Safety profile of the adjuvanted recombinant zoster vaccine : Pooled analysis of two large randomised phase 3 trials

Safety profile of the adjuvanted recombinant zoster vaccine: Pooled analysis of two large randomised phase 3 trials q Marta López-Fauqued a,1 , Laura Campora a,1, ⇑ , Frédérique Delannois a , Mohamed El Idrissi b , Lidia Oostvogels a,2 , Ferdinandus J. De Looze c , Javier Diez-Domingo d , Thomas C. Heineman e,3 , Himal Lal e,4 , Janet E. McElhaney f , Shelly A. McNeil g , Wilfred Yeo h , Fernanda Tavares-Da-Silva a , for the ZOE-50/70 Study Group Anitta Ahonen i , Thiago Junquera Avelino-Silva j , Jose Fernando Barba-Gomez k , Johan Berglund l , Carlos Brotons Cuixart m , Covadonga Caso n , Roman Chlibek o , Won Suk Choi p , Anthony L. Cunningham q , Maria Guiseppina Desole r , Peter Eizenberg s , Meral Esen t , Emmanuelle Espié u , Pierre Gervais v , Wayne Ghesquiere w , Olivier Godeaux x , Iris Gorfinkel y , David Shu Cheong Hui z , Shinn-Jang Hwang aa , Tiina Korhonen ab , Martina Kovac ac , Edouard Ledent ad , Edward Leung ae , Myron J. Levin af , Silvia Narejos Perez ag , Jose Luiz Neto ah , Karlis Pauksens ai , Airi Poder aj , Maria Luisa Rodriguez de la Pinta ak , Lars Rombo al , Tino F. Schwarz am , Jan Smetana an , Tommaso Staniscia ao , Juan Carlos Tinoco ap , Azhar Toma aq , Ilse Vastiau ar , Timo Vesikari as , Antonio Volpi at , Daisuke Watanabe au , Lily Yin Weckx av , Toufik Zahaf aw a GSK, Wavre, Belgium b GSK, Rixensart, Belgium c AusTrials Pty Ltd, Sherwood and School of Medicine, University of Queensland, Brisbane, Queensland, Australia d Vaccine Research Unit, Fundación para el Fomento de la Investigación Sanitaria y Biomédica, Valencia, Spain e GSK, King of Prussia, PA, USA f Health Sciences North Research Institute, Sudbury, Ontario, Canada g Canadian Center for Vaccinology, IWK Health Centre and Nova Scotia Health Authority, Dalhousie University, Halifax, Nova Scotia, Canada h School of Medicine, University of Wollongong, Wollongong, Australia i University of Tampere, Järvenpää Vaccine Clinic, Finland j University of São Paulo Medical School, Brazil k Instituto Dermatológico de Jalisco, Mexico l Blekinge Institute of Technology, Sweden m EAP Sardenya, Spain n Hospital Clínico San Carlos, Spain o University of Defence, Faculty of Military Health Sciences, Czech Republic p Korea University College of Medicine, Republic of Korea q Westmead Institute for Medical Research, University of Sydney, Australia r Servizio di Igiene Pubblica, Italy s Doctors of Ivanhoe, Australia t Institut für Tropenmedizin, University Clinic of Tübingen, Germany u GSK, Belgium v Q&T Research Sherbrooke, Canada w University of British Columbia, Canada x GSK, Belgium, during the conduct of the ZOE-50/70 trials, Belgium y York University, Canada z Prince of Wales Hospital, Hong Kong aa Taipei Veterans General Hospital and National Yang Ming University School of Medicine, Taiwan ab Vaccine Research Centre, University of Tampere Medical School, Tampere, Finland ac GSK, USA ad GSK, Belgium ae Hong Kong Association of Gerontology, Hong Kong af University of Colorado Anschutz Medical Campus, USA ag CAP Centelles, Spain ah Instituto A. Z. de Pesquisa e Ensino, Brazil https://doi.org/10.1016/j.vaccine.2019.03.043 0264-410X/Ó2019 GlaxoSmithKline Biologicals SA. Published by Elsevier Ltd. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). Abbreviations: HZ, herpes zoster; RZV, adjuvanted recombinant zoster vaccine; VZV, varicella-zoster virus; gE, VZV glycoprotein E; AE, adverse event; SAE, serious AE; pIMD, potential immune-mediated disease; D, day; M, month; Y, year; YOA, years of age; ZOE-50/70, the pivotal RZV efficacy trials in adults 50/70 YOA; MedDRA, medical dictionary for regulatory activities; SOC, system organ class; PT, preferred term; CI, confidence interval; RR, relative risk; AML, acute myeloid leukemia. q Previous presentation: Part of these data have been presented at the Vaccines and Related Biological Products Advisory Committee Meeting, 13 September 2017, Silver Spring, MD, and at IDWeek, 04-08 October 2017, San Diego, CA (USA). Trademark statement: Shingrix is a trademark of the GSK group of companies. Vaccine 37 (2019) 2482–2493 Contents lists available at ScienceDirect Vaccine journal homepage: www.elsevier.com/locate/vaccine ai Uppsala University Hospital, Sweden aj Kliiniliste Uuringute Keskus, Estonia ak Hospital Puerta de Hierro, Spain al Uppsala University, Sweden am Standort Juliusspital, Germany an University of Defence, Faculty of Military Health Sciences, Czech Republic ao University G. d’Annunzio of Chieti-Pescara, Italy ap Hospital General de Durango, Mexico aq Manna Research, Canada ar GSK, Belgium as University of Tampere, Finland at A.O. Univesitaria Policlinico Tor Vergata, Italy au Kobe University Graduate School of Medicine, Japan av Federal University of Sao Paulo, Brazil aw GSK, Belgium article info Article history: Received 15 November 2018 Received in revised form 14 March 2019 Accepted 20 March 2019 Available online 29 March 2019 Keywords: Varicella-zoster virus Vaccine Safety Reactogenicity abstract Background: The ZOE-50 (NCT01165177) and ZOE-70 (NCT01165229) phase 3 clinical trials showed that the adjuvanted recombinant zoster vaccine (RZV) was 90% efficacious in preventing herpes zoster in adults. Here we present a comprehensive overview of the safety data from these studies. Methods: Adults aged 50 (ZOE-50) and 70 (ZOE-70) years were randomly vaccinated with RZV or placebo. Safety analyses were performed on the pooled total vaccinated cohort, consisting of participants receiving at least one dose of RZV or placebo. Solicited and unsolicited adverse events (AEs) were collected for 7 and 30 days after each vaccination, respectively. Serious AEs (SAEs) were collected from the first vaccination until 12 months post-last dose. Fatal AEs, vaccination-related SAEs, and potential immune-mediated diseases (pIMDs) were collected during the entire study period. Results: Safety was evaluated in 14,645 RZV and 14,660 placebo recipients. More RZV than placebo recipients reported unsolicited AEs (50.5% versus 32.0%); the difference was driven by transient injection site and solicited systemic reactions that were generally seen in the first week post-vaccination. The occurrence of overall SAEs (RZV: 10.1%; Placebo: 10.4%), fatal AEs (RZV: 4.3%; Placebo: 4.6%), and pIMDs (RZV: 1.2%; Placebo: 1.4%) was balanced between groups. The occurrence of possible exacerbations of pIMDs was rare and similar between groups. Overall, except for the expected local and systemic symptoms, the safety results were comparable between the RZV and Placebo groups irrespective of participant age, gender, or race. Conclusions: No safety concerns arose, supporting the favorable benefit-risk profile of RZV. Ó2019 GlaxoSmithKline Biologicals SA. Published by Elsevier Ltd. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). 1. Introduction Herpes zoster (HZ) results from reactivation of latent varicellazoster virus (VZV) in the dorsal root ganglia, usually years after primary VZV infection. HZ is typically characterized by a unilateral dermatomal vesicular rash, generally accompanied by pain. Its most common complication is postherpetic neuralgia, a chronic pain that can persist for months or years after the rash has resolved [1]. HZ incidence increases substantially with age, from 3 to 5 cases per 1000 person-years in the general population of all ages [2],to 4–8 cases per 1000 person-years in adults 50 years of age (YOA) and 8–12 cases per 1000 person-years for those 80 YOA [2,3]. An adjuvanted recombinant zoster vaccine, RZV (Shingrix, GSK), consisting of a truncated form of VZV glycoprotein E (gE) and the AS01 B adjuvant system, is currently licensed in different regions worldwide for the prevention of HZ in adults 50 YOA. Two pivotal phase 3 efficacy trials (ZOE-50/70) demonstrated that RZV reduces the risk of HZ by over 90% in all age groups among adults 50YOA [4,5]. Although the vaccine induces transient local and systemic reactions, no safety concerns were identified during these clinical trials. In both studies, serious adverse events (SAEs) and potential immune-mediated diseases (pIMDs) were balanced between participants in the RZV and Placebo groups [4,5]. The similar enrollment criteria, study procedures, and safety follow-up period for the ZOE-50/70 trials allowed us to pool study data. We present here a comprehensive analysis of the safety data from pooled ZOE 50/70 studies. 2. Methods 2.1. Study design and participants ZOE-50 (NCT01165177) and ZOE-70 (NCT01165229) were phase 3, randomized, placebo-controlled, observer-blinded clinical trials ⇑ Corresponding author at: GSK, Avenue Fleming 20, 1300 Wavre, Belgium. E-mail addresses: [email protected] (M. López-Fauqued), [email protected] (L. Campora), [email protected] (F. Delannois), mohamed. [email protected] (M. El Idrissi), [email protected] (L. Oostvogels), [email protected] (F.J. Oostvogels), [email protected] (F.J. Oostvogels), [email protected] (F.J. Oostvogels), [email protected] (F.J. Oostvogels), [email protected] (F.J. De Looze), jdiezdomingo@ gmail.com (J. Diez-Domingo), [email protected] (T.C. Heineman), [email protected] (H. Lal), [email protected] (J.E. McElhaney), [email protected] (S.A. McNeil), [email protected] (W. Yeo), [email protected] (F. Tavares-Da-Silv). 1 Both authors contributed equally to the manuscript. 2 Current affiliation: CureVac AG, Tübingen, Germany. 3 Current affiliation: Halozyme Therapeutics, San Diego, California, USA. 4 Current affiliation: Pfizer Vaccine Inc, Collegeville, Pennsylvania, USA. M. López-Fauqued et al. / Vaccine 37 (2019) 2482–2493 2483 conducted concurrently at the same sites in 18 countries in Europe, North and South America, Asia and Australia. Adults aged 50 YOA (ZOE-50) or 70 YOA (ZOE-70) were randomized and vaccinated with RZV or placebo (Supplementary Fig. 1). A full list of eligibility criteria was previously presented [4,5], and is provided here in the Supplementary Material. The two studies were conducted in an identical manner, and adults 70 YOA were randomly enrolled to participate in either the ZOE-50 or ZOE-70 study. Additional study design details are presented in the primary publications [4,5]. The clinical study reports are available at http://www.gsk-clinicalstudyregister.com (IDs 110390 and 113077). Anonymized individual participant data and study documents can be requested for further research from www.clinicalstudydatarequest.com. 2.2. Study vaccines RZV contains 50 l g of gE antigen and the GSK proprietary AS01 B Adjuvant System (containing 50 l g of 3-O-desacyl-4 0 -monopho sphoryl lipid A, 50 l gofQuillaja saponaria Molina, fraction 21 [licensed by GSK from Antigenics LLC, a wholly owned subsidiary of Agenus Inc., a Delaware, USA corporation] and liposome). Placebo consisted of 0.5 mL 150 mM NaCl solution. 