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 KEYWORDS in the pooled (ZOE-50/70) population according to the number and type of selected medical conditions Varicella-zoster virus; present at enrollment. adjuvanted recombinant At enrollment, 82.3% of RZV and 82.7% of placebo recipients reported ≥1 of the 15 selected medical zoster vaccine; vaccine conditions. Efficacy against HZ ranged from 84.5% (95% Confidence Interval [CI]: 46.4–97.1) in partici- efficacy; vaccine safety; underlying chronic disease; pants with respiratory disorders to 97.0% (95%CI: 82.3–99.9) in those with coronary heart disease. comorbidity Moreover, efficacy remained >90% irrespective of the number of selected medical conditions reported by a participant. 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. Introduction some of these conditions may result from the immunosuppressive therapy prescribed to treat the disease and/or from underlying Herpes zoster (HZ) results from reactivation of latent vari- cell-mediated immunosuppression associated with the disease. cella-zoster virus (VZV) in sensory ganglia long after primary 6–9 Vaccination decreases the risk of HZ. The adjuvanted infection. Worldwide, the incidence of HZ ranges between recombinant zoster vaccine (RZV, Shingrix), containing a 3–5 cases per 1,000 person-years in the general population truncated form of VZV glycoprotein E and the AS01 adju- and increases markedly with age, with more than two-thirds vant system, demonstrated 97.2% and 91.3% vaccine efficacy 1,2 of HZ cases occurring in adults over 50 years of age (YOA). (VE) against HZ in adults ≥50 (ZOE-50) and ≥70 YOA (ZOE- Medical conditions previously identified as increasing the risk 70), respectively, over an approximate 4-year follow-up per- of HZ include systemic lupus erythematosus, rheumatoid arthri- 7,8 iod. Efficacy remained >90% among participants ≥80 YOA. tis, inflammatory bowel disease, chronic obstructive pulmonary 7,8,10 RZV also demonstrated an acceptable safety profile. It is disease, asthma, chronic kidney disease, renal failure, hyperten- currently licensed in multiple countries for the prevention of sion, diabetes mellitus (predominantly type I), depression, and HZ in adults ≥50 YOA. 3–5 spinal disc herniation. The increase in HZ risk associated with 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. Although adults with a life expectancy of less than 4 years, at enrollment. For the purpose of the analysis, medical con- with immunosuppressive conditions (e.g., resulting from ditions were defined as individual Medical Dictionary for malignancy or HIV infection) or requiring treatment with Regulatory Authorities preferred terms (PTs) or grouped immune-modifying drugs (e.g., medications used during can- PTs representing conditions of similar pathophysiological cer chemotherapy or organ transplantation) were excluded origin. Details on PT grouping are provided in the 7,8 from entry into the ZOE-50/70 trials, the eligibility criteria Supplementary Table 1. Participants reporting more than allowed enrollment of adults with medical conditions that are one of the PTs within the 15 selected medical conditions common in the general older adult population. The study were only counted once for the respective analyses. population was therefore considered broadly representative For the analysis of VE, a suspected HZ case was defined as of the general older adult population. The two studies were new unilateral rash with pain that had no alternative diagnosis. conducted in parallel at the same sites and in an identical Participants were followed for at least 90 days after the onset of manner, allowing the analysis of pooled data from both trials. HZ or until the rash resolved and the participant was pain-free Adults ≥70 YOA were randomly assigned to the ZOE-50 or for 4 weeks. Suspected HZ cases were evaluated and confirmed ZOE-70 study before being randomized to a study group. as described previously by polymerase-chain-reaction or an 7,8 The objective of this post-hoc pooled analysis is to evaluate adjudication committee. Efficacy was assessed similar to the RZV efficacy against the first or only episode of HZ and to primary analysis on the pooled modified total vaccinated cohort 7,8 examine RZV safety in participants with selected medical (mTVC). This included all participants from the pooled TVC conditions at enrollment. who had received both doses of vaccine/placebo 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 Methods group to that in the placebo group. For assessment of safety, serious adverse events (SAEs) The ZOE-50/70 studies were phase III, randomized, observer- were recorded for all participants for up to 12 months post- blind, controlled trials conducted in parallel in 18 countries in dose 2; any events resulting in death, and potentially immune- Europe, North America, Latin America, Asia and Australia in mediated diseases (pIMDs) were evaluated in all participants adults ≥50 YOA (NCT01165177) and ≥70 YOA over the entire study period. Safety was evaluated in the (NCT01165229). Participants were randomized 1:1 to receive 2 7,8 pooled TVC from the ZOE-50/70 studies, which included all doses of either RZV or saline placebo 2 months (M) apart. participants administered with at least one dose of RZV. Protocol summaries are available for both studies at http://www. gsk-clinicalstudyregister.com (studies 110390 and 113077). Anonymized individual participant data and study documents Results can be requested for further research from www.clinicalstudyda tarequest.com. Of the 30,977 participants enrolled in the ZOE-50/70 studies, Persons with a confirmed or suspected immunosuppressive 