Persistence of Immunogenicity of a Purified Inactivated Zika Virus Vaccine Candidate in Healthy Adults: 2 Years of Follow-up Compared With Natural Infection.

BACKGROUND: We report 2-year persistence of immune response to Takeda's prophylactic purified formalin-inactivated whole Zika virus vaccine candidate (TAK-426) compared with that observed after natural infection. METHODS: A randomized, observer-blind, placebo-controlled, dose-selection, phase 1 trial was conducted in 18-49-year-old adults at 9 centers (7 in the United States, 2 in Puerto Rico) from 13 November 2017 to 24 November 2020. Primary objectives were safety, tolerability, and immunogenicity of 3 increasing doses of TAK-426 administered as 2 doses 28 days apart to flavivirus (FV)-naive and FV-primed adults. Here, we report on safety and persistence of immunity up to 2 years after primary vaccination with 10-µg TAK-426, the highest dose, and compare neutralizing antibody responses with those observed after natural infection. RESULTS: TAK-426 at 10-µg had an acceptable safety profile in FV-naive and FV-primed adults up to 24 months after dose 2. Seropositivity for neutralizing antibodies was 100% at 1 year, and 93.8% and 76.2% at 2 years in FV-naive and FV-primed groups, respectively. TAK-426 responses were comparable in magnitude and kinetics with those elicited by natural Zika virus infection. CONCLUSIONS: These results support the further clinical development of TAK-426 for both FV-naive and FV-primed populations. CLINICAL TRIALS REGISTRATION: NCT03343626.

Safety and immunogenicity of a purified inactivated Zika virus vaccine candidate in healthy adults: an observer-blind, randomised, phase 1 trial.

BACKGROUND: Zika virus, a flavivirus transmitted by Aedes aegypti and Aedes albopictus mosquitoes, is associated with cases of congenital malformations and neurological complications. Absence of specific treatment makes a prophylactic Zika virus vaccine an unmet medical need. We assessed safety and immunogenicity of three doses of a purified, inactivated, Zika virus vaccine candidate in healthy flavivirus-naive and flavivirus-primed adults. METHODS: This two-part, multicentre, observer-blind, randomised, placebo-controlled, phase 1 trial was done at seven medical clinics in the USA and two in Puerto Rico. Eligible participants were healthy adults aged 18-49 years. Participants were randomly assigned (1:1:1:1), using a sponsor-supplied randomisation scheme, to four groups to receive two intramuscular injections, 28 days apart, of saline placebo or TAK-426 containing 2 µg, 5 µg, or 10 µg antigen. Participants, investigators, and vaccine administrating personnel were masked to group assignment. Part 1 of the study assessed flavivirus-naive participants and part 2 assessed flavivirus-primed participants. The primary outcomes were safety, tolerability, and immunogenicity based on solicited local reactions and solicited systemic adverse events in the 7 days after each dose; unsolicited adverse events and serious adverse events in the 28 days after each dose; and geometric mean titres (GMTs) of neutralising anti-Zika virus antibodies at 28 days after the second dose. Safety assessments were done in all participants who received at least one dose of vaccine. Immunogenicity assessments were in the per-protocol set, comprising all participants who received at least one dose of vaccine and provided valid serology results at baseline and at least one post-vaccination timepoint, with no major protocol violations. The trial is ongoing and is registered at ClinicalTrials.gov (NCT03343626). FINDINGS: Between Nov 13, 2017, and Oct 24, 2018, 894 volunteers were screened and 271 enrolled (125 flavivirus-naive and 146 flavivirus-primed participants). All TAK-426 doses were well tolerated with no deaths, no vaccine-related serious adverse events, and similar rates of mainly mild to moderate adverse events. TAK-426 elicited dose-dependent increases in antibody GMTs in both flavivirus-naive and flavivirus-primed participants. 28 days after dose 2, plaque-reduction neutralisation test GMTs in flavivirus-naive participants were 1130 (95% CI 749-1703) in the 2 µg TAK-426 group, 1992 (1401-2833) in the 5 µg TAK-426 group, and 3690 (2677-5086) in the 10 µg TAK-426 group. In pairwise comparisons, responses after two vaccinations in the 10 µg group were significantly greater than in the 2 µg group (GMT ratio 3·27 [95% CI 1·98-5·39], p<0·0001) and the 5 µg group (GMT ratio 1·85 [1·15-2·98], p=0·012). INTERPRETATION: TAK-426 was well tolerated, with an acceptable safety profile, and was immunogenic in both flavivirus-naive and flavivirus-primed adults. Based on the safety and immunogenicity profiles of all TAK-426 doses assessed, the 10 µg TAK-426 dose was selected for further clinical development. FUNDING: Takeda Vaccines and the US Biomedical Advanced Research and Development Authority. TRANSLATION: For the Spanish translation of the abstract see Supplementary Materials section.

Evaluating the impact of frailty on periprocedural adverse events and mortality among patients with GI bleeding.

