A self-controlled case series study on the safety of a live attenuated herpes zoster vaccine in China

Objective To evaluate the preclinical safety and immunogenicity of live attenuated herpes zoster vaccine. Method BALB/c mice were immunized subcutaneously with different doses of herpes zoster vaccine 1 or 2 times. The clinical presentation was observed.The serum and spleen lymphocytes were collected at 2 weeks after last immunization. The antibody against varicella-zoster virus in serum was detected by fluorescent antibody to membrane antigen method and glycoprotein ELISA. The numbers of IFN-γ-secreting T cells were detected by enzyme-linked immunospot assay. The frequency of different T cells was measured by flow cytometry. Results There were no side effects in BALB/c mice with 1 or 2 vaccinations. The balance of T cells was not affected in mice. Humoral and cellular immune responses in mice were induced by both 1 and 2 immunizations, and enhanced by booster injection. The dose of vaccine was correlated with the strength of humoral and cellular immune responses. Conclusion The live attenuated herpes zoster vaccine has good safety and immunogenicity. Key words: Herpes zoster vaccine; Safety; Immunity, humoral; Immunity, cellular

BackgroundEfficacy of the live-attenuated herpes zoster (HZ) vaccine (ZVL) wanes substantially over time. We evaluated immunogenicity and safety of the adjuvanted recombinant zoster vaccine (RZV) in previous ZVL recipients.MethodsAdults aged ≥65 years who were previously vaccinated with ZVL ≥5 years earlier (n = 215) were group-matched with ZVL-naive individuals (n = 215) and vaccinated with RZV. Glycoprotein E (gE)–specific humoral and cell-mediated immune responses and the correlation between them, polyfunctional gE-specific CD4 T-cell responses, safety, and confirmed HZ cases were assessed.ResultsThrough 12 months after dose 2, anti-gE antibody concentrations, gE-specific CD4 T-cell frequencies, and activation marker profiles were similar between groups. Safety outcomes were also similar. No HZ episodes were confirmed.ConclusionsRZV induced strong humoral and polyfunctional cell-mediated immune responses that persisted above prevaccination levels through 1 year after dose 2 in adults aged ≥65 years irrespective of previous ZVL vaccination. The RZV safety profile was not affected.Clinical Trials RegistrationNCT02581410.

The varicella zoster virus, a neurotropic herpesvirus, has been hypothesized to play a role in the pathophysiology of dementia, such as through neuroinflammatory processes or intracerebral vasculopathy. Using unique natural experiments, our group has previously found that live-attenuated herpes zoster (HZ) vaccination reduced the incidence of new diagnoses of dementia in both Wales and Australia. To inform further research and ultimately clinical care, it is crucial to understand at which stage of the disease course of dementia the HZ vaccine has its effect. Representing the two opposing ends of the dementia disease course as it can be ascertained from electronic health record data, the aims of this study were twofold: to determine the effect of HZ vaccination on i) new diagnoses of mild cognitive impairment (MCI) among individuals without any record of cognitive impairment, and ii) deaths due to dementia among individuals living with dementia. Our approach took advantage of the fact that at the time of the start date (September 1 2013) of the HZ vaccination program in Wales, individuals who had their eightieth birthday just after this date were eligible for HZ vaccination for one year whereas those who had their eightieth birthday just before were ineligible and remained ineligible for life. This eligibility rule created comparison groups just on either side of the September 2 1933 date-of-birth eligibility threshold who differed in their age by merely a week but had a large difference in their probability of receiving HZ vaccination. The key strength of our study is that these comparison groups should be similar in their health characteristics and behaviors except for a minute difference in age. We used regression discontinuity analysis to estimate the difference in our outcomes between individuals born just on either side of the date-of-birth eligibility threshold for HZ vaccination. Our dataset consisted of detailed country-wide electronic health record data from primary care in Wales, linked to hospital records and death certificates. We restricted our dataset to individuals born between September 1 1925 and September 1 1942. Among our study cohort of 282,557 without any record of cognitive impairment at baseline, HZ vaccination eligibility and receipt reduced the incidence of a new MCI diagnosis by 1.5 (95% CI: 0.5 - 2.9, p=0.006) and 3.1 (95% CI: 1.0 - 6.2, p=0.007) percentage points over nine years, respectively. Similarly, among our study cohort of 14,350 individuals who were living with dementia at baseline, being eligible for and receiving HZ vaccination reduced deaths due to dementia by 8.5 (95% CI: 0.6 - 18.5, p=0.036) and 29.5 (95% CI: 0.6 - 62.9, p=0.046) percentage points over nine years, respectively. Except for dementia, HZ vaccination did not have an effect on any of the ten most common causes of morbidity and mortality among adults aged 70 years and older in Wales in either of our two study cohorts. The protective effects of HZ vaccination for both MCI and deaths due to dementia were larger among women than men. Our findings suggest that the live-attenuated HZ vaccine has benefits for the dementia disease process at both ends of the disease course of dementia.

