Epidemiology and risk factors
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Prevention through vaccination: The ZOE programme - RZV pivotal and extension studies in individuals over 50 years of age
The efficacy of the Recombinant Zoster Vaccine (RZV) was evaluated in two Phase 3 clinical trials, Zoster Efficacy Study in Adults 50 Years of Age or Older (ZOE-50, NCT01165177) and Zoster Efficacy Study in Adults 70 Years of Age or Older (ZOE-70, NCT01165229).1,2 The Zoster-049 study (NCT02723773) is an ongoing long-term follow-up (LTFU) study of the ZOE-50 and ZOE-70 studies.3,4
ZOE-50 and ZOE-70 studies
Both pivotal Phase 3 trials were randomised, placebo-controlled studies conducted in 18 countries in Europe, North America, Latin America and Asia-Australia.1-3
Participants received two doses of herpes zoster/su or placebo (assigned in a 1:1 ratio) administered intramuscularly 2 months apart.1,2 Vaccine efficacy against herpes zoster was assessed in participants above 50 years of age in ZOE-50.1,2 Pooled analysis of ZOE-50 and ZOE-70 inform on efficacy in participants above 70 years of age as well as post-herpetic neuralgia (PHN).1,2 In the respective studies vaccine efficacy assessed reduction in risk of herpes zoster compared to placebo.1,2
Total vaccinated cohort: ZOE-50: N=7698 (RZV) and N=7713 (Placebo); ZOE-70: N=6950 (RZV) and N=6950 (Placebo). Blood sampling: all subjects at Visit 1 and Visit 3; humoral and cellular-mediated immunity subsets of subjects at the other visits. *In case of suspected herpes zoster, the subject had additional visits and contacts for follow-up of herpes zoster. NaCI, sodium chloride; RZV, recombinant zoster vaccine.
ZOE-50 and ZOE-70 study results
Vaccine efficacy by subject age and time post vaccination.1,2
Vaccine efficacy against herpes zoster in ZOE-50 (subjects ≥50 years old) and pooled data from ZOE-50/-70 (subjects ≥70 years old).1,2
mTVC in ZOE-50: RZV=7,344 and Placebo=7,415. mTVC in pooled ZOE-50/-70 for 70+ years of age: RZV=8,250 and Placebo=8,346. p<0.001 for all age groups versus placebo. *Mean follow-up 3.2 years (ZOE-50); †Mean follow-up 3.7 years (pooled ZOE-50/-70 data for subjects ≥70 years old); ‡Modified vaccinated cohort (excludes subjects not receiving dose 2 or who developed herpes zoster within 1 month after dose 2). mTVC, modified total vaccinated cohort; VE, vaccine efficacy.
VE against herpes zoster-related complications by age group.1,5
Vaccine efficacy against herpes zoster-related complications (post-herpetic neuralgia [PHN] or non-PHN) for pooled data from ZOE-50/-70 (subjects ≥50 years and ≥70 years old). Number of PHN and non-PHN complications are shown in the table below the graph.1,5
mTVC in pooled ZOE-50/-70 for 50+ years of age: RZV=13,881 and Placebo=14,035. mTVC in pooled ZOE-50/-70 for 70+ years of age: RZV=8,250 and Placebo=8,346. *Mean follow-up periods: overall, 3.8 years; ZOE-50, 3.9 years; and ZOE-70, 3.7 years; †p<0.01 vs placebo; ‡Numbers of cases in the placebo group were not sufficient to obtain a significant result; §HZ vasculitis, disseminated, ophthalmic, and neurological disease. PHN defined as zoster-associated pain rated as ≥3 (on a 0‒10 scale), persisting or appearing more than 90 days after onset of zoster rash. mTVC, modified total vaccinated cohort; PHN, postherpetic neuralgia; RZV, recombinant zoster vaccine; VE, vaccine efficacy.
