Safety and immunogenicity of a live-attenuated influenza virus vector-based intranasal SARS-CoV-2 vaccine in adults: randomised, double-blind, placebo-controlled, phase 1 and 2 trials.
Safety and immunogenicity of a live-attenuated influenza virus vector-based intranasal SARS-CoV-2 vaccine in adults: randomised, double-blind, placebo-controlled, phase 1 and 2 trials.
复制标题
基于减毒活流感病毒载体的鼻内 SARS-CoV-2 疫苗在成人中的安全性和免疫原性：随机、双盲、安慰剂对照、1 期和 2 期试验
DOI：
10.1016/s2213-2600(22)00131-x
复制
发表时间：
2022-08
影响因子：
76.2
通讯作者：
Xia, Ning-Shao
中科院分区：
文献类型：
--
作者：
Zhu, Fengcai;Zhuang, Chunlan;Chu, Kai;Zhang, Liang;Zhao, Hui;Huang, Shoujie;Su, Yingying;Lin, Hongyan;Yang, Changlin;Jiang, Hanmin;Zang, Xia;Liu, Donglin;Pan, Hongxing;Hu, Yuemei;Liu, Xiaohui;Chen, Qi;Song, Qiaoqiao;Quan, Jiali;Huang, Zehong;Zhong, Guohua;Chen, Junyu;Han, Jinle;Sun, Hong;Cui, Lunbiao;Li, Jingxin;Chen, Yixin;Zhang, Tianying;Ye, Xiangzhong;Li, Changgui;Wu, Ting;Zhang, Jun;Xia, Ning-Shao
目前所有可用的SARS-CoV-2疫苗都是通过肌肉注射的方式接种。我们的目的是评价基于SARS-CoV-2载体的减毒活病毒疫苗(dNS1-RBD)在健康成人鼻腔喷雾接种的安全性和免疫原性。我们在江苏的中国中心进行了双盲、随机、安慰剂对照的1期和2期试验，随后是2期推广试验。入选的健康成人(≥18岁)，血清或指端血中SARS-CoV2总抗体检测为阴性(第1和第2期)，没有流行的SARS-CoV2感染或感染史，没有SARS-CoV2疫苗接种史(在所有三个试验中)。参与者被随机分配(第一阶段为4：1，第二阶段为2：1，扩展试验为1：1)，在第0天和第14天接受两次鼻腔注射dNS1-RBD疫苗或安慰剂，对于第二阶段的一半参与者，在第0天和第21天接受两次鼻腔注射。为了避免接种过程中的交叉污染，在扩展试验中，疫苗接受者和安慰剂接受者在不同的房间接种疫苗。第一阶段的主要结果是安全性(不良事件记录在第0-44天；严重不良事件记录在第二次服药后的第0天至12个月)。在第二阶段和延伸试验中，主要的免疫原性结果是在第二剂免疫原性方案中第二剂疫苗接种后1个月，外周血中SARS-CoV-2特异性T细胞应答(用干扰素-γELISpot法测定)，SARS-CoV-2受体结合域(RBD)特异性Ig G和分泌型Ig A抗体(S-Ig A)阳性转换率，以及血清中SARS-CoV-2RBD Ig G和鼻咽中SARS-CoV-2 RBD S-Ig A的浓度(EL ISA法)。分类资料分析采用χ-2检验和Fisher‘s精确检验，计量资料组间比较采用t检验和Wilcoxon秩和检验。这些试验在中国临床试验注册中心注册(ChiCTR2000037782、ChiCTR2000039715和ChiCTR2100048316)。在2020年9月1日至2021年7月4日期间，分别有63、724和297名没有SARS-CoV-2疫苗接种史的参与者参加了第一阶段、第二阶段和扩大试验。在疫苗组的684名参与者中，有133人(19%)在接种疫苗后至少报告了一次不良反应。大多数不良反应都很轻微。未发现与疫苗相关的严重不良事件。在第二阶段试验中，455名疫苗接受者中有211人(46%[95%可信区间42-51])和120名疫苗接受者中有48人(40%[31-49])观察到了特异性T细胞免疫应答，而在扩大试验中，111名安慰剂接受者中只有一人(1%[0-5])观察到了特异性T细胞免疫应答(P<；0.0001)。在第二阶段试验中，466名疫苗接受者中有48人(10%[95%CI 8-13])观察到RBD特异性免疫球蛋白血清转换(在应答者中几何平均滴度[GMT]3·8[95%CI 3·4-4·3])，在扩大试验中，143名疫苗接受者(GMT 4·4[3·3-5·8])中31人(22%[15-29])，147名安慰剂接受者(P<；0·0001)中0(0%[0-2])。在2期试验中，57例(12%[95%可信区间9~16])S-免疫球蛋白A(GMT 3·8[95%CI 3·5~4·1]应答者)、18例(13%[8~19])疫苗接受者(GMT 5·2[4·0~6·8])和0(0%[0~2])在147例安慰剂接受者(P&0001)中。成人对dNS1-RBD耐受性良好。疫苗接受者外周血中T细胞免疫功能较弱，对SARS-CoV-2的体液和粘膜免疫反应较弱。有必要进行进一步的研究，以验证鼻腔疫苗作为目前肌肉注射SARS-CoV-2疫苗池的潜在补充的安全性和有效性。应在今后的研究中采取措施，减少疫苗株气雾剂在给药过程中造成交叉污染的可能性。中国国家重点研究发展计划、国家科学、福建省科学、中国医学科学院医学创新基金、北京万泰生物制药企业。
All currently available SARS-CoV-2 vaccines are administered by intramuscular injection. We aimed to evaluate the safety and immunogenicity of a live-attenuated influenza virus vector-based SARS-CoV-2 vaccine (dNS1-RBD) administered by intranasal spray in healthy adults. We did double-blind, randomised, placebo-controlled phase 1 and 2 trials, followed by a phase 2 extension trial, at a single centre in Jiangsu, China. Healthy adults (≥18 years) who had negative serum or fingertip blood total antibody tests for SARS-CoV-2 (in phases 1 and 2), with no prevalent SARS-CoV-2 infection or history of infection and no SARS-CoV-2 vaccination history (in all three trials reported here), were enrolled. Participants were randomly allocated (4:1 in phase 1, 2:1 in phase 