Live Attenuated Herpes Zoster Vaccine Research Articles

Recombinant Zoster Vaccine (Shingrix®): A Review in Herpes Zoster.

Shingrix® is a recombinant zoster vaccine (RZV) that contains a varicella zoster virus glycoprotein E antigen and the AS01B adjuvant system. The subunit vaccine is approved for the prevention of herpes zoster (HZ) [EU, USA, Japan, Canada and Australia] and postherpetic neuralgia (PHN) [EU and Australia] in adults aged ≥ 50years. In the pivotal trials in adults aged ≥ 50years (ZOE-50) and ≥ 70years (ZOE-70), RZV significantly reduced the risk of HZ and PHN. Its protective efficacy waned minimally over 4years and was well preserved in adults aged ≥ 70years. In patients with breakthrough disease, RZV reduced HZ-related pain severity, burden of illness and burden of interference with activities of daily living. RZV was more reactogenic than placebo, with injection-site reactions, myalgia and fatigue being the most common solicited adverse reactions. However, most solicited adverse reactions were transient and were mild to moderate in severity. RZV represents a novel, highly effective and well-tolerated vaccine option for HZ and PHN in adults aged ≥ 50years. RZV is not contraindicated in immunocompromised individuals, and is preferred over a live attenuated HZ vaccine in immunocompetent individuals, according to the US and Canadian guidelines.

Efficacy of Live Attenuated Herpes Zoster Vaccine in Patients With Inflammatory Bowel Diseases

The risk of herpes zoster virus infection is increased among patients with inflammatory bowel diseases (IBD). The herpes zoster vaccine (HZV) is therefore recommended for these patients, but little is known about its effectiveness, resulting in low use. We conducted a retrospective cohort study using data from the national veterans Affairs Healthcare System (VAHS) from January 1, 2000 through June 30, 2016. We collected data from 39,983 veterans with IBD who had not received the HZV by an age of 60 years. The follow-up period started at age 60 or the date of first IBD medication prescription (whichever was later) and ended with the earliest diagnosis of herpes zoster infection, the end of the study period, or date of death. We identified veterans who received the HZV during the follow-up period and compared the incidence of herpes zoster between vaccinated vs unvaccinated patients. We performed multivariable Cox regression with time-dependent analysis to determine the risk of herpes zoster associated with vaccination status in the entire cohort and stratified by IBD medication. We identified 7170 patients who received the HZV during the follow-up period (17.9% of total cohort; 96.6% male and 94.2% Caucasian). The crude incidence rate of herpes zoster infection during the follow-up period for unvaccinated patients was 6.97/1000 person-years and for vaccinated patients was 4.09/1000 person-years. Vaccination was associated with significantly lower risk of herpes zoster infection, compared to lack of vaccination (adjusted hazard ratio, 0.54; 95% CI, 0.44 - 0.68). Vaccination was associated with a significantly reduced risk of herpes zoster infection among veterans with IBD. This vaccine is therefore effective in patients with IBD, but underused.

Herpes Zoster.

Primary care providers and hospitalists frequently encounter older or immunocompromised patients with herpes zoster accompanied by debilitating pain. Atypical presentations and zosteriform herpes simplex may present diagnostic challenges to clinicians. This article summarizes the background, evidence, and guidelines for the diagnosis, complications, treatment, and prevention of herpes zoster. Diagnosis of challenging cases relies on polymerase chain reaction as the preferred test. Treatment focuses on optimal use of antiviral therapy and analgesics. Prevention emphasizes utilization of a new recombinant zoster vaccine, which reduces the incidence of herpes zoster by more than 90% and is preferred to the live attenuated herpes zoster vaccine.

Cost-effectiveness of an Adjuvanted Recombinant Zoster Vaccine in older adults in the United States