13,881 RZV and 14,035 placebo recipients were included in or immunodeficient conditions resulting from disease (e.g., the mTVC. Of these, 82.3% of RZV recipients and 82.7% of malignancy, human immunodeficiency virus infection) or placebo recipients had at least 1 of the 15 selected medical immunosuppressive/cytotoxic therapy (e.g., medications used conditions at enrollment. A majority (RZV: 59.6%, Placebo: during cancer therapy, organ transplantation or to treat auto- 59.8%) had 2 or more (Figure 1). In the pooled mTVC, immune disorders) were excluded. Persons who had received demographic characteristics, including proportions of partici- immunosuppressants or immune-modifying drugs for >15 pants reporting each of the selected medical conditions, were consecutive days within 6 months prior to the first vaccine balanced between study groups (Table 1). dose, were also excluded (prednisone <20 mg/day, or equiva- Medical conditions in order of decreasing frequency lent, and inhaled/topical steroids were allowed). Full inclusion included hypertension, osteoarthritis and vertebral disorders, 7,8 and exclusion criteria have previously been published. and dyslipidemia. The most frequently reported conditions Medical conditions of the approximately 30,000 partici- known to increase HZ risk included in this analysis were pants were recorded at enrollment in the ZOE-50/70 trials, depression and asthma (Table 1). and those most frequently reported in the ZOE-70 trial were Efficacy against HZ ranged from 84.5% (95% Confidence selected and applied for analysis utilizing data from both Interval [CI]: 46.4–97.1) in participants with respiratory dis- trials, since the prevalence of most underlying medical condi- orders to 97.0% (95% CI: 82.3–99.9) in those with coronary tions increases with age. Efficacy and safety analyses were heart disease at enrollment. Efficacy was 88.8% (95% CI: 63.6– performed post-hoc in the pooled ZOE-50/70 population (i) 97.8) in participants with asthma, and 91.2% (95% CI: 81.1– according to medical conditions reported by at least 500 96.6) in those with diabetes. The only medical condition that participants from either arm of the ZOE-70 study at enroll- RZV efficacy did not achieve statistical significance was renal ment (considered to provide an adequate sample size for the disorders (VE: 86.6% [95% CI: −4.5–99.7]). The low number purpose of a descriptive analysis), and according to additional of participants with this condition limited the statistical power medical conditions reported by less than 500 participants in to assess VE. Overall, RZV efficacy was >90% irrespective of the ZOE-70 study at enrollment but associated with an the number of the selected medical conditions reported at increased risk of HZ (asthma, depression, respiratory disor- enrollment by a participant (Table 2). 3–5 ders, and renal disorders), and (ii) according to the number In RZV or placebo recipients reporting at least 1 of the 15 of selected medical conditions reported by study participants selected medical conditions at enrollment, the proportion of 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. participants experiencing SAEs or deaths was highest among least 1 of the specified conditions. Other studies have shown that those with chronic conditions such as renal disorders, respira- RZV also confers strong protection against HZ in immunocom- tory disorders, or coronary heart disease. The numbers of promised populations who are at highest HZ risk, such as SAEs, deaths, or pIMDs were similar in the vaccine and hematopoietic stem cell transplant recipients and patients with 12,13 placebo groups for each of the medical conditions (Table 3). hematological malignancies. The frequency of SAEs and deaths increased with the number The high proportion of participants reporting at least 1 of the of medical conditions present at enrollment; however, the selected medical conditions can be explained by the relatively frequency of pIMDs did not. Frequencies of SAEs, deaths, permissive inclusion and exclusion criteria for the ZOE-50/70 and pIMDs were balanced between RZV and placebo recipi- studies and the age of study participants. Previous studies have ents reporting any number of these conditions (Table 3). shown that frailty correlates with the number, rather than the nature of accumulated biopsychosocial deficits, which are mostly 14,15 medical conditions. Our analysis was consistent with this Discussion finding in that the frequency of SAEs and deaths increased with the number of conditions reported at enrollment. Although the Older adults enrolled in the ZOE-50/70 studies reported under- point estimates for efficacy were <90% for 5 of the 15 selected lying medical conditions at a frequency expected in these age medical conditions, the observed trend suggest that a high VE was groups. The observed efficacy across the 15 medical condi- maintained in participants having up to 6 or more of those con- tions, including the ones associated with an increased HZ risk, ditions. This contrasts with the observed decline in influenza was consistent with the efficacy in the overall pooled ZOE-50/70 vaccination effectiveness as the level of frailty increases in elderly population ≥70 YOA. This is in line with the fact that >80% of people. This further underscores the ability of RZV to induce the overall ZOE-50 and ZOE-70 study population reported at 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. robust protection against HZ in older adults with multiple medical estimate. Therefore, owing to the inclusion/exclusion criteria, conditions. persons with some of the conditions associated with the high- Overall, frequencies