Quality of life impact of an adjuvanted recombinant zoster vaccine in adults aged 50 years and older

© The Author(s) 2018. Published by Oxford University Press on behalf of The Gerontological Society of America. 1231 Journals of Gerontology: Medical Sciences cite as: J Gerontol A Biol Sci Med Sci, 2019, Vol. 74, No. 8, 1231–1238 doi:10.1093/gerona/gly150 Advance Access publication June 27, 2018 This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/ by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact [email protected] Translational Section Research Article Quality of Life Impact of an Adjuvanted Recombinant Zoster Vaccine in Adults Aged 50 Years and Older Desmond Curran, PhD,1 Lidia Oostvogels, MD,1,21 Thomas Heineman, MD, PhD,2,19 Sean Matthews, MSc,3 Janet McElhaney, MD,4 Shelly McNeil, MD,5 Javier Diez-Domingo, MD, PhD,6 Himal Lal, MD,2,20 Charles Andrews, MD,7 Eugene Athan, MPH, MD,8 Johan Berglund, PhD,9,10 Laura Campora, MD,1 Ferdinandus de Looze, MSc,11,12 Tiina Korhonen, MD,13 Edward Leung, MD,14 MyronLevin, MD,15,16 AntonioVolpi, MD,17 and Robert W.Johnson, MD18; on behalf of the ZOE-50/70 Study Group 1GSK, Wavre, Belgium. 2GSK, King of Prussia, Pennsylvania. 3Freelance, on behalf of GSK, Wavre, Belgium. 4Health Sciences North Research Institute, Sudbury, Ontario, Canada. 5Canadian Center for Vaccinology, IWK Health Centre and Nova Scotia Health Authority, Dalhousie University, Halifax, Canada. 6FISABIO-Public Health, Valencia, Spain. 7Diagnostics Research Group, San Antonio, Texas. 8Department of Infectious Disease, Barwon Health, Deakin University, Geelong, Victoria, Australia. 9Department of Medical Radiation Physics, Karolinska University Hospital, Stockholm, Sweden. 10Department of Clinical Science, Intervention and Technology, Karolinska Institutet, Stockholm, Sweden. 11AusTrials Pty Ltd, Sherwood, Queensland, Australia. 12School of Medicine, University of Queensland, Brisbane, Australia. 13Tampere Vaccine Research Clinic, Tampere, Finland. 14United Christian Hospital, Kowloon, Hong Kong. 15Department of Pediatrics and 16Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora. 17University of Rome Tor Vergata, Italy. 18University of Bristol, UK. 19Present address: Genocea Biosciences, Cambridge, Massachusetts. 20Present address: Pfizer Vaccine Inc, Collegeville, Philadelphia, Pennsylvania. 21Present address: CureVac AG, Tübingen, Germany. Address correspondence to: Desmond Curran, PhD, Health Economics Department, GSK, Avenue Fleming 20, 1300 Wavre, Belgium. E-mail: [email protected] Received: March 5, 2018; Editorial Decision Date: June 15, 2018 Decision Editor: Anne Newman, MD, MPH Abstract Background: To determine the efficacy of an adjuvanted recombinant zoster vaccine in reducing the herpes zoster (HZ) burden of illness, HZ burden of interference with activities of daily living, and HZ impact on quality of life. Methods: The assessments were integrated in two Phase III trials, ZOE-50 (NCT01165177) and ZOE-70 (NCT01165229). HZ burden of illness and HZ burden of interference with activities of daily living were assessed by the Zoster Brief Pain Inventory (ZBPI) instrument and quality of life by the EuroQol-5 Dimension (EQ-5D) utility index and the SF-36 health survey. We report the ZOE-50 results and a pooled analysis of patients aged 70years and older from the trials combined. Results: The estimated vaccine efficacy in reducing HZ burden of illness and HZ burden of interference was greater than 90% in both the ZOE-50 and the pooled ZOE-70 analysis. In confirmed HZ cases, adjuvantedrecombinant zoster vaccine reduced the maximal ZBPI worstpain score in the pooled ZOE-70 analysis (p=.032) and the maximal ZBPI average-pain scores in both the ZOE-50 (p=.049) and the pooled ZOE-70 analysis (p=.043). In breakthrough HZ cases, trends for diminished loss of quality of life compared with placebo-recipient HZ cases were observed, with differences up to 0.14 on the EQ-5D index at time points during the 4 weeks following HZ onset. Conclusions: Adjuvanted recombinant zoster vaccine reduced the HZ burden of illness significantly, particularly due to its very high vaccine efficacy in preventing HZ. For breakthrough HZ cases, the results suggest that the adjuvantedrecombinant zoster vaccine mitigated severity of HZ-related pain, burden of interference with activities of daily living, and recipients’ utility loss. Keywords: Burden of illness, Burden of interference, Activities of daily living Downloaded from https://academic.oup.com/biomedgerontology/article-abstract/74/8/1231/5046047 by Tampere University Library user on 16 July 2019 Herpes zoster (HZ) results from reactivation of the varicella-zoster virus (VZV). HZ typically manifests as a unilateral, painful dermatomal rash. Most cases of HZ resolve completely within about 1month of rash onset, but 10%–20% of HZ patients develop postherpetic neuralgia, a condition of debilitating pain that may last for months or even years and is very difficult to treat (1–3). The pain and discomfort