BACKGROUND AND AIMS: Frailty is a known predictor of mortality and adverse events in the inpatient setting; however, it has not been studied as a modality to assess risk among patients undergoing endoscopy for GI bleeding (GIB). We aimed to determine the association between frailty status and risk of adverse events in hospitalized patients with GIB who underwent endoscopy. METHODS: We performed a cohort study using the 2016 and 2017 National Inpatient Sample database, using International Classification of Diseases diagnostic codes to identify adult patients with GIB who underwent endoscopic procedures within 2 days of admission and the Hospital Frailty Risk Score to classify patients as frail or nonfrail. Univariable and multivariable logistic regression models were constructed to assess the predictors of periprocedural adverse events, and marginal standardization analysis was performed to assess for possible interaction between age and frailty. RESULTS: A total of 757,920 patients met inclusion criteria, of which 44.4% (336,895) were identified as frail and 55.6% (421,025) as nonfrail; 49.2% of frail patients had composite periprocedural adverse events compared with 25.5% of nonfrail patients (P < .001). Frail patients notably had more cardiovascular (32.1% vs 17.1%, P < .001), pulmonary (18.5% vs 4.3%, P < .001), GI (10.1% vs 6.1%, P < .001), and infectious (9.9% vs .7%, P < .001) adverse events compared with nonfrail patients. Frail patients also had higher all-cause inpatient mortality rates (4.8% vs .5%, P < .001). On multivariable analysis, positive frailty status was associated with a 2.13 times increased likelihood of having composite periprocedural adverse events. CONCLUSIONS: In hospitalized patients undergoing endoscopy for GIB, frailty status is associated with increased periprocedural adverse events including all-cause mortality. The use of frailty assessments can thus further guide clinical decision-making when considering endoscopy and risk of adverse events in adult patients with GI hemorrhage.

A Phase II Trial of Safety, Tolerability and Immunogenicity of V114, a 15-Valent Pneumococcal Conjugate Vaccine, Compared With 13-Valent Pneumococcal Conjugate Vaccine in Healthy Infants.

BACKGROUND: Pneumococcal disease remains a public health priority worldwide. This phase 2 study (V114-008; NCT02987972; EudraCT 2016-001117-25) compared safety and immunogenicity of 2 clinical lots of V114 (investigational 15-valent pneumococcal vaccine: 1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19F, 19A, 22F*, 23F, 33F*) to 13-valent pneumococcal conjugate vaccine (PCV13) in healthy infants (*serotypes unique to V114). METHODS: Healthy infants 6-12 weeks old were randomized to receive a 4-dose regimen of V114 Lot 1, V114 Lot 2 or PCV13 at 2, 4, 6 and 12-15 months old. Adverse events were evaluated after each dose. Primary immunogenicity endpoint was to demonstrate noninferiority of V114 Lot 1 and V114 Lot 2 relative to PCV13 based on proportion of infants achieving serotype-specific IgG concentration ≥0.35 µg/mL for 13 serotypes shared with PCV13 at 1 month postdose 3 (PD3). Serotype-specific IgG geometric mean concentrations (GMCs) for all 15 V114 serotypes were measured at PD3, predose 4 and 1 month postdose 4 (PD4). RESULTS: Overall, 1044 of 1051 randomized infants received ≥1 dose of vaccine (V114 Lot 1 [n = 350], V114 Lot 2 [n = 347] or PCV13 [n = 347]). Adverse events were generally comparable across groups. At PD3, both V114 lots met noninferiority criteria for all 13 serotypes shared with PCV13. IgG GMCs were comparable among V114 and PCV13 recipients at PD3 and PD4. Serotype 3 responses were higher following receipt of V114 than PCV13. Both V114 lots induced higher GMCs than PCV13 to the 2 unique V114 serotypes. CONCLUSIONS: Immunogenicity of both V114 lots was noninferior to PCV13 for all 13 shared serotypes between the 2 vaccines and displayed comparable safety and tolerability profiles to PCV13.

Hepatitis B and pertussis antibodies in 4- to 5-year-old children previously vaccinated with different hexavalent vaccines.