of SAEs, deaths, and pIMDs were est HZ risk were not enrolled in the study. Some of these balanced between RZV and placebo recipients within each conditions were studied as part of the parallel clinical pro- of the analyzed sub-groups. No vaccine-related safety con- gram with RZV in immune compromised adults (e.g. hema- cerns were identified in participants with any type or number topoietic stem cell transplant recipients and patients with of the selected medical conditions. hematological malignancies). No standard definitions were This post-hoc analysis has some limitations that should be used in the diagnosis; therefore, each selected medical condi- taken into account when interpreting its results. The ZOE-50/ tion could vary with respect to severity, stage, treatment, 70 studies were not statistically powered to evaluate RZV progression, or type (e.g., diabetes mellitus type). The data- efficacy and safety by the number and type of participants’ base did not capture this level of detail. Medical conditions medical conditions. In addition, the number of participants in with onset after enrollment were not considered for this some sub-groups was limited. This includes medical condi- analysis. Older adults with severe frailty (e.g., bedridden tions reported by less than 500 participants in the ZOE-70 elderly persons) were also unlikely to participate. Despite study at enrollment but associated with an increased risk of their broad geographic diversity, study participants were HZ (asthma, depression, respiratory disorders, and renal dis- mostly Caucasian. Nonetheless, the most common diseases orders) and participants with ≥6 of the selected conditions. in the targeted age group were well represented. The present analysis was not adjusted for multiplicity, and In summary, this study showed that >80% of participants being exploratory, its significance level was not controlled. had at least 1 of the 15 selected medical conditions present at The efficacy and safety analyses by medical condition category enrollment. As indicated by the similarity of the point esti- did not detect any additional underlying medical condition at mates, this post-hoc analysis suggests that RZV efficacy enrollment that might have an additive or synergistic effect on remains high in all selected medical conditions, as well as the risk of HZ. As the study groups were comparable as a with increasing number of medical conditions. Point esti- result of randomization, this should have a limited effect on mates for efficacy ranged between 84.5–97.0% according to the analyses by type or number of conditions. In addition, the type of the selected medical conditions (with overlapping study participants were not fully representative of the overall 95% confidence intervals) and were >90% even among parti- older adult population. Individuals with a life expectancy of cipants reporting at least 6 of these at enrollment. No safety less than 4 years at the time of study entry were to be concern was identified in adults ≥50 YOA presenting these excluded. Persons with diseases requiring treatment with medical conditions. immune-modifying drugs, as well as persons with diseases A plain language summary contextualizing the results and that are immunosuppressive by nature, were also excluded, potential clinical research relevance and impact is displayed in limiting the conditions for which we could provide a VE the Focus on Patient Section (Supplementary Figure 1). 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 Acknowledgments ZOE-50/70 study group Anitta Ahonen, Eugene Athan, Johan Berglund, Won Suk Choi, The authors would like to thank all study participants, the clinical Ferdinandus J. de Looze, Maria Giuseppina Desole, Meral Esen, Brecht investigators and study nurses involved in the ZOE-50 and ZOE-70 Geeraerts, Wayne Ghesquiere, Lars Rombo, Antonio Volpi. trials. The authors are also grateful to Anne Schuind (GSK) for draft 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 Disclosure of potential conflicts of interest Robert W. Johnson http://orcid.org/0000-0002-8376-7412 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, Shinn-Jang Hwang http://orcid.org/0000-0003-3217-6193 funding from Sanofi Pasteur MSD to organize a scientific meeting, and Hideyuki Ikematsu http://orcid.org/0000-0002-3548-4231 honoraria as a consultant for GSK. MJL received fees for serving on George Kalema http://orcid.org/0000-0002-0535-5930 advisory boards from Merck and GSK and grant support from Merck Himal Lal http://orcid.org/0000-0001-7174-1314 and GSK. JEM reports receiving honoraria and fees paid to her institu- Shelly A. McNeil http://orcid.org/0000-0001-5444-4166 tion from GSK, Sanofi Pasteur, Merck and Pfizer, as well as travel Karlis Pauksens http://orcid.org/0000-0003-2626-7574 support from GSK, Sanofi Pasteur, Merck and Pfizer outside the sub- Jan Smetana http://orcid.org/0000-0002-3770-1754 mitted work. RC reports receiving lecture fees from Pfizer outside the Daisuke Watanabe http://orcid.org/0000-0001-6817-3993 submitted work. JDD reports personal fees from GSK for serving on an Lily Yin Weckx http://orcid.org/0000-0003-4949-3582 advisory board, as well as grants and personal fees from Sanofi Pasteur Anthony L. Cunningham http://orcid.org/0000-0002-6744-5667 MSD for an epidemiological study on herpes zoster and an advisory board on Zostavax, respectively, outside the submitted work. ISG received lecture fees and grant support from GSK outside the submitted work and served on the Advisory Board for Shingrix in Canada. In References addition, ISG has received research grants and lecture fees from several 1. Yawn BP, Gilden D. The global epidemiology of herpes zoster. other pharmaceutical companies in work done for Prime Health Clinical Neurology. 