experienced during an acute HZ episode may substantially reduce patients’ health-related quality of life (QoL) by impairing their physical, emotional, and social functioning. The pain may interfere with patients’ ability to perform activities of daily living (ADLs), diminish vitality, and impair physical and mental health (4–6). The incidence of HZ increases substantially from around the age of 50 years, concurrent with the natural age-related decline of cell-mediated immunity, which is considered an important risk factor for reactivation of VZV (7). The lifetime risk of developing HZ is estimated at approximately 30%, increasing to 50% or more in people living beyond the age of 85years (8,9). The principal available treatments for HZ, analgesics, and antivirals have shown efficacy in the context of clinical trials but in clinical-practice patient satisfaction with their perceived effectiveness in alleviating symptoms was found to be low (9). HZ is preventable by vaccination, and an HZ vaccine containing live attenuated VZV was licensed in the United States and Europe in 2006 (10). Adjuvantedrecombinant zoster vaccine (RZV; Shingrix, GSK) is a two-dose adjuvanted nonlive subunit vaccine combining recombinant VZV glycoprotein E and the AS01B adjuvant system. Two multinational Phase III randomized, observer-blinded, placebocontrolled clinical trials were conducted concurrently at the same study sites using the same methods to assess the efficacy of RZV in preventing HZ in two adult populations. The ZOE-50 study (NCT01165177) included patients aged 50years and older (11) and ZOE-70 study (NCT01165229) included patients aged 70years and older (12). For patients developing HZ, the trials also collected data for assessing the burden of illness of HZ, its burden of interference with the patients’ ADLs and its impact on theirQoL. A protocol prespecified pooled analysis of all patients aged 70 years and older from the two trials (henceforth “the pooled ZOE-70 analysis”) was performed to obtain more robust estimates of the vaccine’s efficacy in people aged 70years and older. In both the ZOE-50 trial and the pooled ZOE-70 analysis, the overall vaccine efficacy (VE) of RZV in preventing HZ was estimated to be more than 90% (11,12). In this article, using data from the ZOE study and the pooled ZOE-70 analysis, we present results showing the efficacy of RZV in preventing the burden of illness of HZ and the HZ burden of interference with ADLs, and its impact on the QoL of patients with HZ. The corresponding comparative results of the ZOE-70 analysis are presented in Supplementary Material for this article. Methods StudyDesign The study design was described in detail in the articles presenting the efficacy and safety results of the trials (11,12). Outcome Measures Patients with suspected HZ were asked to attend assessment visits and to complete the Zoster Brief Pain Inventory (ZBPI) daily for 28 days after rash onset and then weekly until either the patient had been pain free for four consecutive weeks or 90days had elapsed after rash onset (whichever came last). For all analyses of data involving HZ episodes, Day 0 was defined as the first day of HZ rash (13). If the rash had started more than 24 hours before the initial assessment, patients were asked to retrospectively complete the ZBPI for the period between rash onset and 24 hours before the first assessmentday. The ZBPI asks the patients to rate four categories of pain (least, worst, average over the last 24 hours, and now) on 11-point Likerttype scales (0–10, with 10 signifying the worst imaginable pain). The “worst pain” over the last 24 hours category is considered the most reliable indicator of pain (13) and was used to measure the VE in reducing the burden of illness related to HZpain. The ZBPI questionnaire also assesses the degree to which the HZ pain interferes with seven ADLs: general activity, mood, walking ability, work, relation with others, sleep, and enjoyment of life. These are all to be rated on 11-point Likert-type scales with Table1. HZ ZBPI Severity and Burden of Illness Scores (Based on ZBPI “Worst-Pain” Score) Age Group (YOA) RZV Placebo VE (%) 95% CI for VE (%)n m ZBPI Severity of Illness Scorea ZBPI Burden of Illness Score n m ZBPI Severity of Illness Scorea ZBPI Burden of Illness Score ZOE-50 study 50–59 4 3,491 0.069 0.018 103 3,523 4.179 1.056 98.3 (83.8, 100) 60–69 3 2,140 0.082 0.020 89 2,165 4.274 1.067 98.1 (79.2, 100) ≥70 2 1,709 0.069 0.019 60 1,723 6.059 1.644 98.9 (72.1, 100) Total 9 7,340 0.073 0.019 252 7,411 4.644 1.188 98.4 (92.2, 100) Pooled ZOE-70 analysis 70–79 19 6,468 0.316 0.084 214 6,552 6.369 1.690 95.1 (92.5, 97.7) ≥80 6 1,782 1.222 0.344 67 1,791 6.777 1.932 82.2 (77.2, 87.2) Total 25 8,250 0.511 0.137 281 8,343 6.457 1.739 92.1 (90.4, 93.8) Notes: CI=confidence interval; HZ=herpes zoster; m=total number of patients in this group; n=number of HZ cases in this group; RZV=adjuvantedrecombinant zoster vaccine; VE=vaccine efficacy; YOA=years of age; ZBPI=Zoster