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Medical conditions at enrollment do not impact efficacy and safety of the adjuvanted recombinant zoster vaccine: a pooled post-hoc analysis of two parallel randomized trials

Medical conditions at enrollment do not impact efficacy and safety of the adjuvanted recombinant... HUMAN VACCINES & IMMUNOTHERAPEUTICS 2019, VOL. 15, NO. 12, 2865–2872 https://doi.org/10.1080/21645515.2019.1627818 SHORT REPORT Medical conditions at enrollment do not impact efficacy and safety of the adjuvanted recombinant zoster vaccine: a pooled post-hoc analysis of two parallel randomized trials a b c d e Lidia Oostvogels , Thomas C. Heineman , Robert W. Johnson , Myron J. Levin , Janet E. McElhaney , a a f g h Peter Van den Steen , Toufik Zahaf , Alemnew F. Dagnew , Roman Chlibek , Javier Diez-Domingo , i a j k l b Iris S. Gorfinkel , Caroline Hervé , Shinn-Jang Hwang , Hideyuki Ikematsu , George Kalema , Himal Lal , m a n g o p Shelly A. McNeil , Tomas Mrkvan , Karlis Pauksens , Jan Smetana , Daisuke Watanabe , Lily Yin Weckx , and Anthony L. Cunningham for the ZOE-50/70 Study Group a b c d GSK, Wavre, Belgium; GSK, King of Prussia, PA, USA; Faculty of Health Sciences, University of Bristol, Bristol, UK; Departments of Pediatrics and Medicine, University of Colorado, Anschutz Medical Campus, Aurora, CO, USA; Health Sciences North Research Institute, Sudbury, Ontario, Canada; f g h GSK, Rockville, MD, USA; Faculty of Military Health Sciences, University of Defense, Hradec Kralove, Czech Republic; Fundación para el Fomento i j de la Investigación Sanitaria y Biomédica, Valencia, Spain; PrimeHealth Clinical Research, Toronto, Ontario, Canada; Department of Family Medicine, Taipei Veterans General Hospital and National Yang Ming University School of Medicine, Taipei, Taiwan; Japan Physicians Association, l m Tokyo, Japan; Keyrus Biopharma, Waterloo, Belgium, on behalf of GSK; Canadian Center for Vaccinology, IWK Health Center and Nova Scotia Health Authority, Dalhousie, University, Halifax, Canada; Department of Infectious Diseases, Uppsala University Hospital, Uppsala, Sweden; o p Department of Dermatology, Aichi Medical University, Nagakute, Japan; Department of Pediatrics, Federal University of Sao Paulo, Sao Paulo, Brazil; The Westmead Institute for Medical Research, Westmead, University of Sydney, Sydney, NSW, Australia ABSTRACT ARTICLE HISTORY Received 15 February 2019 In two pivotal efficacy studies (ZOE-50; ZOE-70), the adjuvanted recombinant zoster vaccine (RZV) Revised 10 May 2019 demonstrated >90% efficacy against herpes zoster (HZ). Accepted 27 May 2019 Adults aged≥50 or ≥70 years (ZOE-50 [NCT01165177]; ZOE-70 [NCT01165229]) were randomized to receive 2 doses of RZV or placebo 2 months apart. Vaccine efficacy and safety were evaluated post-hoc in the pooled (ZOE- KEYWORDS 50/70) population according to the number and type of selected medical conditions present at enrollment. Varicella-zoster virus; At enrollment, 82.3% of RZV and 82.7% of placebo recipients reported ≥1 of the 15 selected medical adjuvanted recombinant conditions. Efficacy against HZ ranged from 84.5% (95% Confidence Interval [CI]: 46.4–97.1) in participants zoster vaccine; vaccine efficacy; vaccine safety; with respiratory disorders to 97.0% (95%CI: 82.3–99.9) in those with coronary heart disease. Moreover, underlying chronic disease; efficacy remained >90% irrespective of the number of selected medical conditions reported by a participant. comorbidity As indicated by the similarity of the point estimates, this post-hoc analysis suggests that RZV efficacy remains high in all selected medical conditions, as well as with increasing number of medical conditions. No safety concern was identified by the type or number of medical conditions present at enrollment. PLAIN LANGUAGE SUMMARY What is the context? Shingles, or herpes zoster (HZ), is a clinical reactivation of the varicella-zoster virus, which causes chickenpox. HZ refers to the resulting skin rash, which is often accompanied by severe, burning or itching, pain. While HZ generally affects adults over 50 years of age, it is also common in people with weakened immune systems, for example patients undergoing chemotherapy, or those with an underlying medical condition such as diabetes, asthma, or other diseases. What is new? ● Clinical trials have demonstrated that the risk of experiencing HZ in adults over 50 years of age is substantially decreased after administration of the adjuvanted recombinant zoster vaccine (RZV, Shingrix). Additional analyses were performed to determine the impact of common medical condi- tions on the efficacy and safety of Shingrix. These show that underlying medical conditions were common among the trial participants, but Shingrix was still protective against HZ despite their presence. A similar safety profile was reported by participants receiving either placebo or RZV. What is the impact? Shingrix is effective in the prevention of HZ in adults over 50 years of age, including those with one or more of the common medical conditions considered. Results may help inform the use of Shingrix in these individuals. CONTACT Peter Van den Steen peter.b.van-den-steen@gsk.com GSK, Avenue Fleming 20, Wavre 1300, Belgium. Present address: Lidia Oostvogels, CureVac AG, Tübingen, Germany Thomas C. Heineman, Halozyme Therapeutics, San Diego, CA, USA Himal Lal, Pfizer Inc., Collegeville, PA, USA Supplemental data for this article can be accessed on the https://doi.org/10.1080/21645515.2019.1627818 publisher’s website. © 2019 GlaxoSmithKline Biologicals SA. Published with license by Taylor & Francis Group, LLC. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. 2866 L. OOSTVOGELS ET AL. Persons with a confirmed or suspected immunosuppressive Introduction or immunodeficient conditions resulting from disease (e.g., Herpes zoster (HZ) results from reactivation of latent vari- malignancy, human immunodeficiency virus infection) or cella-zoster virus (VZV) in sensory ganglia long after primary immunosuppressive/cytotoxic therapy (e.g., medications used infection. Worldwide, the incidence of HZ ranges between during cancer therapy, organ transplantation or to treat auto- 3–5 cases per 1,000 person-years in the general population immune disorders) were excluded. Persons who had received and increases markedly with age, with more than two-thirds immunosuppressants or immune-modifying drugs for >15 1,2 of HZ cases occurring in adults over 50 years of age (YOA). consecutive days within 6 months prior to the first vaccine Medical conditions previously identified as increasing the dose, were also excluded (prednisone <20 mg/day, or equiva- risk of HZ include systemic lupus erythematosus, rheumatoid lent, and inhaled/topical steroids were allowed). Full inclusion arthritis, inflammatory bowel disease, chronic obstructive pul- 7,8 and exclusion criteria have previously been published. monary disease, asthma, chronic kidney disease, renal failure, Medical conditions of the approximately 30,000 participants hypertension, diabetes mellitus (predominantly type I), were recorded at enrollment in the ZOE-50/70 trials, and those 3–5 depression, and spinal disc herniation. The increase in most frequently reported in the ZOE-70 trial were selected and HZ risk associated with some of these conditions may result applied for analysis utilizing data from both trials, since the from the immunosuppressive therapy prescribed to treat the prevalence of most underlying medical conditions increases disease and/or from underlying cell-mediated immunosup- with age. Efficacy and safety analyses were performed post-hoc pression associated with the disease. in the pooled ZOE-50/70 population (i) according to medical 6–9 Vaccination decreases the risk of HZ. The adjuvanted conditions reported by at least 500 participants from either arm recombinant zoster vaccine (RZV, Shingrix), containing a trun- of the ZOE-70 study at enrollment (considered to provide an cated form of VZV glycoprotein E and the AS01 adjuvant system, adequate sample size for the purpose of a descriptive analysis), demonstrated 97.2% and 91.3% vaccine efficacy (VE) against HZ and according to additional medical conditions reported by less in adults ≥50 (ZOE-50) and ≥70 YOA (ZOE-70), respectively, than 500 participants in the ZOE-70 study at enrollment but over an approximate 4-year follow-up period. Efficacy remained associated with an increased risk of HZ (asthma, depression, 7,8 >90% among participants ≥80 YOA. RZV also demonstrated an 3–5 respiratory disorders, and renal disorders), and (ii) according 7,8,10 acceptable safety profile. It is currently licensed in multiple to the number of selected medical conditions reported by study countries for the prevention of HZ in adults ≥50 YOA. participants at enrollment. For the purpose of the analysis, Although adults with a life expectancy of less than 4 years, medical conditions were defined as individual Medical with immunosuppressive conditions (e.g., resulting from Dictionary for Regulatory Authorities preferred terms (PTs) or malignancy or HIV infection) or requiring treatment with grouped PTs representing conditions of similar pathophysiolo- immune-modifying drugs (e.g., medications used during can- gical origin. Details on PT grouping are provided in the cer chemotherapy or organ transplantation) were excluded Supplementary Table 1. Participants reporting more than one 7,8 from entry into the ZOE-50/70 trials, the eligibility criteria of the PTs within the 15 selected medical conditions were only allowed enrollment of adults with medical conditions that are counted once for the respective analyses. common in the general older adult population. The study For the analysis of VE, a suspected HZ case was defined as population was therefore considered broadly representative new unilateral rash with pain that had no alternative diagnosis. of the general older adult population. The two studies were Participants were followed for at least 90 days after the onset of conducted in parallel at the same sites and in an identical HZ or until the rash resolved and the participant was pain-free manner, allowing the analysis of pooled data from both trials. for 4 weeks. Suspected HZ cases were evaluated and confirmed Adults ≥70 YOA were randomly assigned to the ZOE-50 or as described previously by polymerase-chain-reaction or an ZOE-70 study before being randomized to a study group. 