In randomized active-comparator controlled studies, DTaP5-HB-IPV-Hib showed comparable immunogenicity and safety to other licensed vaccines. This study assessed persistence of anti-hepatitis B surface antigen (HBs) and anti-pertussis antibodies, when children were 4 to 5 years of age, 3 to 4 years after initial infant/toddler hexavalent vaccination. This was an extension of 2 European studies in which infants/toddlers received either DTaP5-HB-IPV-Hib or DTaP3-HB-IPV/Hib on a 2 + 1 or 3 + 1 schedule. Primary endpoints included percentages with anti-HBs ≥10 mIU/mL, and anti-pertussis toxin (PT), anti-filamentous hemagglutinin (FHA), anti-pertactin (PRN), and anti-fimbriae types 2 & 3 (FIM) greater than or equal to the lower limit of quantitation (LLOQ). One month after 2 + 1 or 3 + 1 dosing, nearly all toddlers had anti-HBs ≥10 mIU/mL, and responded to the received pertussis antigens. Approximately 3 to 4 years later, 65.8%-70.2% in the DTaP5-HB-IPV-Hib and 82.0%-83.7% in the DTaP3-HB-IPV/Hib groups, respectively, had anti-HBs ≥10 mIU/mL. Percentages of children with pertussis antibodies above LLOQ after 2 + 1 dosing were 58.4% and 41.5% (anti-PT), 80.9% and 88.3% (anti-FHA), 66.1% and 72.6% (anti-PRN), and 94.4% and 3.3% (anti-FIM), in the DTaP5-HB-IPV-Hib and DTaP3-HB-IPV/Hib groups, respectively. This study demonstrated, as expected, waning of hepatitis B and pertussis antibodies during the 3 to 4 years after completion of a 3 + 1 or 2 + 1 hexavalent vaccination schedule. Nonetheless, anti-HBs levels ≥10 IU/mL and detectable antibodies against acellular pertussis antigens persisted in most study participants. The implications of these findings for the long-term prevention of hepatitis B and pertussis are further discussed.

Correction to: Public health impact and cost effectiveness of routine childhood vaccination for hepatitis a in Jordan: a dynamic model approach.

Following publication of the original article1, the authors noted the following.

Safety and immunogenicity of 15-valent pneumococcal conjugate vaccine (PCV-15) compared to PCV-13 in healthy older adults.

BACKGROUND: Pneumococcal disease remains a public health priority in adults. Safety and immunogenicity of 2 different formulations of 15-valent pneumococcal conjugate vaccine (PCV15) containing 13 serotypes included in 13-valent pneumococcal conjugate vaccine (PCV13) plus 2 additional serotypes (22F and 33F) were evaluated in adults ≥ 50 years (V114-006; NCT02547649). METHODS: A total of 690 subjects (230/arm) received a single dose of either PCV15 Formulation A, PCV15 Formulation B, or PCV13 and were followed for safety for 14 days postvaccination. Serotype-specific opsonophagocytic activity (OPA) geometric mean titers (GMTs) and Immunoglobulin G (IgG) geometric mean concentrations (GMCs) were measured immediately prior and 30 days postvaccination. RESULTS: Both PCV15 formulations had generally comparable safety profiles to PCV13. Baseline IgG GMCs and OPA GMTs were comparable across vaccination groups. At 30 days postvaccination, both PCV15 formulations induced serotype specific antibodies to all 15 serotypes in the vaccine. IgG GMCs and OPA GMTs in recipients of either PCV15 formulation were non-inferior (≤ 2-fold margin) to those measured in recipients of PCV13 for shared serotypes and superior (> 1.0-fold difference) for serotypes unique to PCV15. Formulation B generally induced higher immune responses than Formulation A. CONCLUSION: In healthy adults ≥ 50 years of age, both new formulations of PCV15 displayed acceptable safety profiles and induced serotype-specific immune responses comparable to PCV13.

Safety and immunogenicity of VAQTA® in children 12-to-23 months of age with and without administration of other US pediatric vaccines.

Safety and immunogenicity data from 5 clinical trials conducted in the US in children 12-to-23 months old where HAVi was administered alone or concomitantly with other pediatric vaccines (M-M-R®II, Varivax®, TRIPEDIA®, Prevnar®, ProQuad®, PedvaxHIB®, and INFANRIX®) were combined. Among 4,374 participants receiving ≥ 1 dose of HAVi, 4,222 (97%) had safety follow-up and the proportions reporting adverse events (AE) were comparable when administered alone (69.4%) or concomitantly with other pediatric vaccines (71.1%). The most common solicited injection-site AEs were pain/tenderness (Postdose 1: 25.8%; Postdose 2: 26.1%) and redness (Postdose 1: 13.6%; Postdose 2: 15.1%). The most common vaccine-related systemic AEs were fever (≥ 100.4ºF, 12.2%) and irritability (8.1%). Serious AEs (SAEs) were observed at a rate of 0.4%; 0.1% were considered vaccine-related. No deaths were reported within 14 days following a dose of HAVi. These integrated analyses also showed that protective antibody concentrations were elicited in 100% of toddlers after two doses and 92% after a single dose, regardless of whether HAVi was given concomitantly with other vaccines or alone. These results demonstrate that HAVi was well-tolerated whether given alone or concomitantly with other vaccines, with a low incidence of vaccine-related SAEs. HAVi was immunogenic in this age group regardless of whether administered with or without other pediatric vaccines and whether 1 or 2 doses were administered. HAVi did not impact the immune response to other vaccines. These data continue to support the routine use of HAVi with other pediatric vaccines in children ≥ 12 months of age.

Impact of Out-of-Pocket Cost on Herpes Zoster Vaccine Uptake: An Observational Study in a Medicare Managed Care Population.

