Vesikari 2013.

Methods	Study design: phase 3, randomised, open‐label Duration: 12 months after the last dose
Participants	Inclusion criteria Setting: outpatient Country: 24 centres: Finland (n = 6), Germany (n = 13), Italy (n = 2), Spain (n = 2), and the Netherlands (n = 1) Number: 759 participants; treatment (N = 506), control (N = 253) Participants' health status: healthy participants with either a history of varicella or > 30 years residency in a country with endemic VZV infection Age: mean 76.1 years Sex: ˜ 56% female Other relevant information: aged ≥ 70 years Exclusion criteria "Individuals were excluded if they had: a history of herpes zoster, previous varicella or herpes zoster vaccination, exposure to varicella or herpes zoster during the preceding 4 weeks, fever (oral temperature 38.3°C) during the preceding 72 hours, live virus vaccination during the preceding 4 weeks and inactivated vaccination during the preceding 2 weeks."
Interventions	Treatment groups Refrigerated live attenuated herpes zoster vaccine 2 doses, 1 month apart schedule: 1 month after first dose SC; N = 255 Refrigerated live attenuated herpes zoster vaccine 2 doses, 3 months apart schedule: 3 months after first dose SC; N = 251 Control group Refrigerated live attenuated herpes zoster vaccine single dose SC; N = 253
Outcomes	Adverse events, immediate and not immediate, both at injection site and/or systemic: Erythema, swelling, and pain within 4 days of vaccination and other injection site reactions were recorded by participants in a diary card. Other injection site reaction and systemic adverse events were recorded in the diary card for up to 28 days following each vaccination. Vaccine‐related serious adverse events, deaths, and occurrences of herpes zoster, varicella, or zoster‐like and varicella‐like rashes were recorded by the investigators until the study was stopped (1 year). Varicella(‐like) rash or herpes zoster(‐like) rash, any serious adverse events, vaccine‐related adverse events
Purpose of the study	"The primary objective of the study was to demonstrate that a second dose of HZ vaccine, administered 1 mo or 3 mo after the first dose, elicits superior VZV antibody titres 4 weeks after vaccination compared with the first dose" "Secondary objectives of the study were to compare VZV antibody titres 12 mo after completion of each two‐dose schedule with those 12 mo after a single dose, and to describe the safety profile of all three HZ vaccination schedules"
Funding sources	Sanofi Pasteur MSD
Conflicts of interest	"R.H. has received financial support from Sanofi Pasteur MSD for travel and accommodation costs related to meetings for the study; he has also participated in a Zostavax advisory board in Germany. The institutions of T.V. and H.C.R. received a grant from Sanofi Pasteur MSD for participating in the study; H.C.R.’s institution has also received payment for lectures organized by several pharmaceutical companies and academic institutions. G.I. has previously participated at speaker’s bureaus and advisory board meetings sponsored by GSK, Pfizer, Sanofi Pasteur and Sanofi Pasteur MSD and has received research funding as principal investigator from Crucell Berna, GSK, Pfizer, Sanofi Pasteur and Sanofi Pasteur MSD. J.M. has no conflicts of interest to declare. S.T. and C.S. are employees of Sanofi Pasteur MSD. A.F. was an employee of Sanofi Pasteur MSD when the study was performed but has since become an employee of Pfizer, a company which does not have any products relating to herpes zoster."
Notes	This was an immunogenicity study. For safety analyses, 1 participant randomised to the 1 month between doses schedule was analysed as receiving the 3‐month schedule. More detailed unpublished data were kindly provided by Sanofi Pasteur MSD SNC. The data for the 3 groups were pooled for the period of the first vaccination. Randomised 1:1:1 ratio to receive: 1 injection only; 2 injections with 1 month between doses (day 28 to 35); and 2 injections with 3 months between doses (day 81 to 97) "Seventeen participants withdrew from study due to adverse events, of whom ten withdrew within 28 d after vaccination" The injection site reactions were generally mild to moderate in intensity and resolved in 3 to 7 days. 19 participants reported serious adverse events between screening and 12 months after the last vaccine dose. 1 participant reported 2 serious adverse events. None of the serious adverse events was considered to be vaccine‐related by the investigator. Serious adverse events occurred within 28 days of the first vaccine dose in 1.2% of participants (N = 9) and within 28 days of the second dose in 0.9% of participants (N = 4). In 7 participants serious adverse events occurred between 28 days and 12 months after the last dose. Before the study was stopped, 12 participants died, 7 within 12 months of the last vaccination and 5 more than 12 months after the last vaccination. No ITT analysis We asked the authors for the outcomes by age, but they kindly answered that there was no analysis of safety by age group. We only used the data for single doses since the authors state in their conclusion: "The results of this study demonstrate that there is no apparent advantage to administering a second dose of Zostavax on a one month or three month schedule among individuals aged ≥ 70 years".
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Used "blocks of randomisation"
Allocation concealment (selection bias)	Low risk	"The allocation schedule was generated using balanced permuted blocks of randomisation"
Blinding (performance bias and detection bias) All outcomes	High risk	Open‐label study
Blinding of participants and personnel (performance bias) All outcomes	Low risk	"Solicited injection‐site reactions (erythema, swelling, and pain) occurring within 4 d of vaccination were recorded by participants in a diary card. Other injection‐site reactions and systemic AEs were recorded in the diary card for up to 28 d following each vaccination"
Blinding of outcome assessment (detection bias) All outcomes	High risk	Although participants completed their diary cards themselves, the other adverse events were not blinded for the evaluator.
Incomplete outcome data (attrition bias) All outcomes	Low risk	Clear patient flow
Selective reporting (reporting bias)	Low risk	All data proposed in the methodology were presented in the results.
Other bias	Unclear risk	Insufficient information