Recombinant Zoster Vaccine Is Efficacious and Safe in Frail Individuals

Desmond Curran, PhD; Joon H. Kim, MD; Sean Matthews, MSc; Christophe Dessart, MSc; Myron J. Levin, MD; Lidia Oostvogels, MD; Megan E. Riley, PhD; Kenneth E. Schmader, MD; Anthony L. Cunningham, MD; Shelly A. McNeil, MD; Anne E. Schuind, MD; Melissa K. Andrew, MD

Disclosures

J Am Geriatr Soc. 2021;69(3):744-752. 

In This Article

Abstract and Introduction

Abstract

Background/Objectives: Frail participants are often under-represented in randomized trials, raising questions about outcomes of interventions in real-world settings. Frailty is strongly associated with vulnerability to illness and adverse health outcomes. We studied the impact of frailty on recombinant zoster vaccine (RZV) clinical outcomes.

Design/Setting: Data from two previously conducted phase III randomized trials of RZV were pooled. These two parent trials were conducted concurrently at the same study sites using the same methods.

Participants/Intervention: In the two parent studies, participants aged ≥50 years (ZOE-50 study) and ≥70 years (ZOE-70 study), respectively, were randomized 1:1 to receive two doses of RZV or placebo.

Measurements: In the current ZOE-Frailty study (NCT03563183), a frailty index was created using previously validated methods. Clinical outcomes assessed by frailty status included vaccine efficacy, immunogenicity, reactogenicity, and safety.

Results: Of 29,305 participants from the pooled ZOE-50 and ZOE-70 total vaccinated cohort, 92% were included in this study. Mean age was 68.8 years; 58.1% were women; 45.6% were pre-frail and 11.3% frail. The percentage of frail participants increased with age from 5.7% aged 50–59 years to 22.7% aged ≥80 years. RZV vaccine efficacy against herpes zoster was >90% for all frailty subgroups (non-frail: 95.8% (95% confidence interval = 91.6–98.2), pre-frail: 90.4% (84.4–94.4), frail: 90.2% (75.4–97.0)). The RZV group demonstrated robust anti-gE antibody and gE-specific CD42+ responses, with mean concentrations remaining above pre-vaccination levels at least 3 years post-dose two, in all frailty subgroups. In the RZV group, the percentage of participants reporting solicited adverse events tended to decrease with increasing frailty.

Conclusion: The relatively nonrestrictive inclusion/exclusion criteria in the parent ZOE studies resulted in a range of participants that included frail and pre-frail older adults. RZV significantly reduced the risk of herpes zoster across all frailty subgroups.

Introduction

Herpes zoster (HZ), or shingles, which results from the reactivation of latent varicella zoster virus (VZV), usually presents as a painful vesicular dermatomal rash.[1] VZV cell-mediated immune (CMI) response declines with age, and this decline correlates with an increase in incidence and severity of HZ.[2,3] Older adults are at an increased risk of having severe pain during the acute phase, and of developing complications such as postherpetic neuralgia (PHN),[4] which can have a devastating impact on quality of life (QoL).[5,6] Particularly in frail individuals, HZ can lead to an inability to recover the lifestyle, interests, and level of functional activity that existed before HZ, and may also be associated with depression.[6,7]

Antiviral therapy can reduce both rash extent and duration and acute pain severity, if administered within 72 hours of rash onset, but has not been shown to decrease the incidence of PHN.[8] Nonsteroidal anti-inflammatory drugs or acetaminophen or opioids are commonly used for the treatment of acute pain and PHN associated with HZ.[1] However, the application of drugs to manage HZ in frail, co-morbid, and often poly-medicated patients must be carefully considered, as frail individuals could be affected more by treatment-related side effects than non-frail individuals.[9]

Vaccines against other infections, such as influenza and pneumococcal disease, are less effective in older or frail individuals, resulting in less benefit.[10–14] Consequently, there is a paradox, that is, the people in most need of protection may benefit less from those vaccines. In contrast, a two-dose adjuvanted recombinant zoster vaccine (RZV; Shingrix, GSK) demonstrated vaccine efficacy (VE) in preventing HZ of 97.2% in the pivotal phase III ZOE-50 study that enrolled adults ≥50 years, and 91.3% in the pooled ZOE-50 and ZOE-70 analysis, that enrolled adults ≥70 years.[15,16] This vaccine consists of the VZV glycoprotein E (gE) antigen and an Adjuvant System (AS01B).

Frail participants and those with multiple comorbidities are often under-represented in randomized controlled trials, raising questions about vaccine efficacy in a real-world setting.[17] Given these questions and the correlation of frailty with low immune responses and poor clinical outcomes with other vaccines, we undertook an additional analysis of data from the ZOE studies, describing the baseline frailty status of ZOE study participants and the impact of frailty on RZV efficacy, immunogenicity, reactogenicity, and safety.

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