Diez‐Domingo 2015

Methods	Phase 3, open‐label, randomised, comparative, 2‐arm, multicentre study 10 centres in Germany and Spain Duration: participants were followed up for a maximum of 35 days post‐vaccination
Participants	353 participants of either gender aged ≥ 50 years on day of vaccination, varicella history‐positive or residence for > 30 years in a country with endemic VZV infection Mean age of the 354 participants was 62.6 years ˜55% were female
Interventions	1. Intramuscular (IM) route: zoster vaccine (refrigerated) 0.65 mL containing not less than 19,400 plaque‐forming units (pfu) of VZV per dose by IM route; N = 176 2. Subcutaneous (SC) route: zoster vaccine (refrigerated): 0.65 mL containing not less than 19,400 pfu of VZV per dose by SC route; N = 177
Outcomes	1. Injection site adverse reactions (ISRs): injection site erythema, injection site swelling and injection site pain were collected from day 0 to day 4 post‐vaccination 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) 2. Fever ‐ temperature > 38.3°C (day 0 to day 28 post‐vaccination) 3. Unsolicited injection site adverse reactions 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 post‐vaccination 4. Serious adverse events were collected any time during the study (day 0 to day 35 post‐vaccination)
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
Notes	This was basically an immunogenicity study and we only used the safety data More detailed unpublished data were kindly provided by Sanofi Pasteur MSD SNC Data by age were not available One participant reported in Group 1 (IM route) a zoster‐like rash (right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 a 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 repot 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 serious AEs (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	We found no more details on this topic