Burden-of-illness vaccine efficacy.

In recent years, many vaccines have been developed for the prevention of a variety of diseases. Although the primary objective of vaccination is to prevent disease, vaccination can also reduce the severity of disease in those individuals who develop breakthrough disease. Observations of apparent mitigation of breakthrough disease in vaccine recipients have been reported for a number of vaccine-preventable diseases such as Herpes Zoster, Influenza, Rotavirus, and Pertussis. The burden-of-illness (BOI) score was developed to incorporate the incidence of disease as well as the severity and duration of disease. A severity-of-illness score S > 0 is assigned to individuals who develop disease and a score of 0 is assigned to uninfected individuals. In this article, we derive the vaccine efficacy statistic (which is the standard statistic for presenting efficacy outcomes in vaccine clinical trials) based on BOI scores, and we extend the method to adjust for baseline covariates. Also, we illustrate it with data from a clinical trial in which the efficacy of a Herpes Zoster vaccine was evaluated.

Recombinant Zoster Vaccine Significantly Reduces the Impact on Quality of Life Caused by Herpes Zoster in Adult Autologous Hematopoietic Stem Cell Transplant Recipients: A Randomized Placebo-Controlled Trial (ZOE-HSCT).

Herpes zoster (HZ) can have a substantial impact on quality of life (QoL). The vaccine efficacy (VE) of a recombinant zoster vaccine (RZV) was 68.2% (95% confidence interval [CI], 55.6% to 77.5%) in a phase 3 study in adult autologous hematopoietic stem cell transplant (HSCT) recipients (NCT01610414). Herein, we report the impact of RZV on patients' QoL. Autologous HSCT recipients were randomized 1:1 to receive 2 doses of RZV or placebo, given 1 to 2 months apart. QoL was measured by the Short Form Survey-36 and Euro-QoL-5 Dimension at baseline, 1 month, and 1 year postdose 2 and during suspected HZ episodes with the Zoster Brief Pain Inventory (ZBPI). The RZV impact on ZBPI burden of illness and burden of interference scores was estimated. The 2 scores were calculated from the area under the curve (days 0 to 182) of the ZBPI worst pain and ZBPI activities of daily living scores, respectively, assuming a score of 0 for patients not having a confirmed HZ episode. The ZBPI maximum worst pain score was significantly lower in the RZV than placebo group (mean: 5.8 versus 7.1, P = .011). Consequently, the VE estimates for HZ burden of illness (82.5%; 95% CI, 73.6 to 91.4) and burden of interference (82.8%; 95% CI, 73.3 to 92.3) were higher than the HZ VE estimate (ie, 68.2%). RZV showed significantly better QoL scores than placebo 1 week following rash onset among patients with confirmed HZ. In addition to reducing the risk of HZ and its complications, RZV significantly reduced the impact of HZ on patients' QoL in those who developed breakthrough disease.

Dynamic occupancy modelling reveals a hierarchy of competition among fishers, grey foxes and ringtails.

Determining how species coexist is critical for understanding functional diversity, niche partitioning and interspecific interactions. Identifying the direct and indirect interactions among sympatric carnivores that enable their coexistence is particularly important to elucidate because they are integral for maintaining ecosystem function. We studied the effects of removing nine fishers (Pekania pennanti) on their population dynamics and used this perturbation to elucidate the interspecific interactions among fishers, grey foxes (Urocyon cinereoargenteus) and ringtails (Bassariscus astutus). Grey foxes (family: Canidae) are likely to compete with fishers due to their similar body sizes and dietary overlap, and ringtails (family: Procyonidae), like fishers, are semi-arboreal species of conservation concern. We used spatial capture-recapture to investigate fisher population numbers and dynamic occupancy models that incorporated interspecific interactions to investigate the effects members of these species had on the colonization and persistence of each other's site occupancy. The fisher population showed no change in density for up to 3 years following the removals of fishers for translocations. In contrast, fisher site occupancy decreased in the years immediately following the translocations. During this same time period, site occupancy by grey foxes increased and remained elevated through the end of the study. We found a complicated hierarchy among fishers, foxes and ringtails. Fishers affected grey fox site persistence negatively but had a positive effect on their colonization. Foxes had a positive effect on ringtail site colonization. Thus, fishers were the dominant small carnivore where present and negatively affected foxes directly and ringtails indirectly. Coexistence among the small carnivores we studied appears to reflect dynamic spatial partitioning. Conservation and management efforts should investigate how intraguild interactions may influence the recolonization of carnivores to previously occupied landscapes.