7,8 adjudication committee. Efficacy was assessed similar to the The objective of this post-hoc pooled analysis is to evaluate primary analysis on the pooled modified total vaccinated RZV efficacy against the first or only episode of HZ and to 7,8 cohort (mTVC). This included all participants from the examine RZV safety in participants with selected medical pooled TVC who had received both doses of vaccine/placebo conditions at enrollment. and who had not developed a confirmed HZ case prior to 30 days post-dose 2. VE was defined as 1 minus the ratio of HZ incidence in the RZV group to that in the placebo group. Methods For assessment of safety, serious adverse events (SAEs) were recorded for all participants for up to 12 months post- The ZOE-50/70 studies were phase III, randomized, observer- dose 2; any events resulting in death, and potentially immune- blind, controlled trials conducted in parallel in 18 countries in mediated diseases (pIMDs) were evaluated in all participants Europe, North America, Latin America, Asia and Australia in over the entire study period. Safety was evaluated in the adults ≥50 YOA (NCT01165177) and ≥70 YOA pooled TVC from the ZOE-50/70 studies, which included all (NCT01165229). Participants were randomized 1:1 to receive 7,8 participants administered with at least one dose of RZV. 2 doses of either RZV or saline placebo 2 months (M) apart. Protocol summaries are available for both studies at http:// www.gsk-clinicalstudyregister.com (studies 110390 and Results 113077). Anonymized individual participant data and study documents can be requested for further research from www. Of the 30,977 participants enrolled in the ZOE-50/70 studies, clinicalstudydatarequest.com. 13,881 RZV and 14,035 placebo recipients were included in HUMAN VACCINES & IMMUNOTHERAPEUTICS 2867 30,977 participants enrolled in the studies 17 not assigned to a study group 30,960 randomized to a study group 15,476 assigned to RZV 15,484 assigned to Placebo Reasons for exclusion: Reasons for exclusion: � 819 Had Good Clinical Practice violation � 815 Had Good Clinical Practice violation � 12 Did not receive intervention � 9 Did not receive intervention 14,645 vaccinated (TVC) 14,660 vaccinated (TVC) Reasons for exclusion: Reasons for exclusion: • 7 Did not receive vaccine according to protocol � 6 Did not receive placebo according to protocol � 21 Received wrong intervention � 13 Received wrong intervention � 728 Did not receive dose 2 � 581 Did not receive dose 2 � 8 Had diagnosis of HZ <30 days after dose 2 � 25 Had diagnosis of HZ <30 days after dose 2 13,881 included in the mTVC for 14,035 included in the mTVC for efficacy assessment efficacy assessment 11,427 (82.3%) reported at least 1 of the 15 selected current 11,608 (82.7%) reported at least 1 of the 15 selected current medical conditions at enrollment medical conditions at enrollment 8,268 (59.6%) reported at least 2 of the 15 selected current 8,397 (59.8%) reported at least 2 of the 15 selected current medical conditions at enrollment medical conditions at enrollment Figure 1. Participant flow (pooled ZOE-50/70 studies) RZV = participants receiving the adjuvanted recombinant zoster vaccine; Placebo = participants receiving placebo; ZOE-50/70 = RZV efficacy studies in adults ≥50 YOA (NCT01165177) and ≥70 YOA (NCT01165229), respectively; (m)TVC = (modified) total vaccinated cohort; HZ, herpes zoster. the mTVC. Of these, 82.3% of RZV recipients and 82.7% of to assess VE. Overall, RZV efficacy was >90% irrespective of placebo recipients had at least 1 of the 15 selected medical the number of the selected medical conditions reported at conditions at enrollment. A majority (RZV: 59.6%, Placebo: enrollment by a participant (Table 2). 59.8%) had 2 or more (Figure 1). In the pooled mTVC, In RZV or placebo recipients reporting at least 1 of the 15 demographic characteristics, including proportions of partici- selected medical conditions at enrollment, the proportion of pants reporting each of the selected medical conditions, were participants experiencing SAEs or deaths was highest among balanced between study groups (Table 1). those with chronic conditions such as renal disorders, respira- Medical conditions in order of decreasing frequency tory disorders, or coronary heart disease. The numbers of included hypertension, osteoarthritis and vertebral disorders, SAEs, deaths, or pIMDs were similar in the vaccine and and dyslipidemia. The most frequently reported conditions placebo groups for each of the medical conditions (Table 3). known to increase HZ risk included in this analysis were The frequency of SAEs and deaths increased with the number depression and asthma (Table 1). of medical conditions present at enrollment; however, the Efficacy against HZ ranged from 84.5% (95% Confidence frequency of pIMDs did not. Frequencies of SAEs, deaths, Interval [CI]: 46.4–97.1) in participants with respiratory dis- and pIMDs were balanced between RZV and placebo recipi- orders to 97.0% (95% CI: 82.3–99.9) in those with coronary ents reporting any number of these conditions (Table 3). heart disease at enrollment. Efficacy was 88.8% (95% CI: 63.6– 97.8) in participants with asthma, and 91.2% (95% CI: 81.1– Discussion 96.6) in those with diabetes. The only medical condition that RZV efficacy did not achieve statistical significance was renal Older adults enrolled in the ZOE-50/70 studies reported disorders (VE: 86.6% [95% CI: −4.5–99.7]). The low number underlying medical conditions at a frequency expected in of participants with this condition limited the statistical power these age groups. The observed efficacy across the 15 2868 L. OOSTVOGELS ET AL. Table 1. Demographic characteristics (pooled ZOE-50/70 modified Total Vaccinated Cohort). RZV (N = 13,881) Placebo (N = 14,035) Age (years) Mean age at first dose ± SD 68.5 ± 9.8 68.5 ± 9.8 Gender, n (%) Female 8,044 (57.9) 8,178 (58.3) Male 5,837 (42.1) 5,857 (41.7) Geographic ancestry, n (%) White – Caucasian/European 10,321 (74.4) 10,403 (74.1) Asian – East Asian 1,908 (13.7) 1,926 (13.7) Asian – Japanese Heritage 575 (4.1) 591 (4.2) African/African American 200 (1.4) 183 (1.3) Other 877 (6.3) 932 (6.6) Selected medical conditions present at enrollment, n (%) Hypertension 7,206 (51.9) 7,226 (51.5) Osteoarthritis and/or vertebral disorders 4,951 (35.7) 5,032 (35.9) Dyslipidemia 4,628 (33.3) 4,707 (33.5) Diabetes 2,350 (16.9) 2,372 (16.9) Osteoporosis/Osteopenia 1,481 (10.7) 1,528 (10.9) Gastroesophageal reflux disease 1,334 (9.6) 1,313 (9.4) Sleep disorder 1,304 (9.4) 1,309 (9.3) Prostatic diseases 1,244 (9.0) 1,285 (9.2) Hypothyroidism 1,167 (8.4) 1,147 (8.2) Depression 1,017 (7.3) 987 (7.0) Coronary heart disease 1,003 (7.2) 1,055 (7.5) Cataract 782 (5.6) 800 (5.7) Asthma 646 (4.7) 689 (4.9) Respiratory disorders 614 (4.4) 560 (4.0) Renal disorders 308 (2.2) 300 (2.1) RZV = participants receiving the adjuvanted recombinant zoster vaccine; Placebo = participants receiving placebo; ZOE-50/70 = RZV efficacy studies in adults ≥50 YOA (NCT01165177) and ≥70 YOA (NCT01165229); N = number of participants in the pooled modified total vaccinated cohorts; n (%) = number (percentage) of participants in each category; SD = standard deviation. Other than asthma. medical conditions, including the ones associated with an concerns were identified in participants with any type or increased HZ risk, was consistent with the efficacy in the number of the selected medical conditions. overall pooled ZOE-50/70 population ≥70 YOA. This is in This post-hoc analysis has some limitations that should be line with the fact that >80% of the overall ZOE-50 and ZOE- taken into account when interpreting its results. The ZOE-50/ 70 study population reported at least 1 of the specified con- 70 studies were not statistically powered to evaluate RZV ditions. Other studies have shown that RZV also confers efficacy and safety by the number and type of participants’ strong protection against HZ in immunocompromised popu- medical conditions. In addition, the number of participants in lations who are at highest HZ risk, such as hematopoietic some sub-groups was limited. This includes medical condi- stem cell transplant recipients and patients with hematological tions reported by less than 500 participants in the