Safety, tolerability, and immunogenicity of the respiratory syncytial virus prefusion F subunit vaccine DS-Cav1: a phase 1, randomised, open-label, dose-escalation clinical trial.
Safety, tolerability, and immunogenicity of the respiratory syncytial virus prefusion F subunit vaccine DS-Cav1: a phase 1, randomised, open-label, dose-escalation clinical trial.
复制标题
DOI：
10.1016/s2213-2600(21)00098-9
复制
发表时间：
2021-10
期刊：
影响因子：
--
通讯作者：
VRC 317 study team
中科院分区：
文献类型：
--
作者：
Ruckwardt TJ;Morabito KM;Phung E;Crank MC;Costner PJ;Holman LA;Chang LA;Hickman SP;Berkowitz NM;Gordon IJ;Yamshchikov GV;Gaudinski MR;Lin B;Bailer R;Chen M;Ortega-Villa AM;Nguyen T;Kumar A;Schwartz RM;Kueltzo LA;Stein JA;Carlton K;Gall JG;Nason MC;Mascola JR;Chen G;Graham BS;VRC 317 study team
已证明多种主动疫苗接种方法在降低婴儿和老年人呼吸道合胞病毒（RSV）引起的显著发病率和死亡率方面无效。可能需要一种在中和活性方面赋予实质性和可持续增强的疫苗来保护免受严重RSV疾病。在一项随机开放标签I期临床试验中，在美国的一个研究中心，在健康成人中评价了稳定的融合前F疫苗DS-Cav 1的剂量、安全性、耐受性和免疫原性。受试者以1：1的比例（每个剂量组有或没有氢氧化铝）随机分配，在第0周和第12周接受递增剂量的50 mcg、150 mcg或500 mcg DS-Cav 1。一个受试者亚组在第0周仅接受单次疫苗接种。主要目的是评价每个剂量水平下的安全性和耐受性，并评价至第44周的中和活性和RSV F结合抗体，作为次要和探索性目的。该试验在ClinicalTrials.gov注册，NCT 03049488，已完成，不再招募。在2017年2月至2018年11月期间，对244名受试者进行了资格筛选，95名受试者入组接受50 mcg（n=30），150（n=35）或500 mcg（n=30）剂量水平的DS-Cav 1。DS-Cav 1安全且耐受性良好，未发现与疫苗相关的严重疫苗相关不良事件。单次接种后，DS-Cav 1疫苗接种引发了强大的中和活性和结合抗体。在第44周，所有组中的F特异性抗体水平和中和活性与基线相比显著增加。虽然与较低剂量或单次免疫相比，较高的疫苗剂量或第二次免疫引起了短暂的优势，但两者都不显著影响长期中和。DS-Cav 1疫苗接种引起RSV F特异性抗体和中和活性的强烈增强，其持续高于基线至少10个月。剂量、疫苗接种次数或佐剂对中和活性无长期影响，表明对有抗原经验的个体进行单次低剂量的F前免疫接种可提供贯穿整个RSV季节的保护。这项工作得到了国家过敏和传染病研究所的内部资助。试验注册号：NCT 03049488
Multiple active vaccination approaches have proven ineffective in reducing the significant morbidity and mortality caused by respiratory syncytial virus (RSV) in infants and the elderly. A vaccine conferring a substantial and sustainable boost in neutralizing activity is likely required to protect against severe RSV disease. In a randomized open-label phase 1 clinical trial, the stabilized prefusion F vaccine DS-Cav1 was evaluated for dose, safety, tolerability, and immunogenicity in healthy adults at a single US site. Participants were randomized at a 1:1 ratio (with or without aluminum hydroxide per dose group) to receive escalating doses of 50 mcg, 150 mcg, or 500 mcg DS-Cav1 at weeks 0 and 12. A subset of subjects received only a single vaccination at week 0. The primary objectives evaluated the safety and tolerability at every dose level, and neutralizing activity and RSV F-binding antibodies were evaluated through week 44 as secondary and exploratory objectives. The trial is registered with ClinicalTrials.gov, NCT03049488, and is complete and no longer recruiting. Between February 2017 and November 2018, 244 participants were screened for eligibility and 95 were enrolled to receive DS-Cav1 at the 50 mcg (n=30), 150 (n=35), or 500 mcg (n=30) dose level. DS-Cav1 was safe and well-tolerated and no serious vaccine-associated adverse events deemed related to the vaccine were identified. DS-Cav1 vaccination elicited robust neutralizing activity and binding antibodies after a single dose. At week 44, F-specific antibody levels and neutralizing activity were significantly increased compared to baseline in all groups. While a higher vaccine dose or second immunization elicited a transient advantage compared to lower doses or a single immunization, neither significantly impacted long-term neutralization. DS-Cav1 vaccination elicited a robust boost in RSV F-specific antibodies and neutralizing activity that was sustained above baseline for at least ten months. There was no long-term impact of dose, number of vaccinations, or adjuvant on neutralizing activity, indicating that a single low-dose of pre-F immunization of antigen-experienced individuals may confer protection that extends through an entire RSV season. This work was supported with intramural funding from the National Institutes of Allergy and Infectious Diseases. Trial Registration Number: NCT03049488