Impact of herpes zoster and postherpetic neuralgia on the quality of life of Germans aged 50 or above.

BACKGROUND: Herpes zoster (HZ) is a painful dermatomal rash caused by reactivation of latent varicella zoster virus surviving in the patient's sensory ganglia after a previous episode of varicella. The incidence of HZ increases markedly with age as does the proportion of HZ patients who develop postherpetic neuralgia (PHN) with often severe and debilitating pain persisting for months and even years. This prospective study aimed to assess the impact of HZ and PHN on the quality of life (QoL) of individuals aged ≥ 50 years in Germany. METHODS: Patients were recruited when consulting primary care physicians for a first HZ episode. PHN was defined as a 'worst' pain score ≥ 3 on the Zoster Brief Pain Inventory (ZBPI) scale persisting or appearing 90 days or more after rash onset. PHN-cases were followed for up to nine months after rash onset. The interference of pain with patients' ability to carry out normal activities was assessed by the ZBPI activities of daily living (ADL) scale and QoL by the EuroQoL five-dimension scale (EQ-5D) utility score. RESULTS: Of 513 patients enrolled, 61 (11.9%) developed PHN. At HZ onset, the mean ZBPI worst pain score of all patients was 5.1, the least square (LS)means estimates of the ZBPI ADL and EQ-5D utility scores were 2.970 and 0.740, respectively. Over three months follow-up, the pain scores decreased and the QoL increased monotonically across all age groups. At Day 90, the mean ZBPI worst pain score of the PHN patients was 4.4, while the LSmeans estimates of the ZBPI ADL and EQ-5D utility scores were 2.899 and 0.826, respectively. For patients with PHN persisting at nine months, the pain scores and QoL remained unchanged over the six months following the development of PHN. CONCLUSION: HZ and PHN had a substantial impact on the patients' QoL and ability to function in their normal activities. There was a clear association in time between the evolution of pain and estimated QoL. The impact on ADL and QoL did not vary with age.

The respiratory syncytial virus prefusion F protein vaccine attenuates the severity of respiratory syncytial virus-associated disease in breakthrough infections in adults ≥60 years of age.

Background: Respiratory syncytial virus (RSV) is a contagious pathogen causing acute respiratory infections (ARIs). Symptoms range from mild upper respiratory tract infections to potentially life-threatening lower respiratory tract disease (LRTD). In adults ≥60 years old, vaccine efficacy of a candidate vaccine for older adults (RSVPreF3 OA) was 71.7% against RSV-ARI and 82.6% against RSV-LRTD (AReSVi-006/NCT04886596). We present the patient-reported outcomes (PROs) from the same trial at the end of the first RSV season in the northern hemisphere (April 2022). Methods: In this phase 3 trial, adults aged ≥60 years were randomized (1:1) to receive one dose of RSVPreF3 OA vaccine or placebo. PROs were assessed using InFLUenza Patient-Reported Outcome (FLU-PRO), Short Form-12 (SF-12), and EuroQol-5 Dimension (EQ-5D) questionnaires. Peak FLU-PRO Chest/Respiratory scores during the first 7 days from ARI episode onset were compared using a Wilcoxon test. Least squares mean (LSMean) of SF-12 physical functioning (PF) and EQ-5D health utility scores were estimated using mixed effects models. Results: In the RSVPreF3 OA group (N = 12,466), 27 first RSV-ARI episodes were observed versus 95 in the Placebo group (N = 12,494). Median peak FLU-PRO Chest/Respiratory scores were lower in RSVPreF3 OA (1.07) versus Placebo group (1.86); p = 0.0258. LSMean group differences for the PF and EQ-5D health utility score were 7.00 (95% confidence interval [CI]: -9.86, 23.85; p = 0.4125) and 0.0786 (95% CI: -0.0340, 0.1913; p = 0.1695). Conclusions: The RSVPreF3 OA vaccine, in addition to preventing infection, attenuated the severity of RSV-associated symptoms in breakthrough infections, with trends of reduced impact on PF and health utility.