In the United States, herpes zoster (HZ) and related complications are estimated to result in approximately $1.3 billion in medical care costs and $1.7 billion in indirect costs annually. In this study, we compared the cost-effectiveness of a new Adjuvanted Recombinant Zoster Vaccine (RZV), containing recombinant varicella-zoster virus glycoprotein E and the AS01B Adjuvant System, versus No Vaccine, as well as versus the live attenuated HZ vaccine (Zoster Vaccine Live (ZVL)) in subjects aged 60+ years of age (YOA) and other age cohorts aged 50+ YOA. A multi-cohort Markov model was developed which follows 1 million individuals over their remaining lifetimes from the year of vaccination with annual cycle lengths. Second dose compliance for RZV was assumed to be 69%. Efficacy and waning parameters were derived from clinical trials for both vaccines. Epidemiological parameters, costs and utility model inputs were derived from US-specific population-based data. Costs and outcomes were discounted at 3% per year. Deterministic and probabilistic sensitivity analysis, along with scenario and threshold analysis were carried out to explore the overall uncertainty in the model. The model estimated that, compared to No Vaccine against HZ, RZV would prevent 103,603 HZ cases, 11,197 postherpetic neuralgia (PHN) cases, and 14,455 other complications, at an incremental cost of $11,863 per quality-adjusted life-year saved from a societal perspective. Compared to ZVL, the model estimated that, RZV would prevent 71,638 additional HZ cases, 6403 PHN cases, and over 10,582 other complications, resulting in net total societal cost savings of over $96 million. The results were robust to a wide range of sensitivity analyses. Vaccination against HZ with RZV is cost-effective compared to No Vaccine and cost-saving compared to ZVL, in the US population aged 60+ YOA.Clinicaltrial.gov. registered#: NA.

Post-licensure safety surveillance of zoster vaccine live (Zostavax®) in the United States, Vaccine Adverse Event Reporting System (VAERS), 2006–2015

ABSTRACTBackground: Herpes zoster (HZ), or shingles, is caused by reactivation of varicella-zoster virus in latently infected individuals. Live-attenuated HZ vaccine (zoster vaccine live, ZVL) is approved in the United States for persons aged ≥50 years and recommended by the CDC for persons ≥60 years. Methods: We analyzed U.S. reports of adverse events (AEs) following ZVL submitted to the Vaccine Adverse Event Reporting System (VAERS), a spontaneous reporting system to monitor vaccine safety, for persons vaccinated May 1, 2006, through January 31, 2015. We conducted descriptive analysis, clinical reviews of reports with selected pre-specified conditions, and empirical Bayesian data mining. Results: VAERS received 23,092 reports following ZVL, of which 22,120 (96%) were classified as non-serious. Of reports where age was documented (n = 18,817), 83% were in persons aged ≥60 years. Reporting rates of AEs were 106 and 4.4 per 100,000 ZVL doses distributed for all reports and serious reports, respectively. When ZVL was administered alone among persons aged ≥50 years, injection site erythema (27%), HZ (17%), injection site swelling (17%), and rash (14%) were the most commonly reported symptoms among non-serious reports; HZ (29%), pain (18%), and rash (16%) were the most commonly reported symptoms among serious reports. Six reports included laboratory evidence of vaccine-strain varicella-zoster virus (Oka/Merck strain) infection; AEs included HZ, HZ- or varicella-like illness, and local reaction with vesicles. In our review of reports of death with sufficient information to determine cause (n = 46, median age 75 years), the most common causes were heart disease (n = 28), sepsis (n = 4), and stroke (n = 3). Empirical Bayesian data mining did not detect new or unexpected safety signals. Conclusions: Findings from our safety review of ZVL are consistent with those from pre-licensure clinical trials and other post-licensure assessments. Transient injection-site reactions, HZ, and rashes were most frequently reported to VAERS following ZVL. Overall, our results are reassuring regarding the safety of ZVL.

Safety, and Humoral and Cell-mediated Immune Responses to Herpes Zoster Vaccine in Patients with Rheumatoid Arthritis.

To examine humoral and cellular immune responses induced by a live attenuated herpes zoster (HZ) vaccine in patients with rheumatoid arthritis (RA) compared with osteoarthritis (OA) patients. This was an observational study of a live attenuated HZ vaccine in 41 patients with RA receiving conventional disease-modifying antirheumatic drugs (cDMARD) and/or low-dose glucocorticoids (GC) and in 28 patients with OA. Blood samples were obtained before and at 12 weeks after HZ vaccination. Immunogenicity was assessed using varicella zoster virus (VZV)-specific interferon gamma ELISA and an in-house ELISA. Clinical outcomes, including adverse events, HZ occurrence, and RA flares, were analyzed. No patients developed vaccination-induced HZ during the followup period (median = 1.6 yrs). The HZ vaccine induced a significant increase in the VZV-specific enzyme-linked immunospot spot-forming units and anti-VZV immunoglobulin G antibodies in patients with RA and OA. The number of spot-forming units was lower in patients with RA than in patients with OA both at baseline and at 12 weeks after vaccination. The disease activity index for patients with RA was similar at baseline and at 12 weeks after vaccination. However, 6 patients with RA (14.6%) experienced a flare during the 12 weeks. Overall, 17 (24.6%) participants reported a mild adverse event such as an injection site reaction (11.6%). The HZ vaccine induced VZV-specific cellular and humoral responses in patients with RA. Although patients with RA showed a weaker vaccine-induced VZV-specific cellular immune response than patients with OA, the vaccine may be considered in patients with RA receiving cDMARD and/or low dose GC.