Brief Pain Inventory. aZBPI severity of illness was calculated as the area under the curve (AUC), Days 0–182, of the ZBPI “worst-pain” score for patients with confirmed HZ cases. Patients without a confirmed HZ case were allocated an AUC score of 0.The ZBPI burden of illness score was calculated as the ZBPI severity of illness score divided by the total follow-up in years. In the ZOE-50 study and pooled ZOE-70 analysis, two and three patients in the placebo groups, respectively, had a confirmed HZ episode but did not have an evaluable ZBPI score and were therefore not included in this table. Score: 0–10, with 10 signifying the worst pain. 1232 Journals of Gerontology: MEDICAL SCIENCES, 2019, Vol. 74, No. 8 Downloaded from https://academic.oup.com/biomedgerontology/article-abstract/74/8/1231/5046047 by Tampere University Library user on 16 July 2019 0 signifying “does not interfere” and 10 “completely interferes.” Asummary ADL score is calculated by averaging the scores for the seven activities. The EuroQol-5 Dimension (EQ-5D) is a utility instrument widely used in assessments of individuals’ health-related QoL. Patients are asked to grade their extent of problems (no problem, some problems, and severe problems) in five dimensions: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. The combination of answers to the five dimensions results in 243 possible health states, each of which may be translated into a utility score ranging from less than 0 (ie, a health state worse than death) to 1 (ie, best possible health state) (14). QoL was also assessed by the Short Form Survey (SF-36) (15). This assessment method and a short summary of the SF-36 results are described in Supplementary Material for this article. All patients were asked to complete the EQ-5D and SF-36 questionnaires at baseline (ie, Day 0, before vaccination Dose 1). Patients not developing HZ were asked to complete the questionnaires at Months 14, 26, and 38. All patients experiencing a suspected HZ episode were to complete both the EQ-5D and SF-36 at the first visit to evaluate suspected HZ and then weekly along with the ZBPI. For patients with suspected HZ, specimens were tested centrally by polymerase chain reaction and reviewed by an adjudication committee. Only HZ cases confirmed by polymerase chain reaction or by the adjudication committee were included in the analyses (11,12). Statistical Analyses For each case of HZ, the maximal ZBPI “worst-pain” and “averagepain” scores during the HZ episode were calculated and compared between the RZV and placebo groups by means of the Wilcoxon nonparametric test. Clinically significant pain was defined as a ZBPI “worst-pain” score greater than or equal to3. A combined measure of pain intensity and duration was calculated by the area under the curve method (13). For each patient, the area under the curve was calculated by multiplying the average of two consecutive ZBPI worst-pain scores by the number of days between the scores and adding up these measures over a specified time period (13). The modified ZBPI scale was used (13), which from Day 30 onwards sets ZBPI “worst-pain” scores of less than 3 equal to 0.The ZBPI severity of illness scores were calculated as the area under the curve from the day of rash onset until Day 182. An area under the curve value of 0 was imputed for patients without confirmed HZ. The burden of illness due to pain was then estimated by aggregating the severity of illness scores over all the Table2. HZ ZBPI Severity and Burden of Interference Scores (Based on ZBPI ADL Summary Scores) Age Group (YOA) RZV Placebo VE 95% CI for VEn m ZBPI Severity of Interference Scorea ZBPI Burden of Interference Score n m ZBPI Severity of Interference Scorea ZBPI Burden of Interference Score ZOE-50 study 50–59 4 3,491 0.024 0.006 103 3,523 2.850 0.720 99.2 (68.0, 100) 60–69 3 2,140 0.038 0.010 89 2,165 2.823 0.705 98.7 (63.8, 100) ≥70 2 1,709 0.024 0.006 60 1,723 4.004 1.087 99.4 (37.0, 100) Total 9 7,340 0.028 0.007 252 7,411 3.110 0.796 99.1 (86.2, 100) Pooled ZOE-70 analysis 70–79 19 6,468 0.180 0.048 214 6,552 4.261 1.130 95.8 (92.3, 99.3) ≥80 6 1,782 1.353 0.381 67 1,791 5.110 1.457 73.8 (69.5, 78.1) Total 25 8,250 0.434 0.116 281 8,343 4.443 1.196 90.3 (88.5, 92.1) Notes: ADL=activities of daily living; CI=confidence interval; HZ=herpes zoster; m=total number of patients in this group; n=number of HZ cases in this group; VE=vaccine efficacy; YOA=years of age; ZBPI=Zoster Brief Pain Inventory. aZBPI severity of interference was calculated as the area under the curve (AUC), Days 0–182, of the ZBPI ADL score for patients with confirmed HZ cases. Patients without a confirmed HZ case were allocated an AUC score of 0.The ZBPI burden of interference score was calculated as the ZBPI severity of interference score divided by the total number of years of follow-up. Score: 0–10, with 0 signifying “does not interfere” and 10“completely interferes.” Figure 1. Mean ZBPI “worst-pain” scores per day during the first 28 days after rash onset (A: ZOE-50 study; B: pooled ZOE-70 analysis). RZV = adjuvanted recombinant zoster vaccine; ZBPI = Zoster Brief Pain Inventory. *Days with statistically significant differences (at the .05 level) in ZBPI worst-pain scores between the two groups. In the ZOE-50 study, no RZV recipient with HZ completed the ZBPI days 0 and 1. Journals of Gerontology: MEDICAL SCIENCES, 2019, Vol. 74, No. 8 1233 Downloaded from https://academic.oup.com/biomedgerontology/article-abstract/74/8/1231/5046047 by Tampere University Library user on 16 July 2019 patients in a group and dividing by the total number of years of patient follow-up. Consequently, this composite measure takes the incidence of HZ as well as the severity and duration of HZ pain into account. VE was defined as the relative reduction in the burden of illness score in the RZV group as compared to the score in the placebo group and calculated as 1 minus the relative risk (ie, the burden of illness score in the RZV group divided by the burden of illness score in the placebo group). The VE in reducing the burden of interference was defined and calculated in a similar way using the combined ZBPI ADL score as the measure. These analyses were performed on the modified total vaccinated cohort, which excluded patients who did not receive two doses or who had a confirmed HZ episode within 1month of receiving Dose 2 and included only HZ patients who completed at least one ZBPI questionnaire. The chop-lump test (16) was used to assess the difference in ZBPI severity of illness scores and ZBPI severity of interference scores between the RZV and placebo groups in the modified total vaccinated cohort. In a post hoc analysis, VE for reducing severe ZBPI pain (score≥7 for “worst-pain”) was estimated in patients in the modified total vaccinated cohort HZ evaluable subgroup which included confirmed HZ cases with a ZBPI questionnaire completed during the first 14days after HZ onset. Standardized asymptotic binomial confidence intervals (CI) for the VE were calculated using the score method of Farrington and Manning (17). A repeated-measures analysis of variance model was fitted to estimate the impact of HZ on EQ-5D utility scores in the placebo group only, stratified by age. There were too few patients in the RZV group with breakthrough HZ to apply this modeling approach. The model included the baseline utility scores, that is, the most recent utility assessment prior to the onset of HZ and the utility scores during the first 4 weeks of the HZ episode. The least squares mean estimates over time are presented. Results Flowcharts of the trials and demographic data of the patients enrolled in the two studies who developed confirmed HZ along with the various study populations are presented in Supplementary FiguresS1 and S2. At the end of study analysis of the ZOE-50 study, 9 HZ cases had occurred among the 7,340 patients receiving RZV compared with 254 cases among the 7,413 patients receiving placebo. In the pooled ZOE-70 analysis, 25 HZ cases occurred among the 8,250 patients receiving RZV and 284 cases among the 8,346 patients receiving placebo (Table1). Table3. Distribution of Maximal ZBPI “Worst-Pain” and ZBPI “Average-Pain” Scores Over the Duration of the Entire HZ Episode ZBPI Scale ZOE-50 Pooled ZOE-70 RZV (N=8) Placebo (N=241) p Value RZV (N=23) Placebo (N=263) p Valuen (%) n (%) n (%) n (%) “Worst-pain” score ≥3 7 (87.5) 211 (87.6) .113 19 (82.6) 239 (90.9) .032 0 1 (12.5) 13 (5.4) 1 (4.3) 18 (6.8) 1 0 10 (4.1) 1 (4.3) 2 (0.8) 2 0 7 (2.9) 2 (8.7) 4 (1.5) 3 0 9 (3.7) 1 (4.3) 21 (8.0) 4 2 (25.0) 13 (5.4) 4 (17.4) 14 (5.3) 5 0 19 (7.9) 2 (8.7) 16 (6.1) 6 1 (12.5) 13 (5.4) 2 (8.7) 8 (3.0) 7 2 (25.0) 33 (13.7) 1 (4.3) 23 (8.7) 8 2 (25.0) 38 (15.8) 3 (13.0) 50 (19.0) 9 0 48 (19.9) 5 (21.7) 43 (16.3) 10 0 38 (15.8) 1 (4.3) 64 (24.3) Mean 5.5 6.7 5.7 7.0 SD 2.73 2.94 2.96 3.02 “Average-pain” score 0 1 (12.5) 14 (5.8) .049 1 (4.3) 19 (7.2) .043 1 0 13 (5.4) 2 (8.7) 8 (3.0) 2 0 15 (6.2) 2 (8.7) 18 (6.8) 3 2 (25.0) 13 (5.4) 4 (17.4) 18 (6.8) 4 1 (12.5) 25 (10.4) 2 (8.7) 21 (8.0) 5 3 (37.5) 23 (9.5) 3 (13.0) 26 (9.9) 6 1 (12.5) 40 (16.6) 4 (17.4) 35 (13.3) 7 0 30 (12.4) 3 (13.0) 46 (17.5) 8 0 38 (15.8) 1 (4.3) 32 (12.2) 9 0 17 (7.1) 0 21 (8.0) 10 0 13 (5.4) 1 (4.3) 19 (7.2) Mean 3.9 5.5 4.5 5.6 SD 1.89 2.74 2.50 2.81 Notes: HZ=herpes zoster; N=number of HZ cases in each group; n=number of HZ cases in each category; ZBPI=Zoster Brief Pain Inventory. Includes only patients in the modified total vaccinated cohort HZ evaluable subgroup, that is, confirmed HZ cases with a ZBPI questionnaire completed during the first 14days after HZ onset. 