An Analysis of How Herpes Zoster Pain Affects Health-related Quality of Life of Placebo Patients From 3 Randomized Phase III Studies.

OBJECTIVES: Herpes zoster (HZ) is a painful condition caused by the reactivation of the varicella-zoster virus, negatively affecting the lives of patients. In this post hoc analysis, we describe the impact of HZ pain on the health-related quality of life (HRQoL) and activities of daily living (ADL) of immunocompetent individuals 50 years of age and older and in hematopoietic stem cell transplantation (HSCT) recipients age 18 years of age and older. MATERIALS AND METHODS: ZOE-50 (NCT01165177), ZOE-70 (NCT01165229), and ZOE-HSCT (NCT01610414) were phase III, randomized studies conducted in immunocompetent adults 50 years of age and older and 70 years of age and older and in HSCT recipients age 18 years of age and older, respectively. This analysis was performed on patients who experienced an HZ episode in the placebo groups. The impact of varying levels of HZ pain on HRQoL and ADL was analyzed using data from the Zoster Brief Pain Inventory (ZBPI) and the Short Form Health Survey 36 (SF-36) and EQ-5D questionnaires. RESULTS: A total of 520 immunocompetent and 172 HSCT individuals with HZ were included. SF-36 and EQ-5D domain scores showed a significant relationship between increased HZ pain and worsening HRQoL. For every increase of 1 in the ZBPI pain score, the estimated mean decrease (worsening) in score in the ZOE-50/70 and ZOE-HSCT, respectively, was 2.0 and 2.4 for SF-36 Role Physical; 2.1 and 1.8 for SF-36 Social Functioning; and 0.041 and 0.045 for EQ-5D utility. Sleep and General activities were the ADL components most affected. DISCUSSION: Moderate and severe HZ pain had a substantial negative impact on all aspects of HRQoL and ADL. This impact was independent of age and immunosuppression.

A hierarchical modeling approach to predict the distribution and density of Sierra Nevada Red Fox (Vulpes vulpes necator).

Carnivores play critical roles in ecosystems, yet many species are declining worldwide. The Sierra Nevada Red Fox (Vulpes vulpes necator; SNRF) is a rare and endangered subspecies of red fox limited to upper montane forests, subalpine, and alpine environments of California and Oregon, United States. Having experienced significant distribution contractions and population declines in the last century, the subspecies is listed as at-risk by relevant federal and state agencies. Updated information on its contemporary distribution and density is needed to guide and evaluate conservation and management actions. We combined 12 years (2009-2020) of detection and nondetection data collected throughout California and Oregon to model the potential distribution and density of SNRFs throughout their historical and contemporary ranges. We used an integrated species distribution and density modeling approach, which predicted SNRF density in sampled locations based on observed relationships between environmental covariates and detection frequencies, and then projected those predictions to unsampled locations based on the estimated correlations with environmental covariates. This approach provided predictions that serve as density estimates in sampled regions and projections in unsampled areas. Our model predicted a density of 1.06 (95% credible interval = 0.8-1.36) foxes per 100 km2 distributed throughout 22,926 km2 in three distinct regions of California and Oregon-Sierra Nevada, Lassen Peak, and Oregon Cascades. SNRFs were most likely to be found in areas with low minimum temperatures and high snow water equivalent. Our results provide a contemporary baseline to inform the development and evaluation of conservation and management actions, and guide future survey efforts.

Respiratory Syncytial Virus Disease Burden in Community-Dwelling and Long-Term Care Facility Older Adults in Europe and the United States: A Prospective Study.