2013;81:928–30. doi:10.1212/WNL.0b013e3182a Research outside the submitted work. HI received grants and personal 3516e. fees from GSK and grants from Japan Vaccine during the conduct of the 2. Kawai K, Gebremeskel BG, Acosta CJ. Systematic review of incidence study, as well as grants and personal fees from Daiichi-Sankyo and grants and complications of herpes zoster: towards a global perspective. BMJ from Sanofi Pasteur and personal fees from Shionogi outside the sub- Open. 2014;4:e004833. doi:10.1136/bmjopen-2014-004833. mitted work. GK is a freelance statistician at Keyrus Biopharma, serving 3. Kawai K, Yawn BP. Risk factors for herpes zoster: a systematic as a paid consultant for GSK. HL is a current employee of Pfizer and review and meta-analysis. Mayo Clinic Proc. 2017;92:1806–21. receives stock as part of his employee remuneration. SAM reports doi:10.1016/j.mayocp.2017.10.009. research grant from Pfizer, personal fees for continuing professional 4. Forbes HJ, Bhaskaran K, Thomas SL, Smeeth L, Clayton T, development talks on adult immunization from Pfizer and Merck, and Langan SM. Quantification of risk factors for herpes zoster: popu- consulting fees from Pfizer and Merck outside the submitted work, as lation based case-control study. Bmj. 2014;348:g2911. doi:10.1136/ well as grant from GSK outside the submitted work. JS reports personal bmj.g2911. fees from GSK and Sanofi Pasteur outside the submitted work. DW 5. Hata A, Kuniyoshi M, Ohkusa Y. Risk of Herpes zoster in patients reports grants and personal fees from GSK, consulting fees from with underlying diseases: a retrospective hospital-based cohort Maruho and Japan Vaccines, lecture fees from Maruho and Mochida, study. Infection. 2011;39:537–44. doi:10.1007/s15010-011-0162-0. and grant support from Maruho. LYW received grant from GSK during 6. OxmanMN, LevinMJ, JohnsonGR, Schmader KE,StrausSE, Gelb the conduct of the study, as well as fees for serving on advisory boards LD,ArbeitRD,Simberkoff MS,Gershon AA,Davis LE,etal.A from Novartis, GSK, AbbVie and Wyeth. ALC received honoraria paid to vaccine to prevent herpes zoster and postherpetic neuralgia in older his institution from GSK, Merck, and BioCSL/Sequirus outside the sub- adults. N Engl J Med. 2005;352:2271–84. doi:10.1056/NEJMoa051016. mitted work. 7. Lal H, Cunningham AL, Godeaux O, Chlibek R, Diez- SJH and KP declare no conflict of interest. DomingoJ, Hwang SJ,Levin MJ,McElhaney JE,Poder A, Puig-Barberà J, et al. Efficacy of an adjuvanted herpes zoster subunit vaccine in older adults. N Engl J Med. Funding 2015;372:2087–96. doi:10.1056/NEJMoa1501184. This work was sponsored by GlaxoSmithKline Biologicals SA. 8. Cunningham AL, Lal H, Kovac M, Chlibek R, Hwang SJ, Diez- GlaxoSmithKline Biologicals SA was involved in all stages of the conduct Domingo J, Godeaux O, Levin MJ, McElhaney JE, Puig-Barberà J, and analysis of the studies. GlaxoSmithKline Biologicals SA covered the et al. Efficacy of the herpes zoster subunit vaccine in adults 70 years of costs associated with the development and the publishing of the present age or older. N Engl J Med. 2016;375:1019–32. doi:10.1056/ manuscript. NEJMoa1603800. 2872 L. OOSTVOGELS ET AL. 9. Schmader KE,Levin MJ,Gnann JW Jr.,McNeil SA,VesikariT,Betts randomized, placebo-controlled ZOE-HSCT clinical trial. BMT RF, Keay S, Stek JE, Bundick ND, Su S-C, et al. Efficacy, safety, and Tandem Meetings, Salt Lake City, Utah. 2018: abstract LBA2. tolerability of herpes zoster vaccine in persons aged 50-59 years. Clin 13. Dagnew AF,Ilhan O, LeeW-S,WoszczykD,KwakJ-Y,BowcockS, Infect Dis. 2012;54:922–28. doi:10.1093/cid/cir970. Sohn SK, Rodriguez Macías G, Chiou T-J, Quiel D, et al. 10. Lecrenier N, Beukelaers P, Colindres R, Curran D, De Kesel Immunogenicity, safety and efficacy assessment of the adjuvanted C, De Saegher J-P, Didierlaurent AM, Ledent EY, Mols JF, recombinant zoster vaccine in adults with hematologic malignancies: Mrkvan T, et al. Development of adjuvanted recombinant a phase 3, randomized clinical trial. ID Week. 2018:abstract 140. zoster vaccine and its implications for shingles prevention. 14. Searle SD, Mitnitski A, Gahbauer EA, Gill TM, Rockwood K. A Expert Rev Vaccines. 2018;17:619–34. doi:10.1080/ standard procedure for creating a frailty index. BMC Geriatr. 14760584.2018.1495565. 2008;8:24. doi:10.1186/1471-2318-8-24. 11. Prince MJ, Wu F, Guo Y, Gutierrez Robledo LM, O’Donnell M, 15. Mitnitski AB, Mogilner AJ, Rockwood K. Accumulation of deficits as a Sullivan R, Yusuf S. The burden of disease in older people and proxy measure of aging. Sci World J. 2001;1:323–36. doi:10.1100/ implications for health policy and practice. Lancet. 2015;385:549– tsw.2001.58. 62. doi:10.1016/S0140-6736(14)61347-7. 16. Andrew MK,ShindeV,YeL,Hatchette T, Haguinet F, Dos 12. de la Serna J, Campora L, Chandrasekar P, El Idrissi M, Gaidano Santos G, McElhaney JE, Ambrose A, Boivin G, Bowie W, G, López Fauqued M, Oostvogels L, Schwartz S, Sullivan K, Szer J, et al. The importance of frailty in the assessment of influenza Bastidas A. Efficacy and safety of an adjuvanted herpes zoster vaccine effectiveness against influenza-related hospitalization subunit vaccine in autologous hematopoietic stem cell transplant in elderly people. J Infect Dis. 2017;216:405–14. doi:10.1093/ recipients 18 years of age or older: first results of the phase 3 infdis/jix282. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Human Vaccines & Immunotherapeutics Pubmed Central

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