ZOE-70 12,13 malignancies. study at enrollment but associated with an increased risk of The high proportion of participants reporting at least 1 of HZ (asthma, depression, respiratory disorders, and renal dis- the selected medical conditions can be explained by the rela- orders) and participants with ≥6 of the selected conditions. tively permissive inclusion and exclusion criteria for the ZOE- The present analysis was not adjusted for multiplicity, and 50/70 studies and the age of study participants. Previous being exploratory, its significance level was not controlled. studies have shown that frailty correlates with the number, The efficacy and safety analyses by medical condition category rather than the nature of accumulated biopsychosocial defi- did not detect any additional underlying medical condition at 14,15 cits, which are mostly medical conditions. Our analysis enrollment that might have an additive or synergistic effect on was consistent with this finding in that the frequency of SAEs the risk of HZ. As the study groups were comparable as a and deaths increased with the number of conditions reported result of randomization, this should have a limited effect on at enrollment. Although the point estimates for efficacy were the analyses by type or number of conditions. In addition, <90% for 5 of the 15 selected medical conditions, the observed study participants were not fully representative of the overall trend suggest that a high VE was maintained in participants older adult population. Individuals with a life expectancy of having up to 6 or more of those conditions. This contrasts less than 4 years at the time of study entry were to be with the observed decline in influenza vaccination effective- excluded. Persons with diseases requiring treatment with ness as the level of frailty increases in elderly people. This immune-modifying drugs, as well as persons with diseases further underscores the ability of RZV to induce robust pro- that are immunosuppressive by nature, were also excluded, tection against HZ in older adults with multiple medical limiting the conditions for which we could provide a VE conditions. estimate. Therefore, owing to the inclusion/exclusion criteria, Overall, frequencies of SAEs, deaths, and pIMDs were persons with some of the conditions associated with the high- balanced between RZV and placebo recipients within each est HZ risk were not enrolled in the study. Some of these of the analyzed sub-groups. No vaccine-related safety conditions were studied as part of the parallel clinical HUMAN VACCINES & IMMUNOTHERAPEUTICS 2869 Table 2. Vaccine efficacy against first or only episode of herpes zoster in ZOE-50/70 participants reporting at least 1 of the 15 selected medical conditions at enrollment (pooled modified Total Vaccinated Cohort). RZV Placebo Cumulative follow-up Rate of HZ cases/ Cumulative follow-up Rate of HZ cases/ Vaccine efficacy Nn py 1,000 py N n py 1,000 py % (95% CI) Selected medical conditions present at enrollment Hypertension 7,206 21 27,202.9 0.8 7,226 254 26,752.4 9.5 91.9 (87.3–95.1) Osteoarthritis and/or vertebral disorders 4,951 16 18,732.8 0.9 5,032 178 18,604.4 9.6 91.1 (85.1–95.0) Dyslipidemia 4,628 15 17578.0 0.9 4,707 169 17,507.2 9.7 91.2 (85.1–95.2) Diabetes 2,350 7 8,723.8 0.8 2,372 80 8,652.7 9.2 91.2 (81.1–96.6) Osteoporosis/Osteopenia 1,481 5 5,551.7 0.9 1,528 72 5,552.1 13.0 92.9 (82.7–97.8) Gastroesophageal reflux disease 1,334 6 5,009.7 1.2 1,313 44 4,816.2 9.1 86.9 (69.0–95.4) Sleep disorder 1,304 4 4,899.3 0.8 1,309 56 4,803.3 11.7 93.1 (81.4–98.2) Prostatic diseases 1,244 2 4,648.4 0.4 1,285 50 4,667.0 10.7 96.1 (85.1–99.5) Hypothyroidism 1,167 4 4,387.0 0.9 1,147 28 4,241.0 6.6 86.2 (60.4–96.5) Depression 1,017 2 3,767.1 0.5 987 29 3,567.5 8.1 93.4 (74.1–99.2) Coronary heart disease 1,003 1 3,773.8 0.3 1,055 35 3,912.8 8.9 97.0 (82.3–99.9) Cataract 782 4 2,964.7 1.3 800 41 2,931.0 14.0 90.4 (73.4–97.5) Asthma 646 3 2,420.9 1.2 689 28 2,575.8 10.9 88.8 (63.6–97.8) Respiratory disorders 614 3 2,220.5 1.4 560 17 1,944.4 8.7 84.5 (46.4–97.1) Renal disorders 308 1 1,064.8 0.9 300 7 1,001.5 7.0 86.6 (-4.5–99.7) Number of selected medical conditions present at enrollment 1 3,159 5 12,269.2 0.4 3,211 109 12,213.4 8.9 95.4 (89.0–98.5) 2 3,080 7 11,797.1 0.6 3,117 97 11,746.4 8.3 92.8 (84.7–97.2) 3 2,316 8 8,803.7 0.9 2,455 88 9,162.6 9.6 90.5 (80.5–96.0) At least 3 5,188 19 19,417.0 1.0 5,280 199 19,338.4 10.3 90.5 (84.8–94.4) At least 4 2,872 11 10,613.3 1.0 2,825 111 10,175.8 10.9 90.6 (82.4–95.4) At least 5 1,406 5 5,132.5 1.0 1,350 52 4,742.4 11.0 91.2 (78.0–97.3) At least 6 569 2 2,039.2 1.0 551 20 1,910.1 10.5 90.9 (62.5–99.0) RZV = participants receiving the adjuvanted recombinant zoster vaccine; Placebo = participants receiving placebo; ZOE-50/70 = RZV efficacy studies in adults ≥50 YOA (NCT01165177) and ≥70 YOA (NCT01165229), respectively; N = number of participants in each category; n = number of confirmed first or only herpes zoster case; HZ, herpes zoster; CI = confidence interval; py = person years. The follow-up period was censored at the first occurrence of a confirmed HZ episode. Other than asthma. 2870 L. OOSTVOGELS ET AL. Table 3. Safety of RZV in ZOE-50/70 participants reporting at least 1 of the 15 selected medical conditions at enrollment (pooled Total Vaccinated Cohort). Reported from dose 1 until Reported during 1 year post-dose 2 the whole post-vaccination period Number of participants in the TVC SAEs Deaths pIMDs RZV Placebo RZV Placebo RZV Placebo RZV Placebo % (95% CI) % (95% CI) % (95% CI) % (95% CI) % (95% CI) % (95% CI) Selected medical conditions present at enrollment Hypertension 7,609 7,556 12.5 (11.8–13.3) 12.6 (11.9–13.4) 5.7 (5.2–6.3) 6.3 (5.7–6.8) 1.2 (1.0–1.5) 1.2 (0.9–1.4) Osteoarthritis and/or vertebral disorders 5,212 5,258 12.5 (11.6–13.4) 13.2 (12.3–14.1) 5.1 (4.5–5.7) 5.5 (4.9–6.1) 1.5 (1.2–1.8) 1.7 (1.4–2.1) Dyslipidemia 4,904 4,953 12.1 (11.2–13.0) 12.1 (11.2–13.0) 4.7 (4.1–5.3) 4.5 (4.0–5.1) 1.1 (0.8–1.4) 1.6 (1.3–2.0) Diabetes 2,480 2,502 15.2 (13.8–16.7) 15.4 (14.0–16.9) 7.3 (6.3–8.4) 8.3 (7.2–9.4) 1.0 (0.6–1.4) 1.3 (0.9–1.8) Osteoporosis/Osteopenia 1,568 1,592 11.9 (10.4–13.6) 12.9 (11.3–14.6) 5.2 (4.1–6.4) 5.2 (4.2–6.4) 1.3 (0.8–2.0) 1.8 (1.2–2.5) Gastroesophageal reflux disease 1,407 1,374 14.4 (12.6–16.4) 15.1 (13.2–17.1) 4.3 (3.3–5.5) 5.6 (4.4–7.0) 1.1 (0.7–1.8) 2.3 (1.6–3.3) Sleep disorder 1,379 1,389 13.6 (11.9–15.6) 13.0 (11.2–14.8) 6.6 (5.3–8.0) 7.3 (6.0–8.8) 1.5 (0.9–2.3) 1.7 (1.1–2.5) Prostatic diseases 1,319 1,353 16.6 (14.6–18.7) 16.5 (14.5–18.6) 8.3 (6.9–10.0) 7.8 (6.4–9.3) 0.8 (0.4–1.5) 1.5 (0.9–2.3) Hypothyroidism 1,218 1,208 11.2 (9.5–13.2) 12.3 (10.5–14.3) 3.4 (2.5–4.6) 4.0 (2.9–5.2) 1.9 (1.2–2.8) 1.8 (1.1–2.7) Depression 1,095 1,070 14.2 (12.2–16.5) 15.4 (13.3–17.7) 6.1 (4.8–7.7) 5.3 (4.1–6.8) 1.0 (0.5–1.8) 1.1 (0.6–2.0) Coronary heart disease 1,065 1,097 20.4 (18.0–22.9) 20.3 (18.0–22.8) 8.6 (7.0–10.5) 9.3 (7.6–11.2) 1.0 (0.5–1.8) 0.9 (0.4–1.7) Cataract 828 836 13.8 (11.5–16.3) 13.2 (10.9–15.6) 5.1 (3.7–6.8) 6.8 (5.2–8.7) 1.0 (0.4–1.9) 0.8 (0.3–1.7) Asthma 698 714 15.3 (12.7–18.2) 12.9 (10.5–15.6) 4.4 (3.0–6.2) 4.2 (2.9–5.9) 2.3 (1.3–3.7) 2.5 (1.5–4.0) Respiratory disorders 651 593 20.0 (17.0–23.3) 23.1 (19.8–26.7) 13.4 (10.8–16.2) 15.0 (12.2–18.1) 0.6 (0.2–1.6) 2.0 (1.0–3.5) Renal disorders 328 319 26.2 (21.5–31.3) 23.5 (19.0–28.6) 15.2 (11.5–19.6) 15.7 (11.9–20.1) 0.6 (0.1–2.2) 1.3 (0.3–3.2) Number of selected medical conditions present at enrollment 1 3,309 3,333 6.9 (6.0–7.8) 7.7 (6.8–8.7) 3.2 (2.6–3.9) 3.4 (2.8–4.0) 1.4 (1.0–1.9) 1.2 (0.9–1.7) 2 3,267 3,238 9.7 (8.7–10.8) 9.7 (8.7–10.8) 3.9 (3.3–4.6) 4.5 (3.8–5.3) 1.3 (1.0–1.8) 1.6 (1.2–2.1) 3 2,449 2,567 12.0 (10.7–13.3) 13.0 (11.7–14.3) 5.6 (4.7–6.5) 5.8 (5.0–6.8) 1.2 (0.8–1.7) 1.2 (0.8–1.7) At least 3 5,487 5,555 14.7 (13.8–15.7) 14.8 (13.9–15.8) 6.4 (5.8–7.1) 6.7 (6.0–7.3) 1.2 (0.9–1.5) 1.5 (1.2–1.8) At least 4 3,038 2,988 16.9 (15.6–18.3) 16.4 (15.1–17.7) 7.1 (6.3–8.1) 7.4 (6.5–8.4) 1.2 (0.8–1.6) 1.7 (1.2–2.2) At least 5 1,490 1,430 19.8 (17.8–21.9) 21.0 (19.0–23.3) 8.6 (7.2–10.1) 9.5 (8.0–11.2) 1.1 (0.7–1.8) 1.6 (1.0–2.4) At least 6 600 591 21.5 (18.3–25.0) 25.2 (21.8–28.9) 10.2 (7.9–12.9) 11.3 (8.9–14.2) 1.2 (0.5–2.4) 1.4 (0.6–2.6) RZV = participants receiving the adjuvanted herpes zoster subunit vaccine; Placebo = participants receiving placebo; ZOE-50/70 = RZV efficacy studies in adults ≥50 YOA (NCT01165177) and ≥70 YOA (NCT01165229), respectively; % = percentage of participants in the category; CI = confidence interval; pIMDs = potential immune-mediated diseases; SAEs = serious adverse events; TVC = total vaccinated cohort. Other than asthma. HUMAN VACCINES & IMMUNOTHERAPEUTICS 2871 board on Zostavax, respectively, outside the submitted work. ISG program with RZV in immune compromised adults (e.g. received lecture fees and grant support from GSK outside the submitted hematopoietic stem cell transplant recipients and patients work and served on the Advisory Board for Shingrix in Canada. In with hematological malignancies). No standard definitions addition, ISG has received research grants and lecture fees from several were used in the diagnosis; therefore, each selected medical other pharmaceutical companies in work done for Prime Health Clinical condition could vary with respect to severity, stage, treatment, Research outside the submitted