Herpes zoster (HZ) vaccination is approved for adults aged 50+ for the prevention of HZ, but it is underutilized. The objective of this study was to evaluate the association between out-of-pocket cost and HZ vaccine utilization. Adults aged 65 or older enrolled for at least 12 months in Medicare Advantage/Part D (MAPD) and Medicare Part D only (PDP) plans from 1 January 2007 to 30 June 2014 were selected. Abandonment was defined as a reversed claim for HZ vaccine with no other paid claim within 90 days. Out-of-pocket costs used were actual amounts recorded in the claim. Overall, the HZ vaccine abandonment rate was 7.3%. Mean out-of-pocket costs were higher for individuals who abandoned versus those who did not ($88 (±$55) versus $80 (± $49)). Logistic regression indicated individuals with out-of-pocket costs of $80⁻$90 were 21% more likely (OR = 1.21, 1.16⁻1.27 95% CI), and those with out-of-pocket costs >$90 were 90% more likely (OR = 1.90, 1.85⁻1.96 95% CI) to abandon than those with out-of-pocket costs <$80. The models also suggested that socioeconomic, racial, and ethnic disparities in vaccine abandonment existed. Different vaccine targeting efforts and pharmacy benefit design strategies may be needed to increase use, improve adherence, and minimize disparities.

A cross-sectional survey of work and income loss consideration among patients with herpes zoster when completing a quality of life questionnaire.

BACKGROUND: Prior research suggests that many patients do not spontaneously include work/income loss when responding to utility assessments, although this remains unconfirmed in the US due to almost no published US-based studies to date, and has not been previously studied among patients with herpes zoster (HZ). The objective of this study was to examine whether patients with HZ consider work and income loss when completing a quality of life survey. METHODS: A cross-sectional survey was administered to 2000 US adult commercial health plan enrollees aged 50-64 years with ≥ 1 HZ medical claim during 2014. The survey collected information related to health status (EQ-5D), work productivity, and HZ severity and clinical features. RESULTS: Mean respondent age was 58.4 years [standard deviation (SD) 4.1] and 62.0% were female. About 3 in 4 (76.8%) patients (N = 772) were employed either full (69.9%) or part time (6.9%). Less than half (45%) spontaneously considered work/income loss when responding to EQ-5D, and mean EQ-5D scores for patients who considered work/income loss were lower than for patients who did not [0.56 (SD = 0.28) vs. 0.69 (SD = 0.24); p < 0.001]. Overall, 43% of patients reported at least one full day missed (mean = 9 full days) and 29% reported at least one partial day missed (mean = 6 partial days) during the most recent shingles episode. Patients who considered work loss were more likely to have missed full (76.4% vs 26.0%, p < 0.001) or partial (70.9% vs. 35.2%, p < 0.001) days. Patients with absenteeism were more likely to consider work/income loss when completing EQ-5D [odds ratio (OR) = 7.91, 95% confidence interval (CI) 5.01-12.31]. Odds of absenteeism/presenteeism increased significantly with increasing levels of HZ severity, and higher odds were associated with pain located on the face/scalp/neck/eye/ear (OR 1.90, 95% CI 1.06-3.40) and with pain lasting 12+ months (OR = 2.91, 95% CI 1.14-7.42). CONCLUSIONS: HZ has considerable impact on the work and productivity of adults aged 50-64 years old. However, many patients with HZ do not spontaneously consider work/income loss when completing a standardized quality of life questionnaire. Studies that use health state utilities in HZ based on EQ-5D may not fully reflect the societal costs of work loss.

Measuring herpes zoster disease burden in São Paulo, Brazil: a clinico-epidemiological single-center study.

OBJECTIVES: Herpes zoster is characterized by acute neuritis and post-herpetic neuralgia. Currently, data concerning the zoster-associated impact on quality of life and healthcare resource utilization in Brazil are scarce. This study measured the zoster-associated burden in a Brazilian population. METHODS: This was a prospective, observational, single-cohort study conducted in a primary hospital's emergency room in São Paulo, Brazil. Patients enrolled at various timepoints during a zoster episode were followed over 180 days. The Zoster Brief Pain Inventory and the Initial Zoster Impact Questionnaire assessed zoster-associated pain. The EuroQoL assessed the impact of herpes zoster and/or zoster-associated pain on quality of life. Healthcare resource utilization was assessed by patient-reported questionnaires. RESULTS: One-hundred forty-six zoster patients were enrolled [mean (SD) age of 69.9 (10.9) years]. Mean (SD) worst pain scores decreased from 5.3 (3.5) at baseline to 1.9 (3.0) 180 days following rash onset. Mean (SD) EuroQoL scores significantly decreased from 0.9 (0.2) before rash appearance to 0.7 (0.2) after rash onset (p<0.001), followed by gradual improvements in quality of life over 180 days, with pre-herpes zoster quality of life achieved at the end of the observation period. The majority of patients purchased prescription medications (89.7%) and required doctor's office visits (65.8%) for zoster episodes. CONCLUSIONS: Herpes zoster is associated with a significant disease burden, including zoster-associated pain, impaired quality of life and increased healthcare resource utilization in Brazil. These results support the implementation of early intervention and prevention programs such as vaccinations to reduce the herpes zoster-associated disease burden in Brazil.

