Vaccine 37 (2019) 2482–2493 Contents lists available at ScienceDirect Vaccine journal homepage: www.elsevier.com/locate/vaccine 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 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. https://doi.org/10.1016/j.vaccine.2019.03.043 0264-410X/Ó 2019 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/). M. López-Fauqued et al. / Vaccine 37 (2019) 2482–2493 2483 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 a r t i c l e i n f o a b s t r a c t Article history: Background: The ZOE-50 (NCT01165177) and ZOE-70 (NCT01165229) phase 3 clinical trials showed that Received 15 November 2018 the adjuvanted recombinant zoster vaccine (RZV) was 90% efficacious in preventing herpes zoster in Received in revised form 14 March 2019 adults. Here we present a comprehensive overview of the safety data from these studies. Accepted 20 March 2019 Methods: Adults aged 50 (ZOE-50) and 70 (ZOE-70) years were randomly vaccinated with RZV or pla- Available online 29 March 2019 cebo. 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 col- Keywords: lected for 7 and 30 days after each vaccination, respectively. Serious AEs (SAEs) were collected from Varicella-zoster virus Vaccine the first vaccination until 12 months post-last dose. Fatal AEs, vaccination-related SAEs, and potential Safety immune-mediated diseases (pIMDs) were collected during the entire study period. Reactogenicity Results: Safety was evaluated in 14,645 RZV and 14,660 placebo recipients. More RZV than placebo recip- ients 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 occur- rence 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 symp- toms, 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. Ó 2019 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 the risk of HZ by over 90% in all age groups among adults 50YOA [4,5]. Although the vaccine induces transient local and systemic Herpes zoster (HZ) results from reactivation of latent varicella- reactions, no safety concerns were identified during these clinical zoster virus (VZV) in the dorsal root ganglia, usually years after pri- trials. In both studies, serious adverse events (SAEs) and potential mary VZV infection. HZ is typically characterized by a unilateral immune-mediated diseases (pIMDs) were balanced between par- dermatomal vesicular rash, generally accompanied by pain. Its ticipants in the RZV and Placebo groups [4,5]. most common complication is postherpetic neuralgia, a chronic The similar enrollment criteria, study procedures, and safety pain that can persist for months or years after the rash has resolved follow-up period for the ZOE-50/70 trials allowed us to pool study [1]. HZ incidence increases substantially with age, from 3 to 5 cases data. We present here a comprehensive analysis of the safety data per 1000 person-years in the general population of all ages [2], to from pooled ZOE 50/70 studies. 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]. 2. Methods An adjuvanted recombinant zoster vaccine, RZV (Shingrix, GSK), consisting of a truncated form of VZV glycoprotein E (gE) and the 2.1. Study design and participants AS01B adjuvant system, is currently licensed in different regions worldwide for the prevention of HZ in adults 50 YOA. Two pivotal ZOE-50 (NCT01165177) and ZOE-70 (NCT01165229) were phase phase 3 efficacy trials (ZOE-50/70) demonstrated that RZV reduces 3, randomized, placebo-controlled, observer-blinded clinical trials ⇑ Corresponding author at: GSK, Avenue Fleming 20, 1300 Wavre, Belgium. E-mail addresses: marta.x.lopez-fauqed@gsk.com (M. López-Fauqued), laura.e.campora@gsk.com (L. Campora), frederique.x.delannois@gsk.com (F. Delannois), mohamed. s.elidrissi@gsk.com (M. El Idrissi), cornelia.oostvogels@orange.fr (L. Oostvogels), cornelia.oostvogels@orange.fr (F.J. Oostvogels), cornelia.oostvogels@orange.fr (F.J. Oostvogels), cornelia.oostvogels@orange.fr (F.J. Oostvogels), cornelia.oostvogels@orange.fr (F.J. Oostvogels), f.delooze@trialworks.com.au (F.J. De Looze), jdiezdomingo@ gmail.com (J. Diez-Domingo), tch3768@gmail.com (T.C. Heineman), himallal@yahoo.com (H. Lal), jmcelhaney@hsnri.ca (J.E. McElhaney), Shelly.McNeil@nshealth.ca (S.A. McNeil), wilf@uow.edu.au (W. Yeo), fernanda.tavares@gsk.com (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. 