Drug Assessment Working Group
Systematic Review Report
Efficacy and safety of adjuvanted herpes zoster subunit vaccine
Herpes zoster (HZ) or “shingles” infection occurs through the reactivation of latent varicella zoster virus (VZV) in the sensory ganglia. The outbreak typically presents as a unilateral vesiculopustular rash along a dermatome, with accompanying pain. The rash and pain usually resolve over a few weeks. However, some paitents develop persistent HZ-related pain referred to as post-herpetic neuralgia, or PHN. Estimates of the proportion of patients with HZ who develop PHN with some degree of pain lasting for at least 3 months range widely. The estimate most relevant to this review is that about 10% of non-immunized people who experience acute HZ still experience some pain at 3 months.
It is postulated that HZ occurs as a result of waning immunity. Vaccination has thus been developed to re-activate VZV cellular and humoral immune responses, and to help prevent a future HZ outbreak. Until early 2018, HZ vaccination was available only as a live attenuated vaccine. Disadvantages to the live vaccine are a reduced efficacy in adults older than 60-69 years, a waning protection over a few years regardless of age, and a contraindication for use in the immunosuppressed population.
Health Canada approved Shingrix, a non-living, recombinant, adjuvanted HZ subunit vaccine, for prevention of Herpes zoster (HZ). The vaccine is not approved by Health Canada for prevention of post-herpetic neuralgia (PHN).
In immunocompetent adults aged ≥50, does vaccination with non-living, recombinant, adjuvanted HZ subunit vaccine differ from placebo, no vaccine or an alternative active vaccine in terms of a hierarchy of clinical safety and efficacy outcomes? Outcomes of interest include: all-cause mortality, SAEs, hospitalizations, quality of life, incidence of HZ, incidence of persistent HZ pain, severity of HZ pain, total physician visits, need for prescription medications, total withdrawals, withdrawals due to adverse events, and total adverse events.
A systematic literature search was conducted across CENTRAL, MEDLINE, EMBASE, CINAHL and LILACS databases to identify relevant randomized controlled trials (RCTs). Data from eligible studies and their associated registry data and clinical study reports (CSRs) were extracted and analyzed by means of a meta-analysis whenever possible, or descriptively. Risk of bias was explored in all included studies and data interpreted according to this assessment. Our review findings were also compared to the conclusions of other independent review groups.
Results and Interpretations
Five RCTs met inclusion criteria, including 32,236 participants aged ≥50 years, of whom 15,009 subjects received at least one dose of adjuvanted HZ subunit vaccine. Three of the five RCTs compared HZ subunit vaccine to placebo and were meta-analyzed.
HZ incidence was significantly reduced in patients who received HZ subunit vaccine as compared with placebo (moderate quality evidence; 42 versus 520 HZ episodes over ~3.5 years; RR 0.07, 95% CI 0.03-0.22; I2= 90%;number needed to vaccinate = 31 over ~3.5 years). As a result of reduced HZ incidence, HZ-related complications such as persistent HZ pain (PHN) also decrease. Because only about 10% of older people experiencing shingles infection (HZ) progress to PHN, theabsolute risk reduction in PHN is much smaller. The pooled PHN incidence in Shingrix vaccine trials was: Shingrix 0.06% vs placebo 0.34%; ARR =0.28%; number needed to vaccinate = 358 over ~3.5 years.