2.3. Collection of safety data Solicited adverse events (AEs) were collected for 7 days (D) after each vaccination (D0-D6) in the reactogenicity sub-cohort, consisting of participants who completed diary cards; severe AEs are described in the Supplementary Material. Unsolicited AEs were collected for 30D after each vaccination and graded on a scale from 1 (mild: not interfering with everyday activities) to 3 (severe: significant at rest and preventing normal everyday activities). Unsolicited AEs comprised both SAEs and non-serious AEs, including all local and systemic reactions reported by participants who were not part of the reactogenicity sub-cohort. Unsolicited AEs with medically attended visits (defined as hospitalizations, emergency room visits, or visits to or from medical personnel), other than routine health care visits, were recorded from first vaccine dose up to 6 months (M) post-last vaccination. SAEs were collected from the first vaccine dose up to 1 year (Y) post-last vaccination. Fatal AEs, SAEs considered causally related to study vaccination by the investigators, and pIMDs (new onset and possible exacerbations) were collected during the entire study period. SAEs were defined according to standard reporting guidelines [6]. AEs were coded by Medical Dictionary for Regulatory Activities (MedDRA) dictionary both per System Organ Class (SOC) and Preferred Term (PT) [7]. Local AEs were considered related to study vaccination. Relatedness of other AEs was determined based on study investigators clinical judgment, in a blinded manner. pIMDs were defined as a subset of AEs that include autoimmune diseases and other inflammatory and/or neurologic disorders of interest that may or may not have an autoimmune etiology. AEs to be recorded as pIMDs were pre-defined in the study protocol (Supplementary Table 1) and, in addition, study investigators were instructed to use their medical judgment to determine whether other events could fall in this category and to record them as pIMDs [8]. 2.4. Statistical analysis Safety analyses were performed on the pooled total vaccinated cohort, consisting of participants who received at least one dose of RZV/placebo. Analyses of unsolicited AEs, SAEs, and pIMDs were descriptive and, for each of these, percentages of participants with at least one event were calculated with their exact 95% Confidence Intervals (CIs) both per SOC and PT. Analyses of SAEs, fatal AEs, and pIMDs were performed up to 30D and 1Y post-last dose. In addition, analyses of fatal AEs and pIMDs were also performed during the entire study period. Exploratory analyses of unsolicited AEs reported within the 30D post-vaccination period, SAEs and pIMDs reported within 1Y post-last dose assessed the relative risks (RRs) and frequencies of selected events of interest using MedDRA queries. RRs and their 95% CIs were calculated by Exact Tests conditional to the number of cases. Additional details are presented in the Supplementary Material. 3. Results 3.1. Study population A total of 14,645 RZV and 14,660 placebo recipients were included in the pooled analysis. The median follow-up duration was 4.4Y. The mean age of the participants was 68.6Y; 58.2% of those were female. Most (73.7%) participants were white/Caucasian. Demographic characteristics were comparable between groups (Supplementary Table 2). 3.2. Reactogenicity In line with previously reported reactogenicity results from the ZOE-50/70 studies [4,5], RZV was more reactogenic than placebo in the pooled reactogenicity sub-cohort. Pain was the most frequent solicited local symptom reported after 68.1% (95% CI: 67.1–69.0) of documented doses in the RZV group and after 6.9% (95% CI: 6.4–7.4) in the Placebo group. Grade 3 pain was reported after 3.8% (95% CI: 3.5–4.3) of documented doses in the RZV group and after 0.2% (95% CI: 0.1–0.3) in the Placebo group. In the RZV group, the most frequently reported solicited general symptoms were myalgia and fatigue, reported after 32.9% (95% CI: 31.9–33.8) and 32.2% (95% CI: 31.3–33.2) of doses, respectively. Grade 3 fatigue was reported after 3.0% (95% CI: 2.6–3.3) of documented doses in the RZV group and after 0.5% (95% CI: 0.4–0.7) in the placebo group (Supplementary Fig. 2). Local and general symptoms in the RZV group were mostly mild to moderate in intensity and transient (median duration was of 3 days or less for local and 2 days or less for general symptoms, including grade 3 symptoms). Overall, there were no differences in the proportions of RZV recipients reporting any grade or grade 3 solicited local events between dose 1 and dose 2. All-grade solicited general symptoms tended to be more frequent after dose 2 compared to dose 1. 