New England Journal of Medicine May 28, 2015

ZOE-50 and ZOE-70: Efficacy of an Adjuvanted Herpes Zoster Subunit Vaccine in Older Adults

Himal Lal et al. (ZOE-50) and Anthony L. Cunningham et al. (ZOE-70)

Bottom Line

The adjuvanted recombinant zoster vaccine (Shingrix) demonstrated unprecedented and age-independent efficacy of over 90% against herpes zoster and postherpetic neuralgia across all age groups 50 and older.

Key Findings

1. In ZOE-50 (adults ≥50 years), vaccine efficacy against herpes zoster was 97.2% (95% CI, 93.7 to 99.0), with 6 confirmed cases in the vaccine group vs. 210 in the placebo group over a mean 3.2-year follow-up.

2. In ZOE-70 (adults ≥70 years), vaccine efficacy against herpes zoster was 89.8% (95% CI, 84.2 to 93.7), with 23 confirmed cases in the vaccine group vs. 223 in the placebo group over a mean 3.7-year follow-up.

3. In a prespecified pooled analysis of ZOE-50 and ZOE-70 participants aged ≥70 years, vaccine efficacy against herpes zoster was 91.3% (95% CI, 86.8 to 94.5).

4. The pooled analysis also demonstrated an 88.8% efficacy (95% CI, 68.7 to 97.1) against postherpetic neuralgia in adults aged ≥70 years.

5. Reactogenicity was significantly higher with the vaccine; in ZOE-50, 17.0% of vaccine recipients reported grade 3 (severe) symptoms compared to 3.2% of placebo recipients, though these symptoms were transient.

Study Design

Design

RCT

Observer-Blind

Sample

29,311

Patients

Duration

3.2 to 3.7 yr

Median

Setting

Multicenter, 18 countries

Population Immunocompetent adults aged ≥50 years (ZOE-50, n=15,411) and ≥70 years (ZOE-70, n=13,900) without a history of previous herpes zoster vaccination.

Intervention Two intramuscular doses of the adjuvanted recombinant zoster subunit vaccine (HZ/su, Shingrix) containing 50 μg of gE and AS01B adjuvant, administered 2 months apart.

Comparator Two intramuscular doses of saline placebo administered 2 months apart.

Outcome Vaccine efficacy against the incidence of confirmed herpes zoster compared to placebo.

Study Limitations

• High rates of local and systemic reactogenicity could deter some patients from completing the required two-dose series in real-world clinical practice.

• The initial pivotal trials excluded severely immunocompromised patients, who are at the highest risk for severe herpes zoster (though subsequent studies evaluated this population).

• The trials did not include a head-to-head active comparator arm with the live-attenuated zoster vaccine (Zostavax), although cross-trial comparisons showed marked superiority.

• The initial reports only captured roughly 3 to 4 years of follow-up, requiring subsequent extension studies to prove long-term durability (which was later confirmed to last over 10 years).

Clinical Significance

The ZOE-50 and ZOE-70 trials were landmark studies that transformed the prevention of shingles. Unlike the older live-attenuated vaccine (Zostavax), which showed rapidly waning efficacy in the elderly, Shingrix maintained >90% efficacy even in the oldest patients (≥80 years). These unprecedented results led the FDA to approve Shingrix and the ACIP to preferentially recommend it over Zostavax for all immunocompetent adults aged 50 and older.

Historical Context

Prior to Shingrix, the only available herpes zoster vaccine was Zostavax, a live-attenuated virus vaccine licensed in 2006. While Zostavax reduced herpes zoster incidence by about 51% overall, its efficacy was heavily age-dependent (dropping to 38% in those ≥70 years) and waned substantially within a few years. The development of Shingrix utilized recombinant glycoprotein E (gE) paired with a potent novel adjuvant system (AS01B) to successfully overcome age-related immune senescence, setting a new paradigm for vaccine development in older adults.

Guided Discussion

High-yield insights from every perspective

Med Student

Medical Student

What is the mechanism by which the recombinant zoster vaccine (Shingrix) achieves such high, age-independent efficacy compared to the older live-attenuated vaccine, and what specific viral component does it target?

Key Response

Shingrix uses a recombinant glycoprotein E (gE) antigen combined with a novel AS01B adjuvant system. Unlike live vaccines which rely on general immune stimulation that wanes with immunosenescence, the AS01B adjuvant strongly stimulates CD4+ T-cell and innate immune responses, successfully overcoming age-related immune decline.