2484 M. López-Fauqued et al. / Vaccine 37 (2019) 2482–2493 conducted concurrently at the same sites in 18 countries in Europe, tion, analyses of fatal AEs and pIMDs were also performed during North and South America, Asia and Australia. Adults aged  50 YOA the entire study period. Exploratory analyses of unsolicited AEs (ZOE-50) or  70 YOA (ZOE-70) were randomized and vaccinated reported within the 30D post-vaccination period, SAEs and pIMDs with RZV or placebo (Supplementary Fig. 1). A full list of eligibility reported within 1Y post-last dose assessed the relative risks (RRs) criteria was previously presented [4,5], and is provided here in the and frequencies of selected events of interest using MedDRA Supplementary Material. The two studies were conducted in an queries. RRs and their 95% CIs were calculated by Exact Tests con- identical manner, and adults 70 YOA were randomly enrolled to ditional to the number of cases. Additional details are presented in participate in either the ZOE-50 or ZOE-70 study. Additional study the Supplementary Material. design details are presented in the primary publications [4,5]. The clinical study reports are available at http://www.gsk-clinical- 3. Results studyregister.com (IDs 110390 and 113077). Anonymized individ- ual participant data and study documents can be requested for 3.1. Study population further research from www.clinicalstudydatarequest.com. A total of 14,645 RZV and 14,660 placebo recipients were 2.2. Study vaccines 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 RZV contains 50 lg of gE antigen and the GSK proprietary AS01B those were female. Most (73.7%) participants were white/Cau- Adjuvant System (containing 50 lg of 3-O-desacyl-40 -monopho casian. Demographic characteristics were comparable between sphoryl lipid A, 50 lg of Quillaja saponaria Molina, fraction 21 groups (Supplementary Table 2). [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. 3.2. Reactogenicity 2.3. Collection of safety data In line with previously reported reactogenicity results from the ZOE-50/70 studies [4,5], RZV was more reactogenic than placebo in Solicited adverse events (AEs) were collected for 7 days (D) after the pooled reactogenicity sub-cohort. Pain was the most frequent each vaccination (D0-D6) in the reactogenicity sub-cohort, consist- solicited local symptom reported after 68.1% (95% CI: 67.1–69.0) ing of participants who completed diary cards; severe AEs are of documented doses in the RZV group and after 6.9% (95% CI: described in the Supplementary Material. Unsolicited AEs were 6.4–7.4) in the Placebo group. Grade 3 pain was reported after collected for 30D after each vaccination and graded on a scale from 3.8% (95% CI: 3.5–4.3) of documented doses in the RZV group and 1 (mild: not interfering with everyday activities) to 3 (severe: sig- after 0.2% (95% CI: 0.1–0.3) in the Placebo group. In the RZV group, nificant at rest and preventing normal everyday activities). Unso- the most frequently reported solicited general symptoms were licited AEs comprised both SAEs and non-serious AEs, including myalgia and fatigue, reported after 32.9% (95% CI: 31.9–33.8) and all local and systemic reactions reported by participants who were 32.2% (95% CI: 31.3–33.2) of doses, respectively. Grade 3 fatigue not part of the reactogenicity sub-cohort. Unsolicited AEs with was reported after 3.0% (95% CI: 2.6–3.3) of documented doses in medically attended visits (defined as hospitalizations, emergency the RZV group and after 0.5% (95% CI: 0.4–0.7) in the placebo group room visits, or visits to or from medical personnel), other than rou- (Supplementary Fig. 2). Local and general symptoms in the RZV tine health care visits, were recorded from first vaccine dose up to group were mostly mild to moderate in intensity and transient 6 months (M) post-last vaccination. SAEs were collected from the (median duration was of 3 days or less for local and 2 days or less first vaccine dose up to 1 year (Y) post-last vaccination. Fatal AEs, for general symptoms, including grade 3 symptoms). Overall, there SAEs considered causally related to study vaccination by the inves- were no differences in the proportions of RZV recipients reporting tigators, and