3.3. Unsolicited adverse events The percentage of participants reporting unsolicited AEs during 30D post-vaccination was greater for RZV than for placebo recipients (7393 [50.5%] versus 4689 [32.0%]; RR: 1.58 [95%CI:1.52– 1.64]; p < 0.0001). RZV recipients reported unsolicited AEs more frequently, irrespective of age group, gender, or race (Table 1). Unsolicited AEs more frequently reported by RZV recipients were injection site and general symptoms that were reported as solicited reactions in the reactogenicity sub-cohort (Table 1). More RZV than placebo recipients reported unsolicited AEs during the first week (D0-D6) post-vaccination (5861 [40.0%] versus 2230 [15.2%]). Unsolicited AEs were balanced between groups during the subsequent 23D (D7-D29) post-vaccination period (3,076 [21.0%] versus 3,280 [22.4%]) (Fig. 1). Unsolicited AEs not categorized as solicited AEs in the reactogenicity sub-cohort, those occurring in >1% of RZV recipients and more frequently than in placebo recipients were, by PT: injection site pruritus, pain, injection site warmth, pain in extremity, malaise, arthralgia, back pain, dizziness, upper respiratory tract infection, and oropharyngeal pain (Table 1). 2484 M. López-Fauqued et al. / Vaccine 37 (2019) 2482–2493 Table 1 Unsolicited Adverse Events reported within 30 days after vaccination (Pooled Total Vaccinated Cohort). RZV (N = 14,645) Placebo (N = 14,660) Relative Risk 95% CI 95% CI 95% CI n % LL UL n % LL UL RR LL UL Unsolicited adverse events (any grade) 7393 50.5 49.67 51.29 4689 32 31.23 32.75 1.58 1.52 1.64 *** Grade 3 1094 7.5 7.0 7.9 563 3.8 3.5 4.2 Considered related 5052 34.5 33.7 35.3 968 6.6 6.2 7.0 Age 50–69 YOA; N = 5887 (RZV), 5887 (Placebo) 3027 51.4 50.1 52.7 1957 33.2 32.0 34.5 70 YOA; N = 8758 (RZV), 8773 (Placebo) 4366 49.9 48.8 50.9 2732 31.1 30.2 32.1 Sex Female; N = 8498 (RZV), 8547 (Placebo) 4578 53.9 2932 34.3 Male; N = 6147 (RZV), 6113 (Placebo) 2815 45.8 1757 28.7 Race White; N = 10,878 (RZV), 10,883 (Placebo) 5360 49.3 3382 31.1 Black; N = 219 (RZV), 196 (Placebo) 77 35.2 50 25.5 Asian; N = 2682 (RZV), 2688 (Placebo) 1527 56.9 934 34.7 Other; N = 866 (RZV), 893 (Placebo) 429 49.5 323 36.2 Reported in > 1% of RZV recipients General disorders and administration site conditions Injection site pain y Any grade 3365 22.98 22.30 23.67 252 1.72 1.51 1.94 13.37 11.76 15.25 *** Grade 3 212 1.4 1.3 1.7 5 0.0 0.0 0.1 Considered related 3362 23.0 22.3 23.6 252 1.7 1.5 1.9 Injection site erythema y Any grade 1357 9.27 8.80 9.75 37 0.25 0.18 0.35 36.71 26.50 52.37 *** Grade 3 58 0.4 0.3 0.5 0.0 0.0 0.0 0.0 Considered related 1356 9.3 8.8 9.7 37 0.3 0.2 0.3 Pyrexia y Any grade 1037 7.08 6.67 7.51 76 0.52 0.41 0.65 13.66 10.81 17.48 *** Grade 3 138 0.9 0.8 1.1 10 0.1 0.0 0.1 Considered related 979 6.7 6.3 7.1 31 0.2 0.1 0.3 Injection site swelling y Any grade 1014 6.92 6.52 7.35 22 0.15 0.09 0.23 46.14 30.30 73.96 *** Grade 3 42 0.3 0.2 0.4 0.0 0.0 0.0 0.0 Considered related 1014 6.9 6.5 7.3 22 0.2 0.1 0.2 Fatigue y Any grade 522 3.56 3.27 3.88 140 0.95 0.80 1.13 3.73 3.09 4.53 *** Grade 3 62 0.4 0.3 0.5 7 0.0 0.0 0.1 Considered related 459 3.1 2.9 3.4 83 0.6 0.5 0.7 Chills y Any grade 516 3.52 3.23 3.83 35 0.24 0.17 0.33 14.76 10.47 21.42 *** Grade 3 87 0.6 0.5 0.7 2 0.0 0.0 0.0 Considered related 498 3.4 3.1 3.7 25 0.2 0.1 0.3 Injection site pruritus Any grade 317 2.16 1.94 2.41 35 0.24 0.17 0.33 9.07 6.38 13.25 *** Grade 3 7 0.0 0.0 0.1 1 0.0 0.0 0.0 Considered related 313 2.1 1.9 2.4 35 0.2 0.2 0.3 Malaise Any grade 254 1.73 1.53 1.96 43 0.29 0.21 0.39 5.91 4.27 8.37 *** Grade 3 25 0.2 0.1 0.3 3 0.0 0.0 0.1 Considered related 237 1.6 1.4 1.8 24 0.2 0.1 0.2 Pain Any grade 204 1.39 1.21 1.60 34 0.23 0.16 0.32 6.01 4.16 8.91 *** Grade 3 30 0.2 0.1 0.3 3 0.0 0.0 0.1 Considered related 170 1.2 1.0 1.3 9 0.1 0.0 0.1 Injection site warmth Any grade 149 1.02 0.86 1.19 5 0.03 0.01 0.08 29.83 12.50 93.22 *** Grade 3 4 0.0 0.0 0.1 0 0.0 0.0 0.0 Considered related 149 1.0 0.9 1.2 5 0.0 0.0 0.1 Nervous system disorders Headache y Any grade 954 6.51 6.12 6.93 445 3.04 2.76 3.33 2.15 1.92 2.41 *** Grade 3 99 0.7 0.5 0.8 27 0.2 0.1 0.3 Considered related 729 5.0 4.6 5.3 167 1.1 1.0 1.3 Dizziness Any grade 182 1.24 1.07 1.44 113 0.77 0.64 0.93 1.61 1.27 2.06 *** Grade 3 22 0.2 0.1 0.2 13 0.1 0.0 0.2 Considered related 110 0.8 0.6 0.9 47 0.3 0.2 0.4 (continued on next page) M. López-Fauqued et al. / Vaccine 37 (2019) 2482–2493 2485 The frequency of grade 3 unsolicited AEs was also higher in RZV than in placebo recipients within D0-D6 post-vaccination (Fig. 1) due to PTs covering the local and general symptoms reported by participants who were not part of the reactogenicity sub-cohort. The most frequent grade 3 unsolicited AEs in the RZV group were injection site pain, pyrexia, and headache. Injection site pain was the only PT under which grade 3 unsolicited AEs were reported by >1% of RZV recipients and had a higher frequency as compared to the Placebo group (Table 1). Unsolicited AEs with medically attended visits were reported by 2751 (18.8%) RZV and 2774 (18.9%) placebo recipients during the 30D post-vaccination, and by 5834 (39.8) RZV and 5983 (40.8%) placebo recipients within 6 M post-last dose. The incidence of unsolicited AEs with medically attended visits was similar between the RZV and Placebo groups in both males and females, in participants of any race, and in both age cohorts within the same period; incidences were also comparable between the age cohorts (Supplementary Table 3). 