Reactogenicity of RZV compared with placebo6
Figure reproduced with permission from López-Fauqued M, et al. Vaccine. 2019;37:2482-2493. Licensed under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
- The most frequently reported local adverse reactions was pain at the injection site; myalgia, fatigue and headache were the most frequently reported general reactions6
- The majority of reactions, both local and systemic, were mild to moderate in intensity and of short duration (1‒3 days)1,2,6
The incidence of serious adverse events (SAEs), deaths and potential immune-mediated diseases (pIMDs) was similar between those who received RZV and those who received placebo in the ZOE-50 and ZOE-70 studies:6
- SAEs: Within 1-year post-last dose, 1482 (10.1%) RZV and 1525 (10.4%) placebo recipients reported ≥1 SAE
- Fatal SAEs: Within 1-year post-last dose, 153 (1.0%) RZV and 168 (1.1%) placebo recipients reported fatal SAEs
- pIMDs: Within 1-year post-last dose, 90 (0.6%) RZV and 105 (0.7%) placebo recipients reported pIMDs
pIMDs, potential immune-mediated disease; RZV, recombinant zoster vaccine; SAE, serious adverse event.
Key results
Efficacy:
- Greater than 91% efficacy against HZ shown in all age groups ‒from 50 to over 80 years of age1,2
- RZV reduced risk of PHN and non-PHN complications including herpes zoster vaculitis, disseminated disease, ophthalmic disease, neurological disease visceral disease, stroke1,5,7
Safety:
- The majority of reactions, both local and systemic, were mild to moderate in intensity and of short duration (1‒3 days)1,2,6
- Overall incidences of SAEs, deaths and pIMDS were similar between RZV and placebo6
Zoster-049 study
The Zoster-049 study (NCT02723773) is an ongoing long-term follow-up (LTFU) study of the ZOE-50 and ZOE-70 studies.3,4
ZOSTER-049 is a phase 3b, open-label, multi-country, multi-center, long-term follow-up study of the pivotal trials introduced above to assess the long-term efficacy, immunopersistence and safety of RZV.4 Participants who received at least 1 dose of RZV in the ZOSTER-50/-70 studies and confirmed their interest to enroll in the study, were considered for entry.4 7413 participants were included in the according-to-protocol cohorts for humoral and CMI (cell-mediated immunity) persistence. At the end of the observation period for the Y4 interim analysis (Data Lock Point: August/2021), the participants had completed approximately 10 years of follow up post vaccination.4
*Samples collected only from participants in the humoral immunogenicity and cell-mediated immunity subsets. Primary long-term vaccine efficacy was assessed in mTVC (N=7277) and included data over Year 6 to Year 10 after vaccination. Secondary long-term vaccine efficacy was assessed in ZOE-50/ZOE-70 mTVC (N=13,881). Immunogenicity persistence was assessed in the according-to-protocol humoral-mediated immune subset (N=813) and the cell-mediated immune subset (N=108) and included data at Year 5 to Year 10 after vaccination. Long term safety was assessed in mTVC (N=7277). DLP, data lock point; YOA, years of age.
Overall VE of RZV against herpes zoster remained above 81% over Zoster-049 and 89%, from 1 month post-second RZV dose in ZOE-50/-70.4
*RZV versus placebo recipients from the ZOE-50/-70 studies in Years 1-4.
^RZV versus matched historical controls from the placebo group in the ZOE-50/-70 studies. The same N and follow-up period were considered for the historical control and vaccinated group. n for historical controls represents the projected number of included placebo group participants from ZOE-50/-70 with at least one confirmed herpes zoster episode based on the estimated incidence rate. More than half of the placebo recipients from ZOE-50/-70 were also vaccinated with RZV in a subsequent study.
Therefore, historical control estimates of incidence rate from the ZOE-50/-70 placebo groups were used to assess vaccine efficacy during ZOE-LTFU.4
†Data collection for Year 10 was incomplete at the data lock point. June 2023 is the end of the interim study, the study is still ongoing. mTVC (N=7277); from 1-month post-dose 2 to Year 4 interim analysis data lock point (August 2021).1 CI, confidence interval; HZ, herpes zoster; M, month; mTVC, modified total vaccinated cohort; N, number of individuals included in each group; n, number of individuals having at least one confirmed herpes zoster episode; RZV, recombinant zoster vaccine; VE, vaccine efficacy; Y, year.