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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 KEYWORDS in the pooled (ZOE-50/70) population according to the number and type of selected medical conditions Varicella-zoster virus; present at enrollment. adjuvanted recombinant At enrollment, 82.3% of RZV and 82.7% of placebo recipients reported ≥1 of the 15 selected medical zoster vaccine; vaccine conditions. Efficacy against HZ ranged from 84.5% (95% Confidence Interval [CI]: 46.4–97.1) in partici- efficacy; vaccine safety; underlying chronic disease; pants with respiratory disorders to 97.0% (95%CI: 82.3–99.9) in those with coronary heart disease. comorbidity Moreover, efficacy remained >90% irrespective of the number of selected medical conditions reported by a participant. 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. Introduction some of these conditions may result from the immunosuppressive therapy prescribed to treat the disease and/or from underlying Herpes zoster (HZ) results from reactivation of latent vari- cell-mediated immunosuppression associated with the disease. cella-zoster virus (VZV) in sensory ganglia long after primary 6–9 Vaccination decreases the risk of HZ. The adjuvanted infection. Worldwide, the incidence of HZ ranges between recombinant zoster vaccine (RZV, Shingrix), containing a 3–5 cases per 1,000 person-years in the general population truncated form of VZV glycoprotein E and the AS01 adju- and increases markedly with age, with more than two-thirds vant system, demonstrated 97.2% and 91.3% vaccine efficacy 1,2 of HZ cases occurring in adults over 50 years of age (YOA). (VE) against HZ in adults ≥50 (ZOE-50) and ≥70 YOA (ZOE- Medical conditions previously identified as increasing the risk 70), respectively, over an approximate 4-year follow-up per- of HZ include systemic lupus erythematosus, rheumatoid arthri- 7,8 iod. Efficacy remained >90% among participants ≥80 YOA. tis, inflammatory bowel disease, chronic obstructive pulmonary 7,8,10 RZV also demonstrated an acceptable safety profile. It is disease, asthma, chronic kidney disease, renal failure, hyperten- currently licensed in multiple countries for the prevention of sion, diabetes mellitus (predominantly type I), depression, and HZ in adults ≥50 YOA. 3–5 spinal disc herniation. The increase in HZ risk associated with 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. Although adults with a life expectancy of less than 4 years, at enrollment. For the purpose of the analysis, medical con- with immunosuppressive conditions (e.g., resulting from ditions were defined as individual Medical Dictionary for malignancy or HIV infection) or requiring treatment with Regulatory Authorities preferred terms (PTs) or grouped immune-modifying drugs (e.g., medications used during can- PTs representing conditions of similar pathophysiological cer chemotherapy or organ transplantation) were excluded origin. Details on PT grouping are provided in the 7,8 from entry into the ZOE-50/70 trials, the eligibility criteria Supplementary Table 1. Participants reporting more than allowed enrollment of adults with medical conditions that are one of the PTs within the 15 selected medical conditions common in the general older adult population. The study were only counted once for the respective analyses. population was therefore considered broadly representative For the analysis of VE, a suspected HZ case was defined as of the general older adult population. The two studies were new unilateral rash with pain that had no alternative diagnosis. conducted in parallel at the same sites and in an identical Participants were followed for at least 90 days after the onset of manner, allowing the analysis of pooled data from both trials. HZ or until the rash resolved and the participant was pain-free Adults ≥70 YOA were randomly assigned to the ZOE-50 or for 4 weeks. Suspected HZ cases were evaluated and confirmed ZOE-70 study before being randomized to a study group. as described previously by polymerase-chain-reaction or an 7,8 The objective of this post-hoc pooled analysis is to evaluate adjudication committee. Efficacy was assessed similar to the RZV efficacy against the first or only episode of HZ and to primary analysis on the pooled modified total vaccinated cohort 7,8 examine RZV safety in participants with selected medical (mTVC). This included all participants from the pooled TVC conditions at enrollment. who had received both doses of vaccine/placebo 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 Methods group to that in the placebo group. For assessment of safety, serious adverse events (SAEs) The ZOE-50/70 studies were phase III, randomized, observer- were recorded for all participants for up to 12 months post- blind, controlled trials conducted in parallel in 18 countries in dose 2; any events resulting in death, and potentially immune- Europe, North America, Latin America, Asia and Australia in mediated diseases (pIMDs) were evaluated in all participants adults ≥50 YOA (NCT01165177) and ≥70 YOA over the entire study period. Safety was evaluated in the (NCT01165229). Participants were randomized 1:1 to receive 2 7,8 pooled TVC from the ZOE-50/70 studies, which included all doses of either RZV or saline placebo 2 months (M) apart. participants administered with at least one dose of RZV. Protocol summaries are available for both studies at http://www. gsk-clinicalstudyregister.com (studies 110390 and 113077). Anonymized individual participant data and study documents Results can be requested for further research from www.clinicalstudyda tarequest.com. Of the 30,977 participants enrolled in the ZOE-50/70 studies, Persons with a