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2905. Long-term Immunological Persistence of the Adjuvanted Recombinant Zoster Vaccine: Clinical Data and Mathematical Modeling

ABSTRACT: Abstract Background The adjuvanted recombinant zoster vaccine (RZV, GSK), administered to adults ? 50 years of age (YOA) demonstrated ? 90% efficacy against herpes zoster across all age cohorts. Vaccine-specific immune responses elicited by two RZV doses in adults ? 60 YOA have been shown to persist above pre-vaccination levels at least up to 9 years after initial vaccination. Here we present persistence of the humoral and cellular immunity and safety up to 10 years after initial vaccination as well as data from mathematical modeling, performed to predict immune persistence up to 15 years. Methods This phase IIIB, open-label extension trial (NCT02735915) included 70 participants who had received two RZV doses in the initial trial (NCT00434577) and builds on a previous extension trial (NCT01295320). Cellular and humoral immune responses up to year 10 after an initial 2-dose vaccination schedule are presented here. Additionally, prediction of immunological persistence at year 15 was assessed by mathematical modeling (Piecewise, Power-law, Fraser), using the individual subject values for available data up to year 10. Results The median frequency of varicella-zoster virus glycoprotein E (gE)-specific CD4+ T-cells expressing ? 2 activation markers plateaued at 3.3-fold above pre-vaccination levels starting around year 4 up to year 10 post-initial vaccination. Anti-gE antibody concentrations plateaued starting around year 3 up to year 10 post-initial vaccination.Ten years after initial vaccination, humoral responses remained 5.9-fold higher as compared with pre-initial vaccination levels (Figure 1). No relevant safety events were identified during the study (year 9–10 post-initial vaccination). In line with previous modeling data, the year 10 analysis predicts that both cellular and humoral immune responses will remain above pre-vaccination levels for at least 15 years after initial vaccination (Figures 2 and 3). Conclusion In adults vaccinated when ? 60 YOA, humoral and cellular immune responses induced by two RZV doses persist above pre-vaccination levels for at least 10 years post-initial vaccination. Mathematical modeling predicts a maintained vaccine-related immune response for at least 15 years after initial vaccination. Funding. GlaxoSmithKline Biologicals SA. Disclosures All Authors: No reported Disclosures.

SUBMITTER: Bastidas A

PROVIDER: S-EPMC6808880 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature

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Project description:Abstract Background Two large-scale phase 3 clinical trials (ZOE-50 [NCT01165177] and ZOE-70 [NCT01165229]) demonstrated that, in adults ≥ 50 years of age followed over a mean period of 3.1 and 3.7 years respectively, the adjuvanted recombinant zoster vaccine (RZV) was efficacious against herpes zoster (HZ), highly immunogenic and had a clinically acceptable safety profile. In this extension study (ZOSTER-049 [NCT02723773]), RZV-induced immunogenicity persistence and long-term vaccine efficacy (VE) against HZ were evaluated; we report interim results after at least 2 years of follow-up (starting and ending ≈5.1 and 7.1 years, respectively, after initial vaccination during the parent studies). Methods The study design is detailed in Figure 1. Primary objective: VE against HZ over the ZOSTER-049 study. Secondary objectives: VE against HZ from 1 month post-dose 2 in ZOE-50/-70 until the end of observation for year (Y)2 of ZOSTER-049, persistence of vaccine-induced humoral immunogenicity (HI) in terms of anti-gE antibody concentrations (by ELISA) and cell-mediated immune (CMI) response in terms of frequency of gE-specific CD4+ T-cells (by intracellular cytokine staining). Figure 1. Study design of the extension study in relation to the parent studies. ZOSTER-049 study procedures, timing, endpoints and cohorts Results Of the 7,413 participants enrolled in ZOSTER-049, 7,277 were included in the VE analysis (Figure 2) and 6,972 reached Y2 of this study. The overall VE against HZ during at least 2 years of follow-up in ZOSTER-049 was 84.0% (95% confidence interval [CI]: 75.9–89.8%). From 1 month post-dose 2 in the ZOE-50/-70 studies until the end of observation for Y2 of ZOSTER-049, the overall VE was 90.9% (95% CI: 88.2–93.2%). Anti-gE antibody concentrations persisted ≈6 times above pre-vaccination levels up to Y8 after vaccination (Figure 3A) and the frequency of gE-specific CD4[2+] T-cells remained above baseline from Y6 to Y8 after vaccination (i.e. until the end of observation for Y2 of ZOSTER-049) (Figure 3B). Figure 2. Demographic characteristics of participants included in the ZOSTER-049 study, for the analysis of vaccine efficacy against herpes zoster (mTVC) Figure 3. Long-term persistence of humoral immunogenicity (HI) and cell-mediated immune (CMI) responses up to year 8 post-vaccination dose 2 administered in the ZOE-50/-70 studies Conclusion RZV demonstrated high VE against HZ until the end of the observation period for this Y2 interim analysis. The HI and CMI responses remained stable and high until the end of observation (i.e. 7.1 years after initial vaccination). Funding: GlaxoSmithKline Biologicals SA Acknowledgements: LA Truta/S Hulsmans (Modis c/o GSK) provided writing/editorial support Disclosures Céline Boutry, PhD, Aixial (Consultant) Andrew Hastie, MD, GSK group of companies (Employee) Meng Shi, MS, GSK group of companies (Employee) Javier Diez-Domingo, MD, GSK group of companies (Board Member, Scientific Research Study Investigator, Advisor or Review Panel member)MSD (Board Member, Scientific Research Study Investigator, Advisor or Review Panel member) Paola Pirrotta, PharmD, GSK group of companies (Employee) George Kalema, PhD, GSK group of companies/Keyrus Biopharma (Consultant) Anne Schuind, MD, GSK (Employee, Other Financial or Material Support, own GSK stock options or restricted shares as part of renumeration)

