Diez‐Domingo 2015.

Methods	Study design: phase 3, open‐label, randomised Duration: participants were followed up for a maximum of 35 days postvaccination
Participants	Inclusion criteria Setting: outpatient Country: 10 centres in Germany and Spain Number: 353 participants; treatment (N = 176), control (N = 177) Participants' health status: healthy participants with a history of varicella or resident for > 30 years in a country with endemic VZV infection Age: mean 62.6 years Sex: ˜ 55% female Other relevant information: aged ≥ 50 years Exclusion criteria "Previously been vaccinated with any VZV‐containing vaccine or had previously been diagnosed with HZ. In addition, were excluded: any subjects with a history of a febrile episode (≥38.3◦C) in the 72 h prior to study vaccination, those who had received any live vaccine within 28 days of study vaccination or inactivated vaccine within 14 days of study vaccination or immunoglobulins or other blood products within 5 months before vaccination and those who were taking systemic antiviral therapy or had an immune deficiency associated with disease (e.g. human immunodeficiency virus, cancer) or medical treatment (e.g. chemotherapy, transplant recipients)"
Interventions	Treatment group Intramuscular route: zoster vaccine (refrigerated): 0.65 mL containing not less than 19,400 pfu of VZV per dose by IM route; N = 176 Control group Subcutaneous route: zoster vaccine (refrigerated): 0.65 mL containing not less than 19,400 pfu of VZV per dose by SC route; N = 177
Outcomes	Injection site adverse reactions: injection site erythema, injection site swelling, and injection site pain were collected from day 0 to day 4 postvaccination. ISRs were mainly mild (< 5 cm in size or defined as awareness of sign or symptom but easily tolerated) or moderate (5 cm to < 10 cm in size or defined as discomfort enough to cause interference with usual activity) in intensity. Few participants reported severe ISRs (≥ 10 cm or defined as incapacitating with inability to work or do usual activity). Fever: temperature ≥ 38.3 °C (day 0 to day 28 postvaccination) Unsolicited ISRs and systemic adverse events and rashes of interest (i.e. varicella, varicella‐like rashes, herpes zoster or shingles and herpes zoster‐like rashes) were collected from day 0 to day 28 postvaccination. Serious adverse events were collected any time during the study (day 0 to day 35 postvaccination).
Purpose of the study	"To evaluate the immunogenicity as measured by VZV antibody titres (gpELISA) at 4 weeks following ZOSTAVAX® administered by IM or SC route" "To evaluate the immune response as measured by a second assay, the VZV Interferon‐gamma (IFN‐Ȗ)‐ELISPOT at 4 weeks following ZOSTAVAX® administered by IM or SC route" "To describe the safety profile of ZOSTAVAX® administered by IM or SC route"
Funding sources	Sanofi Pasteur MSD
Conflicts of interest	“JDD has been and is the principal investigator in trials sponsored by Sanofi Pasteur MSD, GSK, Merck, Baxter, Novartis and Pfizer. His institutions have received research grants from Sanofi Pasteur MSD, Pfizer and Baxter. He has received grants for attending meeting and has been a member of advisory boards for GSK, Pfizer and Sanofi Pasteur MSD. TW has received honoraria for lecturing and consulting activities from Novartis Vaccines and Sanofi Pasteur MSD. JGDL and CUM have no potential conflicts of interest to declare. IB, CE, ST and CS are employed by Sanofi Pasteur MSD, the company that commercialises the herpes zoster live‐attenuated vaccine (Zostavax®) in Europe.”
Notes	This was basically an immunogenicity study; only the safety data were used in this review. Not ITT analyses More detailed unpublished data were kindly provided by Sanofi Pasteur MSD SNC. Data by age were not available. 1 participant in Group 1 (IM route) reported a zoster‐like rash (right thoracic dermatome) of mild intensity that occurred on day 12 after vaccine administration and lasted 6 days. No specimen was obtained for PCR testing. No participant was withdrawn due to an AE at any time after vaccine administration. No deaths were reported. 3 participants reported an SAE: 1 participant (hernia obstructive) in Group 1 (IM route) and 2 participants (humerus fracture and deep vein thrombosis) in Group 2 (SC route). None were assessed as vaccine‐related by the investigator. No participant was withdrawn due to an AE at any time after vaccine administration.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	"The subjects were randomised using an electronic case report form (e‐CRF)"
Allocation concealment (selection bias)	Low risk	"Allocation schedules were generated using a 1:1 ratio with permuted blocks of 4‐6"
Blinding (performance bias and detection bias) All outcomes	High risk	Open‐label study
Blinding of participants and personnel (performance bias) All outcomes	Low risk	"Between visit 1 and 2, the participants were given a diary card to record their temperature if they were febrile (oral temperature ≥38.3 ◦C), occurrence of any solicited injection site (erythema, swelling and pain) adverse reactions (Days 0–4) and any unsolicited injection site adverse reactions, varicella, varicella‐like rashes, HZ and zoster‐like rashes and other systemic adverse events (AEs) (Days 0–28). They were also asked to report any serious AEs (SAEs) that occurred at any time during the study"
Blinding of outcome assessment (detection bias) All outcomes	High risk	The participants did not put any SAEs in their diary cards themselves, therefore this was not blinded for the staff. "They were also asked to report any serious AEs (SAEs) that occurred at any time during the study"
Incomplete outcome data (attrition bias) All outcomes	Low risk	Clear patient flow
Selective reporting (reporting bias)	Low risk	All data on adverse events that the authors proposed in their methodology were described in the results for both groups.
Other bias	Unclear risk	Insufficient information