pIMDs (new onset and possible exacerbations) were any grade or grade 3 solicited local events between dose 1 and dose collected during the entire study period. SAEs were defined accord- 2. All-grade solicited general symptoms tended to be more fre- ing to standard reporting guidelines [6]. AEs were coded by Medi- quent after dose 2 compared to dose 1. cal Dictionary for Regulatory Activities (MedDRA) dictionary both per System Organ Class (SOC) and Preferred Term (PT) [7]. Local 3.3. Unsolicited adverse events AEs were considered related to study vaccination. Relatedness of other AEs was determined based on study investigators clinical The percentage of participants reporting unsolicited AEs during judgment, in a blinded manner. pIMDs were defined as a subset 30D post-vaccination was greater for RZV than for placebo recipi- of AEs that include autoimmune diseases and other inflammatory ents (7393 [50.5%] versus 4689 [32.0%]; RR: 1.58 [95%CI:1.52– and/or neurologic disorders of interest that may or may not have 1.64]; p < 0.0001). RZV recipients reported unsolicited AEs more an autoimmune etiology. AEs to be recorded as pIMDs were frequently, irrespective of age group, gender, or race (Table 1). pre-defined in the study protocol (Supplementary Table 1) and, Unsolicited AEs more frequently reported by RZV recipients were in addition, study investigators were instructed to use their medi- injection site and general symptoms that were reported as solicited cal judgment to determine whether other events could fall in this reactions in the reactogenicity sub-cohort (Table 1). More RZV than category and to record them as pIMDs [8]. placebo recipients reported unsolicited AEs during the first week (D0-D6) post-vaccination (5861 [40.0%] versus 2230 [15.2%]). 2.4. Statistical analysis Unsolicited AEs were balanced between groups during the subse- quent 23D (D7-D29) post-vaccination period (3,076 [21.0%] versus Safety analyses were performed on the pooled total vaccinated 3,280 [22.4%]) (Fig. 1). cohort, consisting of participants who received at least one dose of Unsolicited AEs not categorized as solicited AEs in the reacto- RZV/placebo. Analyses of unsolicited AEs, SAEs, and pIMDs were genicity sub-cohort, those occurring in >1% of RZV recipients and descriptive and, for each of these, percentages of participants with more frequently than in placebo recipients were, by PT: injection at least one event were calculated with their exact 95% Confidence site pruritus, pain, injection site warmth, pain in extremity, Intervals (CIs) both per SOC and PT. Analyses of SAEs, fatal AEs, and malaise, arthralgia, back pain, dizziness, upper respiratory tract pIMDs were performed up to 30D and 1Y post-last dose. In addi- infection, and oropharyngeal pain (Table 1). M. López-Fauqued et al. / Vaccine 37 (2019) 2482–2493 2485 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 painy 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 erythemay 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 Pyrexiay 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 swellingy 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 Fatiguey 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 Chillsy 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 Headachey 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) 2486 M. López-Fauqued et al. / Vaccine 37 (2019) 2482–2493 Table 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 Myalgiay 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 Nauseay 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. y denotes 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. The frequency of grade 3 unsolicited AEs was also higher in RZV between the RZV and Placebo groups in both males and females, than in placebo recipients within D0-D6 post-vaccination (Fig. 1) in participants of any race, and in both age cohorts within the same due to PTs covering the local and general symptoms reported by period; incidences were also comparable between the age cohorts participants who were not part of the reactogenicity sub-cohort. (Supplementary Table 3). The most frequent grade 3 unsolicited AEs in the RZV group were injection site pain, pyrexia, and headache. Injection site pain was 3.4. Serious