Public health impact and cost effectiveness of routine childhood vaccination for hepatitis a in Jordan: a dynamic model approach.

BACKGROUND: As the socioeconomic conditions in Jordan have improved over recent decades the disease and economic burden of Hepatitis A has increased. The purpose of this study is to assess the potential health and economic impact of a two-dose hepatitis A vaccine program covering one-year old children in Jordan. METHODS: We adapted an age-structured population model of hepatitis A transmission dynamics to project the epidemiologic and economic impact of vaccinating one-year old children for 50 years in Jordan. The epidemiologic model was calibrated using local data on hepatitis A in Jordan. These data included seroprevalence and incidence data from the Jordan Ministry of Health as well as hospitalization data from King Abdullah University Hospital in Irbid, Jordan. We assumed 90% of all children would be vaccinated with the two-dose regimen by two years of age. The economic evaluation adopted a societal perspective and measured benefits using the quality-adjusted life-year (QALY). RESULTS: The modeled vaccination program reduced the incidence of hepatitis A in Jordan by 99%, 50 years after its introduction. The model projected 4.26 million avoided hepatitis A infections, 1.42 million outpatient visits, 22,475 hospitalizations, 508 fulminant cases, 95 liver transplants, and 76 deaths over a 50 year time horizon. In addition, we found, over a 50 year time horizon, the vaccination program would gain 37,502 QALYs and save over $42.6 million in total costs. The vaccination program became cost-saving within 6 years of its introduction and was highly cost-effective during the first 5 years. CONCLUSION: A vaccination program covering one-year old children is projected to be a cost-saving intervention that will significantly reduce the public health and economic burden of hepatitis A in Jordan.

Herpes zoster incidence and cost in patients receiving autologous hematopoietic stem-cell transplant.

OBJECTIVE: Among patients receiving autologous hematopoietic stem cell transplant (Auto-HSCT), this study estimated the incidence of herpes zoster (HZ), compared healthcare costs among patients with and without HZ, and evaluated antiviral prophylaxis (AP) use. RESEARCH DESIGN AND METHODS: A retrospective study was conducted using data from a large health plan to identify patients ≥18 years with ≥1 claim for an Auto-HSCT procedure during 2006-2011 (n = 2,530). Patients were followed from date of Auto-HSCT until risk-end date, defined as development of HZ, end of enrollment, death, or December 31, 2011. HZ incidence was calculated as cases observed after Auto-HSCT, divided by accrued time-at-risk in person-years (PY). AP use and duration were defined by prescription fills. One-year medical and pharmacy costs were calculated as combined health plan and patient paid amounts. MAIN OUTCOME MEASURES: HZ incidence and healthcare costs were calculated using administrative claims data. RESULTS: Overall HZ incidence was 62.2/1,000 PY (95% CI = 54.3-70.9). Most (72.3%) patients were prescribed AP. During the first 90-days post-Auto-HSCT, patients without AP had increased incidence (151.6/1,000 PY, 95% CI = 88.3-242.6) compared to those prescribed AP pre- (30.9/1,000 PY, 95% CI = 11.3-67.2) or post-Auto-HSCT (33.0/1,000 PY, 95% CI = 13.3-67.9). Total adjusted mean 1-year all-cause healthcare costs were $74,875 for patients who developed HZ and $70,279 for patients who did not (difference = $4,596 (cost ratio = 1.07, 95% CI = 0.86-1.32, p = .566)). CONCLUSIONS: HZ incidence was high, despite AP use. Mean annual healthcare costs were higher for patients with HZ, but the difference was not statistically significant. An effective vaccine against HZ could be useful in decreasing both incidence of and cost for HZ in this population.

Measuring herpes zoster disease burden in São Paulo, Brazil: a clinico-epidemiological single-center study

OBJECTIVES: Herpes zoster is characterized by acute neuritis and post-herpetic neuralgia. Currently, data concerning the zoster-associated impact on quality of life and healthcare resource utilization in Brazil are scarce. This study measured the zoster-associated burden in a Brazilian population. METHODS: This was a prospective, observational, single-cohort study conducted in a primary hospital's emergency room in São Paulo, Brazil. Patients enrolled at various timepoints during a zoster episode were followed over 180 days. The Zoster Brief Pain Inventory and the Initial Zoster Impact Questionnaire assessed zoster-associated pain. The EuroQoL assessed the impact of herpes zoster and/or zoster-associated pain on quality of life. Healthcare resource utilization was assessed by patient-reported questionnaires. RESULTS: One-hundred forty-six zoster patients were enrolled [mean (SD) age of 69.9 (10.9) years]. Mean (SD) worst pain scores decreased from 5.3 (3.5) at baseline to 1.9 (3.0) 180 days following rash onset. Mean (SD) EuroQoL scores significantly decreased from 0.9 (0.2) before rash appearance to 0.7 (0.2) after rash onset (p<0.001), followed by gradual improvements in quality of life over 180 days, with pre-herpes zoster quality of life achieved at the end of the observation period. The majority of patients purchased prescription medications (89.7%) and required doctor's office visits (65.8%) for zoster episodes. CONCLUSIONS: Herpes zoster is associated with a significant disease burden, including zoster-associated pain, impaired quality of life and increased healthcare resource utilization in Brazil. These results support the implementation of early intervention and prevention programs such as vaccinations to reduce the herpes zoster-associated disease burden in Brazil.