3.4. Serious adverse events Overall, the occurrence of SAEs was similar in both groups for all time periods analyzed. Within 30D post-last dose, 342 (2.3%) RZV and 327 (2.2%) placebo recipients reported at least one SAE. Within 1Y post-last dose, SAEs were reported by 1482 (10.1%) and 1525 (10.4%) participants in the RZV and Placebo groups, respectively (RR = 0.97 [95%CI:0.91–1.05]; p = 0.46). During the entire study period, SAEs considered causally related to vaccinaTable 1 (continued) RZV (N = 14,645) Placebo (N = 14,660) Relative Risk 95% CI 95% CI 95% CI n % LL UL n % LL UL RR LL UL Infections and infestations Nasopharyngitis Any grade 492 3.36 3.07 3.66 538 3.67 3.37 3.99 0.92 0.81 1.04 Grade 3 32 0.2 0.1 0.3 25 0.2 0.1 0.3 Considered related 75 0.5 0.4 0.6 36 0.2 0.2 0.3 Upper respiratory tract infection Any grade 231 1.58 1.38 1.79 182 1.24 1.07 1.43 1.27 1.04 1.55 * Grade 3 18 0.1 0.1 0.2 16 0.1 0.1 0.2 Considered related 16 0.1 0.1 0.2 11 0.1 0.0 0.1 Musculoskeletal and connective tissue disorders Myalgia y Any grade 478 3.26 2.98 3.56 105 0.72 0.59 0.87 4.56 3.68 5.68 *** Grade 3 63 0.4 0.3 0.6 8 0.1 0.0 0.1 Considered related 431 2.9 2.7 3.2 43 0.3 0.2 0.4 Arthralgia Any grade 252 1.72 1.52 1.94 171 1.17 1.00 1.35 1.48 1.21 1.80 *** Grade 3 27 0.2 0.1 0.3 15 0.1 0.1 0.2 Considered related 131 0.9 0.7 1.1 25 0.2 0.1 0.3 Pain in extremity Any grade 155 1.06 0.90 1.24 107 0.73 0.60 0.88 1.45 1.13 1.87 * Grade 3 14 0.1 0.1 0.2 9 0.1 0.0 0.1 Considered related 50 0.3 0.3 0.4 10 0.1 0.0 0.1 Back pain Any grade 211 1.44 1.25 1.65 186 1.27 1.09 1.46 1.14 0.93 1.39 Grade 3 27 0.2 0.1 0.3 22 0.2 0.1 0.2 Considered related 45 0.3 0.2 0.4 18 0.1 0.1 0.2 Respiratory, thoracic and mediastinal disorders Cough Any grade 209 1.43 1.24 1.63 210 1.43 1.25 1.64 1.00 0.82 1.21 Grade 3 14 0.1 0.1 0.2 16 0.1 0.1 0.2 Considered related 19 0.1 0.1 0.2 12 0.1 0.0 0.1 Oropharyngeal pain Any grade 165 1.13 0.96 1.31 154 1.05 0.89 1.23 1.07 0.86 1.34 Grade 3 6 0.0 0.0 0.1 8 0.1 0.0 0.1 Considered related 37 0.3 0.2 0.3 20 0.1 0.1 0.2 Gastrointestinal disorders Nausea y Any grade 197 1.35 1.16 1.55 69 0.47 0.37 0.60 2.86 2.16 3.82 *** Grade 3 26 0.2 0.1 0.3 6 0.0 0.0 0.1 Considered related 167 1.1 1.0 1.3 32 0.2 0.1 0.3 Adverse events are presented by System Organ Class and Preferred Term, in order of most frequently reported in RZV recipients. Only adverse events reported by > 1% of RZV recipients are presented here. Significance testing on relative risks was performed on all-grade events, irrespective of relatedness. RZV = participants receiving the adjuvanted Recombinant Zoster Vaccine; Placebo = participants receiving placebo; N = number of participants in the pooled total vaccinated cohort; n/% = number/percentage of participants reporting an event in each category; YOA = years of age; 95% CI = 95% Confidence Interval; RR = Relative Risk; LL/UL = Lower Limit/Upper Limit of 95% Confidence Interval. ydenotes adverse events classified as solicited adverse events in the reactogenicity sub-cohort; Stars indicate significance of difference as expressed by the relative risk: * = p 0.05; ** = p 0.01; *** = p 0.001. 2486 M. López-Fauqued et al. / Vaccine 37 (2019) 2482–2493 tion by investigators were reported by 15 (0.1%) participants in each group (Table 2,Supplementary Table 4). Within 1Y post-last dose, SAE incidence was similar between the RZV and Placebo groups in both age cohorts, in both males and females, and in participants of any race (Table 2). In both study groups, the most frequently reported SAEs by SOC were: infections and infestations (RZV: 299 [2.04%], Placebo: 302 [2.06%]), cardiac disorders (RZV: 290 [1.98%], Placebo: 318 [2.17%]), and neoplasms benign, malignant and unspecified (RZV: 226 [1.54%], Placebo: 225 [1.53%], Fig. 2). By PT, the most frequently reported SAEs in both groups were pneumonia (RZV: 83 [0.57%], Placebo: 66 [0.45%]) and atrial fibrillation (RZV: 55 [0.38%], Placebo: 58 [0.40%], Table 2). Statistically significant imbalances based on the nominal unadjusted p-value (p < 0.05) between RZV and placebo recipients were found for four individual SAEs by PT (Table 2). Six (<0.05%) RZV recipients reported SAEs under the supraventricular tachycardia PT versus no participants in the Placebo arm. By grouping supraventricular tachycardia with other PTs that are pathophysiologically similar to or synonymous with supraventricular tachycardia (i.e. arrhythmia supraventricular, atrial fibrillation, atrial flutter, atrial tachycardia, cardiac flutter, tachyarrhythmia, and tachycardia paroxysmal), the data showed no imbalance between RZV and placebo recipients (69 [0.47%] versus 66 [0.45%]; RR = 1.05 [95%CI:0.74–1.49]; p = 0.86). PTs under which SAEs were reported more frequently in placebo than in RZV recipients, were aortic stenosis (0 [0.00%] versus 10 [0.07%]; RR = 0.00 [95% CI:0.00–0.35]; p = 0.0020), cardio-respiratory arrest (0 [0.00%] versus 6 [0.04%]; RR = 0.00 [95%CI:0.00–0.65]; p = 0.0313), and retinal detachment (1 [0.01%] versus 8 [0.05%]; RR = 0.13 [95%CI:0.00– 0.93]; p = 0.0392). 