Frequency of gE-specific CD4+ T cells.3,4,9
![Frequency of gE-specific CD4[2+]T cells.](/content/dam/cf-pharma/medicalaffairs/en_PM/vaccines/herpes-zoster/prevention-through-vaccination/box-and-whisker-plot-showing.png "Frequency of gE-specific CD4[2+]T cells.")
*The frequency of gE-specific CD4+ T cells was assessed per 106 total CD4+ T cells.3 For Y1-Y3, annual ZOE-50/-70 data was used. For Y4, data were not available due to the gap between the ZOE-50/-70 and ZOSTER-049.3 ‡Data not shown because only 3 participants had available results for this analysis.4 §Data collection was incomplete at the time of data lock for the second interim analysis.4
Figure adapted with permission from Boutry C, et al. Clin Infect Dis. 2022;74:1459-1467, Cunningham AL, et al. J Infect Dis. 2018;217:1750-1760 and Strezova A, et al. Open Forum Infect Dis. 2022; ofac485. All licensed under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
Humoral immune response by year post vaccination.3,4,9
For Y1–Y3, annual ZOE-50/-70 data was used. For Y4, data were not available due to the gap between the ZOE-50/-70 and the present LTFU study.3 ‡Data collection was incomplete at the time of data lock for the second interim analysis.4
Figure adapted with permission from Boutry C, et al. Clin Infect Dis. 2022;74:1459-1467, Cunningham AL, et al. J Infect Dis. 2018;217:1750-1760 and Strezova A, et al. Open Forum Infect Dis. 2022; ofac485. All licensed under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
Results from Zoster-049 study:3,4
- No deaths or SAEs were considered causally related to vaccination by the investigator.
- 5 participants reported herpes zoster-related complications; there were 3 cases of PHN and 2 cases of disseminated herpes zoster (all cases resolved).
Zoster-049 results summary
- RZV demonstrated VE against HZ of 81.6% at Year 4 interim analysis4 (over a mean follow-up of 5.6±0.3 years to 9.6±0.3 years after initial vaccination). VE against HZ from 1-month post dose 2 to ~10 years post-vaccination was 89.0%
- The humoral and cell-mediated responses remained stable until the end of observation (ie ~10 years after initial vaccination)4
- Anti-gE antibody concentrations persisted >5x above pre-vaccination levels up to ~Year 10 after vaccination
- Median gE-specific CD4+ T-cell frequencies persisted at >6-fold above pre-vaccination levels up to ~Year 10 after vaccination
- Safety profile remains clinically acceptable, and no new safety signals were identified up to DLP for Year 4 interim analysis3,4
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Abbreviations
ATP, according to protocol; CI, confidence interval; CMI, cell-mediated immunity; DLP, data lock point; gE, glycoprotein E; GM, geometric mean; GMC, geometric mean concentration; HMI, humoral mediated immunity; LTFU, long-term follow-up; max, maximum; min, minimum; mTVC, modified total vaccinated cohort; N, number of participants with available results; pIMDs, potential immune-mediated disease; PHN, post-herpetic neuralgia; RZV, recombinant zoster vaccine; SAE, serious adverse event; VE, vaccine efficacy; Y, year; YOA, years of age; ZOE-50, Zoster Efficacy Study in Adults 50 Years of Age or Older; ZOE-70, Zoster Efficacy Study in Adults 70 Years of Age or Older.
References
- Cunningham AL, et al. N Engl J Med. 2016;375:1019-1032.
- Lal H, et al. N Engl J Med. 2015;372:2087-2096.
- Boutry C, et al. Clin Infect Dis. 2022;74:1459-1467.
- Strezova A, et al. Open Forum Infect Dis. 2022; ofac485. https://doi.org/10.1093/ofid/ofac485
- Kovac M, et al. Vaccine. 2018;36:1537-1541.
- López-Fauqued M, et al. Vaccine. 2019;37:2482-2493.
- Study 113077 clinical study summary; 2016. Available from: https://www.gskstudyregister.com/study/3822
- ClinicalTrials.gov. NCT02723773. https://clinicaltrials.gov/ct2/show/NCT02723773 (accessed August 2022).
- Cunningham AL, et al. J Infect Dis. 2018;217:1750-1760.
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