Immunogenicity and safety of different dose levels of Ad26.RSV.preF/RSV preF protein vaccine in adults aged 60 years and older: A randomized, double-blind, placebo-controlled, phase 2a study

IF 4.5 3区医学 Q2 IMMUNOLOGY Vaccine Pub Date : 2024-09-13 DOI:10.1016/j.vaccine.2024.126273

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Abstract

Background

Respiratory syncytial virus (RSV) can cause severe illness in older adults. A combination vaccine containing Ad26.RSV.preF and purified recombinant RSV preF protein has previously demonstrated efficacy and tolerability in older adults. We report results of a dose-ranging study to determine immunogenicity and safety of different doses of the Ad26.RSV.preF component in the combined Ad26.RSV.preF/RSV preF protein vaccine to support Ad26.RSV.preF drug product release and stability specifications.

Methods

In this randomized, double-blind, placebo-controlled, phase 2a study, adults aged ≥60 years in good or stable health were randomly assigned within 1 of 3 cohorts to receive either placebo or Ad26.RSV.preF/RSV preF protein, composed of different doses of Ad26.RSV.preF with a fixed dose of RSV preF protein (150 μg). Ad26.RSV.preF doses in Cohort 1 (4 dose-down groups) ranged from 3.7 × 10⁹ to 1.0 × 10¹¹ viral particles (vp). Doses in Cohorts 2 and 3 (2 dose-up groups, each) ranged from 1.0 to 1.6 × 10¹¹ vp. Primary endpoints were immunogenicity (RSV preF protein antibody titers) for Cohort 1 and safety (solicited local and systemic adverse events [AEs] and unsolicited AEs) for Cohorts 2 and 3. Immunogenicity analyses (RSV preF protein antibody titers, RSV A2 neutralizing antibodies, and RSV-F–specific interferon-γ enzyme-linked immunosorbent spot) were performed on the day of vaccination and 14 days, 3 months, and 6 months postvaccination. Safety was monitored from vaccination until study end.

Results

Overall, 454 participants were enrolled and received 1 dose of study vaccine or placebo (Cohort 1, n = 226; Cohort 2, n = 124; Cohort 3, n = 104). No substantial differences in measured immune responses were observed between lower or higher Ad26.RSV.preF doses compared with Ad26.RSV.preF 1.0 × 10¹¹ vp across all postvaccination time points. All Ad26.RSV.preF doses between 3.7 × 10⁹ vp and 1.6 × 10¹¹ vp were well tolerated, with no safety issues identified.

Conclusions

Results of this dose-ranging study may be used to inform the refinement of Ad26.RSV.preF drug product release and stability specifications.

Clinical Trial Registration: ClinicalTrials.gov Identifier: NCT04453202

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不同剂量水平的 Ad26.RSV.preF/RSV preF 蛋白疫苗对 60 岁及以上成人的免疫原性和安全性：一项随机、双盲、安慰剂对照的 2a 期研究

背景呼吸道合胞病毒（RSV）可导致老年人患重病。含有 Ad26.RSV.preF 和纯化重组 RSV preF 蛋白的联合疫苗曾在老年人中证实了有效性和耐受性。我们报告了一项剂量范围研究的结果，该研究旨在确定Ad26.RSV.preF/RSV preF蛋白联合疫苗中不同剂量Ad26.RSV.preF成分的免疫原性和安全性，以支持Ad26.RSV.preF药物产品的释放和稳定性规范。方法在这项随机、双盲、安慰剂对照的 2a 期研究中，年龄≥60 岁、健康状况良好或稳定的成年人被随机分配到 3 个队列中的 1 个，接受安慰剂或 Ad26.RSV.preF/RSV preF 蛋白，后者由不同剂量的 Ad26.RSV.preF 和固定剂量的 RSV preF 蛋白（150 μg）组成。第 1 组（4 个剂量递减组）的 Ad26.RSV.preF 剂量介于 3.7 × 109 到 1.0 × 1011 病毒粒子 (vp) 之间。第 2 组和第 3 组（各 2 个剂量增加组）的剂量范围为 1.0 至 1.6 × 1011 vp。第 1 组的主要终点是免疫原性（RSV preF 蛋白抗体滴度），第 2 组和第 3 组的主要终点是安全性（主动要求的局部和全身不良事件 [AEs]，以及主动要求的 AEs）。免疫原性分析（RSV preF 蛋白抗体滴度、RSV A2 中和抗体和 RSV-F 特异性干扰素-γ 酶联免疫吸附斑）在接种当天、接种后 14 天、3 个月和 6 个月进行。从接种疫苗到研究结束，对安全性进行了监测。结果总共有 454 人参加了研究，并接种了 1 剂研究疫苗或安慰剂（队列 1，n = 226；队列 2，n = 124；队列 3，n = 104）。在接种后的所有时间点上，与 Ad26.RSV.preF 1.0 × 1011 vp 相比，较低或较高剂量的 Ad26.RSV.preF 在测得的免疫反应上均未见明显差异。Ad26.RSV.preF 剂量介于 3.7 × 109 vp 和 1.6 × 1011 vp 之间的所有 Ad26.RSV.preF 均具有良好的耐受性，未发现任何安全性问题。结论这项剂量范围研究的结果可用于完善 Ad26.RSV.preF 药物产品的释放和稳定性规范：临床试验注册：ClinicalTrials.gov Identifier：NCT04453202

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来源期刊

Vaccine 医学-免疫学

CiteScore

8.70

自引率

5.50%

发文量

992

审稿时长

131 days

期刊介绍： Vaccine is unique in publishing the highest quality science across all disciplines relevant to the field of vaccinology - all original article submissions across basic and clinical research, vaccine manufacturing, history, public policy, behavioral science and ethics, social sciences, safety, and many other related areas are welcomed. The submission categories as given in the Guide for Authors indicate where we receive the most papers. Papers outside these major areas are also welcome and authors are encouraged to contact us with specific questions.