dose	60 600	205	20	10.34	(8.92–11.75)	37.0	(27.4%–45.4%)
Two doses	40 442	143	24	5.85	(4.89–6.81)	64.1	(57.2%–69.8%)
Autoimmune disease
Unvaccinated (Ref)	886 123	20 640	1387	14.89	(14.68–15.09)	...	...
One dose	92 069	186	30	6.25	(5.35–7.15)	57.7	(50.9%–63.6%)
Two doses	61 999	167	38	4.44	(3.77–5.12)	68.0	(62.3%–72.8%)

HZ Outcome (Per 1000 Person-Years)Vaccine EffectivenessCharacteristicBeneficiariesNo. of HZ OutcomesPerson-Time (1000 Person-Years)Rate95% CI%95% CI

Overall unvaccinated (Ref)	15 589 546	258 293	25 026	10.32	(10.28–10.36)	...	...
Overall 1 dose	1 498 275	2152	479	4.50	(4.31–4.69)	56.9	(55.0%–58.8%)
Overall 2 doses	1 006 446	1880	609	3.09	(2.95–3.23)	70.1	(68.6%–71.5%)
Age, y
65–79
Unvaccinated (Ref)	11 486 608	191 424	18 962	10.10	(10.05–10.14)	...	...
One dose	1 222 612	1654	386	4.29	(4.08–4.49)	58.6	(56.5%–60.7%)
Two doses	821 731	1473	495	2.98	(2.82–3.13)	70.6	(68.9%–72.1%)
80 +
Unvaccinated (Ref)	4 102 938	66 869	6064	11.03	(10.94–11.11)	...	...
One dose	275 663	498	93	5.38	(4.91–5.85)	50.9	(46.2%–55.1%)
Two doses	184 715	407	114	3.57	(3.22–3.91)	68.5	(65.1%–71.6%)
Timing of second dose, d
≤180	912 258	1746	564	3.09	(2.95–3.24)	70.0	(68.4%–71.5%)
>180	94 188	134	44	3.01	(2.50–3.52)	71.7	(66.1%–76.3%)
Time since first dose, da
≤180	…	…	…	…	…	59.5	(57.4%–61.4%)
>180	…	…	…	…	…	43.5	(37.9%–48.7%)
Zoster vaccine live status within 5 y
No
Unvaccinated (Ref)	13 514 350	229 674	21 667	10.60	(10.56–10.64)	...	...
One dose	1 228 423	1790	392	4.56	(4.35–4.77)	57.6	(55.4%–59.6%)
Two doses	831 079	1558	507	3.07	(2.92–3.23)	71.1	(69.5%–72.6%)
Yes
Unvaccinated (Ref)	2 075 196	28 619	3359	8.52	(8.42–8.62)	...	...
One dose	269 852	362	86	4.20	(3.76–4.63)	51.0	(45.4%–56.0%)
Two doses	175 367	322	102	3.15	(2.81–3.50)	63.0	(58.3%–67.2%)
Immunocompromised status
No
Unvaccinated (Ref)	14 842 892	239 789	23 947	10.01	(9.97–10.05)	...	...
One dose	1 437 675	1947	459	4.24	(4.06–4.43)	58.4	(56.4%–60.3%)
Two doses	966 004	1737	584	2.97	(2.83–3.11)	70.5	(69.0%–72.0%)
Yes
Unvaccinated (Ref)	746 654	18 504	1079	17.15	(16.90–17.40)	...	...
One dose	60 600	205	20	10.34	(8.92–11.75)	37.0	(27.4%–45.4%)
Two doses	40 442	143	24	5.85	(4.89–6.81)	64.1	(57.2%–69.8%)
Autoimmune disease
Unvaccinated (Ref)	886 123	20 640	1387	14.89	(14.68–15.09)	...	...
One dose	92 069	186	30	6.25	(5.35–7.15)	57.7	(50.9%–63.6%)
Two doses	61 999	167	38	4.44	(3.77–5.12)	68.0	(62.3%–72.8%)

The beneficiary counts included in this table are not mutually exclusive across vaccination status rows because vaccinated beneficiaries can contribute person-time during unvaccinated time. Table 2 represents beneficiaries at the end of the study period.

Abbreviations: CI, confidence interval; HZ, herpes zoster.

a One-dose vaccine effectiveness based on the amount of time that has passed since the initial administration. Outcome count and person-time estimates for time since first dose have been suppressed because time since first dose is a time-varying variable.

Table 1.

Primary Analysis Vaccine Effectiveness Summary, Herpes Zoster Outcome for the General Medicare Population

HZ Outcome (Per 1000 Person-Years)Vaccine EffectivenessCharacteristicBeneficiariesNo. of HZ OutcomesPerson-Time (1000 Person-Years)Rate95% CI%95% CI

Overall unvaccinated (Ref)	15 589 546	258 293	25 026	10.32	(10.28–10.36)	...	...
Overall 1 dose	1 498 275	2152	479	4.50	(4.31–4.69)	56.9	(55.0%–58.8%)
Overall 2 doses	1 006 446	1880	609	3.09	(2.95–3.23)	70.1	(68.6%–71.5%)
Age, y
65–79
Unvaccinated (Ref)	11 486 608	191 424	18 962	10.10	(10.05–10.14)	...	...
One dose	1 222 612	1654	386	4.29	(4.08–4.49)	58.6	(56.5%–60.7%)
Two doses	821 731	1473	495	2.98	(2.82–3.13)	70.6	(68.9%–72.1%)
80 +
Unvaccinated (Ref)	4 102 938	66 869	6064	11.03	(10.94–11.11)	...	...
One dose	275 663	498	93	5.38	(4.91–5.85)	50.9	(46.2%–55.1%)
Two doses	184 715	407	114	3.57	(3.22–3.91)	68.5	(65.1%–71.6%)
Timing of second dose, d
≤180	912 258	1746	564	3.09	(2.95–3.24)	70.0	(68.4%–71.5%)
>180	94 188	134	44	3.01	(2.50–3.52)	71.7	(66.1%–76.3%)
Time since first dose, da
≤180	…	…	…	…	…	59.5	(57.4%–61.4%)
>180	…	…	…	…	…	43.5	(37.9%–48.7%)
Zoster vaccine live status within 5 y
No
Unvaccinated (Ref)	13 514 350	229 674	21 667	10.60	(10.56–10.64)	...	...
One dose	1 228 423	1790	392	4.56	(4.35–4.77)	57.6	(55.4%–59.6%)
Two doses	831 079	1558	507	3.07	(2.92–3.23)	71.1	(69.5%–72.6%)
Yes
Unvaccinated (Ref)	2 075 196	28 619	3359	8.52	(8.42–8.62)	...	...
One dose	269 852	362	86	4.20	(3.76–4.63)	51.0	(45.4%–56.0%)
Two doses	175 367	322	102	3.15	(2.81–3.50)	63.0	(58.3%–67.2%)
Immunocompromised status
No
Unvaccinated (Ref)	14 842 892	239 789	23 947	10.01	(9.97–10.05)	...	...
One dose	1 437 675	1947	459	4.24	(4.06–4.43)	58.4	(56.4%–60.3%)
Two doses	966 004	1737	584	2.97	(2.83–3.11)	70.5	(69.0%–72.0%)
Yes
Unvaccinated (Ref)	746 654	18 504	1079	17.15	(16.90–17.40)	...	...
One dose	60 600	205	20	10.34	(8.92–11.75)	37.0	(27.4%–45.4%)
Two doses	40 442	143	24	5.85	(4.89–6.81)	64.1	(57.2%–69.8%)
Autoimmune disease
Unvaccinated (Ref)	886 123	20 640	1387	14.89	(14.68–15.09)	...	...
One dose	92 069	186	30	6.25	(5.35–7.15)	57.7	(50.9%–63.6%)
Two doses	61 999	167	38	4.44	(3.77–5.12)	68.0	(62.3%–72.8%)