Background: Data on respiratory syncytial virus (RSV) disease burden in adults remain scarce. We assessed the burden of confirmed RSV-acute respiratory infections (cRSV-ARIs) in community-dwelling (CD) adults and those in long-term care facilities (LTCFs). Methods: In this prospective cohort study covering 2 RSV seasons (October 2019-March 2020 and October 2020-June 2021), RSV-ARIs were identified through active surveillance, in medically stable CD-adults ≥50 years (Europe) or adults ≥65 years in LTCFs (Europe and the United States). RSV infection was confirmed by polymerase chain reaction from combined nasal and throat swabs. Results: Of 1981 adults enrolled, 1251 adults in CD and 664 LTCFs (season 1) and 1223 adults in CD and 494 LTCFs (season 2) were included in the analyses. During season 1, overall incidence rates ([IRs] cases/1000 person-years) and attack rates (ARs) for cRSV-ARIs were 37.25 (95% confidence interval [CI], 22.62-61.35) and 1.84% in adults in CD and 47.85 (CI, 22.58-101.4) and 2.26% in adults in LTCFs. Complications occurred for 17.4% (CD) and 13.3% (LTCFs) of cRSV-ARIs. One cRSV-ARI occurred in season 2 (IR = 2.91 [CI, 0.40-20.97]; AR = 0.20%), without complications. No cRSV-ARIs led to hospitalization or death. Viral pathogens were codetected in ≤17.4% of cRSV-ARIs. Conclusions: RSV is an important cause of disease burden in adults in CD and LTCFs. Despite the observed low severity of cRSV-ARI, our results support the need for RSV prevention strategies among adults ≥50 years old.

Natural History of Herpes Zoster in the Placebo Groups of Three Randomized Phase III Clinical Trials.

INTRODUCTION: The risk of herpes zoster (HZ) is associated with a decline in immune system function, linked to aging and/or immunocompromising or immunosuppressive diseases or therapies. In this post hoc analysis we describe the incidence of HZ, rash characteristics, and burden of HZ pain in immunocompetent adults ≥ 50 years of age (YOA) and in hematopoietic stem cell transplantation (HSCT) recipients ≥ 18 YOA. METHODS: ZOE-50 (NCT01165177), ZOE-70 (NCT01165229), and ZOE-HSCT (NCT01610414) were phase III, observer-blind, placebo-controlled, randomized studies conducted in immunocompetent adults ≥ 50 YOA and ≥ 70 YOA; and in HSCT recipients ≥ 18 YOA, respectively. A similar methodology for study design, case definition, and data collection were applied in all three studies. The participants received either two doses of the adjuvanted recombinant zoster vaccine or placebo, 1-2 months apart. This analysis focuses on all confirmed HZ cases from the placebo groups of the three studies. HZ pain and interference with activities of daily living were assessed using the Zoster Brief Pain Inventory instrument. RESULTS: Overall, 280, 240, and 172 placebo participants with an HZ confirmed episode aged ≥ 50, ≥ 70, and ≥ 18 YOA were included in the ZOE-50, ZOE-70, and ZOE-HSCT analyses, respectively. The incidence of HZ was 9.1/1000 person-years in both the ZOE-50 and ZOE-70 placebo groups and 95.6/1000 person-years in the ZOE-HSCT study placebo group. In the three studies, most individuals with HZ had severe pain, with approximately 90% of individuals reporting clinically significant pain. An estimated 12.3%, 16.9%, and 21.8% of patients in the ZOE-50, ZOE-70, and ZOE-HSCT studies, respectively, developed post-herpetic neuralgia. CONCLUSION: The incidence and burden of HZ is high in immunocompetent adults aged ≥ 50 YOA and even more so in HSCT recipients aged ≥ 18 YOA.

An Easy-to-Implement Clinical-Trial Frailty Index Based on Accumulation of Deficits: Validation in Zoster Vaccine Clinical Trials.

Purpose: Despite being among those most in need of protection, frail older adults are often not well represented in clinical trials. Although frailty likely influences responses to treatments and vaccines, frailty may not be explicitly considered in trials even when frail participants are enrolled due to the perception that frailty is difficult to measure effectively and efficiently without adding to participant or data collection burden. We developed an easy-to-implement frailty index, the Clinical Trial-Frailty Index (CT-FI), based on baseline medical history and standard patient-reported outcomes using data from clinical trials of recombinant Zoster vaccine (the ZOE-50 and ZOE-70 studies). Our objective was to demonstrate that the CT-FI is a robust measure that may be used retrospectively or prospectively in clinical trials where sufficient patient data have been collected. Methods: The CT-FI was based on baseline medical history and Quality of Life questionnaires (SF-36 and EQ-5D). Items meeting criteria for inclusion were scored from 0 to 1, then summed for each participant and divided by the total number of deficits considered. Validation analyses included descriptive verification of distribution and age- and sex-associations in relation to usual patterns of the frailty index, regressions in relation to outcomes hypothesized to be related to frailty, and resampling methods within the index. Results: The CT-FI distribution was well represented by a gamma distribution with a range of 0-0.70. Deficit accumulation increased with chronological age and was higher for females. Multivariate Cox regression survival analysis showed that the CT-FI, age, and sex were significant predictors of mortality. Jackknife and Bootstrap resampling methods highlighted the robustness of the CT-FI, which was not sensitive to inclusion/exclusion of specific individual or groups of variables. Conclusion: We have developed a reliable, robust and easy-to-implement CT-FI with potential retrospective or prospective application in other clinical trials.