work. HI received grants and personal fees from GSK and grants from Japan Vaccine during the conduct of the progression, or type (e.g., diabetes mellitus type). The data- study, as well as grants and personal fees from Daiichi-Sankyo and grants base did not capture this level of detail. Medical conditions from Sanofi Pasteur and personal fees from Shionogi outside the sub- with onset after enrollment were not considered for this mitted work. GK is a freelance statistician at Keyrus Biopharma, serving as analysis. Older adults with severe frailty (e.g., bedridden a paid consultant for GSK. HL is a current employee of Pfizer and receives elderly persons) were also unlikely to participate. Despite stock as part of his employee remuneration. SAM reports research grant from Pfizer, personal fees for continuing professional development talks their broad geographic diversity, study participants were on adult immunization from Pfizer and Merck, and consulting fees from mostly Caucasian. Nonetheless, the most common diseases Pfizer and Merck outside the submitted work, as well as grant from GSK in the targeted age group were well represented. outside the submitted work. JS reports personal fees from GSK and Sanofi In summary, this study showed that >80% of participants Pasteur outside the submitted work. DW reports grants and personal fees had at least 1 of the 15 selected medical conditions present at from GSK, consulting fees from Maruho and Japan Vaccines, lecture fees from Maruho and Mochida, and grant support from Maruho. LYW enrollment. As indicated by the similarity of the point estimates, received grant from GSK during the conduct of the study, as well as fees this post-hoc analysis suggests that RZV efficacy remains high for serving on advisory boards from Novartis, GSK, AbbVie and Wyeth. in all selected medical conditions, as well as with increasing ALC received honoraria paid to his institution from GSK, Merck, and number of medical conditions. Point estimates for efficacy BioCSL/Sequirus outside the submitted work. ranged between 84.5–97.0% according to the type of the selected SJH and KP declare no conflict of interest. medical conditions (with overlapping 95% confidence intervals) and were >90% even among participants reporting at least 6 of Funding these at enrollment. No safety concern was identified in adults ≥50 YOA presenting these medical conditions. This work was sponsored by GlaxoSmithKline Biologicals SA. A plain language summary contextualizing the results and GlaxoSmithKline Biologicals SA was involved in all stages of the conduct and analysis of the studies. GlaxoSmithKline Biologicals SA covered the potential clinical research relevance and impact is displayed in costs associated with the development and the publishing of the present the Focus on Patient Section (Supplementary Figure 1). manuscript. Acknowledgments ZOE-50/70 study group The authors would like to thank all study participants, the clinical Anitta Ahonen, Eugene Athan, Johan Berglund, Won Suk Choi, investigators and study nurses involved in the ZOE-50 and ZOE-70 Ferdinandus J. de Looze, Maria Giuseppina Desole, Meral Esen, Brecht trials. The authors are also grateful to Anne Schuind (GSK) for draft Geeraerts, Wayne Ghesquiere, Lars Rombo, Antonio Volpi. reviewing and scientific input, and to Modis c/o GSK for editorial assistance and manuscript coordination. Medical writing services were provided by Alpár Pöllnitz and editorial assistance and publication Trademark statement coordination were provided by Quentin Deraedt. Shingrix is a trademark owned by or licensed to the GSK group of companies. Authors’ contributions Detailed authors’ contributions are provided in the supplementary ORCID materials. Lidia Oostvogels http://orcid.org/0000-0003-1298-0360 Thomas C. Heineman http://orcid.org/0000-0003-4500-5676 Robert W. Johnson http://orcid.org/0000-0002-8376-7412 Disclosure of potential conflicts of interest Myron J. Levin http://orcid.org/0000-0002-7468-106X TCH, HL, and LO are former employees, and AFD, CH, TM, PVdS, TZ Janet E. McElhaney http://orcid.org/0000-0002-0690-1446 and TM spouse are employees, of the GSK group of companies (GSK). Peter Van den Steen http://orcid.org/0000-0001-7931-1781 LO, TCH, AFD, HL, TM, PVdS, TZ and TM spouse hold shares or/and Toufik Zahaf http://orcid.org/0000-0002-2049-5210 stock options from GSK as per their former or current employee remu- Alemnew F. Dagnew http://orcid.org/0000-0003-4181-058X neration. LO is an employee of CureVac AG. LO and TCH are inventors Roman Chlibek http://orcid.org/0000-0002-7387-3844 on a patent owned by GSK and relevant to RZV. TCH served as a paid Javier Diez-Domingo http://orcid.org/0000-0003-1008-3922 consultant to GSK outside the submitted work. RWJ received honoraria Iris S. Gorfinkel http://orcid.org/0000-0002-8812-941X for consultancy and funding for a meeting he organized from Merck, Caroline Hervé http://orcid.org/0000-0002-0794-8748 funding from Sanofi Pasteur MSD to organize a scientific meeting, and Shinn-Jang Hwang http://orcid.org/0000-0003-3217-6193 honoraria as a consultant for GSK. MJL received fees for serving on Hideyuki Ikematsu http://orcid.org/0000-0002-3548-4231 advisory boards from Merck and GSK and grant support from Merck George Kalema http://orcid.org/0000-0002-0535-5930 and GSK. JEM reports receiving honoraria and fees paid to her institu- Himal Lal http://orcid.org/0000-0001-7174-1314 tion from GSK, Sanofi Pasteur, Merck and Pfizer, as well as travel Shelly A. McNeil http://orcid.org/0000-0001-5444-4166 support from GSK, Sanofi Pasteur, Merck and Pfizer outside the sub- Karlis Pauksens http://orcid.org/0000-0003-2626-7574 mitted work. RC reports receiving lecture fees from Pfizer outside the Jan Smetana http://orcid.org/0000-0002-3770-1754 submitted work. JDD reports personal fees from GSK for serving on an Daisuke Watanabe http://orcid.org/0000-0001-6817-3993 advisory board, as well as grants and personal fees from Sanofi Pasteur Lily Yin Weckx http://orcid.org/0000-0003-4949-3582 MSD for an epidemiological study on herpes zoster and an advisory Anthony L. Cunningham http://orcid.org/0000-0002-6744-5667 2872 L. OOSTVOGELS ET AL. 50-59 years. Clin Infect Dis. 2012;54:922–28. doi:10.1093/cid/ References cir970. 1. Yawn BP, Gilden D. The global epidemiology of herpes zoster. 10. Lecrenier N, Beukelaers P, Colindres R, Curran D, De Kesel C, De Neurology. 2013;81:928–30. doi:10.1212/WNL.0b013e3182a3516e. Saegher J-P, Didierlaurent AM, Ledent EY, Mols JF, Mrkvan T, 2. Kawai K, Gebremeskel BG, Acosta CJ. Systematic review of inci- et al. Development of adjuvanted recombinant zoster vaccine and dence and complications of herpes zoster: towards a global per- its implications for shingles prevention. Expert Rev Vaccines. spective. BMJ Open. 2014;4:e004833. doi:10.1136/bmjopen-2014- 2018;17:619–34. doi:10.1080/14760584.2018.1495565. 11. Prince MJ, Wu F, Guo Y, Gutierrez Robledo LM, O’Donnell M, 3. Kawai K, Yawn BP. Risk factors for herpes zoster: a systematic Sullivan R, Yusuf S. The burden of disease in older people and review and meta-analysis. Mayo Clinic Proc. 2017;92:1806–21. implications for health policy and practice. Lancet. 2015;385:549– doi:10.1016/j.mayocp.2017.10.009. 62. doi:10.1016/S0140-6736(14)61347-7. 4. Forbes HJ, Bhaskaran K, Thomas SL, Smeeth L, Clayton T, de la Serna J, Campora L, Chandrasekar P, El Idrissi M, Gaidano Langan SM. Quantification of risk factors for herpes zoster: popu- G, López Fauqued M, Oostvogels L, Schwartz S, Sullivan K, Szer lation based case-control study. Bmj. 2014;348:g2911. doi:10.1136/ J, Bastidas A. Efficacy and safety of an adjuvanted herpes zoster bmj.g2911. subunit vaccine in autologous hematopoietic stem cell trans- 5. Hata A, Kuniyoshi M, Ohkusa Y. Risk of Herpes zoster in patients plant recipients 18 years of age or older: first results of the with underlying diseases: a retrospective hospital-based cohort phase 3 randomized, placebo-controlled ZOE-HSCT clinical study. Infection. 2011;39:537–44. doi:10.1007/s15010-011-0162-0. trial. BMT Tandem Meetings, Salt Lake City, Utah. 2018: 6. Oxman MN, Levin MJ, Johnson GR, Schmader KE, Straus SE, abstract LBA2. Gelb LD, Arbeit RD, Simberkoff MS, Gershon AA, Davis LE, et al. 13. Dagnew AF, Ilhan O, Lee W-S, Woszczyk D, Kwak J-Y, A vaccine to prevent herpes zoster and postherpetic neuralgia in Bowcock S, Sohn SK, Rodriguez Macías G, Chiou T-J, Quiel older adults. N Engl J Med. 2005;352:2271–84. doi:10.1056/ D, et al. Immunogenicity, safety and efficacy assessment of the NEJMoa051016. adjuvanted recombinant zoster vaccine in adults with hematolo- 7. Lal H, Cunningham AL, Godeaux O, Chlibek R, Diez-Domingo J, gic malignancies: a phase 3, randomized clinical trial. ID Week. Hwang SJ, Levin MJ, McElhaney JE, Poder A, Puig-Barberà J, 2018:abstract 140. et al. Efficacy of an adjuvanted herpes zoster subunit vaccine in 14. Searle SD, Mitnitski A, Gahbauer EA, Gill TM, Rockwood K. A older adults. N Engl J Med. 2015;372:2087–96. doi:10.1056/ standard procedure for creating a frailty index. BMC Geriatr. NEJMoa1501184. 2008;8:24. doi:10.1186/1471-2318-8-24. 8. Cunningham AL, Lal H, Kovac M, Chlibek R, Hwang SJ, Diez- 15. Mitnitski AB, Mogilner AJ, Rockwood K. Accumulation of deficits Domingo J, Godeaux O, Levin MJ, McElhaney JE, Puig-Barberà J, as a proxy measure of aging. Sci World J. 2001;1:323–36. et al. Efficacy of the herpes zoster subunit vaccine in adults 70 doi:10.1100/tsw.2001.58. years of age or older. N Engl J Med. 2016;375:1019–32. 16. Andrew MK, Shinde V, Ye L, Hatchette T, Haguinet F, Dos doi:10.1056/NEJMoa1603800. Santos G, McElhaney JE, Ambrose A, Boivin G, Bowie W, et al. 9. Schmader KE, Levin MJ, Gnann JW Jr., McNeil SA, Vesikari T, The importance of frailty in the assessment of influenza vaccine Betts RF, Keay S, Stek JE, Bundick ND, Su S-C, et al. Efficacy, effectiveness against influenza-related hospitalization in elderly safety, and tolerability of herpes zoster vaccine in persons aged people. J Infect Dis. 2017;216:405–14. doi:10.1093/infdis/jix282. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Human Vaccines & Immunotherapeutics Taylor & Francis