Herpes Zoster Vaccine Coverage in Older Adults in the U.S., 2007-2013.

INTRODUCTION: This study aimed to assess the coverage of herpes zoster (HZ) vaccine among a large cohort of insured individuals aged ≥50 years from 2007 to 2013, and to determine the factors associated with being vaccinated for adults aged ≥60 years. METHODS: This was a retrospective, observational study using the MarketScan® database conducted in 2015. The study population was U.S. adults aged ≥60 years during 2007-2013 and 50-59 years during 2011-2013. The claims of each eligible subject were evaluated post-index date to assess HZ vaccine uptake. Multivariate analyses were performed to understand factors associated with receiving HZ vaccine. RESULTS: A total of 6,746,476 adults aged ≥60 years and 6,770,294 adults aged 50-59 years were identified. By 2013, 1.7% of adults aged 50-59 years, 23.9% of adults aged 60-64 years, and 14.5% of adults aged ≥65 years received HZ vaccine. Adults aged ≥65 years were less likely to receive HZ vaccine than those aged 60-64 years (hazard ratio [HR]=0.543; 95% CI=0.539, 0.547). Adults who were female, immunocompetent, and had more outpatient hospital, doctor office, and pharmacy visits were more likely to receive HZ vaccine. Adults who received influenza vaccine were more likely to receive HZ vaccine (HR=1.841; 95% CI=1.830, 1.853). CONCLUSIONS: Estimated HZ vaccine coverage is 19.5% in adults aged ≥60 years, which is lower than the Healthy People 2020 target of 30%. Providers should identify every opportunity for HZ vaccination to assure that older adults are protected from HZ, a vaccine-preventable disease.

Association between work time loss and quality of life in patients with Herpes Zoster: a pooled analysis of the MASTER studies.

BACKGROUND: Herpes zoster (HZ) has a significant negative effect on the productive work life of individuals, and has been shown to be responsible for cases of absenteeism, presenteeism and decreased work effectiveness. The aim of this study was to evaluate health utility scores and associated predictors in an actively employed population of Herpes Zoster (HZ) patients with and without work time loss (WTL). METHODS: This was a pooled analysis of the prospective, observational MASTER cohort studies, conducted in 8 countries across North America, Latin America and Asia. A total of 428 HZ patients engaged in full or part time work were included. WTL, defined as missing ≥ 1 partial or full work day, and work effectiveness, reported on a scale of 0-100%, were evaluated with the Work and Productivity Questionnaire (WPQ). The Pearson product-moment correlation was used to assess the correlation between work effectiveness and HRQoL. Mixed models with repeated measures assessed the relationship between HZ-related WTL over a 6-month follow-up period, and HRQoL, as evaluated by the EQ-5D. Additional predictors of HRQoL were also identified. RESULTS: Overall, 57.7% of respondents reported WTL. Mean (SD) percent work effectiveness of patients in the WTL group was significantly lower compared to non-WTL (NWTL) patients at baseline [50.3 (31.6) vs. 71.4 (27.8); p < 0.001]. Patients in the WTL group also reported lower health utility scores at baseline and overall than their NWTL counterparts, with WTL identified as an independent negative predictor of both the EQ-5D summary scores and the EQ-5D VAS (p < 0.001). Decrease in work effectiveness was negatively associated with HRQoL overall (p < 0.001). Predictors of lower HRQoL were worst Zoster Brief Pain Inventory (ZBPI) pain score, the presence of HZ complications and country income (predictor of EQ-5D VAS only). CONCLUSIONS: HZ adversely impacts the work and productive life of actively employed individuals. In turn, HZ-related reductions in work effectiveness and work time are associated with a negative effect on HRQoL.

Dolor, calidad de vida relacionada con la salud y utilización de servicios médicos asociados al herpes zoster en Argentina / Herpes zoster-associated pain, health-related quality of life, and healthcare utilization in Argentina