HZ Outcome (Per 1000 Person-Years)Vaccine EffectivenessCharacteristicBeneficiariesNo. of HZ OutcomesPerson-Time (1000 Person-Years)Rate95% CI%95% CI

Overall unvaccinated (Ref)	15 589 546	258 293	25 026	10.32	(10.28–10.36)	...	...
Overall 1 dose	1 498 275	2152	479	4.50	(4.31–4.69)	56.9	(55.0%–58.8%)
Overall 2 doses	1 006 446	1880	609	3.09	(2.95–3.23)	70.1	(68.6%–71.5%)
Age, y
65–79
Unvaccinated (Ref)	11 486 608	191 424	18 962	10.10	(10.05–10.14)	...	...
One dose	1 222 612	1654	386	4.29	(4.08–4.49)	58.6	(56.5%–60.7%)
Two doses	821 731	1473	495	2.98	(2.82–3.13)	70.6	(68.9%–72.1%)
80 +
Unvaccinated (Ref)	4 102 938	66 869	6064	11.03	(10.94–11.11)	...	...
One dose	275 663	498	93	5.38	(4.91–5.85)	50.9	(46.2%–55.1%)
Two doses	184 715	407	114	3.57	(3.22–3.91)	68.5	(65.1%–71.6%)
Timing of second dose, d
≤180	912 258	1746	564	3.09	(2.95–3.24)	70.0	(68.4%–71.5%)
>180	94 188	134	44	3.01	(2.50–3.52)	71.7	(66.1%–76.3%)
Time since first dose, da
≤180	…	…	…	…	…	59.5	(57.4%–61.4%)
>180	…	…	…	…	…	43.5	(37.9%–48.7%)
Zoster vaccine live status within 5 y
No
Unvaccinated (Ref)	13 514 350	229 674	21 667	10.60	(10.56–10.64)	...	...
One dose	1 228 423	1790	392	4.56	(4.35–4.77)	57.6	(55.4%–59.6%)
Two doses	831 079	1558	507	3.07	(2.92–3.23)	71.1	(69.5%–72.6%)
Yes
Unvaccinated (Ref)	2 075 196	28 619	3359	8.52	(8.42–8.62)	...	...
One dose	269 852	362	86	4.20	(3.76–4.63)	51.0	(45.4%–56.0%)
Two doses	175 367	322	102	3.15	(2.81–3.50)	63.0	(58.3%–67.2%)
Immunocompromised status
No
Unvaccinated (Ref)	14 842 892	239 789	23 947	10.01	(9.97–10.05)	...	...
One dose	1 437 675	1947	459	4.24	(4.06–4.43)	58.4	(56.4%–60.3%)
Two doses	966 004	1737	584	2.97	(2.83–3.11)	70.5	(69.0%–72.0%)
Yes
Unvaccinated (Ref)	746 654	18 504	1079	17.15	(16.90–17.40)	...	...
One dose	60 600	205	20	10.34	(8.92–11.75)	37.0	(27.4%–45.4%)
Two doses	40 442	143	24	5.85	(4.89–6.81)	64.1	(57.2%–69.8%)
Autoimmune disease
Unvaccinated (Ref)	886 123	20 640	1387	14.89	(14.68–15.09)	...	...
One dose	92 069	186	30	6.25	(5.35–7.15)	57.7	(50.9%–63.6%)
Two doses	61 999	167	38	4.44	(3.77–5.12)	68.0	(62.3%–72.8%)

Abbreviations: CI, confidence interval; HZ, herpes zoster.

Table 2.

Cohort Demographic Distribution of Eligible Beneficiaries at Study End for the General Medicare Population

Shingrix CohortCovariate (Evaluated at Baseline)UnvaccinatedOne-DoseTwo-DoseMax. Standardized Mean Difference a