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Abstract

HUMAN VACCINES & IMMUNOTHERAPEUTICS 2019, VOL. 15, NO. 12, 2865–2872 https://doi.org/10.1080/21645515.2019.1627818 SHORT REPORT Medical conditions at enrollment do not impact efficacy and safety of the adjuvanted recombinant zoster vaccine: a pooled post-hoc analysis of two parallel randomized trials a b c d e Lidia Oostvogels , Thomas C. Heineman , Robert W. Johnson , Myron J. Levin , Janet E. McElhaney , a a f g h Peter Van den Steen , Toufik Zahaf , Alemnew F. Dagnew , Roman Chlibek , Javier Diez-Domingo , i a j k l b Iris S. Gorfinkel , Caroline Hervé , Shinn-Jang Hwang , Hideyuki Ikematsu , George Kalema , Himal Lal , m a n g o p Shelly A. McNeil , Tomas Mrkvan , Karlis Pauksens , Jan Smetana , Daisuke Watanabe , Lily Yin Weckx , and Anthony L. Cunningham for the ZOE-50/70 Study Group a b c d GSK, Wavre, Belgium; GSK, King of Prussia, PA, USA; Faculty of Health Sciences, University of Bristol, Bristol, UK; Departments of Pediatrics and Medicine, University of Colorado, Anschutz Medical Campus, Aurora, CO, USA; Health Sciences North Research Institute, Sudbury, Ontario, Canada; f g h GSK, Rockville, MD, USA; Faculty of Military Health Sciences, University of Defense, Hradec Kralove, Czech Republic; Fundación para el Fomento i j de la Investigación Sanitaria y Biomédica, Valencia, Spain; PrimeHealth Clinical Research, Toronto, Ontario, Canada; Department of Family Medicine, Taipei Veterans General Hospital and National Yang Ming University School of Medicine, Taipei, Taiwan; Japan Physicians Association, l m Tokyo, Japan; Keyrus Biopharma, Waterloo, Belgium, on behalf of GSK; Canadian Center for Vaccinology, IWK Health Center and Nova Scotia Health Authority, Dalhousie, University, Halifax, Canada; Department of Infectious Diseases, Uppsala University Hospital, Uppsala, Sweden; o p Department of Dermatology, Aichi Medical University, Nagakute, Japan; Department of Pediatrics, Federal University of Sao Paulo, Sao Paulo, Brazil; The Westmead Institute for Medical Research, Westmead, University of Sydney, Sydney, NSW, Australia ABSTRACT ARTICLE HISTORY Received 15 February 2019 In two pivotal efficacy studies (ZOE-50; ZOE-70), the adjuvanted recombinant zoster vaccine (RZV) Revised 10 May 2019 demonstrated >90% efficacy against herpes zoster (HZ). Accepted 27 May 2019 Adults aged≥50 or ≥70 years (ZOE-50 [NCT01165177]; ZOE-70 [NCT01165229]) were randomized to receive 2 doses of RZV or placebo 2 months apart. Vaccine efficacy and safety were evaluated post-hoc in the pooled (ZOE- KEYWORDS 50/70) population according to the number and type of selected medical conditions present at enrollment. Varicella-zoster virus; At enrollment, 82.3% of RZV and 82.7% of placebo recipients reported ≥1 of the 15 selected medical adjuvanted recombinant conditions. Efficacy against HZ ranged from 84.5% (95% Confidence Interval [CI]: 46.4–97.1) in participants zoster vaccine; vaccine efficacy; vaccine safety; with respiratory disorders to 97.0% (95%CI: 82.3–99.9) in those with coronary heart disease. Moreover, underlying chronic disease; efficacy remained >90% irrespective of the number of selected medical conditions reported by a participant. comorbidity As indicated by the similarity of the point estimates, this post-hoc analysis suggests that RZV efficacy remains high in all selected medical conditions, as well as with increasing number of medical conditions. No safety concern was identified by the type or number of medical conditions present at enrollment. PLAIN LANGUAGE SUMMARY What is the context? Shingles, or herpes zoster (HZ), is a clinical reactivation of the varicella-zoster virus, which causes chickenpox. HZ refers to the resulting skin rash, which is often accompanied by severe, burning or itching, pain. While HZ generally affects adults over 50 years of age, it is also common in people with weakened immune systems, for example patients undergoing chemotherapy, or those with an underlying medical condition such as diabetes, asthma, or other diseases. What is new? ● Clinical trials have demonstrated that the risk of experiencing HZ in adults over 50 years of age is substantially decreased after administration of the adjuvanted recombinant zoster vaccine (RZV, Shingrix). Additional analyses were performed to determine the impact of common medical condi- tions on the efficacy and safety of Shingrix. These show that underlying medical conditions were common among the trial participants, but Shingrix was still protective against HZ despite their presence. A similar safety profile was reported by participants receiving either placebo or RZV. What is the impact? Shingrix is effective in the prevention of HZ in adults over 50 years of age, including those with one or more of the common medical conditions considered. Results may help inform the use of Shingrix in these individuals. CONTACT Peter Van den Steen peter.b.van-den-steen@gsk.com GSK, Avenue Fleming 20, Wavre 1300, Belgium. Present address: Lidia Oostvogels, CureVac AG, Tübingen, Germany Thomas C. Heineman, Halozyme Therapeutics, San Diego, CA, USA Himal Lal, Pfizer Inc., Collegeville, PA, USA Supplemental data for this article can be accessed on the https://doi.org/10.1080/21645515.2019.1627818 publisher’s website. © 2019 GlaxoSmithKline Biologicals SA. Published with license by Taylor & Francis Group, LLC. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. 2866 L. OOSTVOGELS ET AL. Persons with a confirmed or suspected immunosuppressive Introduction or immunodeficient conditions resulting from disease (e.g., Herpes zoster (HZ) results from reactivation of latent vari- malignancy, human immunodeficiency virus infection) or cella-zoster virus (VZV) in sensory ganglia long after primary immunosuppressive/cytotoxic therapy (e.g., medications used infection. Worldwide, the incidence of HZ ranges between during cancer therapy, organ transplantation or to treat auto- 3–5 cases per 1,000 person-years in the general population immune disorders) were excluded. Persons who had received and increases markedly with age, with more than two-thirds immunosuppressants or immune-modifying drugs for >15 1,2 of HZ cases occurring in adults over 50 years of age (YOA). consecutive days within 6 months prior to the first vaccine Medical conditions previously identified as increasing the dose, were also excluded (prednisone <20 mg/day, or equiva- risk of HZ include systemic lupus erythematosus, rheumatoid lent, and inhaled/topical steroids were allowed). Full inclusion arthritis, inflammatory bowel disease, chronic obstructive pul- 7,8 and exclusion criteria have previously been published. monary disease, asthma, chronic kidney disease, renal failure, Medical conditions of the approximately 30,000 participants hypertension, diabetes mellitus (predominantly type I), were recorded at enrollment in the ZOE-50/70 trials, and those 3–5 depression, and spinal disc herniation. The increase in most frequently reported in the ZOE-70 trial were selected and HZ risk associated with some of these conditions may result applied for analysis utilizing data from both trials, since the from the immunosuppressive therapy prescribed to treat the prevalence of most underlying medical conditions increases disease and/or from underlying cell-mediated immunosup- with age. Efficacy and safety analyses were performed post-hoc pression associated with the disease. in the pooled ZOE-50/70 population (i) according to medical 6–9 Vaccination decreases the risk of HZ. The adjuvanted conditions reported by at least 500 participants from either arm recombinant zoster vaccine (RZV, Shingrix), containing a trun- of the ZOE-70 study at enrollment (considered to provide an cated form of VZV glycoprotein E and the AS01 adjuvant system, adequate sample size for the purpose of a descriptive analysis), demonstrated 97.2% and 91.3% vaccine efficacy (VE) against HZ and according to additional medical conditions reported by less in adults ≥50 (ZOE-50) and ≥70 YOA (ZOE-70), respectively, than 500 participants in the ZOE-70 study at enrollment but over an approximate 4-year follow-up period. Efficacy remained associated with an increased risk of HZ (asthma, depression, 7,8 >90% among participants ≥80 YOA. RZV also demonstrated an 3–5 respiratory disorders, and renal disorders), and (ii) according 7,8,10 acceptable safety profile. It is currently licensed in multiple to the number of selected medical conditions reported by study countries for the prevention of HZ in adults ≥50 YOA. participants at enrollment. For