3.5. Fatal adverse events Overall, the percentage of participants reporting fatal AEs was similar between RZV and placebo recipients during all time periods analyzed. Within 30D post-last dose, 17 (0.1%) RZV and 21 (0.1%) placebo recipients reported fatal AEs. Within 1Y post-last dose, fatal AEs were reported by 153 (1.1%) and 168 (1.1%) participants in the RZV and Placebo groups, respectively (Table 3). During the entire study period, fatal AEs were reported by 634 (4.3%) participants in the RZV group and by 680 (4.6%) participants in the Placebo group. The occurrence of fatal AEs was similar between groups in both age cohorts, but higher in participants 70 YOA compared to those 50–69 YOA (Table 3). The most frequently reported fatal AEs by SOC in each study group were neoplasms benign, malignant and unspecified (RZV: 182 [1.2%], Placebo: 177 [1.2%]), followed by cardiac disorders (RZV: 174 [1.2%], Placebo: 193 [1.3%]), and infections and infestations (RZV: 103 [0.7%], Placebo: 107 [0.7%]). The most frequently reported fatal AEs by PT were cardiac failure, pneumonia, myocardial infarction, death (with no specified cause), and cardiac arrest (Table 3). One fatal AE was assessed as possibly vaccine-related by the investigator. A 90-year-old male study participant with a past medical history of stable immune-mediated thrombocytopenia for approximately 10Y prior to vaccination developed pancytopenia and was diagnosed, on the basis of a bone marrow biopsy, with acute myeloid leukemia (AML) 75D after receiving the first RZV dose. He was hospitalized and withdrawn from study treatment. The study participant died 97D post-dose 1 due to neutropenic sepsis. 3.6. Potential immune-mediated diseases Overall, the occurrence of pIMDs (new onset and possible exacerbations) was similar between RZV and placebo recipients during all time periods analyzed. Up to 30D post-last dose, pIMDs were reported by 30 (0.2%) participants in each group. pIMDs were reported by 90 (0.6%) RZV and 105 (0.7%) placebo recipients up to 1Y post-last dose, and by 179 (1.2%) RZV and 202 (1.4%) placebo recipients during the entire study period. Up to 1Y post-last dose, 0 10 20 30 40 50 60 70 80 90 100 RZV Placebo RZV Placebo Days 0–6 Days 7–29 Participants reporting unsolicited adverse events (%) Grades 1 & 2 Grade 3 Fig. 1. Unsolicited Adverse Events reported in the 30 days after vaccination – days 0–6 and 7–29 post-vaccination (Pooled Total Vaccinated Cohort). RZV = participants receiving the adjuvanted Recombinant Zoster Vaccine; Placebo = participants receiving placebo. Bars present percentage of study population experiencing any unsolicited event, error bars present 95% Confidence Intervals. M. López-Fauqued et al. / Vaccine 37 (2019) 2482–2493 2487 Table 2 Serious Adverse Events reported during the ZOE-50/70 clinical trials (Pooled Total Vaccinated Cohort). RZV (N = 14,645) Placebo (N = 14,660) Relative Risk 95% CI 95% CI 95% CI n % LL UL n % LL UL RR LL UL Reported within 30 days post-last dose Any event 342 2.3 2.1 2.6 327 2.2 2.0 2.5 Reported within 1 year post-last dose Any event 1482 10.1 9.6 10.6 1525 10.4 9.9 10.9 0.97 0.91 1.05 Age 50–69 YOA; N = 5887 (RZV), 5887 (Placebo) 367 6.2 5.6 6.9 359 6.1 5.5 6.7 70 YOA; N = 8758 (RZV), 8773 (Placebo) 1115 12.7 12.0 13.4 1166 13.3 12.6 14.0 Sex Female; N = 8498 (RZV), 8547 (Placebo) 748 8.8 763 8.9 Male; N = 6147 (RZV), 6113 (Placebo) 734 11.9 762 12.5 Race White; N = 10,878 (RZV), 10,883 (Placebo) 1118 10.3 1149 10.6 Black; N = 219 (RZV), 196 (Placebo) 23 10.5 26 13.3 Asian; N = 2682 (RZV), 2688 (Placebo) 280 10.4 288 10.7 Other; N = 866 (RZV), 893 (Placebo) 61 7.0 62 6.9 Reported during the entire study period Considered related 15 0.1 0.1 0.2 15 0.1 0.1 0.2 Reported in > 0.3% of RZV recipients Cardiac disorders Atrial Fibrillation 55 0.38 0.28 0.49 58 0.40 0.30 0.51 0.95 0.64 1.4 Infections and Infestations Pneumonia 83 0.57 0.45 0.7 66 0.45 0.35 0.57 1.26 0.90 1.77 Statistically significant differences in occurrence between RZV and Placebo Vascular Disorders Aortic Stenosis** 0 0 0 0.03 10 0.07 0.03 0.13 0.00 0.00 0.35 Cardiac Disorders Supraventricular Tachycardia* 6 0.04 0.02 0.09 0 0 0 0.03 INF 1.55 INF Cardio-respiratory arrest* 0 0 0 0.03 6 0.04 0.02 0.09 0.00 0.00 0.65 Eye Disorders Retinal detachment* 1 0.01 0 0.04 8 0.05 0.02 0.11 0.13 0.00 0.93 Serious adverse events are presented by System Organ Class and Preferred Term, in order of most frequently reported in RZV recipients. Only serious adverse events reported by > 0.3% of RZV recipients are presented here. Significance testing on relative risks was performed irrespective of relatedness. Details on serious adverse events considered related to vaccination by study investigators are provided in Supplementary Table 4. RZV = participants receiving the adjuvanted Recombinant Zoster Vaccine; Placebo = participants receiving placebo; N = number of participants in the pooled total vaccinated cohort; n/% = number/percentage of participants reporting an event in each category; YOA = years of age; 95% CI = 95% Confidence Interval; RR = Relative Risk; LL/UL = Lower Limit/Upper Limit of 95% Confidence Interval; INF = estimation considered infinite. Stars indicate significance of difference as expressed by the relative risk: * = p 0.05; ** = p 0.01. 