Emerging Infectious Diseases Branch, Center for Infectious Disease Research, Walter Reed Army Institute of Research, Silver Spring, MD, USA.
Emerging Infectious Diseases Branch, Center for Infectious Disease Research, Walter Reed Army Institute of Research, Silver Spring, MD, USA; Henry M. Jackson Foundation for the Advancement of Military Medicine, Bethesda, MD, USA.
Lancet Infect Dis. 2024 Dec;24(12):1393-1402. doi: 10.1016/S1473-3099(24)00406-7. Epub 2024 Aug 14.
Recent outbreaks between 2015-17 and production delays have led to a yellow fever vaccine shortage. Therefore, there is an urgent need for new yellow fever vaccines with improved production scalability. A next-generation live-attenuated yellow fever vaccine candidate (vYF), produced in a Vero cell line has shown similar immunogenicity to licensed yellow fever vaccines in preclinical studies. In this study, we aimed to report the safety and immunogenicity of vYF in human clinical trial participants.
In this first in-human, phase 1 randomised, observer-blind, active-controlled, dose-ranging clinical trial conducted at a single centre in the USA (Walter Reed Army Institute of Research, Silver Spring, MD, USA), 72 healthy adults (aged 18-60 years), without a known history of flavivirus infection or vaccination were randomly assigned (1:1:1:1) using interactive response technology to receive one dose of either vYF at 4, 5 or 6 Log CCID or the licensed YF-VAX (18 individuals per group). The primary outcomes were safety, neutralising antibody (NAb) titres through D180 post-vaccination in the per-protocol analysis set (comprised of yellow fever-naive participants who received their intended vaccine and provided a valid post-vaccination blood sample), and occurrence, and level of yellow fever viraemia in each vaccine group through D14 post-vaccination.
All vYF doses had a safety and tolerability profile similar to YF-VAX. The most frequently reported solicited injection site reactions (vYF groups vs YF-VAX group) were pain (22% [12 of 54 participants, 95% CI 12-36] vs 28% [five of 18 participants, 10-54]), and erythema (13% [seven of 54 participants, 5-25] vs 39% [seven of 18 participants, 17-64]), with headache (32% [17 of 54 participants, 20-46] vs 44% [eight of 18 participants, 22-69]) and malaise (26% [14 of 54 participants, 15-40] vs 33% [six of 18 participants, 13-59]) as the most frequently reported solicited systemic reactions. One grade 3 solicited reaction (erythema) reported in the YF-VAX group resolved spontaneously. No serious unsolicited adverse events or deaths were reported. Viraemia was transiently detected in 50 participants between D4 and D10 in all groups and was observed in more participants or for a longer time in the vYF 6 Log CCID and YF-VAX groups. All yellow fever-naive vaccine recipients across the study groups seroconverted yielding four-fold increase from baseline in yellow fever NAb titres measured by yellow fever microneutralisation assay by D28 and were seroprotected with yellow fever NAb titres of at least 10 [1/dil]). Overall, 100% (18 of 18 participants, 95% CI 82-100), 89% (16 participants, 65-99), 100% (18 participants, 82-100), and 94% (17 participants, 73-100) of participants in the vYF 4 Log, vYF 5 Log, vYF 6 Log CCID groups, and YF-VAX group, respectively, remained seroprotected through D180.
vYF has a similar safety and immunogenicity profile to YF-VAX. In general, the vYF 5 Log CCID dose appeared to show optimal viraemia, safety, and immunogenicity, and was chosen for subsequent development.
Sanofi.
2015-17 年的几次暴发以及生产延迟导致黄热病疫苗短缺。因此，迫切需要具有改进的生产可扩展性的新型黄热病疫苗。一种在 Vero 细胞系中生产的下一代减毒活黄热病疫苗候选物（vYF）在临床前研究中显示出与已批准的黄热病疫苗相似的免疫原性。在这项研究中，我们旨在报告 vYF 在人体临床试验参与者中的安全性和免疫原性。
这是在美国一家单中心（美国沃尔特·里德陆军研究所，马里兰州银泉）进行的首次人体、1 期随机、观察者盲、主动对照、剂量范围临床试验。72 名健康成年人（年龄 18-60 岁），无已知的黄病毒感染或疫苗接种史，使用交互式反应技术随机分配（1:1:1:1），接受 vYF 4、5 或 6 Log CCID 中的一种剂量或已批准的 YF-VAX（每组 18 人）。主要终点是安全性、通过接种后 180 天的中和抗体（NAb）滴度（在符合方案分析集（由接受预期疫苗接种且提供有效接种后血样的黄热病初免参与者组成）中），以及在接种后 14 天内每组黄热病病毒血症的发生和水平。
所有 vYF 剂量的安全性和耐受性与 YF-VAX 相似。最常报告的局部注射部位反应（vYF 组与 YF-VAX 组）为疼痛（22%[54 名参与者中的 12 名，95%CI 12-36]与 28%[18 名参与者中的 5 名，10-54]）和红斑（13%[54 名参与者中的 7 名，5-25]与 39%[18 名参与者中的 7 名，17-64]），头痛（32%[54 名参与者中的 17 名，20-46]与 44%[18 名参与者中的 8 名，22-69]）和不适（26%[54 名参与者中的 14 名，15-40]与 33%[18 名参与者中的 6 名，13-59]）是最常报告的全身反应。YF-VAX 组报告了 1 例 3 级局部反应（红斑），自发消退。没有报告严重的非预期不良事件或死亡。在所有组中，50 名参与者在 D4 至 D10 之间检测到短暂的病毒血症，vYF 6 Log CCID 和 YF-VAX 组中观察到更多参与者或更长时间的病毒血症。所有黄热病初免疫苗接种者在研究组中均产生血清转化，通过黄热病微量中和测定，黄热病 NAb 滴度在接种后 28 天增加 4 倍，黄热病 NAb 滴度至少为 10 [1/dil]，达到血清保护。总体而言，vYF 4 Log、vYF 5 Log、vYF 6 Log CCID 组和 YF-VAX 组的 18 名（95%CI 82-100）、16 名（65-99）、18 名（82-100）和 17 名（73-100）参与者分别保持血清保护至 180 天。
vYF 与 YF-VAX 具有相似的安全性和免疫原性。一般来说，vYF 5 Log CCID 剂量似乎显示出最佳的病毒血症、安全性和免疫原性，并被选为后续开发。
赛诺菲。
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