the purpose of the analysis, Although adults with a life expectancy of less than 4 years, medical conditions were defined as individual Medical with immunosuppressive conditions (e.g., resulting from Dictionary for Regulatory Authorities preferred terms (PTs) or malignancy or HIV infection) or requiring treatment with grouped PTs representing conditions of similar pathophysiolo- immune-modifying drugs (e.g., medications used during can- gical origin. Details on PT grouping are provided in the cer chemotherapy or organ transplantation) were excluded Supplementary Table 1. Participants reporting more than one 7,8 from entry into the ZOE-50/70 trials, the eligibility criteria of the PTs within the 15 selected medical conditions were only allowed enrollment of adults with medical conditions that are counted once for the respective analyses. common in the general older adult population. The study For the analysis of VE, a suspected HZ case was defined as population was therefore considered broadly representative new unilateral rash with pain that had no alternative diagnosis. of the general older adult population. The two studies were Participants were followed for at least 90 days after the onset of conducted in parallel at the same sites and in an identical HZ or until the rash resolved and the participant was pain-free manner, allowing the analysis of pooled data from both trials. for 4 weeks. Suspected HZ cases were evaluated and confirmed Adults ≥70 YOA were randomly assigned to the ZOE-50 or as described previously by polymerase-chain-reaction or an ZOE-70 study before being randomized to a study group. 7,8 adjudication committee. Efficacy was assessed similar to the The objective of this post-hoc pooled analysis is to evaluate primary analysis on the pooled modified total vaccinated RZV efficacy against the first or only episode of HZ and to 7,8 cohort (mTVC). This included all participants from the examine RZV safety in participants with selected medical pooled TVC who had received both doses of vaccine/placebo conditions at enrollment. and who had not developed a confirmed HZ case prior to 30 days post-dose 2. VE was defined as 1 minus the ratio of HZ incidence in the RZV group to that in the placebo group. Methods For assessment of safety, serious adverse events (SAEs) were recorded for all participants for up to 12 months post- The ZOE-50/70 studies were phase III, randomized, observer- dose 2; any events resulting in death, and potentially immune- blind, controlled trials conducted in parallel in 18 countries in mediated diseases (pIMDs) were evaluated in all participants Europe, North America, Latin America, Asia and Australia in over the entire study period. Safety was evaluated in the adults ≥50 YOA (NCT01165177) and ≥70 YOA pooled TVC from the ZOE-50/70 studies, which included all (NCT01165229). Participants were randomized 1:1 to receive 7,8 participants administered with at least one dose of RZV. 2 doses of either RZV or saline placebo 2 months (M) apart. Protocol summaries are available for both studies at http:// www.gsk-clinicalstudyregister.com (studies 110390 and Results 113077). Anonymized individual participant data and study documents can be requested for further research from www. Of the 30,977 participants enrolled in the ZOE-50/70 studies, clinicalstudydatarequest.com. 13,881 RZV and 14,035 placebo recipients were included in HUMAN VACCINES & IMMUNOTHERAPEUTICS 2867 30,977 participants enrolled in the studies 17 not assigned to a study group 30,960 randomized to a study group 15,476 assigned to RZV 15,484 assigned to Placebo Reasons for exclusion: Reasons for exclusion: � 819 Had Good Clinical Practice violation � 815 Had Good Clinical Practice violation � 12 Did not receive intervention � 9 Did not receive intervention 14,645 vaccinated (TVC) 14,660 vaccinated (TVC) Reasons for exclusion: Reasons for exclusion: • 7 Did not receive vaccine according to protocol � 6 Did not receive placebo according to protocol � 21 Received wrong intervention � 13 Received wrong intervention � 728 Did not receive dose 2 � 581 Did not receive dose 2 � 8 Had diagnosis of HZ <30 days after dose 2 � 25 Had diagnosis of HZ <30 days after dose 2 13,881 included in the mTVC for 14,035 included in the mTVC for efficacy assessment efficacy assessment 11,427 (82.3%) reported at least 1 of the 15 selected current 11,608 (82.7%) reported at least 1 of the 15 selected current medical conditions at enrollment medical conditions at enrollment 8,268 (59.6%) reported at least 2 of the 15 selected current 8,397 (59.8%) reported at least 2 of the 15 selected current medical conditions at enrollment medical conditions at enrollment Figure 1. Participant flow (pooled ZOE-50/70 studies) RZV = participants receiving the adjuvanted recombinant zoster vaccine; Placebo = participants receiving placebo; ZOE-50/70 = RZV efficacy studies in adults ≥50 YOA (NCT01165177) and ≥70 YOA (NCT01165229), respectively; (m)TVC = (modified) total vaccinated cohort; HZ, herpes zoster. the mTVC. Of these, 82.3% of RZV recipients and 82.7% of to assess VE. Overall, RZV efficacy was >90% irrespective of placebo recipients had at least 1 of the 15 selected medical the number of the selected medical conditions reported at conditions at enrollment. A majority (RZV: 59.6%, Placebo: enrollment by a participant (Table 2). 59.8%) had 2 or more (Figure 1). In the pooled mTVC, In RZV or placebo recipients reporting at least 1 of the 15 demographic characteristics, including proportions of partici- selected medical conditions at enrollment, the proportion of pants reporting each of the selected medical conditions, were participants experiencing SAEs or deaths was highest among balanced between study groups (Table 1). those with chronic conditions such as renal disorders, respira- Medical conditions in order of decreasing frequency tory disorders, or coronary heart disease. The numbers of included hypertension, osteoarthritis and vertebral disorders, SAEs, deaths, or pIMDs were similar in the vaccine and and dyslipidemia. The most frequently reported conditions placebo groups for each of the medical conditions (Table 3). known to increase HZ risk included in this analysis were The frequency of SAEs and deaths increased with the number depression and asthma (Table 1). of medical conditions present at enrollment; however, the Efficacy against HZ ranged from 84.5% (95% Confidence frequency of pIMDs did not. Frequencies of SAEs, deaths, Interval [CI]: 46.4–97.1) in participants with respiratory dis- and pIMDs were balanced between RZV and placebo recipi- orders to 97.0% (95% CI: 82.3–99.9) in those with coronary ents reporting any number of these conditions (Table 3). heart disease at enrollment. Efficacy was 88.8% (95% CI: 63.6– 97.8) in participants with asthma, and 91.2% (95% CI: 81.1– Discussion 96.6) in those with diabetes. The only medical condition that RZV efficacy did not achieve statistical significance was renal Older adults enrolled in the ZOE-50/70 studies reported disorders (VE: 86.6% [95% CI: −4.5–99.7]). The low number underlying medical conditions at a frequency expected in of participants with this condition limited the statistical power these age groups. The observed efficacy across the 15 2868 L. OOSTVOGELS ET AL. Table 1. Demographic characteristics (pooled ZOE-50/70 modified Total Vaccinated Cohort). RZV (N = 13,881) Placebo (N = 14,035) Age (years) Mean age at first dose ± SD 68.5 ± 9.8 68.5 ± 9.8 Gender, n (%) Female 8,044 (57.9) 8,178 (58.3) Male 5,837 (42.1) 5,857 (41.7) Geographic ancestry, n (%) White – Caucasian/European 10,321 (74.4) 10,403 (74.1) Asian – East Asian 1,908 (13.7) 1,926 (13.7) Asian – Japanese Heritage 575 (4.1) 591 (4.2) African/African American 200 (1.4) 183 (1.3) Other 877 (6.3) 932 (6.6) Selected medical conditions present at enrollment, n (%) Hypertension 7,206 (51.9) 7,226 (51.5) Osteoarthritis and/or vertebral disorders 4,951 (35.7) 5,032 (35.9) Dyslipidemia 4,628 (33.3) 4,707 (33.5) Diabetes 2,350 (16.9) 2,372 (16.9) Osteoporosis/Osteopenia 1,481 (10.7) 1,528 (10.9) Gastroesophageal reflux disease 1,334 (9.6) 1,313 (9.4) Sleep disorder 1,304 (9.4) 1,309 (9.3) Prostatic diseases 1,244 (9.0) 1,285 (9.2) Hypothyroidism 1,167 (8.4) 1,147 (8.2) Depression 1,017 (7.3) 987 (7.0) Coronary heart disease 1,003 (7.2) 1,055 (7.5) Cataract 782 (5.6) 800 (5.7) Asthma 646 (4.7) 689 (4.9) Respiratory disorders 614 (4.4) 560 (4.0) Renal disorders 308 (2.2) 300 (2.1) RZV = participants receiving the adjuvanted recombinant zoster vaccine; Placebo = participants receiving placebo; ZOE-50/70 = RZV efficacy studies in adults ≥50 YOA (NCT01165177) and ≥70 YOA (NCT01165229); N = number of participants in the pooled modified total vaccinated cohorts; n (%) = number (percentage) of participants in each category; SD = standard deviation. Other than asthma. medical conditions, including the ones associated with an concerns were identified in participants with any type or increased HZ risk, was consistent with the efficacy in the number of the selected medical conditions. overall pooled ZOE-50/70 population ≥70 YOA. This is in This post-hoc analysis has some limitations that should be line with the fact that >80% of the overall ZOE-50 and ZOE- taken into account when interpreting its results. The ZOE-50/ 70 study population reported at least 1 of the