confirmed or suspected immunosuppressive 13,881 RZV and 14,035 placebo recipients were included in or immunodeficient conditions resulting from disease (e.g., the mTVC. Of these, 82.3% of RZV recipients and 82.7% of malignancy, human immunodeficiency virus infection) or placebo recipients had at least 1 of the 15 selected medical immunosuppressive/cytotoxic therapy (e.g., medications used conditions at enrollment. A majority (RZV: 59.6%, Placebo: during cancer therapy, organ transplantation or to treat auto- 59.8%) had 2 or more (Figure 1). In the pooled mTVC, immune disorders) were excluded. Persons who had received demographic characteristics, including proportions of partici- immunosuppressants or immune-modifying drugs for >15 pants reporting each of the selected medical conditions, were consecutive days within 6 months prior to the first vaccine balanced between study groups (Table 1). dose, were also excluded (prednisone <20 mg/day, or equiva- Medical conditions in order of decreasing frequency lent, and inhaled/topical steroids were allowed). Full inclusion included hypertension, osteoarthritis and vertebral disorders, 7,8 and exclusion criteria have previously been published. and dyslipidemia. The most frequently reported conditions Medical conditions of the approximately 30,000 partici- known to increase HZ risk included in this analysis were pants were recorded at enrollment in the ZOE-50/70 trials, depression and asthma (Table 1). and those most frequently reported in the ZOE-70 trial were Efficacy against HZ ranged from 84.5% (95% Confidence selected and applied for analysis utilizing data from both Interval [CI]: 46.4–97.1) in participants with respiratory dis- trials, since the prevalence of most underlying medical condi- orders to 97.0% (95% CI: 82.3–99.9) in those with coronary tions increases with age. Efficacy and safety analyses were heart disease at enrollment. Efficacy was 88.8% (95% CI: 63.6– performed post-hoc in the pooled ZOE-50/70 population (i) 97.8) in participants with asthma, and 91.2% (95% CI: 81.1– according to medical conditions reported by at least 500 96.6) in those with diabetes. The only medical condition that participants from either arm of the ZOE-70 study at enroll- RZV efficacy did not achieve statistical significance was renal ment (considered to provide an adequate sample size for the disorders (VE: 86.6% [95% CI: −4.5–99.7]). The low number purpose of a descriptive analysis), and according to additional of participants with this condition limited the statistical power medical conditions reported by less than 500 participants in to assess VE. Overall, RZV efficacy was >90% irrespective of the ZOE-70 study at enrollment but associated with an the number of the selected medical conditions reported at increased risk of HZ (asthma, depression, respiratory disor- enrollment by a participant (Table 2). 3–5 ders, and renal disorders), and (ii) according to the number In RZV or placebo recipients reporting at least 1 of the 15 of selected medical conditions reported by study participants selected medical conditions at enrollment, the proportion of 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. participants experiencing SAEs or deaths was highest among least 1 of the specified conditions. Other studies have shown that those with chronic conditions such as renal disorders, respira- RZV also confers strong protection against HZ in immunocom- tory disorders, or coronary heart disease. The numbers of promised populations who are at highest HZ risk, such as SAEs, deaths, or pIMDs were similar in the vaccine and hematopoietic stem cell transplant recipients and patients with 12,13 placebo groups for each of the medical conditions (Table 3). hematological malignancies. The frequency of SAEs and deaths increased with the number The high proportion of participants reporting at least 1 of the of medical conditions present at enrollment; however, the selected medical conditions can be explained by the relatively frequency of pIMDs did not. Frequencies of SAEs, deaths, permissive inclusion and exclusion criteria for the ZOE-50/70 and pIMDs were balanced between RZV and placebo recipi- studies and the age of study participants. Previous studies have ents reporting any number of these conditions (Table 3). shown that frailty correlates with the number, rather than the nature of accumulated biopsychosocial deficits, which are mostly 14,15 medical conditions. Our analysis was consistent with this Discussion finding in that the frequency of SAEs and deaths increased with the number of conditions reported at enrollment. Although the Older adults enrolled in the ZOE-50/70 studies reported under- point estimates for efficacy were <90% for 5 of the 15 selected lying medical conditions at a frequency expected in these age medical conditions, the observed trend suggest that a high VE was groups. The observed efficacy across the 15 medical condi- maintained in participants having up to 6 or more of those con- tions, including the ones associated with an increased HZ risk, ditions. This contrasts with the observed decline in influenza was consistent with the efficacy in the overall pooled ZOE-50/70 vaccination effectiveness as the level of frailty increases in elderly population ≥70 YOA. This is in line with the fact that >80% of people. This further underscores the ability of RZV to induce the overall ZOE-50 and ZOE-70 study population reported at 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. robust protection against HZ in older adults with multiple medical estimate. Therefore, owing to the inclusion/exclusion criteria, conditions. persons with some of the conditions