Influence of demographic changes on the impact of vaccination against varicella and herpes zoster in Germany \u2013 a mathematical modelling study

BackgroundEpidemiological studies suggest that reduced exposure to varicella might lead to an increased risk for herpes zoster (HZ). Reduction of exposure to varicella is a consequence of varicella vaccination but also of demographic changes. We analyzed how the combination of vaccination programs and demographic dynamics will affect the epidemiology of varicella and HZ in Germany over the next 50 years.MethodsWe used a deterministic dynamic compartmental model to assess the impact of different varicella and HZ vaccination strategies on varicella and HZ epidemiology in three demographic scenarios, namely the projected population for Germany, the projected population additionally accounting for increased immigration as observed in 2015/2016, and a stationary population.ResultsProjected demographic changes alone result in an increase of annual HZ cases by 18.3% and a decrease of varicella cases by 45.7% between 1990 and 2060. Independently of the demographic scenario, varicella vaccination reduces the cumulative number of varicella cases until 2060 by approximately 70%, but also increases HZ cases by 10%. Unlike the currently licensed live attenuated HZ vaccine, the new subunit vaccine candidate might completely counteract this effect. Relative vaccine effects were consistent across all demographic scenarios.ConclusionDemographic dynamics will be a major determinant of HZ epidemiology in the next 50 years. While stationary population models are appropriate for assessing vaccination impact, models incorporating realistic population structures allow a direct comparison to surveillance data and can thus provide additional input for immunization decision-making and resource planning.

Cost-effectiveness of the Adjuvanted Herpes Zoster Subunit Vaccine in Older Adults

The live attenuated herpes zoster vaccine (ZVL) is recommended for immunocompetent adults 60 years or older, but the efficacy wanes with age and over time. A new adjuvanted herpes zoster subunit vaccine (HZ/su) has higher efficacy but might be more expensive. The choice of vaccines depends on their relative values. To assess the cost-effectiveness of HZ/su. Markov decision model with transition probabilities based on the US medical literature. Participants were immunocompetent adults 60 years or older. Data were derived from participant groups ranging in number from less than 100 to more than 30 000 depending on the variable assessed. The study dates were July 1 to 31, 2017. No vaccination, ZVL (single dose), and HZ/su (2-dose series) vaccine administered at different ages. Total costs and quality-adjusted life-years (QALYs) were estimated. Based on randomized clinical trial data, at a price of $280 per series ($140 per dose), HZ/su was more effective and less expensive than ZVL at all ages. The incremental cost-effectiveness ratios compared with no vaccination ranged from $20 038 to $30 084 per QALY, depending on vaccination age. The finding was insensitive to variations in most model inputs other than the vaccine price and certain combinations of low adherence rate with a second dose and low efficacy of a single dose of HZ/su. At the current ZVL price ($213 per dose), HZ/su had lower overall costs than ZVL up to a price of $350 per 2-dose series. In probabilistic sensitivity analysis, HZ/su had 73% probability of being cost-effective for 60-year-olds at $50 000 per QALY. Under conservative assumptions, at a price of $280 per series ($140 per dose), HZ/su would cost less than ZVL and has a high probability of offering good value.

Cost Effectiveness of a Shingles Vaccine Booster for Currently Vaccinated Adults in the U.S.