Long-term efficacy data for the recombinant zoster vaccine: impact on public health and cost effectiveness in Germany.

The aim of the study was to update previously published public health impact and cost-effectiveness analyses of the recombinant zoster vaccine (RZV), in the German population aged ≥50 years of age (YOA), with the latest vaccine efficacy (VE) estimates against herpes zoster (HZ). The updated estimates are derived from a long-term follow-up study. A previously published multi-cohort Markov model following age cohorts over their lifetime was used. Demographic, epidemiological, cost, and utility data were based on German specific sources. Vaccine coverage was assumed to be 40%, with a second dose compliance of 70%. The estimated VE at time 0 was 98.9% (95% C.I.: 94.0-100%) with an annual waning of 1.5% (95% CI: 0.0-3.4%) for the age group 50-69 YOA. Corresponding values were 95.4% (95% C.I.: 89.7-100%) and 2.3% (95% CI: 0.3-4.4%) for the age group ≥70 YOA. It was estimated that, over the remaining lifetime since vaccination, RZV would prevent approximately 884 thousand (K), 603 K, and 538 K HZ cases in three age cohorts 50-59, 60-69, and ≥70 YOA, respectively. The number needed to vaccinate to prevent one HZ and one postherpetic neuralgia case was 6 and 36 (50-59 YOA cohort), 6 and 34 (60-69 YOA cohort), 10 and 48 (≥70 YOA cohort). The incremental cost-effectiveness ratio of vaccination ranged from €26 K/quality-adjusted life year (QALY) in 60 YOA to €35 K/QALY in 70 YOA. Due to the higher, sustained, RZV VE, improved public health and cost-effectiveness results were observed compared to previous analyses.

PLAIN LANGUAGE SUMMARYWhat is the context?Shingles is a viral infection caused by the reactivation of the chickenpox virus. It causes a painful rash that lasts for several weeks.The incidence and severity of shingles increase with age. In Germany alone there are approximately 400,000 new cases annually.Vaccination can help prevent shingles.Previous studies, based on data collected up to four years post-vaccination, estimated the number of shingles cases prevented. What is new?Here, we use data from the same studies followed over a longer-term to update previous analyses in the German population.We found, based on data up to 8 years following vaccination, that:○ In adults 50-69 years: the vaccine initially prevents 98.9% of cases, with a reduction of 1.5% each year(for example, after one year, it would prevent 97.4% of cases).○ In adults over 70 years of age: the vaccine initially prevents 95.4% of cases, with a reduction of 2.3% each year (for example, after one year, it would prevent 93.1% of cases).○ Vaccination would reduce the number of shingles cases by 0.9 million in a cohort of adults aged 50-59 years, 0.6 million in adults 60-69 years, and 0.5 million in adults older than 70 years, over the remainder of their lifetime.What is the impact?The study provides more certainty regarding results as it is based on the most complete/up to date data. The results showed the potential of Shingrix to prevent shingles while at the same time providing good value for money.

Economic Burden and Impact on Quality of Life of Herpes Zoster in Spanish Adults Aged 50 Years or Older: A Prospective Cohort Study.

