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Prevention through vaccination: ZOE Programmes

50歳以上の人を対象とした組み換え帯状疱疹ワクチン（RZV）の主要試験および延長試験について

RZVの有効性は、2つの第3相臨床試験、成人50歳以上におけるZoster Efficacy Study（ZOE-50、NCT01165177）および成人70歳以上におけるZoster Efficacy Study（ZOE-70、NCT01165229）において評価されました1,2。
Zoster-049試験（NCT02723773）は、ZOE-50試験およびZOE-70試験の長期フォローアップ（LTFU）試験として実施中です3,4。

ZOE-50 and ZOE-70 studies

両試験は、欧州、北米、中南米、アジア・オーストラリアの18カ国で実施された無作為化プラセボ対照試験です1-3。
参加者は、RZVまたはプラセボ（1：1の割合で割り当てられた）を2ヶ月間隔で2回筋肉内投与されました1,2。 ZOE-50では、50歳以上の参加者を対象に帯状疱疹に対するワクチンの有効性が評価されました。
ZOE-50とZOE-70のプール解析では、70歳以上の被験者における有効性と帯状疱疹後神経痛
（PHN）について報告されています1,2。それぞれの試験において、ワクチンの有効性は、プラセボと比較した帯状疱疹発症の減少を評価しました1,2。

Study Design 1,2

Study design

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

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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

VE against herpes zoster across age groups

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

VE against herpes zoster-related complications*

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

Reactogenicity of RZV compared with placebo

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
SAEs, fatal SAEs and pIMDs in adults 50 years and older within 1-year post-last dose

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

【有効性】

50 歳から 80 歳以上のすべての年齢層で、HZ に対する 91％以上の有効性が確認されました1,2。
RZVは、血管炎、びまん性疾患、眼疾患、神経疾患、内臓疾患、脳卒中など、PHNおよび非PHN合併症のリスクを減少させました1,5,7。

【安全性】

局所および全身性の副反応の大部分は、軽度から中等度の強さで、短期間（1～3日）でした1,2,6。
SAE、死亡、pIMDSの全体的な発生率は、RZVとプラセボで同程度でした6。

Zoster-049 study

Zoster-049試験（NCT02723773）は、ZOE-50試験およびZOE-70試験の長期追跡（LTFU）試験として進行中です3,4。

ZOSTER-049試験は、RZVの長期有効性、免疫持続性、安全性を評価する上記で紹介した主要試験の第3b相、非盲検、多施設、長期フォローアップ試験です4。ZOE-50/70試験でRZVの投与を1回以上受け、試験への登録の意思が確認できた参加者が含まれ、一部の被験者では液性免疫とCMI（細胞性免疫）も評価されました4。 中間解析の観察期間終了時（データロックポイント：2021年8月）には、参加者の多くはワクチン接種後約10年のフォローアップを完了していました4。

Study Design 3,4

Zoster-049 study design

*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.

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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

Overall VE of RZV against herpes zoster remained above 80% over Zoster-049 and from 1 month post-second RZV dose in ZOE-50/-70

*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.

*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

Humoral immune response by year post vaccination

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の結果概要

RZV は、LTFUの中間解析4 において、帯状疱疹に対する予防効果が 81.6%でした（初回接種後 5.6±0.3 年から 9.6±0.3 年の平均フォローアップ期間）。2 回目接種後 1 ヵ月から 10 年後までの HZ に対する予防効果は 89.0％でした。
液性および細胞性免疫応答は、観察終了時（初回接種から10年後）まで安定して維持されていました4 。すなわち、抗gE抗体価はワクチン接種後10年目までワクチン接種前の5倍以上、gE特異的CD4+T細胞の出現数の中央値はワクチン接種後10年目までワクチン接種前の6倍以上で維持されていました。
安全性プロファイルは引き続き臨床的に忍容性があり、4年目の中間解析のDLPまで新たな安全性シグナルは確認されませんでした3,4。

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

  1. Cunningham AL, et al. N Engl J Med. 2016;375:1019-1032.
  2. Lal H, et al. N Engl J Med. 2015;372:2087-2096.
  3. Boutry C, et al. Clin Infect Dis. 2022;74:1459-1467.
  4. Strezova A, et al. Open Forum Infect Dis. 2022; ofac485. https://doi.org/10.1093/ofid/ofac485
  5. Kovac M, et al. Vaccine. 2018;36:1537-1541.
  6. López-Fauqued M, et al. Vaccine. 2019;37:2482-2493.
  7. Study 113077 clinical study summary; 2016. Available from: https://www.gskstudyregister.com/study/3822
  8. ClinicalTrials.gov. NCT02723773. https://clinicaltrials.gov/ct2/show/NCT02723773 (accessed August 2022).
  9. Cunningham AL, et al. J Infect Dis. 2018;217:1750-1760.

NX-JP-SGX-WCNT-230007 | March 2023