Cunningham 2016.

Methods	Study design: randomised, double‐blind, placebo controlled Duration: mean follow‐up period of 3.7 years for efficacy and 4.0 years for safety
Participants	Inclusion criteria Setting: outpatient Country: 18 countries in Europe, North America, Latin America, Asia, and Australia Number: 13,900 participants; treatment (N = 6950), control (N = 6950) Participants' health status: healthy participants Age: mean 75.6 years Sex: ˜ 55% female Other relevant information: aged ≥ 70 years 76.9% Caucasian (understood to be white) Exclusion criteria History of herpes zoster, had been vaccinated previously against varicella or herpes zoster, or had an immunosuppressive condition
Interventions	Treatment group Recombinant zoster vaccine (2 doses: first dose month 0 and second dose on month 2) (N = 6950) Control group Placebo (2 doses: first dose month 0 and second dose on month 2) (N = 6950)
Outcomes	Cases of herpes zoster Subgroup of participants recorded injection site reactions (pain, redness and swelling) and systemic reactions (fatigue, fever, gastrointestinal symptoms, headache, myalgia, and shivering) on diary cards for 7 days after each injection. "Unsolicited reports of adverse events were recorded for 30 days after each dose for all participants" "Serious adverse events were recorded for all participants for 12 months after the second dose" "Serious adverse events that were considered to be related to the study vaccine or to trial participation, events resulting in death, and potential immune‐mediated diseases were evaluated in all participants throughout the trial"
Purpose of the study	"The primary objective of ZOE‐70 was to evaluate the efficacy of HZ/su, as compared with placebo, in reducing the risk of herpes zoster among adults 70 years of age or older." "The secondary objectives included the evaluation of vaccine efficacy against postherpetic neuralgia and the evaluation of vaccine safety and reactogenicity."
Funding sources	GlaxoSmithKline Biologicals
Conflicts of interest	"Dr. Cunningham reports receiving consulting fees from Merck, BioCSL/Sequirus, and the GSK group of companies (GSK), all paid to his institution. Dr. Kovac, Dr. Campora, Ms. Vanden Abeele, Dr. Zahaf, and Dr. Oostvogels report being employees of GSK; Drs. Kovac, Zahaf, and Oostvogels also report holding stock in the company as part of their employee remuneration. Drs. Heineman, Lal, and Godeaux report being employees of and holding stock in GSK as part of their employee remuneration at the time of the study; Dr. Heineman is a current employee of Genocea Biosciences, Dr. Lal is a current employee of Pfizer, and Dr. Godeaux is a current employee of Crucell Holland. Dr. Chlibek reports receiving lecture fees from Pfizer and Gilead Sciences and grant support from Gilead Sciences; Dr. Díez‐Domingo, receiving fees for serving on advisory boards from GSK and Sanofi Pasteur MSD and grant support from Sanofi Pasteur MSD; Dr. Levin, receiving fees for serving on an advisory board from Merck, grant support from Merck and GSK, and royalties from a patent related to a zoster vaccine that he holds with Merck; Dr. McElhaney, receiving honoraria from GSK, Pfizer, Merck, and Sanofi Pasteur, paid to her institution, and travel support from Pfizer, Merck, and Sanofi Pasteur; Dr. Puig‐Barberà, receiving personal fees and grant support from GSK and Novartis; Dr. Vesikari, receiving fees for serving on an advisory board from Sanofi Pasteur MSD, lecture fees from GSK and Merck, and grant support from Merck; Dr. Watanabe, receiving consulting fees from Maruho and Japan Vaccines, lecture fees from Maruho and Mochida, and grant support from Maruho; Dr. de Looze, receiving grant support from GSK and Novartis; Dr. Gorfinkel, receiving lecture fees and grant support from GSK, Astellas, Ferring, Forest, Novo Nordisk, Janssen‐Ortho, Bayer, Wyeth, Combinator, Pfizer, Pharmanet, AstraZeneca, Lundbeck, Bristol‐Myers Squibb, Romark, McNeil, and Johnson & Johnson; Dr. McNeil, receiving consulting and lecture fees from Pfizer and Merck and grant support from Pfizer and GSK; Dr. Rombo, receiving lecture fees from GSK, Sanofi Pasteur, and Valneva; Dr. Smetana, receiving fees for serving on a board from Pfizer and lecture fees and travel support from GSK; and Dr. Weckx, receiving fees for serving on advisory boards from Novartis, GSK, AbbVie, and Wyeth."