adverse events the only PT under which grade 3 unsolicited AEs were reported by >1% of RZV recipients and had a higher frequency as compared Overall, the occurrence of SAEs was similar in both groups for to the Placebo group (Table 1). all time periods analyzed. Within 30D post-last dose, 342 (2.3%) Unsolicited AEs with medically attended visits were reported by RZV and 327 (2.2%) placebo recipients reported at least one SAE. 2751 (18.8%) RZV and 2774 (18.9%) placebo recipients during the Within 1Y post-last dose, SAEs were reported by 1482 (10.1%) 30D post-vaccination, and by 5834 (39.8) RZV and 5983 (40.8%) and 1525 (10.4%) participants in the RZV and Placebo groups, placebo recipients within 6 M post-last dose. The incidence of respectively (RR = 0.97 [95%CI:0.91–1.05]; p = 0.46). During the unsolicited AEs with medically attended visits was similar entire study period, SAEs considered causally related to vaccina- M. López-Fauqued et al. / Vaccine 37 (2019) 2482–2493 2487 100 Grades 1 & 2 Grade 3 Participants reporting unsolicited adverse events (%) 90 80 70 60 50 40 30 20 10 0 RZV Placebo RZV Placebo Days 0–6 Days 7–29 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. tion by investigators were reported by 15 (0.1%) participants in analyzed. Within 30D post-last dose, 17 (0.1%) RZV and 21 (0.1%) each group (Table 2, Supplementary Table 4). placebo recipients reported fatal AEs. Within 1Y post-last dose, Within 1Y post-last dose, SAE incidence was similar between fatal AEs were reported by 153 (1.1%) and 168 (1.1%) participants the RZV and Placebo groups in both age cohorts, in both males in the RZV and Placebo groups, respectively (Table 3). and females, and in participants of any race (Table 2). In both study During the entire study period, fatal AEs were reported by 634 groups, the most frequently reported SAEs by SOC were: infections (4.3%) participants in the RZV group and by 680 (4.6%) participants and infestations (RZV: 299 [2.04%], Placebo: 302 [2.06%]), cardiac in the Placebo group. The occurrence of fatal AEs was similar disorders (RZV: 290 [1.98%], Placebo: 318 [2.17%]), and neoplasms between groups in both age cohorts, but higher in participants benign, malignant and unspecified (RZV: 226 [1.54%], Placebo: 225 70 YOA compared to those 50–69 YOA (Table 3). The most fre- [1.53%], Fig. 2). By PT, the most frequently reported SAEs in both quently reported fatal AEs by SOC in each study group were neo- groups were pneumonia (RZV: 83 [0.57%], Placebo: 66 [0.45%]) plasms benign, malignant and unspecified (RZV: 182 [1.2%], and atrial fibrillation (RZV: 55 [0.38%], Placebo: 58 [0.40%], Placebo: 177 [1.2%]), followed by cardiac disorders (RZV: 174 Table 2). [1.2%], Placebo: 193 [1.3%]), and infections and infestations (RZV: Statistically significant imbalances based on the nominal unad- 103 [0.7%], Placebo: 107 [0.7%]). The most frequently reported fatal justed p-value (p < 0.05) between RZV and placebo recipients were AEs by PT were cardiac failure, pneumonia, myocardial infarction, found for four individual SAEs by PT (Table 2). Six (<0.05%) RZV death (with no specified cause), and cardiac arrest (Table 3). recipients reported SAEs under the supraventricular tachycardia One fatal AE was assessed as possibly vaccine-related by the PT versus no participants in the Placebo arm. By grouping investigator. A 90-year-old male study participant with a past supraventricular tachycardia with other PTs that are pathophysio- medical history of stable immune-mediated thrombocytopenia logically similar to or synonymous with supraventricular tachycar- for approximately 10Y prior to vaccination developed pancytope- dia (i.e. arrhythmia supraventricular, atrial fibrillation, atrial nia and was diagnosed, on the basis of a bone marrow biopsy, with flutter, atrial tachycardia, cardiac flutter, tachyarrhythmia, and acute myeloid leukemia (AML) 75D after receiving the first RZV tachycardia paroxysmal), the data showed no imbalance between dose. He was hospitalized and withdrawn from study treatment. RZV and placebo recipients (69 [0.47%] versus 66 [0.45%]; The study participant died 97D post-dose 1 due to neutropenic RR = 1.05 [95%CI:0.74–1.49]; p = 0.86). PTs under which SAEs were sepsis. 