associated with the high- Overall, frequencies of SAEs, deaths, and pIMDs were est HZ risk were not enrolled in the study. Some of these balanced between RZV and placebo recipients within each conditions were studied as part of the parallel clinical pro- of the analyzed sub-groups. No vaccine-related safety con- gram with RZV in immune compromised adults (e.g. hema- cerns were identified in participants with any type or number topoietic stem cell transplant recipients and patients with of the selected medical conditions. hematological malignancies). No standard definitions were This post-hoc analysis has some limitations that should be used in the diagnosis; therefore, each selected medical condi- taken into account when interpreting its results. The ZOE-50/ tion could vary with respect to severity, stage, treatment, 70 studies were not statistically powered to evaluate RZV progression, or type (e.g., diabetes mellitus type). The data- efficacy and safety by the number and type of participants’ base did not capture this level of detail. Medical conditions medical conditions. In addition, the number of participants in with onset after enrollment were not considered for this some sub-groups was limited. This includes medical condi- analysis. Older adults with severe frailty (e.g., bedridden tions reported by less than 500 participants in the ZOE-70 elderly persons) were also unlikely to participate. Despite study at enrollment but associated with an increased risk of their broad geographic diversity, study participants were HZ (asthma, depression, respiratory disorders, and renal dis- mostly Caucasian. Nonetheless, the most common diseases orders) and participants with ≥6 of the selected conditions. in the targeted age group were well represented. The present analysis was not adjusted for multiplicity, and In summary, this study showed that >80% of participants being exploratory, its significance level was not controlled. had at least 1 of the 15 selected medical conditions present at The efficacy and safety analyses by medical condition category enrollment. As indicated by the similarity of the point esti- did not detect any additional underlying medical condition at mates, this post-hoc analysis suggests that RZV efficacy enrollment that might have an additive or synergistic effect on remains high in all selected medical conditions, as well as the risk of HZ. As the study groups were comparable as a with increasing number of medical conditions. Point esti- result of randomization, this should have a limited effect on mates for efficacy ranged between 84.5–97.0% according to the analyses by type or number of conditions. In addition, the type of the selected medical conditions (with overlapping study participants were not fully representative of the overall 95% confidence intervals) and were >90% even among parti- older adult population. Individuals with a life expectancy of cipants reporting at least 6 of these at enrollment. No safety less than 4 years at the time of study entry were to be concern was identified in adults ≥50 YOA presenting these excluded. Persons with diseases requiring treatment with medical conditions. immune-modifying drugs, as well as persons with diseases A plain language summary contextualizing the results and that are immunosuppressive by nature, were also excluded, potential clinical research relevance and impact is displayed in limiting the conditions for which we could provide a VE the Focus on Patient Section (Supplementary Figure 1). 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 Acknowledgments ZOE-50/70 study group Anitta Ahonen, Eugene Athan, Johan Berglund, Won Suk Choi, The authors would like to thank all study participants, the clinical Ferdinandus J. de Looze, Maria Giuseppina Desole, Meral Esen, Brecht investigators and study nurses involved in the ZOE-50 and ZOE-70 Geeraerts, Wayne Ghesquiere, Lars Rombo, Antonio Volpi. trials. The authors are also grateful to Anne Schuind (GSK) for draft 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 Disclosure of potential conflicts of interest Robert W. Johnson http://orcid.org/0000-0002-8376-7412 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, Shinn-Jang Hwang http://orcid.org/0000-0003-3217-6193 funding from Sanofi Pasteur MSD to organize a scientific meeting, and Hideyuki Ikematsu http://orcid.org/0000-0002-3548-4231 honoraria as a consultant for GSK. MJL received fees for serving on George Kalema http://orcid.org/0000-0002-0535-5930 advisory boards from Merck and GSK and grant support from Merck Himal Lal http://orcid.org/0000-0001-7174-1314 and GSK. JEM reports receiving honoraria and fees paid to her institu- Shelly A. McNeil http://orcid.org/0000-0001-5444-4166 tion from GSK, Sanofi Pasteur, Merck and Pfizer, as well as travel Karlis Pauksens http://orcid.org/0000-0003-2626-7574 support from GSK, Sanofi Pasteur, Merck and Pfizer outside the sub- Jan Smetana http://orcid.org/0000-0002-3770-1754 mitted work. RC reports receiving lecture fees from Pfizer outside the Daisuke Watanabe http://orcid.org/0000-0001-6817-3993 submitted work. JDD reports personal fees from GSK for serving on an Lily Yin Weckx http://orcid.org/0000-0003-4949-3582 advisory board, as well as grants and personal fees from Sanofi Pasteur Anthony L. Cunningham http://orcid.org/0000-0002-6744-5667 MSD for an epidemiological study on herpes zoster and an advisory board on Zostavax, respectively, outside the submitted work. ISG received lecture fees and grant support from GSK outside the submitted work and served on the Advisory Board for Shingrix in Canada. In References addition, ISG has received research grants and lecture fees from several 1. Yawn BP, Gilden D. The global epidemiology of herpes zoster. other pharmaceutical companies in work done for Prime Health Clinical Neurology. 