New England Journal of Medicine MAY 28, 2015

Efficacy of the Herpes Zoster Subunit Vaccine in Older Adults (ZOE-50 and ZOE-70 Trials)

Himal Lal, Anthony L. Cunningham, Olivier Godeaux, et al. (ZOE-50) and Anthony L. Cunningham, Himal Lal, Mikaela Kovac, et al. (ZOE-70)

Source: View publication →

Bottom Line

The adjuvanted recombinant zoster vaccine (HZ/su) demonstrates high and sustained efficacy in preventing herpes zoster and postherpetic neuralgia in adults aged 50 and older, significantly outperforming historical live-attenuated vaccine benchmarks.

Key Findings

1. In the ZOE-50 trial (adults ≥50), the HZ/su vaccine demonstrated a 97.2% vaccine efficacy (VE) against herpes zoster compared to placebo (incidence rate of 0.3 vs. 9.1 per 1,000 person-years).

2. In the ZOE-70 trial (adults ≥70), the vaccine achieved an 89.8% VE against herpes zoster (0.9 vs. 9.2 per 1,000 person-years).

3. Pooled analyses from ZOE-50 and ZOE-70 showed 91.3% VE against herpes zoster and 88.8% VE against postherpetic neuralgia in adults aged 70 and older.

4. The high level of protection remained durable, with efficacy maintained at approximately 88% reduction in risk in the fourth year post-vaccination.

5. Injection-site reactions (e.g., pain, redness, swelling) and systemic symptoms (e.g., myalgia, fatigue) were significantly more frequent in the vaccine arm (79.0%) compared to the placebo arm (29.5%).

Study Design

Design

RCT

Observer-Blind

Sample

31,900

Patients

Duration

3.7 yr

Median

Setting

Multinational, 18 countries

Population Healthy adults aged 50 years and older (ZOE-50) and 70 years and older (ZOE-70).

Intervention Two doses of recombinant zoster vaccine (50 μg of varicella-zoster virus glycoprotein E and AS01B adjuvant) administered intramuscularly two months apart.

Comparator Two doses of 0.9% saline placebo administered intramuscularly two months apart.

Outcome Vaccine efficacy against the development of herpes zoster.

Study Limitations

• The clinical trials specifically excluded certain high-risk immunocompromised populations, limiting the initial generalizability to these groups.

• The high reactogenicity profile of the AS01B-adjuvanted vaccine may affect patient adherence to the required two-dose series in real-world clinical practice.

• Long-term efficacy beyond the initial four-year study window required subsequent extension studies (e.g., ZOSTER-049) to confirm sustained protection.

• The study design was powered for efficacy against clinical disease; it was not designed to assess impact on all-cause mortality.

Clinical Significance

The HZ/su vaccine (Shingrix) represents a transformative advancement in geriatric immunization, providing robust and durable protection against shingles and its most severe complication, postherpetic neuralgia, across all older age strata, including those aged 80 and above, where older live-attenuated vaccines were notably less effective.

Historical Context

Prior to the development of the recombinant zoster vaccine, the only available option was the live-attenuated Zostavax vaccine, which showed limited durability and significant waning of efficacy, particularly in individuals over the age of 70. The ZOE-50 and ZOE-70 trials provided the pivotal data for the licensure of the first non-live, adjuvanted subunit vaccine specifically engineered to overcome age-related immunosenescence.

Guided Discussion

High-yield insights from every perspective

Med Student

Medical Student

How does the mechanism of the HZ/su vaccine differ from the traditional live-attenuated zoster vaccine (Zostavax), and why is this distinction critical for preventing infection in geriatric patients?

Key Response

HZ/su is a recombinant subunit vaccine containing glycoprotein E and the AS01B adjuvant, whereas the older vaccine was a live-attenuated virus. The subunit approach is critical because it avoids the risk of vaccine-induced viral replication in older adults and uses an adjuvant to overcome 'immunosenescence'—the natural decline in T-cell mediated immunity that makes older adults more susceptible to both shingles and reduced vaccine response.

Resident

A 72-year-old patient received the live-attenuated zoster vaccine five years ago. Based on the ZOE-50 and ZOE-70 trial data, what is the clinical recommendation regarding re-vaccination with HZ/su?

Key Response

The ZOE trials demonstrated that HZ/su maintains >90% efficacy even in the oldest age cohorts, significantly outperforming the historical efficacy of the live vaccine (which drops to ~18% in those over 80). Therefore, current guidelines recommend HZ/su for all adults over 50 regardless of prior live-vaccine history, typically waiting at least two months after the live dose to ensure an optimal immune response to the new subunit series.