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%] ver- sus 6 [0.04%]; RR = 0.00 [95%CI:0.00–0.65]; p = 0.0313), and retinal 3.6. Potential immune-mediated diseases detachment (1 [0.01%] versus 8 [0.05%]; RR = 0.13 [95%CI:0.00– 0.93]; p = 0.0392). Overall, the occurrence of pIMDs (new onset and possible exac- erbations) was similar between RZV and placebo recipients during all time periods analyzed. Up to 30D post-last dose, pIMDs were 3.5. Fatal adverse events reported by 30 (0.2%) participants in each group. pIMDs were reported by 90 (0.6%) RZV and 105 (0.7%) placebo recipients up Overall, the percentage of participants reporting fatal AEs was to 1Y post-last dose, and by 179 (1.2%) RZV and 202 (1.4%) placebo similar between RZV and placebo recipients during all time periods recipients during the entire study period. Up to 1Y post-last dose, 2488 M. López-Fauqued et al. / Vaccine 37 (2019) 2482–2493 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. Infections and infestations Cardiac disorders Neoplasms benign, malignant and unspecified (incl cysts and polyps) Injury, poisoning and procedural complications Nervous system disorders Gastrointestinal disorders Musculoskeletal and connective tissue disorders Vascular disorders Respiratory, thoracic and mediastinal disorders General disorders and administration site conditions Renal and urinary disorders Metabolism and nutrition disorders Hepatobiliary disorders Blood and lymphatic system disorders Reproductive system and breast disorders Psychiatric disorders Eye disorders Skin and subcutaneous tissue disorders Ear and labyrinth disorders Immune system disorders RZV (N=14,645) Endocrine disorders Investigations Placebo (N=14,660) Congenital, familial and genetic disorders Surgical and medical procedures 0 0.5 1 1.5 2 2.5 % of participants reporting SAEs by MedDRA SOC 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. M. López-Fauqued et al. / Vaccine 37 (2019) 2482–2493 2489 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. pIMDs considered related to vaccination by study investigators 4. Discussion were reported by 15 (0.1%) participants in each group (Table 4). Overall, occurrences of pIMDs during the entire study period Overall, the pooled safety data from ZOE-50/70 studies did not were similar between RZV and placebo recipients irrespective of reveal any safety concerns. A plain language summary contextual- age cohort, gender, or race (Table 4). The most frequently reported izing the results and potential clinical research relevance and pIMDs by PT were polymyalgia rheumatica, rheumatoid arthritis, impact is displayed in the Focus on Patient Section (Supplementary psoriasis, and autoimmune thyroiditis (Table 4, Supplementary Fig. 4). Table 5). Unsolicited symptoms were more frequent in RZV recipients, The additional analysis of participants with pre-existing pIMDs driven by local and systemic reactions reported during D0-D6 revealed that 983 (6.7%) RZV and 960 (6.5%) placebo recipients had post-vaccination by participants who were not part of the reacto- a pre-existing pIMD at enrollment (Table 5, Supplementary Fig. 3). genicity sub-cohort [4,5]. Data published previously showed that The most common pre-existing pIMDs at baseline by PT were pso- RZV induces transient local and systemic reactions, such as injec- riasis (RZV: 215 [21.9%], Placebo: 239 [24.9%]), spondyloarthropa- tion site pain and, to a lesser extent, fatigue and myalgia [4,5,9– thy (RZV: 109 [11.1%], Placebo: 89 [9.3%]), and rheumatoid 11]. In line with these findings, the pooled analysis presented here arthritis (RZV: 96 [9.8%], Placebo: 94 [9.8%]). Over 95% of partici- shows a similar profile of transient local and systemic reactions to pants with a pre-existing pIMD did not experience a possible exac- the vaccine (including those of grade 3 intensity) occurring during erbation of a pre-existing pIMD nor an onset of a new pIMD during D0-D6 post-vaccination. No clinically significant imbalance in the study. Among participants with pre-existing pIMDs, onset of other unsolicited AEs was observed. new pIMDs were reported by 16 (1.6%) RZV and 23 (2.4%) placebo The nature of the SAEs reported in the pooled ZOE-50/70 stud- recipients, and possible exacerbation of pre-existing pIMD by 27 ies reflects those