2, and 1:1 in the extension trial) to receive two intranasal doses of the dNS1-RBD vaccine or placebo on days 0 and 14 or, for half of the participants in phase 2, on days 0 and 21. To avoid cross-contamination during administration, vaccine and placebo recipients were vaccinated in separate rooms in the extension trial. The phase 1 primary outcome was safety (adverse events recorded on days 0–44; serious adverse events recorded from day 0 until 12 months after the second dose). In the phase 2 and extension trials, the primary immunogenicity outcomes were SARS-CoV-2-specific T-cell response in peripheral blood (measured by IFN-γ ELISpot), proportion of participants with positive conversion for SARS-CoV-2 receptor-binding domain (RBD)-specific IgG and secretory IgA (s-IgA) antibodies, and concentration of SARS-CoV-2 RBD IgG in serum and SARS-CoV-2 RBD s-IgA in the nasopharynx (measured by ELISA) at 1 month after the second dose in the per-protocol set for immunogenicity. χ2 test and Fisher's exact test were used to analyse categorical data, and t test and Wilcoxon rank sum test to compare the measurement data between groups. These trials were registered with the Chinese Clinical Trial Registry (ChiCTR2000037782, ChiCTR2000039715, and ChiCTR2100048316). Between Sept 1, 2020, and July 4, 2021, 63, 724, and 297 participants without a history of SARS-CoV-2 vaccination were enrolled in the phase 1, phase 2, and extension trials, respectively. At least one adverse reaction after vaccination was reported in 133 (19%) of 684 participants in the vaccine groups. Most adverse reactions were mild. No vaccine-related serious adverse event was noted. Specific T-cell immune responses were observed in 211 (46% [95% CI 42–51]) of 455 vaccine recipients in the phase 2 trial, and in 48 (40% [31–49]) of 120 vaccine recipients compared with one (1% [0–5]) of 111 placebo recipients (p<0·0001) in the extension trial. Seroconversion for RBD-specific IgG was observed in 48 (10% [95% CI 8–13]) of 466 vaccine recipients in the phase 2 trial (geometric mean titre [GMT] 3·8 [95% CI 3·4–4·3] in responders), and in 31 (22% [15–29]) of 143 vaccine recipients (GMT 4·4 [3·3–5·8]) and zero (0% [0–2]) of 147 placebo recipients (p<0·0001) in the extension trial. 57 (12% [95% CI 9–16]) of 466 vaccine recipients had positive conversion for RBD-specific s-IgA (GMT 3·8 [95% CI 3·5–4·1] in responders) in the phase 2 trial, as did 18 (13% [8–19]) of 143 vaccine recipients (GMT 5·2 [4·0–6·8]) and zero (0% [0–2]) of 147 placebo recipients (p<0·0001) in the extension trial. dNS1-RBD was well tolerated in adults. Weak T-cell immunity in peripheral blood, as well as weak humoral and mucosal immune responses against SARS-CoV-2, were detected in vaccine recipients. Further studies are warranted to verify the safety and efficacy of intranasal vaccines as a potential supplement to current intramuscular SARS-CoV-2 vaccine pools. Steps should be taken in future studies to reduce the potential for cross-contamination caused by the vaccine strain aerosol during administration. National Key Research and Development Program of China, National Science, Fujian Provincial Science, CAMS Innovation Fund for Medical Sciences, and Beijing Wantai Biological Pharmacy Enterprise.