specified con- 70 studies were not statistically powered to evaluate RZV ditions. Other studies have shown that RZV also confers efficacy and safety by the number and type of participants’ strong protection against HZ in immunocompromised popu- medical conditions. In addition, the number of participants in lations who are at highest HZ risk, such as hematopoietic some sub-groups was limited. This includes medical condi- stem cell transplant recipients and patients with hematological tions reported by less than 500 participants in the ZOE-70 12,13 malignancies. study at enrollment but associated with an increased risk of The high proportion of participants reporting at least 1 of HZ (asthma, depression, respiratory disorders, and renal dis- the selected medical conditions can be explained by the rela- orders) and participants with ≥6 of the selected conditions. tively permissive inclusion and exclusion criteria for the ZOE- The present analysis was not adjusted for multiplicity, and 50/70 studies and the age of study participants. Previous being exploratory, its significance level was not controlled. studies have shown that frailty correlates with the number, The efficacy and safety analyses by medical condition category rather than the nature of accumulated biopsychosocial defi- did not detect any additional underlying medical condition at 14,15 cits, which are mostly medical conditions. Our analysis enrollment that might have an additive or synergistic effect on was consistent with this finding in that the frequency of SAEs the risk of HZ. As the study groups were comparable as a and deaths increased with the number of conditions reported result of randomization, this should have a limited effect on at enrollment. Although the point estimates for efficacy were the analyses by type or number of conditions. In addition, <90% for 5 of the 15 selected medical conditions, the observed study participants were not fully representative of the overall trend suggest that a high VE was maintained in participants older adult population. Individuals with a life expectancy of having up to 6 or more of those conditions. This contrasts less than 4 years at the time of study entry were to be with the observed decline in influenza vaccination effective- excluded. Persons with diseases requiring treatment with ness as the level of frailty increases in elderly people. This immune-modifying drugs, as well as persons with diseases further underscores the ability of RZV to induce robust pro- that are immunosuppressive by nature, were also excluded, tection against HZ in older adults with multiple medical limiting the conditions for which we could provide a VE conditions. estimate. Therefore, owing to the inclusion/exclusion criteria, Overall, frequencies of SAEs, deaths, and pIMDs were persons with some of the conditions associated with the high- balanced between RZV and placebo recipients within each est HZ risk were not enrolled in the study. Some of these of the analyzed sub-groups. No vaccine-related safety conditions were studied as part of the parallel clinical HUMAN VACCINES & IMMUNOTHERAPEUTICS 2869 Table 2. Vaccine efficacy against first or only episode of herpes zoster in ZOE-50/70 participants reporting at least 1 of the 15 selected medical conditions at enrollment (pooled modified Total Vaccinated Cohort). RZV Placebo Cumulative follow-up Rate of HZ cases/ Cumulative follow-up Rate of HZ cases/ Vaccine efficacy Nn py 1,000 py N n py 1,000 py % (95% CI) Selected medical conditions present at enrollment Hypertension 7,206 21 27,202.9 0.8 7,226 254 26,752.4 9.5 91.9 (87.3–95.1) Osteoarthritis and/or vertebral disorders 4,951 16 18,732.8 0.9 5,032 178 18,604.4 9.6 91.1 (85.1–95.0) Dyslipidemia 4,628 15 17578.0 0.9 4,707 169 17,507.2 9.7 91.2 (85.1–95.2) Diabetes 2,350 7 8,723.8 0.8 2,372 80 8,652.7 9.2 91.2 (81.1–96.6) Osteoporosis/Osteopenia 1,481 5 5,551.7 0.9 1,528 72 5,552.1 13.0 92.9 (82.7–97.8) Gastroesophageal reflux disease 1,334 6 5,009.7 1.2 1,313 44 4,816.2 9.1 86.9 (69.0–95.4) Sleep disorder 1,304 4 4,899.3 0.8 1,309 56 4,803.3 11.7 93.1 (81.4–98.2) Prostatic diseases 1,244 2 4,648.4 0.4 1,285 50 4,667.0 10.7 96.1 (85.1–99.5) Hypothyroidism 1,167 4 4,387.0 0.9 1,147 28 4,241.0 6.6 86.2 (60.4–96.5) Depression 1,017 2 3,767.1 0.5 987 29 3,567.5 8.1 93.4 (74.1–99.2) Coronary heart disease 1,003 1 3,773.8 0.3 1,055 35 3,912.8 8.9 97.0 (82.3–99.9) Cataract 782 4 2,964.7 1.3 800 41 2,931.0 14.0 90.4 (73.4–97.5) Asthma 646 3 2,420.9 1.2 689 28 2,575.8 10.9 88.8 (63.6–97.8) Respiratory disorders 614 3 2,220.5 1.4 560 17 1,944.4 8.7 84.5 (46.4–97.1) Renal disorders 308 1 1,064.8 0.9 300 7 1,001.5 7.0 86.6 (-4.5–99.7) Number of selected medical conditions present at enrollment 1 3,159 5 12,269.2 0.4 3,211 109 12,213.4 8.9 95.4 (89.0–98.5) 2 3,080 7 11,797.1 0.6 3,117 97 11,746.4 8.3 92.8 (84.7–97.2) 3 2,316 8 8,803.7 0.9 2,455 88 9,162.6 9.6 90.5 (80.5–96.0) At least 3 5,188 19 19,417.0 1.0 5,280 199 19,338.4 10.3 90.5 (84.8–94.4) At least 4 2,872 11 10,613.3 1.0 2,825 111 10,175.8 10.9 90.6 (82.4–95.4) At least 5 1,406 5 5,132.5 1.0 1,350 52 4,742.4 11.0 91.2 (78.0–97.3) At least 6 569 2 2,039.2 1.0 551 20 1,910.1 10.5 90.9 (62.5–99.0) RZV = participants receiving the adjuvanted recombinant zoster vaccine; Placebo = participants receiving placebo; ZOE-50/70 = RZV efficacy studies in adults ≥50 YOA (NCT01165177) and ≥70 YOA (NCT01165229), respectively; N = number of participants in each category; n = number of confirmed first or only herpes zoster case; HZ, herpes zoster; CI = confidence interval; py = person years. The follow-up period was censored at the first occurrence of a confirmed HZ episode. Other than asthma. 2870 L. OOSTVOGELS ET AL. Table 3. Safety of RZV in ZOE-50/70 participants reporting at least 1 of the 15 selected medical conditions at enrollment (pooled Total Vaccinated Cohort). Reported from dose 1 until Reported during 1 year post-dose 2 the whole post-vaccination period Number of participants in the TVC SAEs Deaths pIMDs RZV Placebo RZV Placebo RZV Placebo RZV Placebo % (95% CI) % (95% CI) % (95% CI) % (95% CI) % (95% CI) % (95% CI) Selected medical conditions present at enrollment Hypertension 7,609 7,556 12.5 (11.8–13.3) 12.6 (11.9–13.4) 5.7 (5.2–6.3) 6.3 (5.7–6.8) 1.2 (1.0–1.5) 1.2 (0.9–1.4) Osteoarthritis and/or vertebral disorders 5,212 5,258 12.5 (11.6–13.4) 13.2 (12.3–14.1) 5.1 (4.5–5.7) 5.5 (4.9–6.1) 1.5 (1.2–1.8) 1.7 (1.4–2.1) Dyslipidemia 4,904 4,953 12.1 (11.2–13.0) 12.1 (11.2–13.0) 4.7 (4.1–5.3) 4.5 (4.0–5.1) 1.1 (0.8–1.4) 1.6 (1.3–2.0) Diabetes 2,480 2,502 15.2 (13.8–16.7) 15.4 (14.0–16.9) 7.3 (6.3–8.4) 8.3 (7.2–9.4) 1.0 (0.6–1.4) 1.3 (0.9–1.8) Osteoporosis/Osteopenia 1,568 1,592 11.9 (10.4–13.6) 12.9 (11.3–14.6) 5.2 (4.1–6.4) 5.2 (4.2–6.4) 1.3 (0.8–2.0) 1.8 (1.2–2.5) Gastroesophageal reflux disease 1,407 1,374 14.4 (12.6–16.4) 15.1 (13.2–17.1) 4.3 (3.3–5.5) 5.6 (4.4–7.0) 1.1 (0.7–1.8) 2.3 (1.6–3.3) Sleep disorder 1,379 1,389 13.6 (11.9–15.6) 13.0 (11.2–14.8) 6.6 (5.3–8.0) 7.3 (6.0–8.8) 1.5 (0.9–2.3) 1.7 (1.1–2.5) Prostatic diseases 1,319 1,353 16.6 (14.6–18.7) 16.5 (14.5–18.6) 8.3 (6.9–10.0) 7.8 (6.4–9.3) 0.8 (0.4–1.5) 1.5 (0.9–2.3) Hypothyroidism 1,218 1,208 11.2 (9.5–13.2) 12.3 (10.5–14.3) 3.4 (2.5–4.6) 4.0 (2.9–5.2) 1.9 (1.2–2.8) 1.8 (1.1–2.7) Depression 1,095 1,070 14.2 (12.2–16.5) 15.4 (13.3–17.7) 6.1 (4.8–7.7) 5.3 (4.1–6.8) 1.0 (0.5–1.8) 1.1 (0.6–2.0) Coronary heart disease 1,065 1,097 20.4 (18.0–22.9) 20.3 (18.0–22.8) 8.6 (7.0–10.5) 9.3 (7.6–11.2) 1.0 (0.5–1.8) 0.9 (0.4–1.7) Cataract 828 836 13.8 (11.5–16.3) 13.2 (10.9–15.6) 5.1 (3.7–6.8) 6.8 (5.2–8.7) 1.0 (0.4–1.9) 0.8 (0.3–1.7) Asthma 698 714 15.3 (12.7–18.2) 12.9 (10.5–15.6) 4.4 (3.0–6.2) 4.2 (2.9–5.9) 2.3 (1.3–3.7) 2.5 (1.5–4.0) Respiratory disorders 651 593 20.0 (17.0–23.3) 23.1 (19.8–26.7) 13.4 (10.8–16.2) 15.0 (12.2–18.1) 0.6 (0.2–1.6) 2.0 (1.0–3.5) Renal disorders 328 319 26.2 (21.5–31.3) 23.5 (19.0–28.6) 15.2 (11.5–19.6) 15.7 (11.9–20.1) 0.6 (0.1–2.2) 1.3 (0.3–3.2) Number of selected medical conditions present at enrollment 1 3,309 3,333 6.9 (6.0–7.8) 7.7 (6.8–8.7) 3.2 (2.6–3.9) 3.4 (2.8–4.0) 1.4 (1.0–1.9) 1.2 (0.9–1.7) 2 3,267 3,238 9.7 (8.7–10.8) 9.7 (8.7–10.8) 3.9 (3.3–4.6) 4.5 (3.8–5.3) 1.3 (1.0–1.8) 1.6 (1.2–2.1) 3 2,449 2,567 12.0 (10.7–13.3) 13.0 (11.7–14.3) 5.6 (4.7–6.5) 5.8 (5.0–6.8) 1.2 (0.8–1.7) 1.2 (0.8–1.7) At least 3 5,487 5,555 14.7 (13.8–15.7) 14.8 (13.9–15.8) 6.4 (5.8–7.1) 6.7 (6.0–7.3) 1.2 (0.9–1.5) 1.5 (1.2–1.8) At least 4 3,038 2,988 16.9 (15.6–18.3) 16.4 (15.1–17.7) 7.1 (6.3–8.1) 7.4 (6.5–8.4) 1.2 (0.8–1.6) 1.7 (1.2–2.2) At least 5 1,490 1,430 19.8 (17.8–21.9) 21.0 (19.0–23.3) 8.6 (7.2–10.1) 9.5 (8.0–11.2) 1.1 (0.7–1.8) 1.6 (1.0–2.4) At least 6 600 591 21.5 (18.3–25.0) 25.2 (21.8–28.9) 10.2 (7.9–12.9) 11.3 (8.9–14.2) 1.2 (0.5–2.4) 1.4 (0.6–2.6) RZV = participants receiving the adjuvanted herpes zoster subunit vaccine; Placebo = participants receiving placebo; ZOE-50/70 = RZV efficacy studies in adults ≥50 YOA (NCT01165177) and ≥70 YOA (NCT01165229), respectively; % = percentage of participants in the category; CI = confidence interval; pIMDs = potential immune-mediated diseases; SAEs = serious adverse events; TVC = total vaccinated cohort. Other than asthma. HUMAN VACCINES & IMMUNOTHERAPEUTICS 2871 board on Zostavax, respectively, outside the submitted work. ISG program with RZV in immune compromised adults (e.g. received lecture