observed in the general older adult population (2.8%) of participants in each group (Table 5). [12,13], and overall, no apparent differences were observed 2490 M. López-Fauqued et al. / Vaccine 37 (2019) 2482–2493 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 VIIth 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 VIIth 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 M. López-Fauqued et al. / Vaccine 37 (2019) 2482–2493 2491 Table 5 (continued) RZV (N = 983) Placebo (N = 960) 95% CI 95% CI n % LL UL n % LL UL Erythema nodosum 0 0 0.0 0.4 1 0.1 0.0 0.6 Pemphigus 0 0 0.0 0.4 1 0.1 0.0 0.6 Psoriasis 9 0.9 0.4 1.7 4 0.4 0.1 1.1 Vitiligo 0 0 0.0 0.4 1 0.1 0.0 0.6 Vascular disorders Raynaud’s phenomenon 1 0.1 0.0 0.6 1 0.1 0.0 0.6 Temporal arteritis 0 0 0.0 0.4 1 0.1 0.0 0.6 New onset pIMD Any event 16 1.6 0.9 2.6 23 2.4 1.5 3.6 Endocrine disorders Autoimmune thyroiditis 0 0 0.0 0.4 1 0.1 0.0 0.6 Basedow’s disease 0 0 0.0 0.4 1 0.1 0.0 0.6 Gastrointestinal disorders Autoimmune pancreatitis 1 0.1 0.0 0.6 0 0 0.0 0.4 Chronic gastritis 1 0.1 0.0 0.6 0 0 0.0 0.4 Coeliac disease 0 0 0.0 0.4 1 0.1 0.0 0.6 Crohn’s disease 1 0.1 0.0 0.6 1 0.1 0.0 0.6 Oral lichen planus 0 0 0.0 0.4 1 0.1 0.0 0.6 Metabolism and nutrition disorders Diabetes mellitus 1 0.1 0.0 0.6 0 0 0.0 0.4 Musculoskeletal and connective tissue disorders Mixed connective tissue disease 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 Rheumatoid arthritis 0 0 0.0 0.4 6 0.6 0.2 1.4 Still’s disease adult onset 1 0.1 0.0 0.6 0 0 0.0 0.4 Systemic lupus erythematosus 0 0 0.0 0.4 1 0.1 0.0 0.6 Nervous system disorders Chronic inflammatory demyelinating polyradiculoneuropathy 0 0 0.0 0.4 1 0.1 0.0 0.6 Guillain-Barré syndrome 1 0.1 0.0 0.6 1 0.1 0.0 0.6 Multiple sclerosis 0 0 0.0 0.4 1 0.1 0.0 0.6 Neuritis cranial 1 0.1 0.0 0.6 0 0 0.0 0.4 Paraneoplastic neurological syndrome 0 0 0.0 0.4 1 0.1 0.0 0.6 Radiculitis brachial 1 0.1 0.0 0.6 0 0 0.0 0.4 Trigeminal nerve paresis 0 0 0.0 0.4 1 0.1 0.0 0.6 Trigeminal neuralgia 1 0.1 0.0 0.6 0 0 0.0 0.4 Renal and urinary disorders Glomerulonephritis 0 0 0.0 0.4 1 0.1 0.0 0.6 IgA nephropathy 1 0.1 0.0 0.6 0 0 0.0 0.4 Respiratory, thoracic and mediastinal disorders Idiopathic pulmonary fibrosis 1 0.1 0.0 0.6 0 0 0.0 0.4 Pulmonary fibrosis 0 0 0.0 0.4 1 0.1 0.0 0.6 Skin and subcutaneous tissue disorders Erythema nodosum 1 0.1 0.0 0.6 0 0 0.0 0.4 Lichen planus 1 0.1 0.0 0.6 2 0.2 0.0 0.8 Psoriasis 1 0.1 0.0 0.6 0 0 0.0 0.4 Vascular disorders Polyarteritis nodosa 0 0 0.0 0.4 1 0.1 0.0 0.6 Potential immune-mediated diseases (pIMDs) are presented by System Organ Class and Preferred Term, in alphabetical order. RZV = participants receiving the adjuvanted Recombinant Zoster Vaccine; Placebo = participants receiving placebo; N = number of participants with a pre-existing pIMD at enrolment; n/% = number/percentage of participants reporting an event in each category; 95% CI = 95% Confidence Interval; LL/UL = Lower Limit/Upper Limit of 95% Confidence Interval. Participants with pre-existing pIMDs were identified by querying the global medical history of the participants included in the Total Vaccinated Cohort with a customized MedDRA query for pIMDs [Tavares 2013]. between the two groups during any of the time intervals assessed, recipients. One fatal AE (neutropenic sepsis) that occurred more irrespective of age, gender or race. Similarly, SAEs considered than 3M post-vaccination, was considered related to vaccination related to study vaccination by the investigator were balanced by the study investigator [4]. The neutropenia and neutropenic between groups. A descriptive analysis revealed that supraventric- sepsis in this participant were likely the result of the induction ular tachycardia was the only SAE by PT with an increased risk in chemotherapy for the treatment of AML. Additionally, there were RZV recipients up to 1Y post-last vaccination. However, given the no clustering of similar events temporally associated with vaccina- high number of comparisons, the probability of obtaining a false tion. Neutropenic fever and sepsis are common AEs for therapeutic significant increase in the incidence of a particular event is inflated. treatment [15–17]. The analysis performed considering grouped PTs referring to the