Fellow

The ZOE-70 trial specifically focused on adults aged 70 and older. When evaluating the pooled analysis for postherpetic neuralgia (PHN) prevention, does the vaccine's efficacy against PHN stem solely from its prevention of herpes zoster (HZ) cases, or is there a distinct 'attenuation effect' in breakthrough cases?

Key Response

While the primary driver of PHN reduction is the high efficacy in preventing HZ cases altogether (>91%), the trials also indicated that in the rare instances of breakthrough infection, the vaccine potentially reduced the severity and duration of pain. This suggests both a primary preventive effect and a secondary protective effect against the chronic neurological sequelae of the virus.

Attending

The HZ/su vaccine shows high reactogenicity, with many patients reporting Grade 3 systemic reactions. How should this data from the ZOE trials influence your clinical counseling to ensure series completion in a two-dose regimen?

Key Response

The trials showed high rates of local and systemic reactions (pain, myalgia, fatigue), which can lead to patient 'ghosting' for the second dose. Attending physicians should emphasize that these symptoms are 'expected' signs of a robust immune response (the adjuvant working) and do not indicate infection, noting that the >90% protection is only fully realized after the completion of the two-dose series.

Scholarly Review

Critical appraisal through the lens of expert reviewers and guideline development

PhD

The ZOE trials utilized a modified intention-to-treat (mITT) analysis for the primary efficacy endpoint, excluding participants who did not receive the second dose or developed HZ within a month of that dose. How might this choice affect the internal vs. external validity of the 97.2% efficacy rate reported?

Key Response

The mITT approach enhances internal validity by measuring the biological potential of the completed vaccine series. However, it may inflate external validity expectations (real-world effectiveness), as real-world populations often have lower compliance with two-dose schedules. A true ITT analysis would likely show lower effectiveness due to 'non-compliance' and 'partial-immunization' cases encountered in clinical practice.

Journal Editor

Considering the high reactogenicity of the AS01B adjuvant, to what extent could 'unblinding' have occurred among trial participants, and how did the study design attempt to mitigate the resulting bias in self-reporting of shingles symptoms?

Key Response

A reviewer would flag that participants experiencing significant local reactions would likely know they received the vaccine rather than the placebo. To mitigate this bias, the ZOE trials used a standardized, blinded clinical evaluation of all suspected HZ cases and confirmed cases using highly specific PCR testing for VZV DNA, ensuring that the primary endpoint was determined by objective laboratory data rather than just patient or physician subjective reporting.

Guideline Committee

Given the ZOE-50 and ZOE-70 findings, should HZ/su be designated as the 'preferred' vaccine over the live-attenuated version, and what is the strength of evidence for its use in patients with a prior history of herpes zoster?

Key Response

Based on the superior efficacy across all age groups (>90% for HZ/su vs 51% for the live vaccine), the ACIP updated guidelines to designate HZ/su as the preferred vaccine. Furthermore, because the trials included patients who might have had HZ previously, and because natural infection does not provide lifelong immunity, the committee recommends vaccination regardless of prior HZ episodes to prevent recurrence, supported by Level 1 evidence from these trials.

Clinical Landscape

Noteworthy Related Trials

2005

SPS Trial

n = 38,546 · NEJM

Tested

Live attenuated zoster vaccine (Zostavax)

Population

Adults aged 60 years or older

Comparator

Placebo

Endpoint

Incidence of herpes zoster

Key result: The live vaccine reduced the incidence of herpes zoster by 51.3% and the burden of illness by 61.1%.

2015

ZOE-50 Trial

n = 15,411 · NEJM

Tested

Recombinant zoster vaccine (HZ/su)

Population

Adults aged 50 years or older

Comparator

Placebo

Endpoint

Incidence of herpes zoster

Key result: The recombinant vaccine showed a vaccine efficacy of 97.2% in preventing herpes zoster across all age groups studied.

2016

ZOE-70 Trial

n = 13,900 · NEJM

Tested

Recombinant zoster vaccine (HZ/su)

Population

Adults aged 70 years or older

Comparator

Placebo

Endpoint

Incidence of herpes zoster

Key result: The vaccine maintained high efficacy of 89.8% in individuals aged 70 and older, overcoming the age-related decline in immune response.

Tailored to your role

Want this tailored to you?

Add your specialty or training stage to get role-specific takeaways and more questions.

Personalize this analysis