Population at study end	10 355 683	100%	463 805	100%	978 348	100%
Age, y
Mean	74.6		73.8		74.0		0.12
Standard deviation	6.7		5.9		5.9
Age Categories, y
65–79	8 039 657	77.6%	383 392	82.7%	805 045	82.3%	0.13
80+	2 316 026	22.4%	80 413	17.3%	173 303	17.7%	0.13
Sex
Male	4 257 943	41.1%	186 382	40.2%	406 862	41.6%	0.03
Female	6 097 740	58.9%	277 423	59.8%	571 486	58.4%	0.03
Race
White	9 077 174	87.7%	414 663	89.4%	888 220	90.8%	0.10
Black	654 384	6.3%	13 073	2.8%	19 177	2.0%	0.22
Other	624 125	6.0%	36 069	7.8%	70 951	7.3%	0.07
Region
West	1 982 181	19.1%	110 017	23.7%	214 981	22.0%	0.11
Midwest	2 410 026	23.3%	102 968	22.2%	224 917	23.0%	0.03
South	3 940 401	38.1%	164 043	35.4%	342 034	35.0%	0.06
Northeast	2 001 856	19.3%	86 531	18.7%	195 993	20.0%	0.03
Other	21 219	0.2%	246	0.1%	423	0.0%	0.05
Reason for entering Medicare
Aged without end stage renal disease/other	9 346 841	90.3%	435 617	93.9%	928 791	94.9%	0.18
Disabled without end stage renal disease	1 008 842	9.7%	28 188	6.1%	49 557	5.1%	0.18
Socioeconomic conditions
Low-income subsidy status
Yes	1 698 287	16.4%	44 823	9.7%	69 945	7.1%	0.29
No	8 657 396	83.6%	418 982	90.3%	908 403	92.9%	0.29
Area deprivation index of residence
0–19	2 356 248	22.8%	159 866	34.5%	347 334	35.5%	0.28
20–39	2 431 136	23.5%	120 308	25.9%	258 393	26.4%	0.07
40–59	2 170 667	21.0%	83 385	18.0%	176 178	18.0%	0.08
60–79	1 834 956	17.7%	56 354	12.2%	113 950	11.6%	0.17
80+	1 235 339	11.9%	30 598	6.6%	56 897	5.8%	0.22
Missing	327 337	3.2%	13 294	2.9%	25 596	2.6%	0.03
Hospitalization stay
One or more	1 299 034	12.5%	51 303	11.1%	104 999	10.7%	0.06
None	9 056 649	87.5%	412 502	88.9%	873 349	89.3%	0.06
Outpatient emergency room visit
One or more	2 213 525	21.4%	88 031	19.0%	176 340	18.0%	0.08
None	8 142 158	78.6%	375 774	81.0%	802 008	82.0%	0.08
General medical visit
0	536 952	5.2%	8 435	1.8%	14 636	1.5%	0.21
1–5	3 735 383	36.1%	149 063	32.1%	302 147	30.9%	0.11
6–10	3 109 528	30.0%	150 863	32.5%	324 129	33.1%	0.07
10+	2 973 820	28.7%	155 444	33.5%	337 436	34.5%	0.12
Vaccinations
Zoster vaccine live in 5 years prior	1 367 802	13.2%	87 731	18.9%	168 452	17.2%	0.16
Pneumococcal	1 793 921	17.3%	105 621	22.8%	222 303	22.7%	0.14
Hepatitis B	36 195	0.3%	2086	0.4%	4321	0.4%	0.02
Tetanus toxoid, reduced diphtheria toxoid, and reduced acellular pertussis	378 784	3.7%	21 861	4.7%	46 048	4.7%	0.05
Health conditions
Asthma	788 626	7.6%	41 084	8.9%	86 290	8.8%	0.05
Blood disorders	2 506 241	24.2%	111 515	24.0%	235 632	24.1%	0.00
Chronic lung disease	1 710 236	16.5%	65 022	14.0%	132 573	13.6%	0.08
Diabetes	3 003 378	29.0%	115 865	25.0%	236 672	24.2%	0.11
Heart disease	4 347 718	42.0%	190 475	41.1%	405 049	41.4%	0.02
Kidney disease	2 175 327	21.0%	90 131	19.4%	188 890	19.3%	0.04
Liver disease	478 358	4.6%	22 991	5.0%	48 060	4.9%	0.02
Neurological conditions	5 219 249	50.4%	243 339	52.5%	512 434	52.4%	0.04
Other malignant neoplasms	1 264 736	12.2%	63 006	13.6%	137 381	14.0%	0.05
Anaphylaxis	9683	0.1%	602	0.1%	1180	0.1%	0.01
Frailty characteristics
Dementia	448 812	4.3%	13 820	3.0%	26 320	2.7%	0.09
Falls	665 812	6.4%	27 190	5.9%	55 976	5.7%	0.03
Fractures	526 703	5.1%	24 317	5.2%	51 094	5.2%	0.01
Home oxygen	295 260	2.9%	8 990	1.9%	17 086	1.7%	0.07
Urinary catheter	65 350	0.6%	2449	0.5%	5158	0.5%	0.01
Walker use	594 478	5.7%	26 280	5.7%	55 165	5.6%	0.00
Wheelchair use	128 399	1.2%	3694	0.8%	6888	0.7%	0.05
Other risk covariates
Alcohol risk	224 333	2.2%	12 402	2.7%	26 450	2.7%	0.03
Medical nutrition therapy	65 812	0.6%	3644	0.8%	7576	0.8%	0.02
Obesity prevention/control	57 891	0.6%	2359	0.5%	4695	0.5%	0.01
Tobacco risk	101 595	1.0%	2642	0.6%	4513	0.5%	0.06
Preventive services
Annual wellness visit
Yes	3 279 522	31.7%	194 926	42.0%	427 071	43.7%	0.25
No	7 076 161	68.3%	268 879	58.0%	551 277	56.3%	0.25
Counseling and health risk assessment
Yes	608 691	5.9%	32 804	7.1%	69 552	7.1%	0.05
No	9 746 992	94.1%	431 001	92.9%	908 796	92.9%	0.05
Other preventive services
0	1 685 219	16.3%	34 808	7.5%	61 152	6.3%	0.32
1	3 086 691	29.8%	105 912	22.8%	206 611	21.1%	0.20
2	2 869 137	27.7%	139 924	30.2%	299 139	30.6%	0.06
3+	2 714 636	26.2%	183 161	39.5%	411 446	42.1%	0.34

Shingrix CohortCovariate (Evaluated at Baseline)UnvaccinatedOne-DoseTwo-DoseMax. Standardized Mean Difference a

