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

Discussion

The ZOE studies included participants across a range of frailty statuses, with 11.3% considered frail in the overall study population aged ≥50 years, increasing to 22.7% in those over age ≥80 years. VE against HZ was >90% across all levels of frailty, and immune responses were robust for all three frailty subgroups. Reactogenicity tended to decrease with increasing frailty in the RZV group, and no safety concerns were identified in any frailty subgroup.

Despite the lack of pre-specified frailty measure in the parent ZOE studies, it was possible to generate a FI measure based on data collected at baseline in those clinical trials, using an approach that we previously validated.[21] Indeed, the FI could be calculated for 99.5% of participants who were included in the present study. In the case of the ZOE studies, even without specific attempts to recruit frail participants, use of relatively nonrestrictive in/exclusion criteria resulted in a broad range of participants. Given increasing awareness of the importance of frailty for responses to therapies and vulnerability to outcomes, the retrospective evaluation of frailty has potential applicability for analyses of other clinical trials.

In this study, results in the placebo group were consistent with published literature on frailty indices in which frailty increased with age, was higher in women than men, and adverse outcomes increased with increasing frailty (for solicited AEs such as headache, myalgia, fatigue and gastrointestinal symptoms, unsolicited AEs, SAEs, and death). Notably, we found that solicited AEs reports within 7 days, and unsolicited AE reports within 30 days of vaccination did not increase with frailty in the RZV group, whereas they did increase as expected in the placebo group. This observation is interesting since, based on literature, one expects to have more AEs with increasing frailty, also in the vaccine group. The finding suggests that the rate of AEs is driven by reactogenicity, and as such decreases with increasing frailty, in line with the lower observed reactogenicity in frailer participants. This result is consistent with decreasing vaccine reactogenicity with increasing age observed in the parent ZOE studies.[15,16] Overall, occurrence of SAEs, pIMDs, and deaths were similar in the vaccine and placebo groups in all frailty subgroups. The safety profile in all subgroups was clinically acceptable and comparable to the known safety profile of RZV vaccine.

RZV VE against HZ and against HZ ZBPI BOI were >90% and >85%, respectively, in all frailty subgroups. Of note, in the placebo group, the HZ ZBPI BOI was twice as high in frail participants compared to non-frail participants; consequently, although the VE tended to be lower in frail participants, the absolute decrease in HZ ZBPI BOI was higher in frail participants compared to pre-frail or non-frail participants. This suggests that during the course of the ZOE studies, with a mean follow-up of approximately 4 years, frail individuals may benefit at least as much from RZV as non-frail individuals. In a previous publication, we estimated that the HZ ZBPI BOI score was 1.932 in individuals aged 80 years of age and older in the placebo group,[26] compared with a score of 2.330 in frail participants in the placebo group in this analysis. This reaffirms the findings of previous studies, that frailty is a better predictor of clinical outcomes than chronological age.[18]

We identified robust immunogenicity responses to RZV across frailty subgroups which persisted at least 36 months post-RZV dose two. Previous studies with other vaccines, for example, for influenza and pneumococcal disease, demonstrated a decline in vaccine effectiveness with age and with frailty.[10–14,25] Frailty has been theorized to be associated with an age-related decline in innate and adaptive humoral and cell-mediated immunity that impairs the ability to resist infection and respond to vaccination, contributing to immunosenescence.[28,29] However, the persistence of strong gE-specific CD4 T-cell responses, and the associated VE estimates of >90% in all frailty subgroups, seen with RZV, suggests that the vaccine can overcome immunosenescence to provide protection against HZ, including in frail individuals.[27,30] Adjuvants, such as AS01B present in RZV, have the potential to improve the efficacy of other vaccines that are intended for use in older adults and other populations that may otherwise have a lower response to vaccination.

In conclusion, adjuvanted RZV was highly effective in reducing the risk of HZ and associated BOI for all frailty subgroups. There was a trend for reduced reactogenicity with increasing frailty, and there were no safety concerns in pre-frail or frail individuals. This study may help inform older adults, their health care providers, and policy makers regarding the benefits of vaccination against HZ with the recombinant zoster vaccine.

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