1234 Journals of Gerontology: MEDICAL SCIENCES, 2019, Vol. 74, No. 8 Downloaded from https://academic.oup.com/biomedgerontology/article-abstract/74/8/1231/5046047 by Tampere University Library user on 16 July 2019 The mean delay between the date of rash onset and the first HZ evaluation was 4.7 and 4.8days in the ZOE-50 and pooled ZOE70 analysis, respectively (range 0–33 in both analyses). Completion rates for the ZBPI questionnaire were approximately 15% on Day 0, more than 60% from Day 3 onwards, and greater than or equal to 80% from Day 6 onwards. For the EQ-5D and SF-36 instruments during an ongoing HZ episode, the completion rates were approximately 50% on Day 0 and greater than or equal to 84% at all time points thereafter. OverallVE The estimated overall VE in reducing the ZBPI burden of illness was 98.4% in the ZOE-50 study and 92.1% in the pooled ZOE-70 analysis (Table1). The VE in reducing burden of illness was lower in patients aged 80years and older (ie, 82.2%). However, the absolute reduction in burden of illness score was higher in these patients compared with younger patients (ie, 1.932–0.344≈ 1.6 in patients aged 80years and older compared with 1.0 in patients aged 50–69years). The estimated overall VE in reducing the burden of interference with ADLs was 99.1% in the ZOE-50 study and 90.3% in the pooled ZOE-70 analysis (Table2). Outcomes for Patients DevelopingHZ Figure1 presents the mean ZBPI “worst-pain” scores per day during the first 28days for all the confirmed HZ cases. The mean “worstpain” scores were at all times lower in the RZV group than in the placebo group, but the differences were only statistically significant for a few days spread over the period in the pooled ZOE-70 analysis. Table3 presents the distribution of the individual maximal ZBPI “worst-pain” and “average-pain” scores experienced over the entire HZ episode. In the ZOE-50 study, a severe ZBPI “worst-pain” score (ie, ≥7) was reported by 50.0% in the RZV group and 65.2% in the placebo group (VE 23.3%, 95% CI = −22.4%–67.2%). The corresponding proportions reporting severe ZBPI “average pain” were 0% and 40.7%, respectively (VE 100%, 95% CI=19.4%–100%). The median time to resolution of clinically significant pain (ie, ZBPI “worst pain” ≥ 3)was 14days in the RZV group and 17days in the placebo group (p=.600). In the pooled ZOE-70 analysis, the proportions reporting severe “worst pain” were 43.5% in the RZV group and 68.4% in the placebo group (VE 36.5%, 95% CI=6.5%–62.8%). The corresponding proportions reporting severe “average pain” were 21.7% in the RZV group and 44.9% in the placebo group (VE 51.6%, 95% CI=4.9%–78.7%). The median time to resolution of clinically significant pain was 14days in the RZV group versus 22days in the placebo group (p=.409). Figure2 presents the mean ZBPI ADL interference scores during the first 28days for the placebo groups only. Sleep, mood, and general activities appear to be the most affected. In both plots, the mean ADL interference scores appeared to peak at Days 3 and 4 after rash onset and gradually diminished overtime. Table4 presents the utility loss of the HZ patients in the placebo groups over the first 28days after rash onset, assessed using the EQ-5D instrument. The estimated utility loss was highest on Day 0 and decreased over time in all age groups as the patients recovered from HZ, but a negative impact of HZ on QoL remained until the end of Week4. The estimated differences over time in mean EQ-5D utility scores between the RZV and placebo groups are presented in Figure3, suggesting that they were greatest at Day 0 (up to 0.14 in ZOE-50) and decreased over time. Using the utility assessments prior to the HZ episode as baseline, the VE in terms of reducing the patients’ utility loss due to HZ over the first 28days after rash onset was estimated to be 63.7% in the ZOE-50 study and 21.2% in the pooled ZOE-70 analysis. Discussion The overall efficacy of the RZV in reducing the burden of illness and the burden of interference in ADLs of HZ was more than 90% in both the ZOE-50 study and the pooled ZOE-70 analysis. These are mainly the results of VE in preventing HZ. However, even with the small number of breakthrough HZ cases compared with the placebo recipients, this study demonstrated that adults who developed HZ despite vaccination with RZV were less likely to have severe pain, and there was a trend for them to have a shorter duration of pain, less burden of interference in ADLs, and higher QoL scores over the first 4 weeks following rash onset. Therefore, RZV not only prevented HZ but also attenuated the severity of disease in individuals who developed HZ despite being vaccinated withRZV. The corresponding comparative results of the ZOE-70 analysis are presented in Supplementary Material for this article. The results are in line with the ZOE-70 pooled analysis presented in the main text and also with those presented by Cunningham and colleagues (12). Note that the two clinical trials, ZOE-50 and ZOE-70, were conducted at the same sites, and patients aged 70years and older were randomly assigned to the ZOE-50 or ZOE-70 study. This ensured that the prespecified pooled analysis could be done appropriately, leading to more robust results in all patients aged 70years andolder. Figure 2. Mean daily ZBPI ADL scores during the first 28 days after rash onset for the placebo groups (A: ZOE-50 study; B: pooled ZOE-70 