00.511.522.5 Surgical and medical procedures Congenital, familial and genetic disorders Investigations Endocrine disorders Immune system disorders Ear and labyrinth disorders Skin and subcutaneous tissue disorders Eye disorders Psychiatric disorders Reproductive system and breast disorders Blood and lymphatic system disorders Hepatobiliary disorders Metabolism and nutrition disorders Renal and urinary disorders General disorders and administration site conditions Respiratory, thoracic and mediastinal disorders Vascular disorders Musculoskeletal and connective tissue disorders Gastrointestinal disorders Nervous system disorders Injury, poisoning and procedural complications Neoplasms benign, malignant and unspecified (incl cysts and polyps) Cardiac disorders Infections and infestations % of participants reporting SAEs by MedDRA SOC RZV (N=14,645) Placebo (N=14,660) Fig. 2. Serious Adverse Events reported within 1 year post-last dose (Pooled Total Vaccinated Cohort). RZV = participants receiving the adjuvanted Recombinant Zoster Vaccine; Placebo = participants receiving placebo; N = number of participants in the pooled total vaccinated cohort; MedDRA = Medical Dictionary for Regulatory Activities; SOC = System Organ Class; SAE = Serious Adverse Event. 2488 M. López-Fauqued et al. / Vaccine 37 (2019) 2482–2493 pIMDs considered related to vaccination by study investigators were reported by 15 (0.1%) participants in each group (Table 4). Overall, occurrences of pIMDs during the entire study period were similar between RZV and placebo recipients irrespective of age cohort, gender, or race (Table 4). The most frequently reported pIMDs by PT were polymyalgia rheumatica, rheumatoid arthritis, psoriasis, and autoimmune thyroiditis (Table 4,Supplementary Table 5). The additional analysis of participants with pre-existing pIMDs revealed that 983 (6.7%) RZV and 960 (6.5%) placebo recipients had a pre-existing pIMD at enrollment (Table 5,Supplementary Fig. 3). The most common pre-existing pIMDs at baseline by PT were psoriasis (RZV: 215 [21.9%], Placebo: 239 [24.9%]), spondyloarthropathy (RZV: 109 [11.1%], Placebo: 89 [9.3%]), and rheumatoid arthritis (RZV: 96 [9.8%], Placebo: 94 [9.8%]). Over 95% of participants with a pre-existing pIMD did not experience a possible exacerbation of a pre-existing pIMD nor an onset of a new pIMD during the study. Among participants with pre-existing pIMDs, onset of new pIMDs were reported by 16 (1.6%) RZV and 23 (2.4%) placebo recipients, and possible exacerbation of pre-existing pIMD by 27 (2.8%) of participants in each group (Table 5). 4. Discussion Overall, the pooled safety data from ZOE-50/70 studies did not reveal any safety concerns. A plain language summary contextualizing the results and potential clinical research relevance and impact is displayed in the Focus on Patient Section (Supplementary Fig. 4). Unsolicited symptoms were more frequent in RZV recipients, driven by local and systemic reactions reported during D0-D6 post-vaccination by participants who were not part of the reactogenicity sub-cohort [4,5]. Data published previously showed that RZV induces transient local and systemic reactions, such as injection site pain and, to a lesser extent, fatigue and myalgia [4,5,9– 11]. In line with these findings, the pooled analysis presented here shows a similar profile of transient local and systemic reactions to the vaccine (including those of grade 3 intensity) occurring during D0-D6 post-vaccination. No clinically significant imbalance in other unsolicited AEs was observed. The nature of the SAEs reported in the pooled ZOE-50/70 studies reflects those observed in the general older adult population [12,13], and overall, no apparent differences were observed Table 3 Adverse Events with fatal outcome reported during the ZOE-50/70 clinical trials (Pooled Total Vaccinated Cohort). RZV (N = 14,645) Placebo (N = 14,660) 95% CI 95% CI n % LL UL n % LL UL Reported within 30 days post-last dose Any event 17 0.1 0.1 0.2 21 0.1 0.1 0.2 Reported within 1 year post-last dose Any event 153 1.0 0.9 1.2 168 1.1 1.0 1.3 Reported during the entire study period Any event 634 4.3 4.0 4.7 680 4.6 4.3 5.0 Age 50–69 YOA; N = 5887 (RZV), 5887 (Placebo) 95 1.6 1.3 2.0 100 1.7 1.4 2.1 70 YOA; N = 8758 (RZV), 8773 (Placebo) 539 6.2 5.7 6.7 580 6.6 6.1 7.2 Reported in 0.1% of RZV recipients during the entire study period Cardiac Disorders Cardiac failure 42 0.3 0.2 0.4 53 0.4 0.3 0.5 Myocardial infarction 39 0.3 0.2 0.4 39 0.3 0.2 0.4 Cardiac arrest 29 0.2 0.1 0.3 23 0.2 0.1 0.2 Acute myocardial infarction 13 0.1 0.0 0.2 24 0.2 0.1 0.2 Cardiac failure congestive 11 0.1 0.0 0.1 15 0.1 0.1 0.2 Cardiogenic shock 9 0.1 0.0 0.1 2 0.0 0.0 0.0 Infections and infestations Pneumonia 39 0.3 0.2 0.4 