INTRODUCTION: The economic burden of herpes zoster (HZ), including its most common complication, postherpetic neuralgia (PHN), and its impact on health-related quality of life (HRQL) is not well described in Spain. The aim of this study was to estimate HZ-related healthcare costs and impact on HRQL in Spanish adults aged 50 years or older. METHODS: A prospective, observational study was performed with patients with HZ recruited through four general practitioner networks in Spain (NCT01521286). HRQL data were collected using the EuroQoL-5 Dimension (EQ-5D) questionnaire; HZ-related pain and associated interference with activities of daily living (ADL) were assessed using the Zoster Brief Pain Inventory (ZBPI) questionnaire at days 0 (HZ rash onset), 15, 30, 60, and 90; patients with PHN were assessed up until day 270. Medical resource utilization was recorded throughout study follow-up. Work loss for patients/caregivers was also assessed. Costs were calculated from both the payer and societal perspectives. RESULTS: A total of 545 patients with Hz were included, of whom 25 developed PHN. During days 0-30 post HZ diagnosis, the mean EQ-5D utility score was 0.738, equating to a utility loss of 0.138. Sleep was the ADL most affected component. The mean costs for HZ in the overall cohort were €240 and €296 from the payer/societal perspective, respectively; €187/€242 for patients with HZ without any HZ-related complications; and €571/€712 for patients who developed PHN. The majority of costs were incurred during days 0-30. CONCLUSIONS: In Spain, HZ and HZ-related complications such as PHN reduce patient HRQL and increase the economic burden for both payers and society in general. TRAIL REGISTRATION: ClinicalTrials.gov identifier NCT01521286.

Impact of Reactogenicity After Two Doses of Recombinant Zoster Vaccine Upon Physical Functioning and Quality of Life: An Open Phase III Trial in Older Adults.

BACKGROUND: Herpes zoster may significantly impact quality of life (QoL) in older adults. The recombinant zoster vaccine (RZV) is efficacious in adults aged ≥50 and older and is associated with increased reactogenicity compared to placebo. We report here on the impact of reactogenicity of the second RZV dose on the QoL and physical functioning (PF) of vaccine recipients, and summarize findings following both doses. METHOD: In this single-arm study, 401 adults aged ≥50 and older were enrolled to receive two RZV doses 2 months apart. Change in mean Short Form Survey-36 (SF-36) PF and EuroQol-5 Dimension (EQ-5D) scores, reactogenicity, safety, productivity loss, and healthcare resource utilization were evaluated. RESULTS: In total, 391 (97.5%) participants received dose 2. Post-dose 2, the most common solicited local symptoms were injection site pain (75.1%), erythema (22.4%), and swelling (13.9%), and the most common systemic symptoms were fatigue (46.3%), headache (37.5%), and myalgia (32.9%). Grade 3 solicited (local and systemic) adverse events were reported by 61 (15.6%) participants and were associated with a transient clinically significant decrease in SF-36 PF score on Days 1-2 post-dose 2 that recovered by Day 3. Overall, no clinically important reduction in mean SF-36 PF scores was observed from baseline to post-dose 2 (mean change -0.4), and no quality-adjusted-life-year loss was recorded. CONCLUSIONS: Overall, QoL and PF of RZV vaccinees were not affected by vaccine-related reactogenicity. A transient reduction was observed in the first 2 days after RZV vaccination in individuals with Grade 3 adverse events. No safety concerns were identified.

Recombinant Zoster Vaccine Is Efficacious and Safe in Frail Individuals.

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.

The Economic Burden and Impact on Quality of Life of Herpes Zoster and Postherpetic Neuralgia in Individuals Aged 50 Years or Older in Italy.

BACKGROUND: To estimate the health care resource utilization, costs, and impact on quality of life (QoL) of herpes zoster (HZ) and postherpetic neuralgia (PHN) in adults aged ≥50 years in Italy. METHODS: This was a prospective, observational, multicenter, community physician-based surveillance study (NCT01772160) in Italy. Health-related QoL data were collected using the EuroQoL-5 Dimension (EQ-5D) and Zoster Brief Pain Inventory (ZBPI) questionnaires. Both questionnaires were assessed at days 0 (HZ rash onset), 15, 30, 60, and 90 for all patients, and monthly thereafter for patients who developed PHN. Resource utilization was recorded for 3 months post-HZ onset and 9 months for PHN patients. Costs from both payer and societal perspectives were estimated and were composed of direct medical costs (general practitioner/specialist visits, procedures, hospitalizations, medications), work loss by patient/caregiver, and transport costs. RESULTS: A total of 391 patients with HZ were included, of whom 40 developed PHN. The mean ZBPI worst pain score was 5.7 at day 0, reducing to 2.6 at day 30 and 0.7 by day 90. Patients with PHN had a mean worst pain score of 5.7 at day 90. We estimated an overall disutility associated with HZ of 0.134. The mean cost per HZ patient from a payer/societal perspective was €153/€298, respectively, and the mean cost per HZ patients who developed PHN was €176/€426, respectively. CONCLUSIONS: HZ is associated with impaired QoL and substantial health care resource use, highlighting the need for preventive strategies. This could reduce the disease burden for the patient and health care system. CLINICALTRIALSGOV STUDY REGISTRY: NCT01772160.

