Efficacy of the Herpes Zoster Subunit Vaccine in Adults 70 Years of Age or Older

Clinical Question

In patients 70 years of age or older does the use of the Zoster subunit vaccine in comparison to lack of preventative therapy decrease the morbidity of herpes zoster and postherpetic neuralgia while minimizing adverse events?

Bottom Line

In patients 70 years of age or older, the administration of Zoster subunit vaccine in comparison to the lack of preventative therapy helps decrease the incidence of herpes zoster and postherpetic neuralgia while limiting adverse events.

Major Points

Herpes Zoster, commonly known as Shingles, is caused by a reactivation of the varicella-zoster virus (VZV) that is in a latent state. VZV is also the same virus that is responsible for chickenpox. People who have had chickenpox will have an inactivated form of VZV that are stored in some nerves. When these people get older or have a weakened immune system the VZV can become active again causing shingles. The reactivated virus will travel along the nerves, to the skin causing symptoms such as red blistering rashes that can be extremely painful. Some people may experience a complication of shingles called postherpetic neuralgia, which can be debilitating neuropathic pain even after the rash has been healed. Currently, a live attenuated herpes zoster vaccine(Zostavax) is approved for use in adults 50 years of age or older and is recommended for adults 60 years of age or older. A zoster subunit vaccine (HZ/su) containing recombinant varicella-zoster glycoprotein E and the AS01B adjuvant system is an investigational vaccine that is being tested for prevention of shingles and postherpetic neuralgia in patients aged 50 years and older. A previous trial (ZOE-50) was conducted and showed that HZ/su was 97.2% effective. In this study (ZOE-70) the HZ/su vaccine was assessed in patients 70 and older for the efficacy against herpes zoster. The ZOE-70 trial was a randomized, placebo controlled, phase 3 trial conducted with 13,900 participants to evaluate the efficacy, immunogenicity, and safety of HZ/su in adults 70 years of age or older. This trial had the same design as the ZOE-50 trial. Participants were randomly assigned in a 1:1 ratio to either the HZ/su group or a placebo group. After a mean follow-up period of 3.7 years the efficacy was recorded. A pooled analysis of participants from this study and participants aged 70 or older in the ZOE-50 trial (16,596 participants total) was also conducted for efficacy in preventing herpes zoster. Pooled data was also analyzed for the vaccine’s efficacy against postherpetic neuralgia. The ZOE-70 trial shows that the HZ/su vaccine is is effective at preventing herpes-zoster. The pooled data using the ZOE-50 trial participants that were aged 70 and older, as well as the results from this study, also showed efficacy in preventing herpes-zoster and postherpetic neuralgia. The results used for the combined data were after a mean follow-up of 3.7 years. The efficacy did decrease as the follow-up time extended, however the differences between the 1 year follow-ups and 4-year follow-ups were not statistically significant. More studies must be done to see if there is a decreases efficacy in correlation with time. Reports of injection-site and systemic reactions within 7 days after injection were more frequent among HZ/su recipients than among placebo recipients. Serious adverse events, potential immune-mediated diseases, and deaths occurred with similar frequencies in the two study groups making the safety for the vaccine favorable.

Guidelines

There are currently two zoster vaccines available through recommended guidelines, recombinant (Shingrix) and live (Zostavax). Advisory Committee on Immunization Practices (ACIP) recommendations that Shingrix is preferred in adults ≥ 50 years old including people with immunocompetence, previous vaccinations of Zostavax, on low dose immunosuppression(<20 mg/day of prednisone or equivalent), anticipating immunosuppression, or recovered from immunocompromising illness. Zostavax is an alternative for adults ≥ 60 years old regardless of history of herpes zoster episode and it is recommended to begin at age 60 years even though licensed by FDA for use in persons ≥ 50 years old.

Design

• Randomized, placebo controlled, triple blind phase III trial
• N= 13,900
  • HZ/su 6950 participants
  • Placebo 6950 participants
• Setting: 18 countries in Europe, North America, Latin America, and Asia–Australia
• Enrollment: August 2, 2010, and July 21, 2011
• Mean Follow-up: 3.7 years
• Analysis: Efficacy Analysis
• Primary Outcome: Presentation or prevention of Herpes Zoster

Population

Inclusion Criteria

• 70 years of age or older at the time of first vaccine
• Investigators felt that the individuals would comply with protocols and follow ups