Notes	Recombinant zoster vaccine (herpes zoster subunit vaccine) contains 50 μg of recombinant VZV glycoprotein E and the liposome‐based AS01B adjuvant system (which contains 50 μg of 3‐O‐desacyl‐4′monophosphoryl lipid A (MPL) and 50 μg of Quillaja saponaria Molina, fraction 21 (QS21, licensed by GSK from Antigenics, a subsidiary of Agenus). A total of 14,816 participants were enrolled and randomised. 13 participants did not receive vaccine or placebo. 903 participants were excluded due to deviations from Good Clinical Practice standards. The remaining 13,900 participants made up the total of the vaccinated cohort, but not ITT analysis. Most participants received 2 doses of the study vaccines (94.4% of herpes zoster subunit vaccine recipients and 95.6% of placebo recipients). 1025 participants were randomly assigned to the reactogenicity subgroup (512 herpes zoster subunit vaccine recipients and 513 placebo recipients). "In this subgroup, solicited reports of reactions ('solicited reactions') that occurred within 7 days after each vaccination. a randomly selected subgroup of age stratified participants recorded injection‐site reactions (pain, redness and swelling) and systemic reactions (fatigue, fever, gastrointestinal symptoms, headache, myalgia, and shivering) on diary cards for 7 days after each injection. Redness and swelling at the injection site were scored as 0 if the affected area was less than 20 mm in diameter, 1 if the affected area was 20 to 50 mm, 2 if the affected area was more than 50 to 100 mm, and 3 if the affected area was more than 100 mm. Fever was scored as 0 for a body temperature lower than 37.5°C, 1 for 37.5°C to 38.0°C, 2 for 38.1°C to 39.0°C, and 3 for higher than 39.0°C (the preferred route for recording temperature was oral). All other symptoms were scored as 0 for absent, 1 for easily tolerated, 2 for interferes with normal activity, and 3 for prevents normal activity. Unsolicited reports of adverse events were recorded for 30 days after each dose for all participants. All serious adverse events were recorded for all participants for 12 months after the second dose. Serious adverse events that were considered to be related to the study vaccine or to trial participation, events resulting in death, and potential immune‐mediated diseases were evaluated in all participants throughout the trial." We asked the author, Dr Cunningham, for details of his study publication, and he kindly sent us the available information. Dr Cunningham responded promptly to our questions and provided us with what answers he could. There was a continuation of this study in Japan, which published a descriptive subgroup analysis in participants enrolled in this country throughout 4 years of follow‐up. Published as Ikamatsu 2018; the data were presented as Cunningham 2016
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Participants "were randomly assigned in a 1:1 ratio to either the HZ/su group or the placebo group with the use of an online centralized randomization system".
Allocation concealment (selection bias)	Unclear risk	Whilst the sequence and random number generation were appropriate, no details were provided regarding allocation.
Blinding (performance bias and detection bias) All outcomes	Low risk	"The investigators were unaware of the study‐group assignments during the trial"
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Cunningham 2016 followed the same methods used by Lal 2015: "Because the appearance of the reconstituted HZ/su vaccine differed from the placebo solution, injections were prepared and administered by study staff who did not participate in any study assessment"
Blinding of outcome assessment (detection bias) All outcomes	High risk	The study "was monitored by an independent data and safety monitoring committee that met regularly during the course of the study to review all safety data in an unblinded manner".
Incomplete outcome data (attrition bias) All outcomes	High risk	No clear participant flow; the number of participants randomised to each group is not described for all outcomes
Selective reporting (reporting bias)	Low risk	All data that the authors proposed in their methodology were described in the results.
Other bias	Unclear risk	Insufficient information