Although concerns have been raised regarding potential associ- same medical context of supraventricular tachyarrhythmias did ations between vaccine adjuvants and the occurrence of pIMDs not show any apparent differences between RZV and placebo [18–20], the association between vaccination and pIMDs has lar- recipients. In addition, no biologically plausible mechanism by gely been extrapolated from isolated case reports, and large epi- which RZV could cause supraventricular tachycardia is known. demiological studies and pooled analyses only showed such an The incidence of AEs with a fatal outcome reflected the age of association for a very limited number of vaccine and autoimmune participants [13,14], and was balanced between RZV and placebo disease combinations [21,22]. The theoretical risk of acquiring 2492 M. López-Fauqued et al. / Vaccine 37 (2019) 2482–2493 autoimmune diseases is considered to be driven by chronic Acknowledgments inflammation, antigen mimicry and inflammation of target organs [23]. However, pre-clinical evidence suggests that RZV is unlikely ZOE-50/70 Study group: Anitta Ahonen (University of Tampere, to cause long-term inflammation, as the innate immune response Järvenpää Vaccine Clinic, Finland), Thiago Junquera Avelino-Silva and activity of pro-inflammatory cytokines are transient [24]. (University of São Paulo Medical School, Brazil), Jose Fernando Nonetheless, in the ZOE-50/70 studies, pIMDs were monitored Barba-Gomez (Instituto Dermatológico de Jalisco, Mexico), Johan through standard data collection methods and disease-specific Berglund (Blekinge Institute of Technology, Sweden), Carlos Bro- standard questionnaires for the collection of the pIMD safety data tons Cuixart (EAP Sardenya, Spain), Covadonga Caso (Hospital [25]. In eligible participants with pre-existing pIMDs at study Clínico San Carlos, Spain), Roman Chlibek (University of Defence , entry, exacerbations as well as new onset of other pIMDs were Faculty of Military Health Sciences, Czech Republic), Won Suk Choi recorded during the entire study period. The analyses of the (Korea University College of Medicine, Republic of Korea), Anthony pooled study population presented here show no evidence for a L. Cunningham (Westmead Institute for Medical Research, Univer- statistical imbalance between RZV and placebo recipients. Overall, sity of Sydney, Australia), Maria Guiseppina Desole (Servizio di the most frequently reported pIMDs were those with the greatest Igiene Pubblica, Italy), Peter Eizenberg (Doctors of Ivanhoe, Aus- prevalence in this age group [26–29]. The occurrence of new onset tralia), Meral Esen (Institut für Tropenmedizin, University Clinic pIMDs was similar between groups, irrespective of time interval of Tübingen, Germany), Emmanuelle Espié (GSK, Belgium), Pierre assessed, participant age, gender, or race. Additionally, in partici- Gervais (Q&T Research Sherbrooke, Canada), Wayne Ghesquiere pants with pre-existing pIMDs, the occurrences of a possible exac- (University of British Columbia, Canada), Olivier Godeaux (GSK, Bel- erbation or a new onset of a different pIMD were also balanced gium, during the conduct of the ZOE-50/70 trials), Iris Gorfinkel between groups. Overall, these data do not show an increased risk (York University, Canada), David Shu Cheong Hui (Prince of Wales of developing a new pIMD or exacerbating an underlying pIMD in Hospital, Hong Kong), Shinn-Jang Hwang (Taipei Veterans General RZV recipients 50 YOA. Hospital and National Yang Ming University School of Medicine, The results of these pooled analyses need to be considered in Taiwan), Tiina Korhonen (Vaccine Research Centre, University of the context of study strengths and weaknesses. The ZOE-50/70 Tampere Medical School, Tampere, Finland) Martina Kovac (GSK, clinical trials included a large and global population of relevant USA), Edouard Ledent (GSK, Belgium), Edward Leung (Hong Kong age, predominantly of Caucasian and Asian ancestries. The statisti- Association of Gerontology, Hong Kong), Myron J. Levin (University cal power of pre-licensure clinical trials to detect very rare events of Colorado Anschutz Medical Campus, USA), Silvia Narejos Perez is limited due to the sample size. Since incidence rates of some (CAP Centelles, Spain), Jose