在人类首次研究中,对狂犬病病毒糖蛋白(RABV-G)-mRNA疫苗的免疫反应取决于给药途径,需要专门的设备。在成功的临床前研究与mRNA封装在脂质纳米颗粒(LNP),我们测试了mRNA-LNP制剂(CV7202)。
在这个阶段1,多中心,在比利时和德国的对照研究中,我们招募了55名健康的18-40岁的年轻人接受5μg的肌肉注射(n=10),1μg(n=16),在第1天或2μg(n=16)CV7202;1μg和2μg组的子集(n=8)在第29天接受第二剂量。对照组(n=10)接受狂犬病疫苗,拉比普尔,在第1天,第8天和第29天。使用日记卡评估疫苗接种后长达28天的安全性和反应原性;通过RFFIT和通过ELISA将免疫原性测量为RABV-G特异性中和滴度(VNT)。
由于最初测试的5μgCV7202的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2μg剂量。没有发生与疫苗相关的严重不良事件或停药。Low,从第15天开始,到第29天可检测到剂量依赖性VNT反应,1、2和5μg组的31%和22%,分别,VNTs≥0·5IU/mL,被认为是世卫组织的适当回应。在两次1或2μg剂量后,到第43天,所有接受者的滴度均≥0.5IU/mL。第57天的GMT并未显着低于拉比普尔的GMT,在两次接种后,所有接种疫苗的人都有足够的反应。CV7202引发的VNT与RABV-G特异性IgG抗体显著相关(r2=0.8319,p<0.0001)。
两个1μg或2μg剂量的CV7202在所有受者中均具有良好的耐受性,并引起符合WHO标准的狂犬病中和抗体反应。但是5μg对预防性疫苗具有不可接受的反应原性。ClinicalTrials.gov标识符:NCT03713086。
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.