analysis). ADL=activities of daily living; ZBPI=Zoster Brief Pain Inventory. Journals of Gerontology: MEDICAL SCIENCES, 2019, Vol. 74, No. 8 1235 Downloaded from https://academic.oup.com/biomedgerontology/article-abstract/74/8/1231/5046047 by Tampere University Library user on 16 July 2019 It is likely that vaccine-induced VZV-specific CD4+ T cells play a role in the attenuation of breakthrough cases for both the live attenuated vaccine and for RZV (especially as such CD4+ T cells are present in the dorsal root ganglion in natural HZ). Plausible hypotheses are that memory CD4+ T cells could have direct antiviral effects (eg, through interferon-γ) or could mobilize natural killer cells, resulting in (antibody-dependent) cytolytic responses. Thus, memory CD4+ T cells would be capable of mounting a rapid antiviral response upon reactivation of VZV. In some cases, this anamnestic immune response may not be able to prevent an HZ episode, but in vaccine recipients with breakthrough disease, the response may be sufficient to more rapidly control the reactivated virus, leading to reduced severity of disease. Observations of apparent mitigation of breakthrough disease in vaccine recipients have also been reported for a number of other vaccinepreventable diseases such as influenza, rotavirus, and pertussis (18–20). The greatest interference of HZ-related pain on ADLs occurred during the first week following rash onset. Sleep was the most impacted activity in the placebo recipients. Another study also found that some 65% of HZ patients did not get sufficient sleep most of the time (21). As both the ZBPI pain and ADL interference scores on the day of rash onset were high, it may be hypothesized that pain started during the prodromal period. Previous studies showing that prodromal pain may last for 1–5days or even longer before rash onset (6,22) suggest that the overall duration of clinically relevant HZ pain and utility loss was greater than we estimated. In the placebo groups, based on the mean utility values estimated for the HZ patients during the first 4 weeks after HZ onset (Table4) and the pre-HZ scores, the monthly values for the utility loss may be estimated at 0.140 and 0.132 (ie, 4.3 and 4.0days of perfect health lost for each month of HZ) for the ZOE-50 and pooled ZOE-70 analysis, respectively. These values are in line with Pellissier and colleagues (23), who also reported quality-adjusted life-years losses for postherpetic neuralgia patients, in unvaccinated patients of 0.106 and 0.156 (ie, 38.7 and 56.9days of perfect health lost during a year). Kawai and colleagues, in a literature review, estimated, based on the values from Pellissier and colleagues, that the overall qualityadjusted life-years lost due to HZ including postherpetic neuralgia was 0.021, 0.049, and 0.058 for patients aged 60–69, 70–79, and 80years and older, respectively. Much higher values were reported by Moore and colleagues based on data from Oster and colleagues (1,24,25). Using these estimates and incidence estimates from Leung and colleagues (26), between 25,000 and 100,000years of perfect health are lost annually in the United States in patients aged 60years and older due toHZ. As a consequence of the high VE against HZ, and the low number of breakthrough cases, the statistical power to identify statistically significant differences between the groups is low. We calculated, using Cohen’s “d” effect size measure, that at the p=.05 level, power was only 29% for the ZOE-50 study and 63% for the pooled ZOE-70 analysis (27). Table4. Estimated Placebo-Group EQ-5D Scores for Utility Loss by Age Group and Time Point During the Acute HZ Period Age Group (YOA) Time Point LS Means Estimate Estimated Utility Loss 95% CI ZOE-50 study 50–59 Pre-HZ 0.880 Day 0 0.622 0.258 (0.204, 0.313) Week 1 0.685 0.195 (0.136, 0.254) Week 2 0.736 0.145 (0.081, 0.208) Week 3 0.821 0.059 (−0.007, 0.125) Week 4 0.872 0.008 (−0.060, 0.076) 60–69 Pre-HZ 0.879 Day 0 0.637 0.242 (0.176, 0.308) Week 1 0.713 0.166 (0.102, 0.230) Week 2 0.791 0.087 (0.020, 0.155) Week 3 0.800 0.078 (0.008, 0.150) Week 4 0.799 0.080 (0.007, 0.152) ≥70 Pre-HZ 0.800 Day 0 0.517 0.284 (0.209, 0.358) Week 1 0.610 0.190 (0.110, 0.270) Week 2 0.703 0.097 (0.011, 0.184) Week 3 0.713 0.087 (0.000, 0.175) Week 4 0.765 0.035 (−0.054, 0.124) Pooled ZOE-70 analysis 70–79 Pre-HZ 0.840 Day 0 0.606 0.234 (0.191, 0.277) Week 1 0.674 0.166 (0.121, 0.210) Week 2 0.686 0.153 (0.107, 0.200) Week 3 0.735 0.105 (0.057, 0.152) Week 4 0.787 0.052 (0.004, 0.100) ≥80 Pre-HZ 0.753 Day 0 0.542 0.211 (0.133, 0.289) Week 1 0.645 0.108 (0.030, 0.187) Week 2 0.686 0.067 (−0.017, 0.150) Week 3 0.682 0.071 (−0.015, 0.157) Week 4 0.749 0.004 (−0.083, 0.091) Notes: CI=confidence interval; EQ-5D=EuroQol-5 Dimension; HZ=herpes zoster; LS=least squares; YOA=years of age. An EQ-5D value of 1 represents the best possible health state. 