47 0.3 0.2 0.4 Sepsis 21 0.1 0.1 0.2 20 0.1 0.1 0.2 Septic shock 10 0.1 0.0 0.1 14 0.1 0.1 0.2 General disorders and administration site conditions Death 28 0.2 0.1 0.3 44 0.3 0.2 0.4 Sudden death 18 0.1 0.1 0.2 11 0.1 0.0 0.1 Multi-organ failure 15 0.1 0.1 0.2 13 0.1 0.0 0.2 Neoplasms benign, malignant and unspecified Lung neoplasm malignant 27 0.2 0.1 0.3 13 0.1 0.0 0.2 Pancreatic carcinoma 12 0.1 0.0 0.1 18 0.1 0.1 0.2 Lung cancer metastatic 8 0.1 0.0 0.1 5 0.0 0.0 0.1 Nervous system disorders Cerebrovascular accident 19 0.1 0.1 0.2 23 0.2 0.1 0.2 Cerebral infarction 9 0.1 0.0 0.1 9 0.1 0.0 0.1 Respiratory, thoracic and mediastinal disorders Respiratory failure 16 0.1 0.1 0.2 19 0.1 0.1 0.2 Chronic obstructive pulmonary disease 9 0.1 0.0 0.1 11 0.1 0.0 0.1 Pneumonia aspiration 8 0.1 0.0 0.1 6 0.0 0.0 0.1 Renal and urinary disorders Acute kidney injury 14 0.1 0.1 0.2 8 0.1 0.0 0.1 Adverse events with fatal outcome are presented by System Organ Class and Preferred Term, in order of most frequently reported in RZV recipients. Only adverse events with fatal outcome reported by 0.1% of RZV recipients are presented here. RZV = participants receiving the adjuvanted Recombinant Zoster Vaccine; Placebo = participants receiving placebo; N = number of participants in the pooled total vaccinated cohort; n/% = number/percentage of participants reporting an event in each category; YOA = years of age; 95% CI = 95% Confidence Interval; LL/UL = Lower Limit/Upper Limit of 95% Confidence Interval. M. López-Fauqued et al. / Vaccine 37 (2019) 2482–2493 2489 Table 4 Potential Immune-Mediated Diseases reported during the ZOE-50/70 clinical trials (Pooled Total Vaccinated Cohort). RZV (N = 14,645) Placebo (N = 14,660) Relative Risk 95% CI 95% CI 95% CI n % LL UL n % LL UL RR LL UL Reported within 30 days post-last dose Any event 30 0.2 0.1 0.3 30 0.2 0.1 0.3 Reported within 1 year post-last dose Any Event 90 0.6 0.5 0.8 105 0.7 0.6 0.9 0.86* 0.64 1.15 Considered related 15 0.1 0.1 0.2 15 0.1 0.1 0.2 Reported during the entire study period Any event 179 1.2 1.1 1.4 202 1.4 1.2 1.6 Age 50–69 YOA; N = 5887 (RZV), 5887 (Placebo) 69 1.2 0.9 1.5 84 1.4 1.1 1.8 70 YOA; N = 8758 (RZV), 8773 (Placebo) 110 1.3 1.0 1.5 118 1.3 1.1 1.6 Sex Female; N = 8498 (RZV), 8547 (Placebo) 115 1.4 128 1.5 Male; N = 6147 (RZV), 6113 (Placebo) 64 1.0 74 1.2 Race White; N = 10,878 (RZV), 10,883 (Placebo) 153 1.4 171 1.6 Black; N = 219 (RZV), 196 (Placebo) 1 0.5 0 0 Asian; N = 2682 (RZV), 2688 (Placebo) 19 0.7 23 0.9 Other; N = 866 (RZV), 893 (Placebo) 6 0.7 8 0.9 Reported in 0.1% of RZV recipients Musculoskeletal and connective tissue disorders Polymyalgia rheumatica 32 0.2 0.1 0.3 29 0.2 0.1 0.3 Rheumatoid arthritis 20 0.1 0.1 0.2 26 0.2 0.1 0.3 Skin and subcutaneous tissue disorders Psoriasis 15 0.1 0.1 0.2 18 0.1 0.1 0.2 Endocrine disorders Autoimmune thyroiditis 13 0.1 0.0 0.2 10 0.1 0.0 0.1 Nervous system disorders VII th nerve paralysis 8 0.1 0.0 0.1 7 0.0 0.0 0.1 Potential immune-mediated diseases are presented by System Organ Class and Preferred Term, in order of most frequently reported in RZV recipients. Only diseases reported by 0.1% of RZV recipients are presented. A full list of potential immune-mediated diseases reported during the clinical trials is presented in Supplementary Table 5. Significance testing on relative risks was performed irrespective of relatedness. * p = 0.3195. RZV = participants receiving the adjuvanted Recombinant Zoster Vaccine; Placebo = participants receiving placebo; N = number of participants in the pooled total vaccinated cohort; n/% = number/percentage of participants reporting an event in each category; YOA = years of age; 95% CI = 95% Confidence Interval; RR = Relative Risk; LL/UL = Lower Limit/Upper Limit of 95% Confidence Interval. Table 5 Potential Immune-Mediated Diseases reported during the ZOE-50/70 clinical trials in participants with a pre-existing potential Immune-Mediated Disease at enrolment (Total Vaccinated Cohort with pre-existing pIMD). RZV (N = 983) Placebo (N = 960) 95% CI 95% CI n % LL UL n % LL UL No pre-existing pIMD exacerbation or new pIMD onset 940 95.6 912 95.0 Exacerbation of a pre-existing pIMD Any Event 27 2.8 1.8 4.0 27 2.8 1.9 4.1 Blood and lymphatic system disorders Immune thrombocytopenic purpura 2 0.2 0.0 0.7 1 0.1 0.0 0.6 Endocrine disorders Basedow’s disease 2 0.2 0.0 0.7 0 0 0.0 0.4 Eye disorders Uveitis 0 0 0.0 0.4 1 0.1 0.0 0.6 Gastrointestinal disorders Colitis ulcerative 1 0.1 0.0 0.6 1 0.1 0.0 0.6 Metabolism and nutrition disorders Type 1 diabetes mellitus 0 0 0.0 0.4 1 0.1 0.0 0.6 Musculoskeletal and connective tissue disorders Crest syndrome 0 0 0.0 0.4 1 0.1 0.0 0.6 Polymyalgia rheumatica 2 0.2 0.0 0.7 3 0.3 0.1 0.9 Psoriatic arthropathy 0 0 0.0 0.4 1 0.1 0.0 0.6 Rheumatoid arthritis 3 0.3 0.1 0.9 5 0.5 0.2 1.2 Spondyloarthropathy 4 0.4 0.1 1.0 2 0.2 0.0 0.8 Nervous system disorders VII th nerve paralysis 1 0.1 0.0 0.6 0 0 0.0 0.4 Respiratory, thoracic and mediastinal disorders Pulmonary fibrosis 2 0.2 0.0 0.7 1 0.1 0.0 0.6 Skin and subcutaneous tissue disorders Alopecia areata 0 0 0.0 0.4 1 0.1 0.0 0.6 2490 M. López-Fauqued et al. / Vaccine 37 (2019) 2482–2493