Population at study end	10 355 683	100%	463 805	100%	978 348	100%
Age, y
Mean	74.6		73.8		74.0		0.12
Standard deviation	6.7		5.9		5.9
Age Categories, y
65–79	8 039 657	77.6%	383 392	82.7%	805 045	82.3%	0.13
80+	2 316 026	22.4%	80 413	17.3%	173 303	17.7%	0.13
Sex
Male	4 257 943	41.1%	186 382	40.2%	406 862	41.6%	0.03
Female	6 097 740	58.9%	277 423	59.8%	571 486	58.4%	0.03
Race
White	9 077 174	87.7%	414 663	89.4%	888 220	90.8%	0.10
Black	654 384	6.3%	13 073	2.8%	19 177	2.0%	0.22
Other	624 125	6.0%	36 069	7.8%	70 951	7.3%	0.07
Region
West	1 982 181	19.1%	110 017	23.7%	214 981	22.0%	0.11
Midwest	2 410 026	23.3%	102 968	22.2%	224 917	23.0%	0.03
South	3 940 401	38.1%	164 043	35.4%	342 034	35.0%	0.06
Northeast	2 001 856	19.3%	86 531	18.7%	195 993	20.0%	0.03
Other	21 219	0.2%	246	0.1%	423	0.0%	0.05
Reason for entering Medicare
Aged without end stage renal disease/other	9 346 841	90.3%	435 617	93.9%	928 791	94.9%	0.18
Disabled without end stage renal disease	1 008 842	9.7%	28 188	6.1%	49 557	5.1%	0.18
Socioeconomic conditions
Low-income subsidy status
Yes	1 698 287	16.4%	44 823	9.7%	69 945	7.1%	0.29
No	8 657 396	83.6%	418 982	90.3%	908 403	92.9%	0.29
Area deprivation index of residence
0–19	2 356 248	22.8%	159 866	34.5%	347 334	35.5%	0.28
20–39	2 431 136	23.5%	120 308	25.9%	258 393	26.4%	0.07
40–59	2 170 667	21.0%	83 385	18.0%	176 178	18.0%	0.08
60–79	1 834 956	17.7%	56 354	12.2%	113 950	11.6%	0.17
80+	1 235 339	11.9%	30 598	6.6%	56 897	5.8%	0.22
Missing	327 337	3.2%	13 294	2.9%	25 596	2.6%	0.03
Hospitalization stay
One or more	1 299 034	12.5%	51 303	11.1%	104 999	10.7%	0.06
None	9 056 649	87.5%	412 502	88.9%	873 349	89.3%	0.06
Outpatient emergency room visit
One or more	2 213 525	21.4%	88 031	19.0%	176 340	18.0%	0.08
None	8 142 158	78.6%	375 774	81.0%	802 008	82.0%	0.08
General medical visit
0	536 952	5.2%	8 435	1.8%	14 636	1.5%	0.21
1–5	3 735 383	36.1%	149 063	32.1%	302 147	30.9%	0.11
6–10	3 109 528	30.0%	150 863	32.5%	324 129	33.1%	0.07
10+	2 973 820	28.7%	155 444	33.5%	337 436	34.5%	0.12
Vaccinations
Zoster vaccine live in 5 years prior	1 367 802	13.2%	87 731	18.9%	168 452	17.2%	0.16
Pneumococcal	1 793 921	17.3%	105 621	22.8%	222 303	22.7%	0.14
Hepatitis B	36 195	0.3%	2086	0.4%	4321	0.4%	0.02
Tetanus toxoid, reduced diphtheria toxoid, and reduced acellular pertussis	378 784	3.7%	21 861	4.7%	46 048	4.7%	0.05
Health conditions
Asthma	788 626	7.6%	41 084	8.9%	86 290	8.8%	0.05
Blood disorders	2 506 241	24.2%	111 515	24.0%	235 632	24.1%	0.00
Chronic lung disease	1 710 236	16.5%	65 022	14.0%	132 573	13.6%	0.08
Diabetes	3 003 378	29.0%	115 865	25.0%	236 672	24.2%	0.11
Heart disease	4 347 718	42.0%	190 475	41.1%	405 049	41.4%	0.02
Kidney disease	2 175 327	21.0%	90 131	19.4%	188 890	19.3%	0.04
Liver disease	478 358	4.6%	22 991	5.0%	48 060	4.9%	0.02
Neurological conditions	5 219 249	50.4%	243 339	52.5%	512 434	52.4%	0.04
Other malignant neoplasms	1 264 736	12.2%	63 006	13.6%	137 381	14.0%	0.05
Anaphylaxis	9683	0.1%	602	0.1%	1180	0.1%	0.01
Frailty characteristics
Dementia	448 812	4.3%	13 820	3.0%	26 320	2.7%	0.09
Falls	665 812	6.4%	27 190	5.9%	55 976	5.7%	0.03
Fractures	526 703	5.1%	24 317	5.2%	51 094	5.2%	0.01
Home oxygen	295 260	2.9%	8 990	1.9%	17 086	1.7%	0.07
Urinary catheter	65 350	0.6%	2449	0.5%	5158	0.5%	0.01
Walker use	594 478	5.7%	26 280	5.7%	55 165	5.6%	0.00
Wheelchair use	128 399	1.2%	3694	0.8%	6888	0.7%	0.05
Other risk covariates
Alcohol risk	224 333	2.2%	12 402	2.7%	26 450	2.7%	0.03
Medical nutrition therapy	65 812	0.6%	3644	0.8%	7576	0.8%	0.02
Obesity prevention/control	57 891	0.6%	2359	0.5%	4695	0.5%	0.01
Tobacco risk	101 595	1.0%	2642	0.6%	4513	0.5%	0.06
Preventive services
Annual wellness visit
Yes	3 279 522	31.7%	194 926	42.0%	427 071	43.7%	0.25
No	7 076 161	68.3%	268 879	58.0%	551 277	56.3%	0.25
Counseling and health risk assessment
Yes	608 691	5.9%	32 804	7.1%	69 552	7.1%	0.05
No	9 746 992	94.1%	431 001	92.9%	908 796	92.9%	0.05
Other preventive services
0	1 685 219	16.3%	34 808	7.5%	61 152	6.3%	0.32
1	3 086 691	29.8%	105 912	22.8%	206 611	21.1%	0.20
2	2 869 137	27.7%	139 924	30.2%	299 139	30.6%	0.06
3+	2 714 636	26.2%	183 161	39.5%	411 446	42.1%	0.34

We determined demographic factors and socioeconomic conditions as of the index date; the other factors were determined based on beneficiaries’ preceding 12 months of health history. Cohort status was considered starting 30 days after vaccination. The median follow-up times for the 1-dose and 2-dose groups were approximately 2.9 months and 7.1 months, respectively. All individuals who received their second dose, regardless of the length of time between first and second dose, were included in the 2- dose cohort. While 15 589 546 beneficiaries were eligible for recombinant zoster vaccine vaccination at the start of the study period, this table represents beneficiaries at the end of the study period.

Abbreviation: Max., maximum.

a Standardized mean difference was used to examine the balance of covariate distribution between vaccinated and unvaccinated cohorts.

Table 2.

