Proof-of-concept of a low-dose unmodified mRNA-based rabies vaccine formulated with lipid nanoparticles in human volunteers: A phase 1 trial.
Proof-of-concept of a low-dose unmodified mRNA-based rabies vaccine formulated with lipid nanoparticles in human volunteers: A phase 1 trial.
复制标题
DOI：
10.1016/j.vaccine.2020.12.070
复制
发表时间：
2021-02-22
期刊：
影响因子：
5.5
通讯作者：
Oostvogels L
中科院分区：
文献类型：
--
作者：
Aldrich C;Leroux-Roels I;Huang KB;Bica MA;Loeliger E;Schoenborn-Kellenberger O;Walz L;Leroux-Roels G;von Sonnenburg F;Oostvogels L
在一项首次人体研究中，对狂犬病病毒糖蛋白（RABV-G）-mRNA疫苗的免疫应答取决于给药途径，需要专门的器械。在成功进行了脂质纳米粒（LNP）中包封mRNA的临床前研究后，我们测试了mRNA-LNP制剂（CV 7202）。在比利时和德国进行的这项I期、多中心、对照研究中，我们入组了55名18-40岁的健康受试者，在第1天接受5 μg（n = 10）、1 μg（n = 16）或2 μg（n = 16）CV 7202肌内注射; 1 μg和2 μg组的亚组（n = 8）在第29天接受第二次给药。对照组（n = 10）在第1、8和29天接种狂犬病疫苗Rabipur。使用日记卡评估接种后28天内的安全性和反应原性;通过RFFIT和ELISA分别测量免疫原性（RABV-G特异性中和滴度（VNT）和IgG）。由于最初测试的5 μg CV 7202剂量引起不可接受的高反应原性，我们随后测试了耐受性更好的1和2 μg剂量。未发生与疫苗相关的严重不良事件或退出。从第15天开始可检测到低剂量依赖性VNT应答，到第29天，1、2和5 μg组中分别有31%和22%的VNT ≥ 0.5 IU/mL，WHO认为这是充分应答。两次1或2 μg给药后，所有受体在第43天的滴度均≥ 0.5 IU/mL。第57天的GMT并不显著低于Rabipur，Rabipur在两次接种后引起了所有接种者的充分反应。CV 7202引起的VNT与RABV-G特异性IgG抗体显著相关（r2 = 0.8319，p < 0.0001）。CV 7202的两个1 μg或2 μg剂量耐受性良好，并在所有接受者中引起符合WHO标准的狂犬病中和抗体应答，但5 μg对于预防性疫苗具有不可接受的反应原性。ClinicalTrials.gov标识符：NCT 03713086。
In a first-in-human study immune responses to rabies virus glycoprotein (RABV-G)-mRNA vaccine were dependent on the route of administration, necessitating specialized devices. Following successful preclinical studies with mRNA encapsulated in lipid nanoparticles (LNP), we tested an mRNA-LNP formulation (CV7202). In this phase 1, multi-center, controlled study in Belgium and Germany we enrolled 55 healthy 18–40-year-olds to receive intramuscular injections of 5 μg (n = 10), 1 μg (n = 16), or 2 μg (n = 16) CV7202 on Day 1; subsets (n = 8) of 1 μg and 2 μg groups received second doses on Day 29. Controls (n = 10) received rabies vaccine, Rabipur, on Days 1, 8 and 29. Safety and reactogenicity were assessed up to 28 days post-vaccination using diary cards; immunogenicity was measured as RABV-G-specific neutralizing titers (VNT) by RFFIT and IgG by ELISA. As initially tested doses of 5 μg CV7202 elicited unacceptably high reactogenicity we subsequently tested 1 and 2 μg doses which were better tolerated. No vaccine-related serious adverse events or withdrawals occurred. Low, dose-dependent VNT responses were detectable from Day 15 and by Day 29%, 31% and 22% of 1, 2 and 5 μg groups, respectively, had VNTs ≥ 0·5 IU/mL, considered an adequate response by the WHO. After two 1 or 2 μg doses all recipients had titers ≥ 0.5 IU/mL by Day 43. Day 57 GMTs were not significantly lower than those with Rabipur, which elicited adequate responses in all vaccinees after two doses. CV7202-elicited VNT were significantly correlated with RABV-G-specific IgG antibodies (r2 = 0.8319, p < 0.0001). Two 1 μg or 2 μg doses of CV7202 were well tolerated and elicited rabies neutralizing antibody responses that met WHO criteria in all recipients, but 5 μg had unacceptable reactogenicity for a prophylactic vaccine. ClinicalTrials.gov Identifier: NCT03713086.
登录
查看更多内容
DOI：
10.1038/nrd.2017.243
发表时间：
2018-04
期刊：
Nature reviews. Drug discovery
影响因子：
--
作者：
Pardi N;Hogan MJ;Porter FW;Weissman D
通讯作者：
Weissman D
影响因子：
9.2
作者：
Lutz J;Lazzaro S;Habbeddine M;Schmidt KE;Baumhof P;Mui BL;Tam YK;Madden TD;Hope MJ;Heidenreich R;Fotin-Mleczek M
通讯作者：
Fotin-Mleczek M
影响因子：
56.9
作者：
Chinazzi, Matteo;Davis, Jessica T.;Vespignani, Alessandro
通讯作者：
Vespignani, Alessandro
影响因子：
3.7
作者：
Kloverpris, Henrik N.;Jackson, Akil;Goulder, Philip
通讯作者：
Goulder, Philip
影响因子：
0.6
作者：
SIEG, A;ARAB, L;KOMMERELL, B
通讯作者：
KOMMERELL, B