The Advisory Committee on Immunization Practices recommends a single dose of the live attenuated herpes zoster vaccine in people aged ≥60 years. Because vaccine-induced protection decreases to zero after 10 years, many vaccinated people will soon be subject to an increased risk of the disease. The study objective was to determine the cost effectiveness of a herpes zoster vaccine booster and its optimal timing among immunocompetent adults first vaccinated at aged ≥60 years. A Markov model was built to follow vaccinated individuals for a lifetime. From the societal perspective, costs and quality-adjusted life years were compared between no booster versus booster options. A booster was given any time between 1 and 20 years after the first dose, and for those who had the first dose at different ages: 60, 70, and 80 years. Because people entered the model already vaccinated, costs and side effects of the first dose were not included. The booster was assumed to have the same efficacy and waning rate as the initial vaccination. Model inputs were based on published literature. A cost effectiveness threshold of $100,000/quality-adjusted life year was used. The analysis was conducted in 2016. Cost effectiveness of a booster varied by age and time since vaccination. The booster cost <$100,000/quality-adjusted life year if given >5 years after the initial dose, but was most cost effective at around 10 years. The finding was robust to wide variations in model inputs. Under current assumptions, a booster dose of herpes zoster vaccine would be cost effective for all vaccinated people 10 years after initial vaccination.

Immunogenicity and Safety of an Adjuvanted Herpes Zoster Subunit Vaccine in Older Adults Previously Vaccinated with a Live-Attenuated Herpes Zoster Vaccine: A Phase III, Group-Matched, Clinical Trial

BackgroundHerpes zoster (HZ), caused by reactivation of varicella-zoster virus (VZV), typically manifests as a dermatomal rash and can lead to postherpetic neuralgia (PHN). HZ and PHN risk increase with age. Efficacy against HZ induced by a live-attenuated zoster vaccine (ZVL; Merck) declines following vaccination (21% in years 5–12 post-vaccination). To ensure protection, revaccination can be considered. Therefore, we assessed immunogenicity and safety of HZ/su, a non-live candidate vaccine containing VZV glycoprotein E (gE) subunit and AS01B adjuvant system (GSK), in adults previously vaccinated with ZVL ≥5 years before, (HZ-PreVac) compared with adults not vaccinated with ZVL (HZ-NonVac).MethodsIn this phase III, group-matched, open, multicenter study (NCT02581410), 2 parallel groups of adults ≥65 years of age (YOA) received 2 HZ/su doses 2 months apart. A co-primary objective was to compare humoral immune responses 1 month post-dose 2 (M3) in the 2 groups (non-inferiority criterion: upper limit [UL] of the 95% confidence interval [CI] for HZ-NonVac/HZ-PreVac adjusted anti-gE antibody geometric mean concentration [GMC] ratio <1.5). Humoral and cellular immune responses were evaluated at various time points. Solicited and unsolicited adverse events (AEs) were recorded for 7 and 30 days post each dose, respectively. Serious AEs (SAEs), HZ cases and potential immune-mediated diseases (pIMDs) will be recorded until study end. Here, we present data up to M3, as the study is still ongoing.Results430 participants were vaccinated. M3 humoral immune responses in HZ-PreVac were non-inferior to those in HZ-NonVac and the co-primary objective was met as the UL of the 95% CI of the adjusted GMC ratio was 1.17 (Table 1). In addition, there were no apparent differences in CD4[2+] T-cell frequencies between groups (Figure 1). No clinically meaningful differences between frequencies of solicited AEs, unsolicited AEs or SAEs in the 2 groups were observed (Table 2). No SAEs considered vaccine-related by investigators, no suspected HZ cases and no pIMDs were reported up to M3.ConclusionHZ/su vaccination in adults ≥65 YOA who previously received ZVL stimulates strong immune responses and does not raise safety concerns.FundingGlaxoSmithKline Biologicals SADisclosures K. Grupping, GSK group of companies: Employee, Salary; L. Campora, GSK group of companies: Employee, Salary; M. Douha, GSK group of companies: Employee, Salary; T. C. Heineman, GSK group of companies: Consultant and Shareholder, Consulting fee; N. P. Klein, GSK group of companies: Investigator, Grant recipient sanofi pasteur: Investigator, Grant recipient; Merck & Co: Investigator, Grant recipient; MedImmune: Investigator, Grant recipient; Protein Science: Investigator, Grant recipient; Pfizer: Investigator, Grant recipient; H. Lal, Pfizer: Employee and Shareholder, Salary and Stock as part of compensation; GSK group of companies: Employee at the time of study and Shareholder, Salary and Stock as part of compensation; J. Peterson, GSK group of companies: Investigator, Principal investigator fees; L. Oostvogels, GSK group of companies: Employee and Shareholder, Salary and Shares

Immunogenicity of Inactivated Varicella Zoster Vaccine (ZVIN) in Autologous Hematopoietic Stem Cell Transplant (auto-HSCT) Recipients