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.

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

Efficacy and safety of a China-developed live attenuated herpes zoster vaccine in Chinese healthy adults aged 40 years and older: a multicentre, randomized, double-blind, placebo-controlled, phase 3 clinical trial.

Herpes zoster (HZ) is caused by the reactivation of latent varicella-zoster virus (VZV) from the sensory ganglia due to aging or immunosuppression. Glycoprotein E (gE) is a widely used vaccine antigen for specific humoral and cellular immune responses. Immediate early protein 63 (IE63) is expressed during latency, suggesting that it is a potential antigen against HZ reactivation. In this study, HZ DNA vaccines encoding gE, IE63, IE63-2A-gE (where 2A is a self-cleaving sequence), or IE63-linker-gE were developed and investigated for immunogenicity in mice. The results showed that each HZ DNA vaccine induced VZV-specific antibody production. The neutralizing antibody titer elicited by IE63-2A-gE was comparable to that elicited by gE or live attenuated HZ vaccine (LAV). IE63-2A-gE-induced gE or IE63-specific INF-γ+ T cell frequencies in splenocytes were comparable to those of LAV. Furthermore, IE63-2A-gE, gE, or IE63 led to a significant increase in IFN-γ (IE63 stimulation) and IL-2 (gE stimulation) secretion compared to LAV, showing a Th1-biased immune response. Moreover, IE63-2A-gE and gE induced cytotoxic activity of CD8+ T cells compared to that of LAV. This study elucidates that the IE63-2A-gE DNA vaccine can induce both humoral and cell-mediated immune responses, which provides a candidate for the development of an HZ vaccine.

BackgroundHerpes zoster (HZ), caused by reactivation of varicella-zoster virus (VZV), typically manifests as a dermatomal rash and can result in complications, such as postherpetic neuralgia. HZ risk increases with age due to age-related decline of immunity. At time of study start, Zoster Vaccine Live (ZVL), containing live-attenuated VZV was recommended for vaccination in adults ≥60 years of age. Efficacy of ZVL declines with time since vaccination and increasing age. We evaluated immunogenicity and safety of Adjuvanted Recombinant Zoster Vaccine (RZV) containing truncated form of VZV glycoprotein E (gE) in adults vaccinated with ZVL ≥5 years before (HZ-PreVac) and ZVL-naïve adults (HZ-NonVac). In October 2017, the Advisory Committee on Immunization Practices recommended revaccination of ZVL recipients with RZV, based on available data, including 1 month (M) post-dose 2 results of this study (M3). Here we present immunogenicity and safety results up to 12 months post-dose 2 (M14).MethodsIn this phase III, multi-center study (NCT02581410), open-label, 2 parallel groups of group-matched adults ≥65 years of age, HZ-PreVac and HZ-NonVac, received 2 RZV doses 2 months apart. Humoral and cellular immune responses were evaluated at various time points up to M14. 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) were recorded throughout the study.Results215 participants were vaccinated in each group. No apparent differences, in pre-vaccination and persistence values of the anti-gE antibody GMCs (Figure 1) and CD4[2+] T-cell frequencies (Figure 2) were observed between HZ-PreVac and HZ-NonVac, up to M14. No clinically relevant differences in frequencies of solicited AEs, unsolicited AEs or SAEs between the two groups were observed. Six pIMDs (two in HZ-PreVac group and four in HZ-NonVac group), were reported up to M14 (Table 1). ConclusionIn both groups, RZV-induced humoral and cellular immune responses persisted above baseline up to M14 at similar levels, irrespective of previous ZVL administration. Safety profile was similar regardless of previous ZVL vaccination. Funding: GlaxoSmithKline Biologicals SA.Disclosures T. Mrkvan, GSK: Employee and Shareholder, Salary and shares and share options. L. Campora, GSK: Employee and Shareholder, Salary. G. Catteau, GSK: Board Member, Salary. M. Douha, GSK: Employee, Salary. K. Grupping, GSK: Employee, Salary. C. Herve, GSK: Employee, Salary. G. Kalema, GSK: Consultant, Consulting fee. T. Heineman, GSK: Consultant, Employee and Shareholder, Consulting fee and Salary. N. P. Klein, GSK: Investigator, Research support. sanofi pasteur: Investigator, Research support. Merck: Investigator, Research support. Pfizer: Investigator, Research support. Protein Science: Investigator, Research support. MedImmune: Investigator, Research support. Dynavax: Investigator, Research support. H. Lal, GSK: Shareholder, Salary. Pfizer: Shareholder, Salary. L. Oostvogels, GSK: Employee, Salary and stock and stock options. A. Schuind, GSK: Employee and Shareholder, Salary.