2013;81:928–30. doi:10.1212/WNL.0b013e3182a Research outside the submitted work. HI received grants and personal 3516e. fees from GSK and grants from Japan Vaccine during the conduct of the 2. Kawai K, Gebremeskel BG, Acosta CJ. Systematic review of incidence study, as well as grants and personal fees from Daiichi-Sankyo and grants and complications of herpes zoster: towards a global perspective. BMJ from Sanofi Pasteur and personal fees from Shionogi outside the sub- Open. 2014;4:e004833. doi:10.1136/bmjopen-2014-004833. mitted work. GK is a freelance statistician at Keyrus Biopharma, serving 3. Kawai K, Yawn BP. Risk factors for herpes zoster: a systematic as a paid consultant for GSK. HL is a current employee of Pfizer and review and meta-analysis. Mayo Clinic Proc. 2017;92:1806–21. receives stock as part of his employee remuneration. SAM reports doi:10.1016/j.mayocp.2017.10.009. research grant from Pfizer, personal fees for continuing professional 4. Forbes HJ, Bhaskaran K, Thomas SL, Smeeth L, Clayton T, development talks on adult immunization from Pfizer and Merck, and Langan SM. Quantification of risk factors for herpes zoster: popu- consulting fees from Pfizer and Merck outside the submitted work, as lation based case-control study. Bmj. 2014;348:g2911. doi:10.1136/ well as grant from GSK outside the submitted work. JS reports personal bmj.g2911. fees from GSK and Sanofi Pasteur outside the submitted work. DW 5. Hata A, Kuniyoshi M, Ohkusa Y. Risk of Herpes zoster in patients reports grants and personal fees from GSK, consulting fees from with underlying diseases: a retrospective hospital-based cohort Maruho and Japan Vaccines, lecture fees from Maruho and Mochida, study. Infection. 2011;39:537–44. doi:10.1007/s15010-011-0162-0. and grant support from Maruho. LYW received grant from GSK during 6. OxmanMN, LevinMJ, JohnsonGR, Schmader KE,StrausSE, Gelb the conduct of the study, as well as fees for serving on advisory boards LD,ArbeitRD,Simberkoff MS,Gershon AA,Davis LE,etal.A from Novartis, GSK, AbbVie and Wyeth. ALC received honoraria paid to vaccine to prevent herpes zoster and postherpetic neuralgia in older his institution from GSK, Merck, and BioCSL/Sequirus outside the sub- adults. N Engl J Med. 2005;352:2271–84. doi:10.1056/NEJMoa051016. mitted work. 7. Lal H, Cunningham AL, Godeaux O, Chlibek R, Diez- SJH and KP declare no conflict of interest. DomingoJ, Hwang SJ,Levin MJ,McElhaney JE,Poder A, Puig-Barberà J, et al. Efficacy of an adjuvanted herpes zoster subunit vaccine in older adults. N Engl J Med. Funding 2015;372:2087–96. doi:10.1056/NEJMoa1501184. This work was sponsored by GlaxoSmithKline Biologicals SA. 8. Cunningham AL, Lal H, Kovac M, Chlibek R, Hwang SJ, Diez- GlaxoSmithKline Biologicals SA was involved in all stages of the conduct Domingo J, Godeaux O, Levin MJ, McElhaney JE, Puig-Barberà J, and analysis of the studies. GlaxoSmithKline Biologicals SA covered the et al. Efficacy of the herpes zoster subunit vaccine in adults 70 years of costs associated with the development and the publishing of the present age or older. N Engl J Med. 2016;375:1019–32. doi:10.1056/ manuscript. NEJMoa1603800. 2872 L. OOSTVOGELS ET AL. 9. Schmader KE,Levin MJ,Gnann JW Jr.,McNeil SA,VesikariT,Betts randomized, placebo-controlled ZOE-HSCT clinical trial. BMT RF, Keay S, Stek JE, Bundick ND, Su S-C, et al. Efficacy, safety, and Tandem Meetings, Salt Lake City, Utah. 2018: abstract LBA2. tolerability of herpes zoster vaccine in persons aged 50-59 years. Clin 13. Dagnew AF,Ilhan O, LeeW-S,WoszczykD,KwakJ-Y,BowcockS, Infect Dis. 2012;54:922–28. doi:10.1093/cid/cir970. Sohn SK, Rodriguez Macías G, Chiou T-J, Quiel D, et al. 10. Lecrenier N, Beukelaers P, Colindres R, Curran D, De Kesel Immunogenicity, safety and efficacy assessment of the adjuvanted C, De Saegher J-P, Didierlaurent AM, Ledent EY, Mols JF, recombinant zoster vaccine in adults with hematologic malignancies: Mrkvan T, et al. Development of adjuvanted recombinant a phase 3, randomized clinical trial. ID Week. 2018:abstract 140. zoster vaccine and its implications for shingles prevention. 14. Searle SD, Mitnitski A, Gahbauer EA, Gill TM, Rockwood K. A Expert Rev Vaccines. 2018;17:619–34. doi:10.1080/ standard procedure for creating a frailty index. BMC Geriatr. 14760584.2018.1495565. 2008;8:24. doi:10.1186/1471-2318-8-24. 11. Prince MJ, Wu F, Guo Y, Gutierrez Robledo LM, O’Donnell M, 15. Mitnitski AB, Mogilner AJ, Rockwood K. Accumulation of deficits as a Sullivan R, Yusuf S. The burden of disease in older people and proxy measure of aging. Sci World J. 2001;1:323–36. doi:10.1100/ implications for health policy and practice. Lancet. 2015;385:549– tsw.2001.58. 62. doi:10.1016/S0140-6736(14)61347-7. 16. Andrew MK,ShindeV,YeL,Hatchette T, Haguinet F, Dos 12. de la Serna J, Campora L, Chandrasekar P, El Idrissi M, Gaidano Santos G, McElhaney JE, Ambrose A, Boivin G, Bowie W, G, López Fauqued M, Oostvogels L, Schwartz S, Sullivan K, Szer J, et al. The importance of frailty in the assessment of influenza Bastidas A. Efficacy and safety of an adjuvanted herpes zoster vaccine effectiveness against influenza-related hospitalization subunit vaccine in autologous hematopoietic stem cell transplant in elderly people. J Infect Dis. 2017;216:405–14. doi:10.1093/ recipients 18 years of age or older: first results of the phase 3 infdis/jix282.

Journal

Human Vaccines & ImmunotherapeuticsPubmed Central

Published: Jun 28, 2019

References

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