BackgroundRecipients of auto-HSCT have an increased risk of herpes zoster (HZ) infection; however, live attenuated varicella-zoster virus (VZV) vaccine is contraindicated in these patients. In this pivotal Phase III study (V212-001; NCT01229267) inactivated VZV vaccine (ZVIN) reduced the rate of HZ infection compared with placebo (estimated vaccine efficacy, 63.8%) and was well tolerated. Immunogenicity of ZVINin recipients of auto-HSCT was assessed in the Phase III study as an exploratory objective.MethodsAdults undergoing auto-HSCT were randomized to receive either ZVIN(n = 560) or placebo (n = 564), administered in a 4-dose regimen. Doses 1 through 4 were administered ~30 days before and ~30, ~60, and ~90 days following auto-HSCT. VZV-specific immune responses were measured at Day 1, ~28 days post-vaccinations 3 and 4, and annually until the end of the study. VZV-specific antibody responses were measured by glycoprotein enzyme-linked immunosorbent assay (gpELISA) in all patients; cell-mediated immune responses were measured by VZV interferon-gamma enzyme-linked immunospot (IFN-γ ELISPOT) assay in a randomized subset of patients (n = 403).ResultsGeometric mean titers (GMT) were significantly higher and the ratios of the gpELISA and IFN-γ ELISPOT were significantly greater in the ZVINgroup compared with the placebo group (Tables 1 and 2).Table 1. GMT 28 days post-dose 4 (PD4) Vaccine Placebo gpELISA n = 102 n = 108 241.8 (95% CI: 186.2, 313.9)105.8 (95% CI: 84.6, 132.3) IFN-γ ELISPOT n = 102 n = 116 62.8 (95% CI: 45.8, 86.2)10.4 (95% CI: 7.9, 13.7)Table 2. Ratios of geometric mean fold rise between the vaccine and placebo groups (ZVIN/placebo) gpELISA (n = 764) IFN-γ ELISPOT (n = 339) Pre-vaccination and 28 days PD4 1.79 (95% CI: 1.39, 2.32)5.41 (95% CI: 3.60, 8.12) Pre-vaccination and 1 year PD4 1.30 (95% CI: 0.99, 1.71)4.12 (95% CI: 2.62, 6.47)ConclusionZVIN elicited higher VZV-specific humoral and cell-mediated responses in adult auto-HSCT recipients when compared with placebo ~28 days and ~1 year post-dose 4. These results indicate that ZVIN is immunogenic in these patients who are ineligible for live attenuated HZ vaccine, which is consistent with previously observed clinical efficacy.Disclosures M. Boeckh, Merck: Investigator, Research Contractor and Scientific Advisor, Consulting fee and Research support; GlaxoSmithKline: Research Contractor, Research support; A. Arvin, Merck: Scientific Advisor, Consulting fee; K. Mullane, Merck: Scientific Advisor, Grant recipient; D. J. Winston, Merck: Grant Investigator and Scientific Advisor, Consulting fee and Grant recipient; J. Brown, Merck: Clinical adjudication and site investigator and Investigator, Consulting fee; Cellerant Therapeutics: Consultant, Cellerant developing and executing clinical trials of myeloid progenitor cells in neutropenia for which I hold the patent; S. Pergam, Merck: Consultant and Investigator, Consulting fee; K. Hurtado, Merck: Employee and Shareholder, Salary; L. Pang, Merck: Employee and Shareholder, Salary; I. Lee, Merck: Employee, Salary; Z. Popmihajlov, Merck & Co., Inc.: Employee and Shareholder, Salary

Immunogenicity and Safety of the HZ/su Adjuvanted Herpes Zoster Subunit Vaccine in Adults Previously Vaccinated With a Live Attenuated Herpes Zoster Vaccine