Analyses of subgroups based on age as well as time following vaccination were pre-specified in the protocols for the ZOE-50 and ZOE-70 trials (the largest efficacy trials to date). HZ incidence was reduced to relatively similar extents when comparing subgroups based on age, with ARRs in incidence at 2.97% for age 50-59, 4.1% for age 60-69, and 3.16% for age ≥70. The absolute risk reduction in HZ incidence rates by year following vaccination was comparable between each annual timeframe. Within year 1 post-vaccination, HZ incidence ARR was deemed to be 0.82%, and during year 4 post-vaccination the ARR was 0.81%
Solicited and freely reported AEs within the first seven days post-vaccination occurred at a significantly greater frequency than placebo (RR 2.24, 95% CI 2.16-2.33; I2= 0%; number needed to harm = 2 over ~3.5 years). Approximately 8 or 9 out of every 10 patients vaccinated experienced an AE, most commonly myalgias, fatigue or injection-site pain. The propensity for AEs did not appear to affect rates of study withdrawal, however, and reactions were typically classified as mild to moderate. Mortality or serious adverse events (SAEs) were not significantly increased with the HZ subunit vaccine versus placebo.
Leroux-Roels 2012 studied the safety and immunogenicity at twelve months post-vaccination with the HZ subunit vaccine versus the live attenuated Oka-strain VZV vaccine (two doses, two months apart), in a Phase I/II trial given as a single vaccine or concurrently. We report on the older (age 50-70) cohort of patients (n = 90) included in this study. Only reports of solicited AEs were available in the publication. Authors deemed the safety of the vaccines to be similar, noting that toxicities were generally mild to moderate in intensity and short-lived. Fatigue, fever, myalgia, headache and injection-site pain were more commonly reported by recipients of the HZ subunit vaccine than the Oka strain vaccine. No study withdrawals occurred on account of an AE.
For Leroux-Roels 2012 study results were not published on the trial registry entries on clinicaltrials.gov, and no CSR was available. Further outcome data was requested from study authors, who in turn forwarded the request to vaccine manufacturer GlaxoSmithKline (GSK). To date, no supplementary outcome data has been provided from GSK.
Chlibek 2014, a Phase II study involving 714 adults ≥60 years, studied the immunogenicity and safety of different formulations of HZ subunit vaccines (ranging from 25 to 100mcg of VZV gE, with or without AS10Badjuvant) as well as different administration schedules for 36 months. Two doses, two months apart of a HZ subunit vaccine adjuvanted with AS01Bwas found to induce an acceptably strong and sustained immune response. Adverse events were more frequent in the adjuvanted vaccine arms. Injection site pain, myalgias and fatigue were the most common solicited adverse reactions.
Strengths of Review
RCT outcome data were available from over 15,000 subjects who received HZ subunit vaccine. Rigorous methods for assessing risk of bias and overall quality of evidence were used.
Limitations of Review
The populations studied had no history of HZ infection or previous HZ vaccination, and were immunocompetent, which may limit generalizability. Duration of protective effect for HZ subunit vaccine on incidence of HZ infection is still unclear. All included studies were manufacturer-funded. The efficacy of the vaccine is studied over a limited time period of 3.5 years and it is not known whether the protective effect will be maintained with time.
Other reviews of HZ subunit vaccine
The HZ subunit vaccine has been independently reviewed by Health Canada and NACI, the EMA, the FDA, and the CDC ACIP. These groups have each independently endorsed the efficacy of HZ subunit vaccine for HZ prevention in adults aged ≥50, with positive benefit to risk ratios. In addition to HZ prevention, the CDC and EMA recognize that the vaccine prevents PHN and other HZ-related complications.
The CDC supports a preferential use of HZ subunit vaccine over live vaccine in immunocompetent adults ≥50, based in part on cost-efficacy analyses.
- The two-dose HZ subunit vaccine series is effective in reducing HZ incidence, and therefore subsequent HZ-related complications (to a smaller absolute extent), in immunocompetent adults aged ≥50 years. Its use is associated with a high rate of adverse events, primarily local pain, myalgias and fatigue, which resolve within days. Its use does not increase the incidence of SAEs over placebo.
- The effectiveness (i.e. maintained protection) and safety of Shingrix are still unknown beyond about four years.
- Discuss the balance of baseline herpes zoster risk, harms, benefits and costs when considering this vaccine.
- Clinical outcome data is lacking in populations who have previously had HZ infection, or have previously received HZ vaccination.