Resident

A 65-year-old patient who received the live-attenuated zoster vaccine three years ago asks if they should receive the new recombinant vaccine. How do you advise them, and what specific side effect profile should you prepare them for based on the ZOE trials?

Key Response

Yes, they should receive the recombinant zoster vaccine (RZV) as it provides superior, longer-lasting protection. Residents must counsel patients on the high reactogenicity of RZV (e.g., severe myalgia, fatigue, fever, injection site pain lasting 1-3 days), which is much higher than the live vaccine but indicates a robust immune response rather than an infection.

Fellow

Given that the ZOE-50 and ZOE-70 trials originally excluded immunocompromised patients, what is the theoretical and clinical rationale for using the AS01B-adjuvanted subunit vaccine in patients with hematologic malignancies or autologous stem cell transplants?

Key Response

Because RZV is a recombinant subunit and not a live virus, there is zero risk of disseminated vaccine-strain infection. The potent AS01B adjuvant promotes strong, targeted Th1 responses even in hosts with suppressed cell-mediated immunity, which paved the way for subsequent trials validating its safety and efficacy in these highly vulnerable populations.

Attending

The ZOE trials demonstrated unprecedented efficacy for RZV, but completion rates for the two-dose series can be suboptimal in practice due to reactogenicity. How does the drop-off in second-dose compliance impact real-world effectiveness, and what strategies can clinics implement to mitigate this?

Key Response

Real-world effectiveness drops significantly if the second dose is missed. The high reactogenicity of the first dose is a major deterrent. Attendings must emphasize proactive patient education regarding anticipated side effects to prevent dose-two abandonment, establishing standard standing orders and automated reminder systems.

Scholarly Review

Critical appraisal through the lens of expert reviewers and guideline development

PhD

The researchers prospectively planned to pool data from ZOE-50 and ZOE-70 to evaluate efficacy against postherpetic neuralgia (PHN) in patients 70 and older. Why was this pre-specified pooled analysis methodologically necessary, and what are the statistical trade-offs of this approach?

Key Response

PHN is a relatively rare complication, making a single trial insufficiently powered to detect a statistically significant reduction in its incidence. Pre-specifying the pooling increases statistical power but assumes no significant heterogeneity between the trial populations, requiring rigorous baseline demographic matching and stratified analyses.

Journal Editor

In reviewing the ZOE trials, a critical editor might flag the high rate of systemic reactogenicity associated with the AS01B adjuvant. How might this high rate of noticeable reactions threaten the blinding of the study, and what implications does this have for the reporting of subjective endpoints like postherpetic neuralgia pain scales?

Key Response

The high reactogenicity in the vaccine group essentially unblinds many participants and investigators. While herpes zoster rash is an objective clinical finding (usually PCR confirmed), the subjective assessment of pain severity for PHN could be influenced if participants know they likely received the active vaccine.

Guideline Committee

Based on the findings of ZOE-50 and ZOE-70, how did the ACIP adjust its recommendations regarding herpes zoster vaccination in older adults, specifically concerning the preference between the recombinant vaccine and the live-attenuated vaccine, and the age of initiation?

Key Response

ACIP used these trials to give RZV a Category A recommendation, lowering the recommended age of initiation from 60 to 50 years. Crucially, ACIP explicitly stated a preference for RZV over the live-attenuated vaccine due to its dramatically higher and longer-lasting efficacy across all age strata, marking a significant, evidence-based shift in national policy.

Clinical Landscape

Noteworthy Related Trials

2005

Shingles Prevention Study

n = 38,546 · NEJM

Tested

Zoster Vaccine Live (Zostavax)

Population

Adults 60 years of age and older

Comparator

Placebo

Endpoint

Incidence of herpes zoster and postherpetic neuralgia

Key result: The live-attenuated vaccine reduced the incidence of herpes zoster by 51.3 percent and postherpetic neuralgia by 66.5 percent.

2012

ZEST Trial

n = 22,439 · Clin Infect Dis

Tested

Zoster Vaccine Live (Zostavax)

Population

Adults aged 50 to 59 years

Comparator

Placebo

Endpoint

Incidence of confirmed herpes zoster

Key result: Vaccination significantly reduced the incidence of herpes zoster by 69.8 percent compared with placebo.

2019

ZOE-HS Trial

n = 1,846 · JAMA

Tested

Recombinant Zoster Vaccine (Shingrix)

Population

Adults post-autologous stem cell transplantation

Comparator

Placebo

Endpoint

Incidence of confirmed herpes zoster

Key result: The recombinant zoster vaccine demonstrated an efficacy of 68.2 percent against herpes zoster in this highly immunocompromised population.

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