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. 2019 Nov 7;2019(11):CD008858. doi: 10.1002/14651858.CD008858.pub4

Chlibek 2014.

Methods Study design: RCT phase II, single‐blind (participants)
Duration: 36 months after first vaccination
Participants Inclusion criteria
Setting: outpatient
Country: 11 centres in the Czech Republic, Germany, the Netherlands, and Sweden
Number: 714 participants; treatment (N = 495), control (N = 219)
Participants' health status: healthy participants
Age: mean ˜ 69.9 years
Sex: ˜ 60% female
Other relevant information: aged ≥ 60 years
99.3% Caucasian (understood to be white)
Exclusion criteria
"Participants were excluded if they had a history of herpes zoster; were previously vaccinated against herpes zoster or with any vaccine containing 3‐O‐desacyl‐ 4‐monophosphoryl lipid A(MPL) or Quillaja saponaria Molina, fraction 21 (QS21), were allergic to any of the vaccine components, had received a vaccine (except influenza) within 2 weeks, an investigational or non‐registered product, chronic immunosuppressants, corticosteroids within 30 days, or immunoglobulins or a blood product within 3 months before the first study vaccine dose, or had a history of drug or alcohol abuse."
Interventions Treatment group

  1. 2 doses 2 months apart 25 µg adjuvant gE/AS01B 0.5 mL IM (N = 164)

  2. 2 doses 2 months apart 50 µg adjuvant gE/AS01B 0.5 mL IM (N = 166)

  3. 2 doses 2 months apart 100 µg adjuvant gE/AS01B 0.5 mL IM (N = 165)


Control group

  1. 1 dose saline + 1 dose 100 µg gE 2 months later 0.5 mL IM (N = 165)

  2. 2 doses 2 months apart 100 µg gE/saline 0.5 mL IM (N = 54)
Outcomes

  1. Participants with solicited general reactions (fatigue, fever, headache, and myalgia): recorded by participants on diary cards for 7 days after each vaccination

  2. Participants with solicited local reactions (pain, redness and swelling at the injection site)

  3. Participants with unsolicited adverse events: recorded for 30 days after each vaccination

  4. Participants with serious adverse events: recorded over the entire study period (36 months)


Intensity of the solicited reactions was scored on a scale from 0 (absent) to 3 (severe). All solicited local reactions were considered vaccination‐related, and causality of the solicited general reactions, unsolicited adverse events, and serious adverse events was assessed by the investigators.
Purpose of the study "The aim of the current study is to evaluate the safety and immunogenicity of different schedules and formulations of gE/AS01B in adults ≥ 60 years of age"
Funding sources GlaxoSmithKline Biologicals SA, Belgium
Conflicts of interest "Dr. Chlibek has been the principal investigator in clinical studies supported by GSK. He has received sponsorship to attend scientific meetings and reimbursement of other expenses from GSK and Pfizer, and receives payment for the development of educational presentations from Pears Health Cyber. Dr. Smetana has received consulting fees and honoraria/travel grants from GSK and Sanofi Pasteur in the past 3 years. Dr. Pauksens has been a principal investigator in clinical trials conducted by GSK, Pfizer, and Sanofi Pasteur. Dr. Rombo has received consulting fees from GSK. Dr. Van den Hoek has no conflict of interest to declare. Dr. Richardus has received grants from GSK for carrying out clinical trials and has received travel grants from GSK in the past 3 years. Dr. Plaßmann has received honoraria for conducting clinical trials from GSK. Dr. Schwarz received honoraria for consultancy, member ship of advisory boards and lecturing from GSK in the past 3 years. Mr. Ledent and Dr. Heineman are full time employees of the GSK group of companies. Dr. Heineman receives stock equity as part of his compensation."
Notes 715 participants were enrolled, but 714 were vaccinated.
701 completed the study through month 3.
Most solicited reactions were transient (1.1 to 3.5 days on average) and were of mild‐to‐moderate intensity (grade 1 or 2), with ≤ 4.8% of participants in each group reporting grade 3 reactions.
A total of 349 serious adverse events were reported in 205 participants during the study. 14 participants died due to an SAE, most due to cancer or heart failure. No serious adverse events were considered by the investigators to be related to the study vaccines.
47 participants (6.6%) were excluded from the according‐to‐protocol immunogenicity cohort. The most common reasons for exclusion were non‐compliance with the blood sampling schedule (N = 27) and the absence of essential serological data (N = 9).
Of the 714 vaccinated participants, 685 (95.9%) were followed through month 12; 665 (93.1%) through month 24; and 646 (90.5%) through month 36.
8 participants were withdrawn from the 25 µg gE/AS01B group (3 not eligible, 2 lost to follow‐up, 2 consent withdrawal, and 1 death); 7 were withdrawn from the 50 µg gE/AS01B group (1 not eligible, 2 consent withdrawal, and 4 deaths); 6 were withdrawn from the 100 µg gE/AS01B group (2 not eligible, 2 consent withdrawal, and 2 deaths); 4 were withdrawn from the saline + 100 µg gE/AS01B group (1 lost to follow‐up, 1 consent withdrawal, and 2 deaths); and 4 were withdrawn from the 100 µg gE/saline group (2 lost to follow‐up and 2 deaths).
"The proportion of subjects with solicited reactions was higher for groups receiving two doses of gE/AS01B but the proportion did not increase between the first and the second vaccination (data not shown)"
We requested information about adverse events by age or vaccination from the study authors, but have only received the published data.
Risk of bias
Bias Authors' judgement Support for judgement
Random sequence generation (selection bias) Unclear risk "Subjects were stratified by age (60–69 years and ≥70 years in a 1:4 ratio) and randomised"; the method of randomisation was not described
Allocation concealment (selection bias) Unclear risk No information was provided regarding this domain.
Blinding (performance bias and detection bias) 
 All outcomes High risk There was no mention of whether the outward appearance of the prepared injections was indistinguishable in all aspects.
Blinding of participants and personnel (performance bias) 
 All outcomes Low risk Single‐blind (only for participants), but the participants completed their diary cards themselves as follows: "solicited local reactions (pain, redness and swelling) and general reactions (fatigue, fever, headache and myalgia) were recorded by subjects on diary cards for seven days after each vaccination"
Blinding of outcome assessment (detection bias) 
 All outcomes High risk Although the participants themselves completed their diary cards, the other adverse events were not blinded for the evaluator.
Incomplete outcome data (attrition bias) 
 All outcomes Low risk The patient flow is clear.
Selective reporting (reporting bias) Low risk The adverse events originally defined by the authors were presented.
Other bias Unclear risk Insufficient information