Luiz Neto (Instituto A. Z. de Pesquisa e medical conditions, such as certain pIMDs and allergic reactions Ensino, Brazil), Karlis Pauksens (Uppsala University Hospital, Swe- vary roughly from 1 to 20 per 100,000 person-years in the general den), Airi Poder (Kliiniliste Uuringute Keskus, Estonia), Maria Luisa population, these AEs will require post-licensure safety monitor- Rodriguez de la Pinta (Hospital Puerta de Hierro, Spain), Lars Rombo ing, during which a larger population will be vaccinated. In addi- (Uppsala University, Sweden), Tino F. Schwarz (Standort Juliusspi- tion, some populations were excluded per protocol from the tal, Germany), Jan Smetana (University of Defence , Faculty of Mil- pivotal studies (e.g. patients with certain underlying diseases trea- itary Health Sciences, Czech Republic), Tommaso Staniscia ted with high dose steroids or immune-modulators). (University G. d’Annunzio of Chieti-Pescara, Italy), Juan Carlos The pooled analyses of the phase 3 ZOE-50/70 clinical trials did Tinoco (Hospital General de Durango, Mexico), Azhar Toma (Manna not identify any safety concerns, and, along with the high vaccine Research, Canada), Ilse Vastiau (GSK , Belgium), Timo Vesikari efficacy demonstrated in these trials, these results support the (University of Tampere, Finland), Antonio Volpi (A.O. Univesitaria favorable benefit-risk profile of RZV in all age-groups studied. Policlinico Tor Vergata, Italy), Daisuke Watanabe (Kobe University Graduate School of Medicine, Japan), Lily Yin Weckx (Federal University of Sao Paulo, Brazil), Toufik Zahaf (GSK, Belgium). 5. Potential conflicts of interest The authors would like to thank all study participants, their families, the clinical investigators and sites’ staff involved in the MLF, LC, FD, MEI and FTdS are employees, and LO, TCH and HL ZOE-50/70 trials, as well as the GSK global and local clinical study are former employees, of the GSK group of companies. FJDL reports teams; Catherine Dettori and Issam Jamiai (4Clinics); Lina Perez- receiving grant support from GSK and Novartis outside the submit- Breva, and Esther Soriano (FISABIO-Public Health, Spain); Arnaud ted work. LO is an employee of CureVac AG. LO and TCH are inven- Didierlaurent, Nicolas Smoes and Anne-Sophie Vilain (GSK). tors on a patent owned by GSK and relevant to RZV. JDD reports The authors also acknowledge XPE Pharma & Science platform receiving personal fees from GSK for an advisory board on a phar- c/o GSK for editorial assistance and manuscript coordination. Jarno macoeconomic study with Synflorix in Spain, as well as grants and Jansen and Alpár Pöllnitz provided medical writing support and personal fees from Sanofi Pasteur MSD for an epidemiological Quentin Deraedt coordinated manuscript development and pro- study on herpes zoster and an advisory board on Zostavax, respec- vided editorial support. tively, outside the submitted work. LO, TCH, HL and FTdS hold shares or stock options from GSK as part of their current or former Funding employee remuneration. TCH served as a paid consultant to GSK outside the submitted work. HL is a current employee of Pfizer The trials were funded by GlaxoSmithKline Biologicals SA, Rue de and receives stock as part of his employee remuneration. JEM l’Institut 89, 1330 Rixensart, Belgium. GlaxoSmithKline Biologicals reports receiving honoraria and fees paid to her institution from SA was involved in all stages of the conduct and analysis of the stud- GSK, Sanofi Pasteur, Merck and Pfizer, as well as travel support ies. GlaxoSmithKline Biologicals SA covered the costs associated from GSK, Sanofi Pasteur, Merck and Pfizer outside the submitted with the development and the publishing of the present manuscript. work. SAM reports research grant from Pfizer, personal fees for continuing professional development talks on adult immunization from Pfizer and Merck, and consulting fees from Pfizer and Merck Authors’ contribution outside the submitted work, as well as grant from GSK outside the submitted work. WY reports financial support from GSK to perform Detailed authors’ contribution is provided in the supplementary the study. materials. M. López-Fauqued et al. / Vaccine 37 (2019) 2482–2493 2493 Appendix A. 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