Protection against herpes zoster (HZ) induced by the live attenuated zoster vaccine Zostavax (ZVL) wanes within 3-7 years. Revaccination may renew protection. We assessed whether (re)vaccination with the adjuvanted HZ subunit vaccine candidate (HZ/su) induced comparable immune responses in previous ZVL recipients and ZVL-naive individuals (HZ-NonVac). In an open-label, multicenter study, adults ≥65 years of age, vaccinated with ZVL ≥5 years previously (HZ-PreVac), were matched to ZVL-naive adults (HZ-NonVac). Participants received 2 doses of HZ/su 2 months apart. The primary objective of noninferiority of the humoral immune response 1 month post-dose 2 was considered demonstrated if the upper limit of the 95% confidence interval (CI) of the adjusted anti-glycoprotein E geometric mean concentration (GMC) ratio of HZ-NonVac over HZ-PreVac was <1.5. HZ/su cellular immunogenicity, reactogenicity, and safety were also assessed. In 430 participants, humoral immune response to HZ/su was noninferior in HZ-PreVac compared with HZ-NonVac (adjusted GMC ratio, 1.04 [95% CI, .92-1.17]). Cellular immunogenicity, reactogenicity, and safety appeared to be comparable between groups. HZ/su was well-tolerated, with no safety concerns raised within 1 month post-dose 2. HZ/su induces a strong immune response irrespective of prior vaccination with ZVL, and may be an attractive option to revaccinate prior ZVL recipients. NCT02581410.

Background paper to the decision not to recommend a standard vaccination with the live attenuated herpes zoster vaccine for the elderly in Germany

A live attenuated vaccine (Zostavax (R)) against herpes zoster (HZ) and posther-petic neuralgia (PHN) was licensed for persons 50 years of age and older in 2006 and became available in Germany in September 2013. Based on the conclusion, that an effective and sustainable reduction of the HZ disease burden cannot be achieved with this vaccine, the STIKO decided against issuing a recommendation for routine HZ vaccination at this time. This decision is based on a systematic review of available data on the efficacy, duration of protection, and safety of the vaccine, and is supported by the results of health economic modelling. Both, the risk of developing HZ and the severity of the illness increase markedly with age. The efficacy of the vaccine, however, decreases with advancing age, from 70% for persons in their 50s to 41% for persons in their 70s to less than 20% for persons 80 years of age and older. The duration of vaccine related protection is limited to only a few years. The modelling results show only a slight, age-dependent reduction in the total number of HZ cases through vaccination with the live attenuated vaccine. The reduction ranged from 2.6% for persons vaccinated at the age of 50 to 0.6% for those vaccinated at the age of 80, based on assumed vaccine coverage of 35.5%. In addition to the vaccine's poor efficacy and duration of protection, HZ vaccination does not offer any added value in terms of herd immunity, since HZ is a disease of an endogenously reactivated pathogen with low transmission potential. Finally, the live attenuated vaccine is often contraindicated in persons who are at greatest risk of HZ and its complications. Thus, in the overall appraisal, the epidemiological benefit-risk assessment of the HZ vaccination did not lead to a recommendation for routine vaccination with the live attenuated vaccine. An individual benefit-risk assessment may, however, lead to a different decision in individual patients.

Herpes zoster prevention: A difficult problem to solve

The clinical relevance of herpes zoster (HZ) and its increased incidence in recent years has prompted a search for more effective measures of prevention and therapy. A number of vaccines has been developed. For two of them, the live attenuated HZ vaccine (LAHZV) and the adjuvanted recombinant subunit HZ vaccine (SUHZV), data regarding immunogenicity, efficacy, safety and reactogenicity have been collected. This information allows us to draw some conclusions about what can be expected from their use and what is still required to definitively solve the problem of HZ prevention. The currently licensed vaccine LAHZV is only partially satisfactory in terms of efficacy, but it is safe and exhibits acceptable reactogenicity. Because LAHZV is also highly cost effective, it should be used as widely as possible until new, more effective preparations are developed. In this regard, preliminary data regarding SUHZV are very promising, although more studies are needed before it can be licensed for routine use. Other vaccines, such as the inactivated VZV vaccine, are in development. It seems likely that in the near future, more effective HZ prevention for older adults can be achieved.

A comparison of the immunogenicity of a live attenuated herpes zoster vaccine (ZV) and the recombinant gE/AS01B candidate vaccine in older adults