Steep increases in herpes zoster (HZ) incidence, hospitalization due to HZ and the risk of post-herpetic neuralgia as a complication of HZ occur in people over 50 years of age. Two HZ vaccines are currently authorized for use in those 50 years of age and older in Canada: a live attenuated zoster vaccine (LZV) authorized in 2008; and a recombinant subunit vaccine (RZV) authorized in October 2017. To review current evidence and develop guidance on whether the previously authorized LZV (Zostavax®) and/or the recently authorized RZV (Shingrix®) vaccine should be offered to Canadians 50 years of age and older: 1) at a population-level, in publicly funded immunization programs; and 2) at an individual-level, to individuals wishing to prevent HZ, or by clinicians wishing to advise individual patients about preventing HZ. The National Advisory Committee on Immunization (NACI) Herpes Zoster Working Group developed a predefined search strategy to identify all eligible studies, assessed their quality, and summarized and analyzed the findings. A Cost Utility Analysis of LZV and RZV was also conducted from a health care system perspective. Recommendations were proposed according to NACI's evidence-based process. The strength of these recommendations was defined, and the Grade of evidence supporting them was identified. In light of the evidence, the recommendations were then considered and approved by NACI. Five recommendations were developed for public health and individual-level decision-making. 1) RZV should be offered to populations/individuals >50 years of age without contraindications (Strong NACI Recommendation, Grade A evidence). 2) RZV should be offered to populations/individuals >50 years of age without contraindications who have previously been vaccinated with LZV (Strong NACI Recommendation, Grade A evidence). Re-immunization with two doses of RZV may be considered one year after LZV (Discretionary NACI Recommendation, Grade I evidence). 3) RZV should be offered to populations/individuals >50 years of age without contraindications who have had a previous episode of HZ (Strong NACI Recommendation, Grade B evidence). Immunization with two doses of RZV may be considered one year after the HZ episode (Discretionary NACI Recommendation, Grade I evidence). 4) LZV may be considered for immunocompetent populations/individuals >50 years of age without contraindications when RZV is contraindicated, unavailable or inaccessible (Discretionary NACI Recommendation, Grade A evidence). 5) RZV (not LZV) may be considered in immunocompromised adults >50 years of age on a case-by-case basis (Discretionary NACI Recommendation, Grade I evidence). Both vaccines have been shown to be safe and immunogenic and to reduce the incidence of HZ and post-herpetic neuralgia. Vaccine efficacy of LZV against HZ decreases with age at, and time since vaccination. The vaccine efficacy of RZV remains higher and appears to decline more slowly than vaccine efficacy of LZV across all age groups. Both vaccines are cost-effective in those 50 years of age and older compared with no vaccination, especially in those 65-79 years of age. RZV is more cost-effective than LZV.

OP0117 Safety and immune response of a live attenuated herpes zoster vaccine in patients with systemic lupus erythematosus: a randomised placebo-controlled trial

ObjectivesTo study the safety and immunogenicity of a live-attenuated herpes zoster (HZ) vaccine in patients with systemic lupus erythematosus (SLE).MethodsAdult SLE patients having a SLEDAI <6 and stable immunosuppressive treatment...

Lower risk for COVID-19 hospitalization among patients in the United States with past vaccinations for herpes zoster and tetanus, diphtheria and pertussis

Long-term effectiveness of live zoster vaccine against herpes zoster and related complications: a nationwide emulated target trial in South Korea.