1236 Journals of Gerontology: MEDICAL SCIENCES, 2019, Vol. 74, No. 8 Downloaded from https://academic.oup.com/biomedgerontology/article-abstract/74/8/1231/5046047 by Tampere University Library user on 16 July 2019 To conclude, this study provided evidence that the RZV vaccine, in addition to its very high efficacy in preventing HZ, has an effect of attenuating the severity of HZ disease in breakthrough cases. This mitigation was most clearly quantified with the HZ-specific ZBPI instrument to assess the severity of pain but was also discernible as trends with the less sensitive, generic QoL instruments. Vaccination with RZV could prevent loss of quality of life associated with both HZ and postherpetic neuralgia. Supplementary Material Supplementary data is available at The Journals of Gerontology, Series A: Biological Sciences and Medical Sciences online. Funding GlaxoSmithKline Biologicals SA was the funding source and was involved in all study (NCT01165177 and NCT01165229) activities and overall data management (collection, analysis, and interpretation). GlaxoSmithKline Biologicals SA also funded all costs associated with the development and the publishing of the present manuscript. All authors had full access to the data, and the corresponding author was responsible for the submission of the manuscript. Acknowledgments The authors thank all study participants, as well as clinical investigators and study nurses, involved in the ZOE-50/70 trials; Toufik Zahaf and Andrea Callegaro from the statistical team; Christophe Sauboin from the health economic team; and Melanie Drolet and Robbert van der Mostfor their participation to the study. The authors thank Business & Decision Life Sciences platform for editorial assistance and publications coordination, on behalf of GSK. Writing support was provided by Niels Neymark, and editorial assistance and publication coordination was provided by Gregory Collet. Compliance With Ethics Guidelines All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. Informed consent was obtained from all individual participants included in the study. Conflict of Interest J.E.M. received honoraria and fees paid to her institution from GSK, Sanofi Pasteur, Merck Sharp & Dohme, and Pfizer, as well as travel support from Sanofi Pasteur, Merck Sharp & Dohme, and Pfizer outside the submitted work. A.V.reports personal fees from Sanofi Pasteur MSD outside the submitted work. J.D.D.reports personal fees from GSK (advisory board: pharmacoeconomic study with Synflorix in Spain), grants from Sanofi Pasteur MSD (epidemiological study on herpes zoster), and personal fees from Sanofi Pasteur MSD (advisory board: Zostavax) outside the submitted work. M.J.L. received fees for serving on advisory boards from Merck Sharp & Dohme and GSK, grant support from Merck Sharp & Dohme and GSK, and royalties from a patent related to a zoster vaccine held with Merck. E.A., C.A., B.J., T.K., and E.L.have nothing to disclose. F.D.L.reports grants from GSK and Novartis outside the submitted work. He is the medical director of a company that conducts clinical trials for a large number of pharmaceutical companies in many different therapeutic areas. S.McN.reports grants and personal fees from Pfizer (continuing professional development talks on adult immunization; research grant; consulting fees), grants from GSK, personal fees from Merck Sharp & Dohme (continuing professional development talks on adult immunization and consulting fees) outside the submitted work. R.J.reports personal fees from GSK. During the conduct of the study, he also reports personal fees from Sanofi Pasteur MSD and Merck Sharp & Dohme. Outside the submitted work, he reports personal fees from Merck Sharp & Dohme and Sanofi Pasteur MSD. H.L.is a current employee of Pfizer and receives stock options as part of his employee remuneration. D.C. and L.C.are employees of the GSK group of companies. D.C.hold shares in the GSK group of companies. T.C.H.,H.L., and L.O.are former employees of the GSK group of companies. T.C.H.,H.L., and L.O.hold shares or stock options from GSK as part of their current or former employee remuneration. T.C.H.is a consultant for GSK and is the coinventor of a patent application related to the vaccine used in this study. S.M.is a freelance consultant working on behalf of GSK. References 1. Oster G, Harding G, Dukes E, Edelsberg J, Cleary PD. Pain, medication use, and health-related quality of life in older persons with postherpetic neuralgia: results from a population-based survey. J Pain. 2005;6:356– 363. doi:10.1016/j.jpain.2005.01.359 2. Lukas K, Edte A, Bertrand I. The impact of herpes zoster and postherpetic neuralgia on quality of life: patient-reported outcomes in six European countries. Z Gesundh Wiss. 2012;20:441–451. doi:10.1007/ s10389-011-0481-8 Figure 3. Mean EQ-5D utility scores during the first 28 days after rash onset (A: ZOE-50 study; B: pooled ZOE-70 analysis). CI = confidence interval; Diff. = difference; EQ-5D = EuroQol-5 Dimension; RZV=adjuvantedrecombinant zoster vaccine. Journals of Gerontology: MEDICAL SCIENCES, 2019, Vol. 74, No. 8 1237 Downloaded from https://academic.oup.com/biomedgerontology/article-abstract/74/8/1231/5046047 by Tampere University Library user on 16 July 2019 3. Pickering G, Marcoux M, Chapiro S, etal. An algorithm for neuropathic pain management in older people. Drugs Aging. 