El herpes zoster (HZ) es causado por reactivación del virus varicela-zoster latente. Se caracteriza por exantema vesicular unilateral, neuri-tis aguda y neuralgia posherpética. Aún hay escasos datos sobre el do-lor asociado al HZ (DAZ), su repercusión en la calidad de vida (CdV) y la utilización de recursos sanitarios (URS) asociada en Argentina. En este estudio prospectivo, observacio-nal, de una cohorte, realizado en 3 centros argenti-nos se valuó la carga de morbilidad asociada al HZ en Argentina en contextos clínicos reales. Los pa-cientes fueron enrolados en diversos momentos du-rante un episodio herpético, y seguidos activamen-te los días 14, 21, 30, 60, 90, 120, 150 y 180. Hubo 96 enrolados(edad 70±10,7 años; tiempo desde el inicio del exantema 16±16,9 días[media±DE]). El puntaje del peor dolor (media±DE) disminuyó de 5,5±3,1 en el enrolamiento a 0,2±0,7 a los 180 días de seguimiento. El puntaje del cuestionario de cali-dad de vida EQ-5D (media±DE) disminuyó significa-tivamente de 0,8±0,1 antes del inicio del exantema a 0,6±0,2 tras su inicio (P<0,001), con mejoría gra-dual de la CdV durante 180 días (0,9±0,1), hasta un puntaje similar al previo al inicio del exantema. La URS más frecuente fueron visitas al consultorio mé-dico (96,9%). La gran mayoría de pacientes compró medicamentos recetados (95,8%) y de venta sin receta (83,3%) para los episodios herpéticos. El DAZ estuvo asociado a gran carga de morbili-dad, deterioro de CdV, aumento de URS y costos asociados en Argenti-na. Esto subraya la importancia de estrategias de intervención precoz o prevención para disminuir la carga de morbilidad asociada al HZ

Herpes zoster (HZ) is caused by re-activation of latent varicella zoster virus and is characterized by unilateral, vesicular cutaneous eruptions, acute neuritis, and post-herpetic neuralgia. To date, data on HZ associated pain (ZAP) and its impact on quality of life (QoL) and associated healthcare resource utilization use (HCRU) in Argentina is scarce. This study assessed the burden of illness associated with HZ in Argentina in a real-life clinical setting. This was a prospective, observational, single-cohort study conducted in 3 sites across Argentina. Patients were enrolled at various time points during the course of a zoster episode and were actively followed on days 14, 21, 30, 60, 90, 120, 150, and 180. There were 96 HZ patients enrolled with a mean±SD age and time since rash onset of 70±10. 7 years and 16±16. 9 days, respectively. Mean±SD worst pain score decreased from 5. 5±3. 1 at enrollment to 0. 2±0.7 at 180 days of follow-up. The mean±SD EQ-5D score significantly decreased from 0. 8±0. 1 before rash onset to 0. 6±0. 2 after rash onset (P <0.001) followed by gradual improvement in QoL over 180 days (0. 9±0.) reaching a similar score to that prior to rash onset. The most common HCRU was visits to the doctor's office with 96.9%. The vast majority of patients purchased prescription medications (95.8%) and over-the-counter medications (83.3%) for HZ episodes. ZAP was found to be associated with severe burden of illness, impaired QoL, increased HCRU, and associated cost in Argentina; highlighting the importance of early intervention or prevention strategies to reduce HZ-associated disease burden

Energy-based constitutive modelling of local material properties of canine aortas.

This study aims at determining the in vitro anisotropic mechanical behaviour of canine aortic tissue. We specifically focused on spatial variations of these properties along the axis of the vessel. We performed uniaxial stretch tests on canine aortic samples in both circumferential and longitudinal directions, as well as histological examinations to derive the tissue's fibre orientations. We subsequently characterized a constitutive model that incorporates both phenomenological and structural elements to account for macroscopic and microstructural behaviour of the tissue. We showed the two fibre families were oriented at similar angles with respect to the aorta's axis. We also found significant changes in mechanical behaviour of the tissue as a function of axial position from proximal to distal direction: the fibres become more aligned with the aortic axis from 46° to 30°. Also, the linear shear modulus of media decreased as we moved distally along the aortic axis from 139 to 64 kPa. These changes derived from the parameters in the nonlinear constitutive model agreed well with the changes in tissue structure. In addition, we showed that isotropic contribution, carried by elastic lamellae, to the total stress induced in the tissue decreases at higher stretch ratios, whereas anisotropic stress, carried by collagen fibres, increases. The constitutive models can be readily used to design computational models of tissue deformation during physiological loading cycles. The findings of this study extend the understanding of local mechanical properties that could lead to region-specific diagnostics and treatment of arterial diseases.

Budget-Impact Analysis of Alternative Herpes Zoster Vaccine Strategies: A U.S. HMO Perspective.