Exclusion Criteria

• History of Herpes Zoster
• Previous vaccination against varicella or HZ, with a registered product or from participation in a previous vaccine study (this included previous vaccination with childhood varicella vaccine)
• Any confirmed or suspected immunosuppressive or immunodeficient condition resulting from disease or immunosuppressive/cytotoxic therapy
• History of allergic disease or reactions likely to be exacerbated by any component of the vaccine, which may include allergic reactions to other material or equipment related to study participation (e.g., materials that may possibly contain latex: gloves, syringes, etc.)
• Significant underlying illness that, in the opinion of the investigator, would be expected to prevent completion of the study
• Concurrent participation in another clinical study, at any time during the study period, in which the subject had been or would be exposed to an investigational or a non investigational product
• Used any investigational or non-registered product (drug or vaccine) other than the study vaccine within 30 days preceding the first dose of study vaccine, or planned to use such a product during the study period
• Received immunoglobulins or any blood products within the 90 days preceding the first dose of study vaccine or planned to receive such products during the study period
• Administration or planned administration of any other immunizations within 30 days before the first or second study vaccination or scheduled within 30 days after study vaccination. However, licensed non-replicating vaccines (i.e., inactivated and subunit vaccines, including inactivated and subunit influenza vaccines for seasonal or pandemic flu, with or without adjuvant) could be administered up to 8 days before each dose or at least 14 days after any dose of study vaccine
• Any other condition (e.g., extensive psoriasis, chronic pain syndrome, cognitive impairment, severe hearing loss) that, in the opinion of the investigator, might interfere with the evaluations required by the study
• Acute disease or fever at the time of enrollment: Fever was defined as an oral, axillary, or tympanic temperature ≥37.5°C or a rectal temperature 38.0°C. The preferred route for recording temperature in this study was oral.
• Subjects with a minor illness without fever could be enrolled at the discretion of the investigator.
• Chronic administration (defined as >15 consecutive days) of immunosuppressants or other immune-modifying drugs within 6 months prior to the first vaccine dose. For corticosteroids, prednisone <20 mg/day, or equivalent, was allowed.

Baseline Characteristics

• Region: Individuals in 18 countries in Europe (54%), North America (19.3%), Latin America (7.7%), Asia-Australia (19%)
• Age: mean age at first dose (75.6 +/- 4.7) , 70-79 years old (77.9%), >/=80 years old (22.1%)
• Sex: female (54.9%), male (45.1%)
• Race: white (76.9%), black (1.1%), asian (17.5%), other (4.5%)

Interventions

• Patients were randomized to one of two groups
  • HZ/su vaccine
  • Placebo
• A second dose of the treatments was administered two months after the first
• 20 participants received the wrong intervention

Outcomes

Primary Outcomes

Vaccine Efficacy against Herpes Zoster in ZOE-50

97.2% (95% confidence interval [CI], 93.7 to 99.0; P<0.001 NNT = 19)

Vaccine Efficacy against Herpes Zoster in ZOE-70

89.8% (95% confidence interval [CI], 84.2 to 93.7; P<0.001, NNT=11)

Vaccine Efficacy against Herpes Zoster in Pooled Analysis

91.3% (95% confidence interval [CI], 86.8 to 94.5; P<0.001, NNT=13)

Secondary Outcomes

Vaccine Efficacy against Postherpetic Neuralgia

88.8% (95% CI, 68.7 to 97.1; P<0.001, NNT=4)

Subgroup Analysis

During a mean follow-up period of 3.7 years, herpes zoster occurred in 23 HZ/su recipients and in 223 placebo recipients (0.9 vs. 9.2 per 1000 person-years).

Adverse Events

• HZ/su group numbers needed to harm (NNH): All are significant
• Any reaction: NNH=14
• Grade 3 reaction: NNH=17
• Injection site reaction: NNH=13
  • Pain: NNH=12
  • Redness: NNH=11
  • Swelling: NNH=13
• Grade 3 injection site reaction: NNH=19
• Systemic reaction: NNH=11
  • Fatigue: NNH=12
  • Myalgia: NNH=12
  • Headache: NNH=13
  • Shivering: NNH=16
  • Fever: NNH=17
  • GI symptoms: NNH=18
• Grade 3 systemic reaction: NNH=23
• Serious adverse event: NNH=56
• Serious adverse event considered related to vaccination: NNH=500
• Potential immune-mediated disease: NNH=200
• Death: NNH=91

Criticisms

Internal:

• Even though the numbers needed to harm are high for the significant adverse events, the numbers needed to harm are very low for many of the adverse effects of the vaccine and most people are unaware of this.
• The study cannot make conclusions regarding the magnitude of a potential decline in efficacy because this was not studied. This should be further studied once the vaccine has been around long enough.
• There is no evidence for additional efficacy against postherpetic neuralgia among HZ/su recipients with breakthrough herpes zoster.

External:

• No criticisms were found
  • Lack of criticisms can be due to how new the study is

Funding

• GlaxoSmithKline Biologicals
• ZOE-50 and ZOE-70 ClinicalTrials.gov numbers, NCT01165177, and NCT01165229