Abstract Herpes zoster (HZ) has high morbidity in older adults. ZV, which is recommended for individuals ≥60 y, is 51% effective against HZ in the 1st 3 y after vaccination; efficacy decreases with the age of the vaccinee; and wanes to ~40% at 5 y. gE/ASO1B is a recombinant adjuvanted vaccine with 97% efficacy against HZ that does not vary with age of the vaccinee and wanes to 87% at 4y. We compared the cell-mediated immunity (CMI) of ZV and gE/ASO1B at 30 d after the last dose of vaccine and at 1 y. Subjects were 50–70+ yoa who never received ZV (1ary) and adults ≥70 yoa who received ZV ≥5 y previously (boosted). Participants received ZV at entry or gE/ASO1B at 0 and 60 d. Blood from days 0, 30 (ZV peak response), 90 (peak gE/ASO1B) and 365 was used to measure CMI to varicella zoster virus (VZV) and to gE by IFNg and IL2 fluorospot [spot forming cells/106 PBMC (SFC)] and by flow cytometry assessing VZV- and gE-specific proliferation and effector (Teff), effector memory (Tem), and central memory (Tcm) outcomes. The higher CMI responses that best distinguished gE/ASO1B from ZV recipients after adjusting for age, gender, prior ZV administration and baseline CMI were: 1) VZV-specific IL2 and gE-specific IL2 and IFNg SFC at peak response (p≤0.004); 2) higher VZV-specific CD8+ and gE-specific CD4+ and CD8+ responses measured by proliferation at peak (p&amp;lt;0.05); 3) higher CD4+ Tcm% and Tem% and lower Teff% at peak response (p≤0.005); 4) higher VZV-specific and gE-specific IL2 and IFNg SFC at 1 y in all gE/ASO1B groups, but only in the boosted ZV group. CMI did not differ among gE/ASO1B recipients by age or prior ZV administration. The higher memory CD4+ and CD8+ responses detected in gE/AS01B recipients might contribute to its superior efficacy and persistence of protection against HZ.

Safety and immunogenicity of inactivated varicella-zoster virus vaccine in adults with hematologic malignancies receiving treatment with anti-CD20 monoclonal antibodies

BackgroundImmunocompromised patients can experience significant morbidity and occasional mortality from complications associated with herpes zoster (HZ), but live attenuated HZ vaccine is contraindicated for these patients. Inactivated zoster vaccine (ZVIN) is in development for prevention of HZ in immunocompromised patients. However, there are limited data in the literature regarding the effect of anti-CD20 monoclonal antibodies on vaccine-related cell-mediated immune response. This study evaluated safety and immunogenicity of ZVIN in patients with hematologic malignancies (HM) receiving anti-CD20 monoclonal antibodies (alone or in combination chemotherapy regimens) and not likely to undergo hematopoietic cell transplant (HCT) (n=80). MethodsThis was an open-label, single-arm, multicenter Phase I study (NCT01460719) of a 4-dose ZVIN regimen (∼30days between doses) in patients ⩾18years old. Blood samples were collected prior to dose 1 and 28days Postdose 4 to measure varicella zoster virus (VZV)-specific T-cell responses using interferon-γ enzyme-linked immunospot (IFN-γ ELISPOT). The primary hypothesis was that ZVIN would elicit significant VZV-specific immune responses at ∼28days Postdose 4, with a geometric fold rise (GMFR) >1.0. All vaccinated patients were evaluated for adverse events (AE) through 28days Postdose 4. ResultsZVIN elicited a statistically significant VZV-specific immune response measured by IFN-γ ELISPOT at 28days Postdose 4 (GMFR=4.34 [90% CI:3.01, 6.24], p-value<0.001), meeting the pre-specified success criterion.Overall, 85% (68/80) of patients reported ⩾1 AE, 44% (35/80) reported ⩾1 injection-site AE, and 74% (59/80) reported ⩾1 systemic AE. The majority of systemic AEs were non-serious and considered unrelated to vaccination by the investigator. Frequencies of AEs did not increase with subsequent doses of vaccine. No recipient of ZVIN had rash polymerase chain reaction (PCR) positive for VZV vaccine strain. ConclusionsIn adults with HM receiving anti-CD20 monoclonal antibodies, ZVIN was well-tolerated and elicited statistically significant VZV-specific T-cell responses ∼28days Postdose 4.CLINICALTRIALS.GOV identifier: NCT01460719.

Effectiveness and Duration of Protection Provided by the Live-attenuated Herpes Zoster Vaccine in the Medicare Population Ages 65 Years and Older.