We included two new studies involving 1736 participants in this update. The review now includes a total of 26 studies involving 90,259 healthy older adults with a mean age of 63.7 years. Only three studies assessed the cumulative incidence of herpes zoster in groups that received vaccines versus placebo. Most studies were conducted in high-income countries in Europe and North America and included healthy Caucasians (understood to be white participants) aged 60 years or over with no immunosuppressive comorbidities. Two studies were conducted in Japan and one study was conducted in the Republic of Korea. Sixteen studies used LZV. Ten studies tested an RZV. The overall certainty of the evidence was moderate, which indicates that the intervention probably works. Most data for the primary outcome (cumulative incidence of herpes zoster) and secondary outcomes (adverse events and dropouts) came from studies that had a low risk of bias and included a large number of participants. The cumulative incidence of herpes zoster at up to three years of follow-up was lower in participants who received the LZV (one dose subcutaneously) than in those who received placebo (risk ratio (RR) 0.49, 95% confidence interval (CI) 0.43 to 0.56; risk difference (RD) 2%; number needed to treat for an additional beneficial outcome (NNTB) 50; moderate-certainty evidence) in the largest study, which included 38,546 participants. There were no differences between the vaccinated and placebo groups for serious adverse events (RR 1.08, 95% CI 0.95 to 1.21) or deaths (RR 1.01, 95% CI 0.92 to 1.11; moderate-certainty evidence). The vaccinated group had a higher cumulative incidence of one or more adverse events (RR 1.71, 95% CI 1.38 to 2.11; RD 23%; number needed to treat for an additional harmful outcome (NNTH) 4.3) and injection site adverse events (RR 3.73, 95% CI 1.93 to 7.21; RD 28%; NNTH 3.6; moderate-certainty evidence) of mild to moderate intensity. These data came from four studies with 6980 participants aged 60 years or older. Two studies (29,311 participants for safety evaluation and 22,022 participants for efficacy evaluation) compared RZV (two doses intramuscularly, two months apart) versus placebo. Participants who received the new vaccine had a lower cumulative incidence of herpes zoster at 3.2 years follow-up (RR 0.08, 95% CI 0.03 to 0.23; RD 3%; NNTB 33; moderate-certainty evidence), probably indicating a favourable profile of the intervention. There were no differences between the vaccinated and placebo groups in cumulative incidence of serious adverse events (RR 0.97, 95% CI 0.91 to 1.03) or deaths (RR 0.94, 95% CI 0.84 to 1.04; moderate-certainty evidence). The vaccinated group had a higher cumulative incidence of adverse events, any systemic symptom (RR 2.23, 95% CI 2.12 to 2.34; RD 33%; NNTH 3.0), and any local symptom (RR 6.89, 95% CI 6.37 to 7.45; RD 67%; NNTH 1.5). Although most participants reported that their symptoms were of mild to moderate intensity, the risk of dropouts (participants not returning for the second dose, two months after the first dose) was higher in the vaccine group than in the placebo group (RR 1.25, 95% CI 1.13 to 1.39; RD 1%; NNTH 100, moderate-certainty evidence). Only one study reported funding from a non-commercial source (a university research foundation). All other included studies received funding from pharmaceutical companies. We did not conduct subgroup and sensitivity analyses AUTHORS' CONCLUSIONS: LZV (single dose) and RZV (two doses) are probably effective in preventing shingles disease for at least three years. To date, there are no data to recommend revaccination after receiving the basic schedule for each type of vaccine. Both vaccines produce systemic and injection site adverse events of mild to moderate intensity. The conclusions did not change in relation to the previous version of the systematic review.

Live-attenuated zoster vaccine (LZV) and adjuvanted recombinant zoster vaccine (RZV) have been approved for use in China. This study aimed to evaluate and compare the cost-effectiveness of these two herpes zoster (HZ) vaccination strategies in a birth cohort of individuals aged 50 years. The cost-effectiveness of RZV and LZV was compared to no vaccination strategy using a lifetime Markov model from a societal perspective. Model parameters were obtained from up-to-date published literature and statistical data. The costs associated with vaccination and medical treatment, quality-adjusted life years (QALYs), the number of herpes zoster and related complication cases averted, and the incremental cost-effectiveness ratio (ICER) were calculated. Sensitivity analyses were performed to assess the robustness of the results. Compared to the no-vaccination strategy, the RZV strategy was estimated to prevent 4,126 HZ cases and 772 postherpetic neuralgia (PHN) cases, while the LZV strategy was estimated to avert 2,355 HZ cases and 467 PHN cases. The ICER was estimated at 711.46 US $/QALY and 914.62 US $/QALY for the RZV and LZV strategies, respectively. HZ vaccination could provide significant health benefits at a reasonable cost. RZV was predicted to be more cost-effective than LZV.