Project description:Abstract Background For the first time, we present data describing vaccine efficacy (VE), immunogenicity persistence and safety up to approximately 10 years after primary vaccination against HZ with RZV. We have previously shown that RZV demonstrated high VE against HZ in adults ≥ 50 years of age (YOA) participating in 2 phase 3 clinical trials (ZOE-50, NCT01165177 and ZOE-70, NCT01165229), and VE persisted up to year (Y) 2 in the interim analysis of the extension study (ZOSTER-049, NCT02723773). Here we describe the interim analysis for Y4 of the extension study. Understanding the persistence of VE and long-term protection against HZ can help to optimize the use of RZV in adults ≥ 50 YOA. Methods The study design is detailed in Figure 1. Primary objective included VE against HZ over the ZOSTER-049 study. Secondary objectives included VE against HZ from 1 month post-dose 2 in the ZOE-50/-70 studies until the end of Y4 of ZOSTER-049 (Y10 after vaccination), persistence of vaccine-induced humoral immunogenicity (HI) in terms of anti-glycoprotein E (gE) antibody and cell-mediated immune (CMI) response in terms of frequency of gE-specific CD4[2+] T-cells and safety. VE analysis for ZOSTER-049 used historical control estimates from the ZOE-50/-70 placebo groups. Results In ZOSTER-049, 7,413 participants were enrolled and 7,277 were included in VE analysis (Figure 2). During 4 years of follow-up in ZOSTER-049, overall VE against HZ was 81.6% (95% confidence interval [CI]: 75.2–86.6). From 1 month post-dose 2 in ZOE-50/-70 until Y4 of ZOSTER-049, the overall VE was 89.0% (95% CI: 85.6–91.3). In ZOSTER-049, anti-gE antibody concentrations persisted > 5 times above pre-vaccination up to Y10 after vaccination (Figure 3A). The frequency of gE-specific CD4[2+] T-cells remained above pre-vaccination from Y6 to Y10 after vaccination (until the end of Y4 of ZOSTER-049) (Figure 3B). No safety signals were identified until the end of Y4 of ZOSTER-049. Conclusion Efficacy against HZ and immune responses to RZV remained high until the end of the observation period for this Y4 interim analysis suggesting that the clinical benefit of the RZV in adults ≥ 50 YOA is sustained for at least 10 years after vaccination. RZV safety profile remained clinically acceptable. Funding GlaxoSmithKline Biologicals SA Disclosures Ana Strezova, MD, MSc, GSK: I am an employee of GSK group of companies and hold shares from GSK group of companies as part of my employee remuneration Javier Diez-Domingo, MD, PhD, GSK: Grant/Research Support|GSK: Honoraria|MSD: Advisor/Consultant|MSD: Grant/Research Support|MSD: Consulting fees to the author and his institution|SANOFI: Advisor/Consultant|SANOFI: Grant/Research Support|SANOFI PASTEUR: Consulting fees to the author and his institution|SEQIRUS: Honoraria|SEQIRUS: Honoraria to the author and his institution Kamal Al Shawafi, MD, Modis: I am an employee of Modis, working on behalf of the GSK group of companies Juan Carlos Tinoco, MD, GSK: Grant/Research Support Meng Shi, MS, GSK: I am an employee of GSK group of companies Paola Pirrotta, n/a, GSK: I am an employee of GSK group of companies and hold shares from GSK group of companies as part of my employee remuneration Agnes Mwakingwe-Omari, MD/PhD, GSK: I am an employee of GSK group of companies.

Project description:IntroductionThis study aimed to update cost-effectiveness and public health impact estimates of the two-dose recombinant zoster vaccine (RZV) compared with no vaccination against herpes zoster (HZ) in the Japanese population aged 65 years. List price of the vaccine and latest RZV efficacy and waning estimates were incorporated.MethodsA multicohort static Markov model with a cycle length of 1 year was used to follow a hypothetical cohort of one million people aged 65 years over their remaining lifetime (base case). Age-stratified vaccine efficacy and waning rates were updated on the basis of the latest clinical trial data (interim ZOE-LTFU; NCT02723773). First-dose coverage was assumed at 40%, and second-dose compliance was assumed at 95%. Costs and outcomes were discounted at 2% annually, and the incremental cost-effectiveness ratio (ICER) was calculated from payer and societal perspectives. The societal perspective considered productivity loss due to suffering HZ, or due to suffering HZ and time required for vaccination. Sensitivity analyses explored the overall uncertainties in the model. Scenario analyses for Japanese adults aged 50, 60, 70, 80, ≥ 50, and ≥ 65 years (main scenario) were conducted. An ICER below ¥5-6 million/quality-adjusted life-year (QALY) was considered cost-effective.ResultsRZV was estimated to prevent 71,423 HZ cases and 15,858 post-herpetic neuralgia (PHN) cases per million people aged 65 years compared with no vaccine in Japan. The ICER was ¥4,205,515 from a payer perspective and was most sensitive to assumptions regarding vaccine efficacy waning, proportion of patients with HZ developing PHN, and HZ incidence. From societal perspectives, ICERs were ¥3,854,192 (productivity loss from suffering HZ only) and ¥4,622,212 (productivity loss from suffering HZ and time required for vaccination). Overall, the results were considered robust under extensive sensitivity and scenario analyses.ConclusionVaccination against HZ with RZV is cost-effective compared with no vaccination in Japanese adults aged 65 years.

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2905. Long-term Immunological Persistence of the Adjuvanted Recombinant Zoster Vaccine: Clinical Data and Mathematical Modeling

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