Cohort Demographic Distribution of Eligible Beneficiaries at Study End for the General Medicare Population

Shingrix CohortCovariate (Evaluated at Baseline)UnvaccinatedOne-DoseTwo-DoseMax. Standardized Mean Difference a

Population at study end	10 355 683	100%	463 805	100%	978 348	100%
Age, y
Mean	74.6		73.8		74.0		0.12
Standard deviation	6.7		5.9		5.9
Age Categories, y
65–79	8 039 657	77.6%	383 392	82.7%	805 045	82.3%	0.13
80+	2 316 026	22.4%	80 413	17.3%	173 303	17.7%	0.13
Sex
Male	4 257 943	41.1%	186 382	40.2%	406 862	41.6%	0.03
Female	6 097 740	58.9%	277 423	59.8%	571 486	58.4%	0.03
Race
White	9 077 174	87.7%	414 663	89.4%	888 220	90.8%	0.10
Black	654 384	6.3%	13 073	2.8%	19 177	2.0%	0.22
Other	624 125	6.0%	36 069	7.8%	70 951	7.3%	0.07
Region
West	1 982 181	19.1%	110 017	23.7%	214 981	22.0%	0.11
Midwest	2 410 026	23.3%	102 968	22.2%	224 917	23.0%	0.03
South	3 940 401	38.1%	164 043	35.4%	342 034	35.0%	0.06
Northeast	2 001 856	19.3%	86 531	18.7%	195 993	20.0%	0.03
Other	21 219	0.2%	246	0.1%	423	0.0%	0.05
Reason for entering Medicare
Aged without end stage renal disease/other	9 346 841	90.3%	435 617	93.9%	928 791	94.9%	0.18
Disabled without end stage renal disease	1 008 842	9.7%	28 188	6.1%	49 557	5.1%	0.18
Socioeconomic conditions
Low-income subsidy status
Yes	1 698 287	16.4%	44 823	9.7%	69 945	7.1%	0.29
No	8 657 396	83.6%	418 982	90.3%	908 403	92.9%	0.29
Area deprivation index of residence
0–19	2 356 248	22.8%	159 866	34.5%	347 334	35.5%	0.28
20–39	2 431 136	23.5%	120 308	25.9%	258 393	26.4%	0.07
40–59	2 170 667	21.0%	83 385	18.0%	176 178	18.0%	0.08
60–79	1 834 956	17.7%	56 354	12.2%	113 950	11.6%	0.17
80+	1 235 339	11.9%	30 598	6.6%	56 897	5.8%	0.22
Missing	327 337	3.2%	13 294	2.9%	25 596	2.6%	0.03
Hospitalization stay
One or more	1 299 034	12.5%	51 303	11.1%	104 999	10.7%	0.06
None	9 056 649	87.5%	412 502	88.9%	873 349	89.3%	0.06
Outpatient emergency room visit
One or more	2 213 525	21.4%	88 031	19.0%	176 340	18.0%	0.08
None	8 142 158	78.6%	375 774	81.0%	802 008	82.0%	0.08
General medical visit
0	536 952	5.2%	8 435	1.8%	14 636	1.5%	0.21
1–5	3 735 383	36.1%	149 063	32.1%	302 147	30.9%	0.11
6–10	3 109 528	30.0%	150 863	32.5%	324 129	33.1%	0.07
10+	2 973 820	28.7%	155 444	33.5%	337 436	34.5%	0.12
Vaccinations
Zoster vaccine live in 5 years prior	1 367 802	13.2%	87 731	18.9%	168 452	17.2%	0.16
Pneumococcal	1 793 921	17.3%	105 621	22.8%	222 303	22.7%	0.14
Hepatitis B	36 195	0.3%	2086	0.4%	4321	0.4%	0.02
Tetanus toxoid, reduced diphtheria toxoid, and reduced acellular pertussis	378 784	3.7%	21 861	4.7%	46 048	4.7%	0.05
Health conditions
Asthma	788 626	7.6%	41 084	8.9%	86 290	8.8%	0.05
Blood disorders	2 506 241	24.2%	111 515	24.0%	235 632	24.1%	0.00
Chronic lung disease	1 710 236	16.5%	65 022	14.0%	132 573	13.6%	0.08
Diabetes	3 003 378	29.0%	115 865	25.0%	236 672	24.2%	0.11
Heart disease	4 347 718	42.0%	190 475	41.1%	405 049	41.4%	0.02
Kidney disease	2 175 327	21.0%	90 131	19.4%	188 890	19.3%	0.04
Liver disease	478 358	4.6%	22 991	5.0%	48 060	4.9%	0.02
Neurological conditions	5 219 249	50.4%	243 339	52.5%	512 434	52.4%	0.04
Other malignant neoplasms	1 264 736	12.2%	63 006	13.6%	137 381	14.0%	0.05
Anaphylaxis	9683	0.1%	602	0.1%	1180	0.1%	0.01
Frailty characteristics
Dementia	448 812	4.3%	13 820	3.0%	26 320	2.7%	0.09
Falls	665 812	6.4%	27 190	5.9%	55 976	5.7%	0.03
Fractures	526 703	5.1%	24 317	5.2%	51 094	5.2%	0.01
Home oxygen	295 260	2.9%	8 990	1.9%	17 086	1.7%	0.07
Urinary catheter	65 350	0.6%	2449	0.5%	5158	0.5%	0.01
Walker use	594 478	5.7%	26 280	5.7%	55 165	5.6%	0.00
Wheelchair use	128 399	1.2%	3694	0.8%	6888	0.7%	0.05
Other risk covariates
Alcohol risk	224 333	2.2%	12 402	2.7%	26 450	2.7%	0.03
Medical nutrition therapy	65 812	0.6%	3644	0.8%	7576	0.8%	0.02
Obesity prevention/control	57 891	0.6%	2359	0.5%	4695	0.5%	0.01
Tobacco risk	101 595	1.0%	2642	0.6%	4513	0.5%	0.06
Preventive services
Annual wellness visit
Yes	3 279 522	31.7%	194 926	42.0%	427 071	43.7%	0.25
No	7 076 161	68.3%	268 879	58.0%	551 277	56.3%	0.25
Counseling and health risk assessment
Yes	608 691	5.9%	32 804	7.1%	69 552	7.1%	0.05
No	9 746 992	94.1%	431 001	92.9%	908 796	92.9%	0.05
Other preventive services
0	1 685 219	16.3%	34 808	7.5%	61 152	6.3%	0.32
1	3 086 691	29.8%	105 912	22.8%	206 611	21.1%	0.20
2	2 869 137	27.7%	139 924	30.2%	299 139	30.6%	0.06
3+	2 714 636	26.2%	183 161	39.5%	411 446	42.1%	0.34

Shingrix CohortCovariate (Evaluated at Baseline)UnvaccinatedOne-DoseTwo-DoseMax. Standardized Mean Difference a