Evaluation of two frailty indices, with practical application in a vaccine clinical trial.

Frail older adults are at increased risk of poor clinical outcomes. Frailty assessment is therefore important in clinical trials to understand the benefits and harms of interventions. However, consensus is lacking on how frailty should be assessed.We developed a prospectively specified index using a battery of formal tests and instruments and a retrospectively generated index using medical comorbidities and patient reported outcomes (PROs) within an adjuvanted recombinant zoster vaccine (RZV) trial (NCT02979639). For both frailty indices (FIs), a total deficit score was calculated as the accumulation of deficits and participants were categorized as non-frail, pre-frail and frail. We assessed (1) the feasibility and validity of both FIs; (2) the impact of RZV vaccine reactogenicity by frailty status on Short Form-36 [SF-36] physical functioning (PF) scores.Of 401 participants, aged ≥50 years, 236 (58.9%) were categorized non-frail, 143 (35.7%), pre-frail, and 22 (5.5%) frail using the prospective FI. Corresponding numbers for the retrospective FI were 192 (47.9%), 169 (42.1%) and 40 (10.0%), respectively. Strong concordance was observed between the frailty status assessments (P < .001). The proportion defined as frail increased from 1.5%, to 10.4% in participants aged 50-59, and ≥70 years, respectively, for the prospective FI. Corresponding numbers for the retrospective FI were 3.7%, and 17.2%, respectively. RZV vaccination was associated with a transient, non-clinically meaningful, decrease on the SF-36 PF score in frail participants.Both frailty indices provided similar results. The retrospectively generated FI offers the advantage of being easier to incorporate into vaccine clinical trials of older adults.

The Impact of Reactogenicity After the First Dose of Recombinant Zoster Vaccine on the Physical Functioning and Quality of Life of Older Adults: An Open-Label, Phase III Trial.

BACKGROUND: Herpes zoster and its related complications are associated with significant medical burden, which negatively affects quality of life and daily functioning of the patients. The recently licensed recombinant zoster vaccine (RZV) offers high efficacy but is associated with local and systemic reactions. This study assessed the impact of RZV on the quality of life and daily functioning of participants and implications for caregivers. METHODS: Four hundred and one adults aged 50 years or older received single RZV doses at 0 and 2 months in this open-label, single-arm, multicenter study (NCT02979639). Change in mean SF-36 Physical Functioning score following first-dose administration, quality of life, reactogenicity, safety, productivity loss, and health care resource utilization was assessed. The current analysis was performed post-vaccine dose-1; safety follow-up will continue until 1 year post-dose-2. RESULTS: The most common solicited local symptoms were injection-site pain (77.5%), redness (23.0%), and swelling (13.3%); the most frequent solicited systemic reactions were fatigue (33.5%), headache (28.3%), and myalgia (26.8%). Grade 3 reactogenicity occurred in 9.5% of participants and was associated with a transient clinically important decrease in SF-36 Physical Functioning score (affecting activities such as walking, carrying groceries, climbing stairs) on Days 1 and 2 post-first vaccination. No clinically meaningful reductions in mean SF-36 Physical Functioning scale scores from pre- to post-RZV dose-1 were observed (mean +1.9 points, primary end point), and no overall quality-adjusted-life-year loss was recorded post-dose-1. Five participants reported lost workdays; caregiver workload was not increased. CONCLUSIONS: Overall, the physical functioning and quality of life of older adults were not affected by a first RZV dose. The observed reactogenicity was consistent with previous studies.

Quality of Life Impact of an Adjuvanted Recombinant Zoster Vaccine in Adults Aged 50 Years and Older.