2016;33:575–583. doi:10.1007/s40266-016-0389-7 4. Katz J, Cooper EM, Walther RR, Sweeney EW, Dworkin RH. Acute pain in herpes zoster and its impact on health-related quality of life. Clin Infect Dis. 2004;39:342–348. doi:10.1086/421942 5. Drolet M, Brisson M, Schmader KE, etal. The impact of herpes zoster and postherpetic neuralgia on health-related quality of life: a prospective study. CMAJ. 2010;182:1731–1736. doi:10.1503/cmaj.091711 6. Johnson RW, Bouhassira D, Kassianos G, Leplège A, Schmader KE, Weinke T. The impact of herpes zoster and post-herpetic neuralgia on quality-oflife. BMC Med. 2010;8:37. doi:10.1186/1741-7015-8-37 7. Gershon AA, Gershon MD. Pathogenesis and current approaches to control of varicella-zoster virus infections. Clin Microbiol Rev. 2013;26:728– 743. doi:10.1128/CMR.00052-13 8. Yoshikawa TT, Schmader K. Herpes zoster in older adults. Clin Infect Dis. 2001;32:1481–1486. doi:doi.org/10.1086/320169 9. Gater A, Abetz-Webb L, Carroll S, Mannan A, Serpell M, Johnson R. Burden of herpes zoster in the UK: findings from the zoster quality of life (ZQOL) study. BMC Infect Dis. 2014;14:402. doi:10.1186/1471-2334-14-402 10. Oxman MN, Levin MJ, Johnson GR, etal. A vaccine to prevent herpes zoster and postherpetic neuralgia in older adults. N Engl J Med. 2005;352:2271–2284. doi:10.1056/NEJMoa051016 11. Lal H, Cunningham AL, Godeaux O, etal.; ZOE-50 Study Group. Efficacy of an adjuvanted herpes zoster subunit vaccine in older adults. N Engl J Med. 2015;372:2087–2096. doi:10.1056/NEJMoa1501184 12. Cunningham AL, Lal H, Kovac M, etal.; ZOE-70 Study Group. Efficacy of the herpes zoster subunit vaccine in adults 70years of age or older. N Engl J Med. 2016;375:1019–1032. doi:10.1056/NEJMoa1603800 13. Coplan PM, Schmader K, Nikas A, etal. Development of a measure of the burden of pain due to herpes zoster and postherpetic neuralgia for prevention trials: adaptation of the brief pain inventory. J Pain. 2004;5:344–356. 14. Rabin R, de Charro F. EQ-5D: a measure of health status from the EuroQol Group. Ann Med. 2001;33:337–343. doi:10.3109/07853890109002087 15. Ware JE Jr. SF-36 health survey update. Spine (Phila Pa 1976). 2000;25:3130–3139. 16. Follmann D, Fay MP, Proschan M. Chop-lump tests for vaccine trials. Biometrics. 2009;65:885–893. doi:10.1111/j.1541-0420.2008.01131.x 17. Farrington CP, Manning G. Test statistics and sample size formulae for comparative binomial trials with null hypothesis of non-zero risk difference or non-unity relative risk. Stat Med. 1990;9:1447–1454. doi:10.1002/ sim.4780091208 18. Ehrlich HJ, Singer J, Berezuk G, et al. A cell culture-derived influenza vaccine provides consistent protection against infection and reduces the duration and severity of disease in infected individuals. Clin Infect Dis. 2012;54:946–954. doi:10.1093/cid/cir959 19. Kendrick P, Eldering GA. Study in active immunization against pertussis. Am J Hyg. 1939;38:133–153. doi:10.1093/oxfordjournals.aje.a118485 20. Vesikari T, Giaquinto C, Huppertz HI. Clinical trials of rotavirus vaccines in Europe. Pediatr Infect Dis J. 2006;25(1 suppl):S42–S47. doi:10.1097/01. inf.0000197565.45345.4e 21. Weinke T, Edte A, Schmitt S, Lukas K. Impact of herpes zoster and post-herpetic neuralgia on patients’ quality of life: a patient-reported outcomes survey. Z Gesundh Wiss. 2010;18:367–374. doi:10.1007/ s10389-010-0323-0 22. Volpi A, Gross G, Hercogova J, Johnson RW. Current management of herpes zoster: the European view. Am J Clin Dermatol. 2005;6:317–325. doi:10.2165/00128071-200506050-00005 23. Pellissier JM, Brisson M, Levin MJ. Evaluation of the cost-effectiveness in the United States of a vaccine to prevent herpes zoster and postherpetic neuralgia in older adults. Vaccine. 2007;25:8326–8337. doi:10.1016/j. vaccine.2007.09.066 24. Moore L, Remy V, Martin M, Beillat M, McGuire A. A health economic model for evaluating a vaccine for the prevention of herpes zoster and post-herpetic neuralgia in the UK. Cost Eff Resour Alloc. 2010;8:7. doi:10.1186/1478-7547-8-7 25. Kawai K, Preaud E, Baron-Papillon F, Largeron N, Acosta CJ. Costeffectiveness of vaccination against herpes zoster and postherpetic neuralgia: a critical review. Vaccine. 2014;32:1645–1653. doi:10.1016/j. vaccine.2014.01.058 26. Leung J, Harpaz R, Molinari N-A, Jumaan A, Zhou F. Herpes zoster incidence among insured persons in the United States, 1993–2006: evaluation of impact of varicella vaccination. Clin Infect Dis. 2011;52:332–340. doi:10.1093/cid/ciq077 27. Sawilowsky S. New effect size rules of thumb. J Mod App Stat Meth. 2009;8:597–599. doi:10.22237/jmasm/1257035100 1238 Journals of Gerontology: MEDICAL SCIENCES, 2019, Vol. 74, No. 8 Downloaded from https://academic.oup.com/biomedgerontology/article-abstract/74/8/1231/5046047 by Tampere University Library user on 16 July 2019