Population at study end	10 355 683	100%	463 805	100%	978 348	100%
Age, y
Mean	74.6		73.8		74.0		0.12
Standard deviation	6.7		5.9		5.9
Age Categories, y
65–79	8 039 657	77.6%	383 392	82.7%	805 045	82.3%	0.13
80+	2 316 026	22.4%	80 413	17.3%	173 303	17.7%	0.13
Sex
Male	4 257 943	41.1%	186 382	40.2%	406 862	41.6%	0.03
Female	6 097 740	58.9%	277 423	59.8%	571 486	58.4%	0.03
Race
White	9 077 174	87.7%	414 663	89.4%	888 220	90.8%	0.10
Black	654 384	6.3%	13 073	2.8%	19 177	2.0%	0.22
Other	624 125	6.0%	36 069	7.8%	70 951	7.3%	0.07
Region
West	1 982 181	19.1%	110 017	23.7%	214 981	22.0%	0.11
Midwest	2 410 026	23.3%	102 968	22.2%	224 917	23.0%	0.03
South	3 940 401	38.1%	164 043	35.4%	342 034	35.0%	0.06
Northeast	2 001 856	19.3%	86 531	18.7%	195 993	20.0%	0.03
Other	21 219	0.2%	246	0.1%	423	0.0%	0.05
Reason for entering Medicare
Aged without end stage renal disease/other	9 346 841	90.3%	435 617	93.9%	928 791	94.9%	0.18
Disabled without end stage renal disease	1 008 842	9.7%	28 188	6.1%	49 557	5.1%	0.18
Socioeconomic conditions
Low-income subsidy status
Yes	1 698 287	16.4%	44 823	9.7%	69 945	7.1%	0.29
No	8 657 396	83.6%	418 982	90.3%	908 403	92.9%	0.29
Area deprivation index of residence
0–19	2 356 248	22.8%	159 866	34.5%	347 334	35.5%	0.28
20–39	2 431 136	23.5%	120 308	25.9%	258 393	26.4%	0.07
40–59	2 170 667	21.0%	83 385	18.0%	176 178	18.0%	0.08
60–79	1 834 956	17.7%	56 354	12.2%	113 950	11.6%	0.17
80+	1 235 339	11.9%	30 598	6.6%	56 897	5.8%	0.22
Missing	327 337	3.2%	13 294	2.9%	25 596	2.6%	0.03
Hospitalization stay
One or more	1 299 034	12.5%	51 303	11.1%	104 999	10.7%	0.06
None	9 056 649	87.5%	412 502	88.9%	873 349	89.3%	0.06
Outpatient emergency room visit
One or more	2 213 525	21.4%	88 031	19.0%	176 340	18.0%	0.08
None	8 142 158	78.6%	375 774	81.0%	802 008	82.0%	0.08
General medical visit
0	536 952	5.2%	8 435	1.8%	14 636	1.5%	0.21
1–5	3 735 383	36.1%	149 063	32.1%	302 147	30.9%	0.11
6–10	3 109 528	30.0%	150 863	32.5%	324 129	33.1%	0.07
10+	2 973 820	28.7%	155 444	33.5%	337 436	34.5%	0.12
Vaccinations
Zoster vaccine live in 5 years prior	1 367 802	13.2%	87 731	18.9%	168 452	17.2%	0.16
Pneumococcal	1 793 921	17.3%	105 621	22.8%	222 303	22.7%	0.14
Hepatitis B	36 195	0.3%	2086	0.4%	4321	0.4%	0.02
Tetanus toxoid, reduced diphtheria toxoid, and reduced acellular pertussis	378 784	3.7%	21 861	4.7%	46 048	4.7%	0.05
Health conditions
Asthma	788 626	7.6%	41 084	8.9%	86 290	8.8%	0.05
Blood disorders	2 506 241	24.2%	111 515	24.0%	235 632	24.1%	0.00
Chronic lung disease	1 710 236	16.5%	65 022	14.0%	132 573	13.6%	0.08
Diabetes	3 003 378	29.0%	115 865	25.0%	236 672	24.2%	0.11
Heart disease	4 347 718	42.0%	190 475	41.1%	405 049	41.4%	0.02
Kidney disease	2 175 327	21.0%	90 131	19.4%	188 890	19.3%	0.04
Liver disease	478 358	4.6%	22 991	5.0%	48 060	4.9%	0.02
Neurological conditions	5 219 249	50.4%	243 339	52.5%	512 434	52.4%	0.04
Other malignant neoplasms	1 264 736	12.2%	63 006	13.6%	137 381	14.0%	0.05
Anaphylaxis	9683	0.1%	602	0.1%	1180	0.1%	0.01
Frailty characteristics
Dementia	448 812	4.3%	13 820	3.0%	26 320	2.7%	0.09
Falls	665 812	6.4%	27 190	5.9%	55 976	5.7%	0.03
Fractures	526 703	5.1%	24 317	5.2%	51 094	5.2%	0.01
Home oxygen	295 260	2.9%	8 990	1.9%	17 086	1.7%	0.07
Urinary catheter	65 350	0.6%	2449	0.5%	5158	0.5%	0.01
Walker use	594 478	5.7%	26 280	5.7%	55 165	5.6%	0.00
Wheelchair use	128 399	1.2%	3694	0.8%	6888	0.7%	0.05
Other risk covariates
Alcohol risk	224 333	2.2%	12 402	2.7%	26 450	2.7%	0.03
Medical nutrition therapy	65 812	0.6%	3644	0.8%	7576	0.8%	0.02
Obesity prevention/control	57 891	0.6%	2359	0.5%	4695	0.5%	0.01
Tobacco risk	101 595	1.0%	2642	0.6%	4513	0.5%	0.06
Preventive services
Annual wellness visit
Yes	3 279 522	31.7%	194 926	42.0%	427 071	43.7%	0.25
No	7 076 161	68.3%	268 879	58.0%	551 277	56.3%	0.25
Counseling and health risk assessment
Yes	608 691	5.9%	32 804	7.1%	69 552	7.1%	0.05
No	9 746 992	94.1%	431 001	92.9%	908 796	92.9%	0.05
Other preventive services
0	1 685 219	16.3%	34 808	7.5%	61 152	6.3%	0.32
1	3 086 691	29.8%	105 912	22.8%	206 611	21.1%	0.20
2	2 869 137	27.7%	139 924	30.2%	299 139	30.6%	0.06
3+	2 714 636	26.2%	183 161	39.5%	411 446	42.1%	0.34

Abbreviation: Max., maximum.

a Standardized mean difference was used to examine the balance of covariate distribution between vaccinated and unvaccinated cohorts.

Figure 1.

Recombinant zoster vaccine second-dose uptake over time since first dose for the general Medicare population.

In the primary analysis, we found a 2-dose VE in preventing community HZ of 70.1% (95% CI, 68.6–71.5; Table 1). Stratifying by age, we found VE was similar between persons aged 65–79 years and those ≥80 years (Table 1).

Our analysis did not find a difference in VE based on the timing of the second dose. The VE for those who received their second dose within 180 days (median = 90) of the first was 70.0% (95% CI, 68.4–71.5), similar to those vaccinated beyond 180 days (median = 230; VE = 71.7%; 95% CI, 66.1–76.3). Also, we found a 1-dose VE in preventing community HZ of 56.9% (95% CI, 55.0–58.8) (Table 1).