fees and grant support from GSK outside the submitted hematopoietic stem cell transplant recipients and patients work and served on the Advisory Board for Shingrix in Canada. In with hematological malignancies). No standard definitions addition, ISG has received research grants and lecture fees from several were used in the diagnosis; therefore, each selected medical other pharmaceutical companies in work done for Prime Health Clinical condition could vary with respect to severity, stage, treatment, Research outside the submitted work. HI received grants and personal fees from GSK and grants from Japan Vaccine during the conduct of the progression, or type (e.g., diabetes mellitus type). The data- study, as well as grants and personal fees from Daiichi-Sankyo and grants base did not capture this level of detail. Medical conditions from Sanofi Pasteur and personal fees from Shionogi outside the sub- with onset after enrollment were not considered for this mitted work. GK is a freelance statistician at Keyrus Biopharma, serving as analysis. Older adults with severe frailty (e.g., bedridden a paid consultant for GSK. HL is a current employee of Pfizer and receives elderly persons) were also unlikely to participate. Despite stock as part of his employee remuneration. SAM reports research grant from Pfizer, personal fees for continuing professional development talks their broad geographic diversity, study participants were on adult immunization from Pfizer and Merck, and consulting fees from mostly Caucasian. Nonetheless, the most common diseases Pfizer and Merck outside the submitted work, as well as grant from GSK in the targeted age group were well represented. outside the submitted work. JS reports personal fees from GSK and Sanofi In summary, this study showed that >80% of participants Pasteur outside the submitted work. DW reports grants and personal fees had at least 1 of the 15 selected medical conditions present at from GSK, consulting fees from Maruho and Japan Vaccines, lecture fees from Maruho and Mochida, and grant support from Maruho. LYW enrollment. As indicated by the similarity of the point estimates, received grant from GSK during the conduct of the study, as well as fees this post-hoc analysis suggests that RZV efficacy remains high for serving on advisory boards from Novartis, GSK, AbbVie and Wyeth. in all selected medical conditions, as well as with increasing ALC received honoraria paid to his institution from GSK, Merck, and number of medical conditions. Point estimates for efficacy BioCSL/Sequirus outside the submitted work. ranged between 84.5–97.0% according to the type of the selected SJH and KP declare no conflict of interest. medical conditions (with overlapping 95% confidence intervals) and were >90% even among participants reporting at least 6 of Funding these at enrollment. No safety concern was identified in adults ≥50 YOA presenting these medical conditions. This work was sponsored by GlaxoSmithKline Biologicals SA. A plain language summary contextualizing the results and GlaxoSmithKline Biologicals SA was involved in all stages of the conduct and analysis of the studies. GlaxoSmithKline Biologicals SA covered the potential clinical research relevance and impact is displayed in costs associated with the development and the publishing of the present the Focus on Patient Section (Supplementary Figure 1). manuscript. Acknowledgments ZOE-50/70 study group The authors would like to thank all study participants, the clinical Anitta Ahonen, Eugene Athan, Johan Berglund, Won Suk Choi, investigators and study nurses involved in the ZOE-50 and ZOE-70 Ferdinandus J. de Looze, Maria Giuseppina Desole, Meral Esen, Brecht trials. The authors are also grateful to Anne Schuind (GSK) for draft Geeraerts, Wayne Ghesquiere, Lars Rombo, Antonio Volpi. reviewing and scientific input, and to Modis c/o GSK for editorial assistance and manuscript coordination. Medical writing services were provided by Alpár Pöllnitz and editorial assistance and publication Trademark statement coordination were provided by Quentin Deraedt. Shingrix is a trademark owned by or licensed to the GSK group of companies. Authors’ contributions Detailed authors’ contributions are provided in the supplementary ORCID materials. Lidia Oostvogels http://orcid.org/0000-0003-1298-0360 Thomas C. Heineman http://orcid.org/0000-0003-4500-5676 Robert W. Johnson http://orcid.org/0000-0002-8376-7412 Disclosure of potential conflicts of interest Myron J. Levin http://orcid.org/0000-0002-7468-106X TCH, HL, and LO are former employees, and AFD, CH, TM, PVdS, TZ Janet E. McElhaney http://orcid.org/0000-0002-0690-1446 and TM spouse are employees, of the GSK group of companies (GSK). Peter Van den Steen http://orcid.org/0000-0001-7931-1781 LO, TCH, AFD, HL, TM, PVdS, TZ and TM spouse hold shares or/and Toufik Zahaf http://orcid.org/0000-0002-2049-5210 stock options from GSK as per their former or current employee remu- Alemnew F. Dagnew http://orcid.org/0000-0003-4181-058X neration. LO is an employee of CureVac AG. LO and TCH are inventors Roman Chlibek http://orcid.org/0000-0002-7387-3844 on a patent owned by GSK and relevant to RZV. TCH served as a paid Javier Diez-Domingo http://orcid.org/0000-0003-1008-3922 consultant to GSK outside the submitted work. RWJ received honoraria Iris S. Gorfinkel http://orcid.org/0000-0002-8812-941X for consultancy and funding for a meeting he organized from Merck, Caroline Hervé http://orcid.org/0000-0002-0794-8748 funding from Sanofi Pasteur MSD to organize a scientific meeting, and Shinn-Jang Hwang http://orcid.org/0000-0003-3217-6193 honoraria as a consultant for GSK. MJL received fees for serving on Hideyuki Ikematsu http://orcid.org/0000-0002-3548-4231 advisory boards from Merck and GSK and grant support from Merck George Kalema http://orcid.org/0000-0002-0535-5930 and GSK. JEM reports receiving honoraria and fees paid to her institu- Himal Lal http://orcid.org/0000-0001-7174-1314 tion from GSK, Sanofi Pasteur, Merck and Pfizer, as well as travel Shelly A. McNeil http://orcid.org/0000-0001-5444-4166 support from GSK, Sanofi Pasteur, Merck and Pfizer outside the sub- Karlis Pauksens http://orcid.org/0000-0003-2626-7574 mitted work. RC reports receiving lecture fees from Pfizer outside the Jan Smetana http://orcid.org/0000-0002-3770-1754 submitted work. JDD reports personal fees from GSK for serving on an Daisuke Watanabe http://orcid.org/0000-0001-6817-3993 advisory board, as well as grants and personal fees from Sanofi Pasteur Lily Yin Weckx http://orcid.org/0000-0003-4949-3582 MSD for an epidemiological study on herpes zoster and an advisory Anthony L. Cunningham http://orcid.org/0000-0002-6744-5667 2872 L. OOSTVOGELS ET AL. 50-59 years. Clin Infect Dis. 2012;54:922–28. doi:10.1093/cid/ References cir970. 1. Yawn BP, Gilden D. The global epidemiology of herpes zoster. 10. Lecrenier N, Beukelaers P, Colindres R, Curran D, De Kesel C, De Neurology. 2013;81:928–30. doi:10.1212/WNL.0b013e3182a3516e. Saegher J-P, Didierlaurent AM, Ledent EY, Mols JF, Mrkvan T, 2. Kawai K, Gebremeskel BG, Acosta CJ. Systematic review of inci- et al. Development of adjuvanted recombinant zoster vaccine and dence and complications of herpes zoster: towards a global per- its implications for shingles prevention. Expert Rev Vaccines. spective. BMJ Open. 2014;4:e004833. doi:10.1136/bmjopen-2014- 2018;17:619–34. doi:10.1080/14760584.2018.1495565. 11. Prince MJ, Wu F, Guo Y, Gutierrez Robledo LM, O’Donnell M, 3. Kawai K, Yawn BP. Risk factors for herpes zoster: a systematic Sullivan R, Yusuf S. The burden of disease in older people and review and meta-analysis. Mayo Clinic Proc. 2017;92:1806–21. implications for health policy and practice. Lancet. 2015;385:549– doi:10.1016/j.mayocp.2017.10.009. 62. doi:10.1016/S0140-6736(14)61347-7. 4. Forbes HJ, Bhaskaran K, Thomas SL, Smeeth L, Clayton T, de la Serna J, Campora L, Chandrasekar P, El Idrissi M, Gaidano Langan SM. Quantification of risk factors for herpes zoster: popu- G, López Fauqued M, Oostvogels L, Schwartz S, Sullivan K, Szer lation based case-control study. Bmj. 2014;348:g2911. doi:10.1136/ J, Bastidas A. Efficacy and safety of an adjuvanted herpes zoster bmj.g2911. subunit vaccine in autologous hematopoietic stem cell trans- 5. Hata A, Kuniyoshi M, Ohkusa Y. Risk of Herpes zoster in patients plant recipients 18 years of age or older: first results of the with underlying diseases: a retrospective hospital-based cohort phase 3 randomized, placebo-controlled ZOE-HSCT clinical study. Infection. 2011;39:537–44. doi:10.1007/s15010-011-0162-0. trial. BMT Tandem Meetings, Salt Lake City, Utah. 2018: 6. Oxman MN, Levin MJ, Johnson GR, Schmader KE, Straus SE, abstract LBA2. Gelb LD, Arbeit RD, Simberkoff MS, Gershon AA, Davis LE, et al. 13. Dagnew AF, Ilhan O, Lee W-S, Woszczyk D, Kwak J-Y, A vaccine to prevent herpes zoster and postherpetic neuralgia in Bowcock S, Sohn SK, Rodriguez Macías G, Chiou T-J, Quiel older adults. N Engl J Med. 2005;352:2271–84. doi:10.1056/ D, et al. 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Journal

Human Vaccines & ImmunotherapeuticsTaylor & Francis

Published: Dec 2, 2019

Keywords: Varicella-zoster virus; adjuvanted recombinant zoster vaccine; vaccine efficacy; vaccine safety; underlying chronic disease; comorbidity

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