Tens of millions of seniors are at risk of herpes zoster (HZ) and its complications. Live attenuated herpes zoster vaccine (HZV) reduces that risk, although questions regarding effectiveness and durability of protection in routine clinical practice remain. We used Medicare data to investigate HZV effectiveness (VE) and its durability. This retrospective cohort study included beneficiaries ages ≥65 years during January 2007 through July 2014. Multiple adjustments to account for potential bias were made. HZV-vaccinated beneficiaries were matched to unvaccinated beneficiaries (primary analysis) and to HZV-unvaccinated beneficiaries who had received pneumococcal vaccination (secondary analysis). HZ outcomes in community and hospital settings were analyzed, including ophthalmic zoster (OZ) and postherpetic neuralgia (PHN). Among eligible beneficiaries (average age 77 years), the primary analysis found VE for community HZ of 33% (95% CI: 32%-35%) and 19% (95% CI: 17%-22%), for the first 3, and subsequent 4+ years postvaccination, respectively. In the secondary analysis, VE was, respectively, 37% (95% CI: 36%-39%) and 22% (95% CI: 20%-25%). In the primary analysis, VE for PHN was 57% (95% CI: 52%-61%) and 45% (95% CI: 36%-53%) in the first 3 and subsequent 4+ years, respectively; VE for hospitalized HZ was, respectively, 74% (95% CI: 67%-79%) and 55% (95% CI: 39%-67%). Differences in VE by age group were not significant. In both the primary and secondary analyses, HZV provided protection against HZ across all ages, but effectiveness declined over time. VE was higher and better preserved over time for PHN and HZ-associated hospitalizations than for community HZ.

Preventing herpes zoster through vaccination: New developments.

Herpes zoster (HZ) affects 1 million Americans every year. The disease burden is higher in immunocompromised patients. The live-attenuated HZ vaccine is effective in preventing HZ and postherpetic neuralgia and has been recommended for immunocompetent adults age 60 and older. However, because protection wanes by 10 years, a booster may be necessary. In 2015, an adjuvanted subunit HZ vaccine was shown to reduce incidence by 97%, even in the elderly, but long-term data on vaccine protection are not available. Clinical trials are under way to investigate a safe and effective vaccine for immunocompromised patients.

Real-World Effectiveness and Safety of a Live-Attenuated Herpes Zoster Vaccine: A Comprehensive Review.

Herpes zoster (HZ) is a common, painful and debilitating disease caused by the reactivation of latent varicella-zoster virus in ganglia. This clinical event occurs more frequently in the elderly and those who are immunocompromised. The most common complication of HZ is post-herpetic neuralgia (PHN) which is responsible for the highest HZ-related burden of illness and is challenging to treat. Due to the important clinical and economic impact of HZ and PHN, and the suboptimal treatments that are currently available, HZ vaccination is an important approach to reduce the burden of illness. Currently, one-dose, live-attenuated vaccine is licensed in the United States and Europe to prevent HZ and it is included in some national immunization programs. The clinical efficacy, safety and tolerability of the vaccine has been demonstrated in two large phase III clinical trials, involving more than 38,000 and 22,000 individuals aged ≥60 and 50–59 years, respectively. This comprehensive review summarizes the extensive “real-world” effectiveness and safety data from both immunocompetent and immunocompromised individuals. These data confirm those from the clinical trials, supporting the use of HZ vaccine in clinical practice and provide evidence that the current recommendations for immunocompromised individuals should be revised. Funding: Funding for the editorial assistance, article processing charges, and open access fee for this publication was provided by Sanofi Pasteur MSD.

Herpes zoster: Risk and prevention during immunomodulating therapy

Herpes zoster can be serious or incapacitating, particularly in patients whose immune system is compromised by a disease or treatment. Immunomodulating drugs can increase the risk of infection. Well-established risk factors include advanced age and glucocorticoid therapy. The data are somewhat conflicting for medications such as methotrexate, tofacitinib, TNFα antagonists (infliximab, adalimumab, etanercept, certolizumab, and golimumab), abatacept, tocilizumab, and rituximab. Nevertheless, the risk of herpes zoster is increased in patients taking biological agents, because of the underlying diseases and/or effects of the drugs. A live attenuated herpes zoster vaccine has been proven effective and safe in immunocompetent individuals. At present, however, it is not recommended for patients with immunodeficiencies, including those taking biological drugs, as no studies have assessed its risk/benefit ratio in this population. This situation may change in the near future, as recent data support the effectiveness and safety of the herpes zoster vaccine in patients who take biotherapies or have other causes of immunodeficiency. Alternative approaches designed to protect these patients from herpes zoster and its complications are also under evaluation. There is a need to define the indications of the herpes zoster vaccine in terms of the target population, timing, modalities, and frequency, according to the underlying chronic systemic disease, age group, varicella-zoster virus status, and exposure to therapeutic agents.