Being immunocompromised resulted in a significantly lower 2-dose VE compared with immunocompetent individuals (HR = 1.22; 95% CI, 1.02–1.46) (Supplementary Table 12). The 2-dose VE among immunocompromised beneficiaries was 64.1% (95% CI, 57.2–69.8), while among immunocompetent beneficiaries it was 70.9% (95% CI, 69.3–72.4).

Among individuals who had received a ZVL vaccination during the 5 years prior to RZV, the 2-dose and 1-dose VE were 63.0% (95% CI, 58.3–67.2) and 51.0% (95% CI, 45.4–56.0), respectively. Having received a prior ZVL vaccination resulted in a HZ incidence of 8.5 (95% CI, 8.4–8.6) per 1000 person-years in the RZV unvaccinated cohort compared with an outcome rate of 10.6 (95% CI, 10.6–10.6) per 1000 person-years in the RZV unvaccinated cohort who did not receive ZVL in the prior 5 years.

The secondary analysis evaluating OZ showed a 2-dose VE of 66.8% (95% CI, 60.7–72.0) and a 1-dose VE of 44.7% (95% CI, 36.0–52.3; Table 3). The PHN secondary analysis showed a 2-dose VE of 76.0% (95% CI, 68.4–81.8) and a 1-dose VE of 51.4% (95% CI, 42.0–59.2). Results for all other subgroup, secondary, and sensitivity analyses demonstrated no VE differences across groups.

Table 3.

Secondary Analysis Vaccine Effectiveness Summary, Ophthalmic Zoster and Postherpetic Neuralgia Outcomes for the General Medicare Population

No. Rate (Per 1000 Person-Years)Vaccine EffectivenessCharacteristicNo. of OutcomesPerson-Time (1000 Person-Years)Rate95% CIvaccine effectiveness95% CI

Ophthalmic zoster
Unvaccinated (Ref)	19 306	25 235	0.77	(0.75–0.78)	...	...
One dose	194	487	0.40	(0.34–0.45)	44.7%	(36.0%–52.3%)
Two doses	157	618	0.25	(0.21–0.29)	66.8%	(60.7%–72.0%)
Postherpetic neuralgia
Unvaccinated (Ref)	19 586	19 857	0.99	(0.97–1.00)	...	...
One dose	131	295	0.44	(0.37–0.52)	51.4%	(42.0%–59.2%)
Two doses	55	240	0.23	(0.17–0.29)	76.0%	(68.4%–81.8%)

No. Rate (Per 1000 Person-Years)Vaccine EffectivenessCharacteristicNo. of OutcomesPerson-Time (1000 Person-Years)Rate95% CIvaccine effectiveness95% CI

Ophthalmic zoster
Unvaccinated (Ref)	19 306	25 235	0.77	(0.75–0.78)	...	...
One dose	194	487	0.40	(0.34–0.45)	44.7%	(36.0%–52.3%)
Two doses	157	618	0.25	(0.21–0.29)	66.8%	(60.7%–72.0%)
Postherpetic neuralgia
Unvaccinated (Ref)	19 586	19 857	0.99	(0.97–1.00)	...	...
One dose	131	295	0.44	(0.37–0.52)	51.4%	(42.0%–59.2%)
Two doses	55	240	0.23	(0.17–0.29)	76.0%	(68.4%–81.8%)

Abbreviation: CI, confidence interval.

Table 3.

Secondary Analysis Vaccine Effectiveness Summary, Ophthalmic Zoster and Postherpetic Neuralgia Outcomes for the General Medicare Population

No. Rate (Per 1000 Person-Years)Vaccine EffectivenessCharacteristicNo. of OutcomesPerson-Time (1000 Person-Years)Rate95% CIvaccine effectiveness95% CI

Ophthalmic zoster
Unvaccinated (Ref)	19 306	25 235	0.77	(0.75–0.78)	...	...
One dose	194	487	0.40	(0.34–0.45)	44.7%	(36.0%–52.3%)
Two doses	157	618	0.25	(0.21–0.29)	66.8%	(60.7%–72.0%)
Postherpetic neuralgia
Unvaccinated (Ref)	19 586	19 857	0.99	(0.97–1.00)	...	...
One dose	131	295	0.44	(0.37–0.52)	51.4%	(42.0%–59.2%)
Two doses	55	240	0.23	(0.17–0.29)	76.0%	(68.4%–81.8%)

No. Rate (Per 1000 Person-Years)Vaccine EffectivenessCharacteristicNo. of OutcomesPerson-Time (1000 Person-Years)Rate95% CIvaccine effectiveness95% CI

Ophthalmic zoster
Unvaccinated (Ref)	19 306	25 235	0.77	(0.75–0.78)	...	...
One dose	194	487	0.40	(0.34–0.45)	44.7%	(36.0%–52.3%)
Two doses	157	618	0.25	(0.21–0.29)	66.8%	(60.7%–72.0%)
Postherpetic neuralgia
Unvaccinated (Ref)	19 586	19 857	0.99	(0.97–1.00)	...	...
One dose	131	295	0.44	(0.37–0.52)	51.4%	(42.0%–59.2%)
Two doses	55	240	0.23	(0.17–0.29)	76.0%	(68.4%–81.8%)

Abbreviation: CI, confidence interval.

Analyses restricting the study population to beneficiaries who had received a prior influenza vaccination were consistent with the primary analyses among the general Medicare population. Full analysis results for this population are available in Supplement S-2 and Supplementary Tables 14–16, 18.

DISCUSSION

In this large real-world effectiveness prospective cohort study of RZV, we were able to compare our estimates of VE to those from clinical trials as well as provide VE estimates across several parameters not previously studied, such as immunocompromised status and timing of the second dose. We found a significantly higher VE against HZ following 2 doses of RZV compared with 1 dose, and the difference was most pronounced for older and immunocompromised beneficiaries. The lower VE for 1 dose highlights the need to ensure adherence to the FDA-indicated [3], CDC-recommended, 2-dose schedule. Reassuringly, given the occurrence of RZV shortages [20], our study provides evidence that delays in the administration of a second dose, at least within the first year post first-dose vaccination, should not undermine RZV effectiveness. Against PHN, the most common complication of HZ [2], we found a 2-dose VE that was slightly lower than the 89% (95% CI, 69–97) estimated from a pooled analysis of clinical trial data [3].