BACKGROUND: A herpes zoster vaccine has been approved by the FDA for use in prevention of herpes zoster in individuals who are aged 50 years or older. The Advisory Committee on Immunization Practices (ACIP) recommends vaccination only in individuals who are aged 60 years and older. OBJECTIVES: To (a) estimate the overall budget and health impact of either the introduction of a new vaccination strategy (individuals over the age of 50 years vs. individuals over the age of 60 years) within a hypothetical health plan or simply an increase in coverage within the population aged 60 years and over and (b) discern what effect copayments and changes to copayments have on the health plan's budget. METHODS: A decision-analytic economic model was developed to inform managed care decision makers of the potential effect on costs and outcomes associated with the use of the herpes zoster vaccine for prevention of herpes zoster (i.e., simple zoster or shingles). The model took a U.S. payer perspective. The number of eligible patients entering the model was estimated by considering the age distribution of the plan population and the percentage of patients contraindicated for vaccination (i.e., those who were immunocompromised or who had a history of anaphylactic/anaphylactoid reaction to gelatin, neomycin, or any other component of the vaccine). Eligible patients were vaccinated based on the projected uptake rates among the unvaccinated population in 2 possible vaccination scenarios: (1) a vaccination strategy in which only individuals over age 60 years can be vaccinated and (2) a vaccination strategy in which individuals over age 50 years can be vaccinated. Vaccination was assumed to reverse the age-related decline in immunity against zoster. The population vaccinated each year was estimated based on the uptake rates (percentage of the eligible unvaccinated that are vaccinated) required to reach a target annual coverage (percentage ever vaccinated). Patients could experience costs and outcomes related to vaccination or related to herpes zoster. Specifically, vaccination could cause adverse events that would require the use of health care resources. Patients who developed zoster could experience postherpetic neuralgia or develop nonpain complications that would require the use of health care resources. Vaccine costs, zoster cases (with and without postherpetic neuralgia or nonpain complication), and vaccine-related adverse events for the 2 vaccination scenarios were estimated for each budget year. RESULTS: For a managed care organization population of 5 million members, the model estimated that a vaccination program that included patients over age 50 years instead of a program limiting vaccination to those over age 60 years was associated with a decrease in the number of patients developing zoster (2,372-3,392 cases avoided over 5 years). Annual incremental per-member-per-month (PMPM) costs associated with this vaccination program change were estimated to range from $0.08 to $0.14. When the vaccination program was kept at age 60 years and over and coverage was increased, the model estimated that the annual incremental PMPM costs ranged from $0.04 to $0.06. Differences in costs were driven primarily by vaccination costs. The results of the scenario analyses showed that lower vaccination costs because of the application of copayments for a managed care organization reduced the magnitude of the total cost increase associated with the increase in uptake. CONCLUSIONS: Vaccinating individuals aged 50 to 59 years with the herpes zoster vaccine would likely have an impact on a health plan's budget because of the expected increase in the total number of individuals being vaccinated in the population, with limited cost savings because of fewer cases of herpes zoster. Higher coverage of vaccinations resulted in a greater increase in total costs each year. However, increasing coverage would also result in a decrease in the number of individuals developing zoster and associated postherpetic neuralgia and nonpain complications over the next 5 years. DISCLOSURES: Merck & Co. funded this study/research and was involved in all stages of study conduct, including analysis of the data. Merck & Co. also undertook all costs associated with the development and publication of this manuscript. Graham and Mauskopf (and/or their institutions) received research funding from Merck & Co. to develop the budget-impact estimates and for other research studies. Johnson, Xu, and Acosta are employees of Merck & Co. Kawai was employed by Merck & Co. during part of the time of this study. Graham and Mauskopf were primarily responsible for the design and programming of the economic model, identification and final selection of the input parameter values, interpretation of the study results, and preparation of the study report. Johnson, Kawai, Xu, and Acosta contributed to model design, input parameter estimation, interpretation of the results, and review of and revisions to the study report. All authors had access to the data, participated in the development of this manuscript, and gave final approval before submission. All authors have agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Healthcare resource utilization and costs associated with herpes zoster in the US.

OBJECTIVES: To evaluate the economic burden of herpes zoster (HZ) on the US healthcare system among an immunocompetent population. METHODS: Claims data from the MarketScan Research databases for 2008-2011 were extracted to determine the incremental healthcare resource utilization (RU) and direct medical costs associated with HZ. Immunocompetent HZ-patients were identified and directly matched 1:1 with immunocompetent non-HZ controls using demographic and clinical variables. Analysis was limited to claims 21 days prior to through the first year following HZ diagnosis. Cases with post-herpetic neuralgia (PHN) were analyzed separately. RESULTS: A total of 98,916 HZ-patients were matched to controls. HZ-patients had a mean age of 50.4 (SD = 18.8) years and 56.6% were females. HZ-cases had significantly higher RU (0.016 inpatient visits, 0.153 ER visits, 2.116 outpatient office visits, and 3.730 other outpatient services) compared to controls (p < 0.001). Differences increased substantially in the presence of PHN. Total mean incremental healthcare costs for HZ-cases were $1308 and quadrupled to $5463 in those with PHN (both p < 0.001). Overall, primary cost drivers were outpatient prescriptions and other outpatient services. For those with PHN, inpatient services also played a significant role. LIMITATIONS: This study was limited to only those individuals with US commercial health coverage or private Medicare supplemental coverage; therefore, results of this analysis may not be generalizable to HZ patients outside of the US, with other health insurance or without coverage. CONCLUSIONS: HZ presents a significant economic and resource burden on the US healthcare system among immunocompetent patients of nearly all ages, particularly when complicated by PHN.