BACKGROUND: To determine the efficacy of an adjuvanted recombinant zoster vaccine in reducing the herpes zoster (HZ) burden of illness, HZ burden of interference with activities of daily living, and HZ impact on quality of life. METHODS: The assessments were integrated in two Phase III trials, ZOE-50 (NCT01165177) and ZOE-70 (NCT01165229). HZ burden of illness and HZ burden of interference with activities of daily living were assessed by the Zoster Brief Pain Inventory (ZBPI) instrument and quality of life by the EuroQol-5 Dimension (EQ-5D) utility index and the SF-36 health survey. We report the ZOE-50 results and a pooled analysis of patients aged 70 years and older from the trials combined. RESULTS: The estimated vaccine efficacy in reducing HZ burden of illness and HZ burden of interference was greater than 90% in both the ZOE-50 and the pooled ZOE-70 analysis. In confirmed HZ cases, adjuvanted recombinant zoster vaccine reduced the maximal ZBPI worst-pain score in the pooled ZOE-70 analysis (p = .032) and the maximal ZBPI average-pain scores in both the ZOE-50 (p = .049) and the pooled ZOE-70 analysis (p = .043). In breakthrough HZ cases, trends for diminished loss of quality of life compared with placebo-recipient HZ cases were observed, with differences up to 0.14 on the EQ-5D index at time points during the 4 weeks following HZ onset. CONCLUSIONS: Adjuvanted recombinant zoster vaccine reduced the HZ burden of illness significantly, particularly due to its very high vaccine efficacy in preventing HZ. For breakthrough HZ cases, the results suggest that the adjuvanted recombinant zoster vaccine mitigated severity of HZ-related pain, burden of interference with activities of daily living, and recipients' utility loss.

Impact of Herpes Zoster and Post-Herpetic Neuralgia on Health-Related Quality of Life in Japanese Adults Aged 60 Years or Older: Results from a Prospective, Observational Cohort Study.

BACKGROUND AND OBJECTIVES: Herpes zoster (HZ) and its most frequent complication, post-herpetic neuralgia (PHN), have been shown to considerably impact quality of life (QoL). This has not yet been demonstrated in Japan. METHODS: QoL in HZ and PHN patients was evaluated using the Zoster Brief Pain Inventory (ZBPI), EuroQoL-5 Dimension (EQ-5D), Short-Form 12 version 2.0, and short-form McGill Pain Questionnaire up to 270 days after rash onset as part of a prospective, observational, cohort study conducted in Kushiro, Hokkaido, Japan. RESULTS: This study involved 412 adults ≥ 60 years of age diagnosed with HZ, 38 of whom developed PHN. QoL in daily activity performance and emotional and physical functioning was impaired at Day 0 (rash onset) and almost resolved by Day 90. Although the mean ZBPI worst pain score for HZ patients without PHN improved from 4.1 at Day 0 to 0.1 at Day 90, the score for HZ patients with PHN at Day 90 was comparable to that for HZ patients without PHN at Day 0. While the EQ-5D score in HZ without PHN improved, on average, from 0.755 to 0.949, the score for HZ with PHN was dependent on PHN duration and did not improve until PHN disappearance. CONCLUSIONS: HZ impaired QoL in daily activity performance and emotional and physical functioning. The negative impact on QoL was more prevalent in patients with a longer PHN duration compared with HZ without PHN. ClinicalTrials.gov identifier: NCT01873365.

Incidence and costs of herpes zoster and postherpetic neuralgia in German adults aged ≥50 years: A prospective study.

OBJECTIVES: Herpes zoster (HZ) mainly affects elderly people and immunocompromised individuals. HZ is usually characterized by a unilateral painful skin rash. Its most common complication, postherpetic neuralgia (PHN), may cause chronic debilitating pain. This study aimed to estimate the HZ incidence in individuals aged ≥50 years in Germany, the proportion of PHN and the economic burden. METHODS: From 2010 to 2014, HZ patients were recruited when consulting physicians in physician networks covering about 157,000 persons aged ≥50 years. PHN was defined as "worst pain" rated ≥3 on the zoster brief pain inventory persisting or appearing over 90 days after rash onset. Costs were calculated based on medical resource utilization and lost working time. RESULTS: HZ incidence was estimated as 6.7/1000 person-years, increasing with age to 9.4/1000 in ≥80 year-olds. Among 513 HZ patients enrolled, the proportion of PHN was 11.9%, rising with age to 14.3% in HZ patients ≥80 years. Estimated total cost per HZ patient was €156 from the healthcare system perspective and €311 from the societal perspective. CONCLUSIONS: The study confirmed previous findings that HZ causes a substantial clinical and economic burden in older German adults. It also confirmed the age-related increasing risk of HZ and PHN.