Our study also produced novel findings by examining effectiveness of RZV by demographic and underlying health conditions as well as prior HZ vaccination. Encouragingly, VE was not significantly lower for beneficiaries aged ≥80 years as long as the 2-dose course was completed (Table 1). Effectiveness among individuals with autoimmune conditions was similar to that of the overall population; among a broadly defined group of immunocompromised beneficiaries, effectiveness was only slightly lower than that for the overall Medicare population. The HR for the interaction of treatment and immunocompromised status was 1.2, which is a small but statistically significant difference in the VE for immunocompetent individuals compared with immunocompromised individuals. Although immunocompromised persons were excluded from prelicensure clinical trials, RZV demonstrated an efficacy of 68% (95% CI, 56–78) in clinical trials among hematologic stem cell transplant patients [21] and a post hoc efficacy estimate of 87% (95% CI, 44–99) among patients with hematologic malignancies [22].

Our finding of a lower RZV VE against HZ for individuals who had received a ZVL vaccination in the prior 5 years, which could be due to the protective effect of the ZVL among Shingrix-unvaccinated beneficiaries, reflected in the lower crude outcome rates among the ZVL-vaccinated group (8.52 vs 10.60 events per 1000 person-years). However, the possibility of ZVL vaccination status misclassification that could result in some beneficiaries receiving ZVL prior to entry into Medicare and of unmeasured confounding cannot be excluded and deserves further investigation.

There are several key differences between our real-world study and clinical trials that must be considered. The overall estimate for RZV effectiveness among Medicare beneficiaries was 70%, which is substantially lower than the 91% efficacy estimated in clinical trials of participants aged ≥70 years. Two potential reasons for this disparity are measurement error in the form of outcome misclassification and population composition differences between studies. While previous studies have found relatively high positive predictive values for identifying HZ in claims, the identification of outcomes in clinical trials with prospective follow-up and laboratory diagnostics has much higher accuracy [12, 13, 23, 24]. Our case identification relied on diagnosis codes and prescriptions observed in Medicare claims; in the clinical trials, all clinically suspected cases of HZ were PCR-confirmed or adjudicated by an expert panel. Using the less specific clinical definition from the trial (“suspected cases”), which more closely mimics the case definition used in our study, efficacy would have been approximately 76% (156 suspected cases among 13 881 vaccinated and 653 suspected cases among 14 035 placebo recipients) [24]. Another factor that may be driving a difference in VE estimates is the underlying population in each study: our study population was older, possibly more frail, and included immunocompromised individuals who demonstrate lower VE. While this represents a difference from the clinical trial population, we believe a strength of the study is the generalizability of the Medicare population to adults aged ≥65 years.

In addition to the specificity of our case definitions, our study had other potential limitations that may bias our results toward the null, including bias associated with a higher likelihood of health-seeking behavior. To decrease this potential bias, we conducted a sensitivity analysis restricting the study cohort to individuals who had received an influenza vaccine within the prior 2 years. These results did not differ from our main analysis, suggesting that health-seeking behavior bias, if present, was not substantial (Supplementary Tables 14–16, 18). This finding was consistent with results from a prior study in a similar population in which we also restricted the analysis to individuals who had received another vaccination [15]. Moreover, in our main analysis, we used MSM methods to optimize the time-varying similarity between vaccinated and unvaccinated cohorts. Because Medicare is an administrative database, outcomes and risk factors were not verified by medical record review. However, previous record validation studies have shown relatively high positive correlation between administrative codes for HZ outcomes and medical records [12, 13, 23, 24]. Finally, because our estimates only cover the first 2 years post-approval for RZV, issues of duration of protection will need to be addressed in future work.

By demonstrating results that both complement and, in some cases, reaffirm those provided by the clinical trials, this study shows that the analysis of real-world data can inform deliberations by public health decision-makers regarding refinement of vaccination recommendations.

Supplementary Data

Supplementary materials are available at Clinical Infectious Diseases online. Consisting of data provided by the authors to benefit the reader, the posted materials are not copyedited and are the sole responsibility of the authors, so questions or comments should be addressed to the corresponding author.

Notes

Author contributions. H. S. I., R. F., J. K., Y. L., Y. C., P. E. A., R. L.-G., J. K., and K. D. contributed to the study conception and design, data interpretation, and manuscript writing and review. X. W., H.-M. S., Y. C., B. L., M. W., and T. E. M. contributed to study design, data collection and analysis, and manuscript writing and review.

Acknowledgments. The authors thank Manzi Ngaiza for assistance with analytics, coordination, and manuscript writing and review.

Financial support. This work was supported by an interagency agreement between the US Food and Drug Administration and the Centers for Medicare & Medicaid Services (IAA 244-18-1067S).

Potential conflicts of interest. All authors: No reported conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest.

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Published by Oxford University Press for the Infectious Diseases Society of America 2021.

This work is written by (a) US Government employee(s) and is in the public domain in the US.

Published by Oxford University Press for the Infectious Diseases Society of America 2021.

What does recombinant zoster vaccine mean?

Recombinant zoster (shingles) vaccine can prevent shingles. Shingles (also called herpes zoster, or just zoster) is a painful skin rash, usually with blisters. In addition to the rash, shingles can cause fever, headache, chills, or upset stomach.

Are there 2 types of shingles vaccine?

Two vaccines are licensed and recommended to prevent shingles in the U.S.. Zoster vaccine live (ZVL, Zostavax) has been in use since 2006. Recombinant zoster vaccine (RZV, Shingrix), has been in use since 2017 and is recommended by ACIP as the preferred shingles vaccine.

Is the zoster vaccine Shingrix?

CDC recommends Shingrix (recombinant zoster vaccine, or RZV) for the prevention of herpes zoster (shingles) and related complications. CDC recommends two doses of Shingrix separated by 2 to 6 months for immunocompetent adults aged 50 years and older: Whether or not they report a prior episode of herpes zoster.

How often do you need to get the recombinant zoster vaccine?

Shingles vaccine is given as a two-dose series. For most people, the second dose should be given 2 to 6 months after the first dose. Some people who have or will have a weakened immune system can get the second dose 1 to 2 months after the first dose. Ask your health care provider for guidance.

Is recombinant zoster vaccine the same as shingrix

Abstract

METHODS

Data Sources and Study Design

Exposure and Index Date Definition

Study Population and Inclusion Criteria

Outcome Definitions and Follow-up

Covariates

Statistical Analyses

Primary Analyses

Secondary Analyses

RESULTS

DISCUSSION

Supplementary Data

Notes

References

What does recombinant zoster vaccine mean?

Are there 2 types of shingles vaccine?

Is the zoster vaccine Shingrix?

How often do you need to get the recombinant zoster vaccine?

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