健康成年人接种两剂新型冠状病毒灭活疫苗后序贯加强免疫重组新型冠状病毒疫苗(CHO细胞)的免疫原性和安全性研究

目的 评价在接种两剂已上市新冠病毒灭活疫苗的人群中序贯加强免疫重组新型冠状病毒疫苗(CHO细胞)后的免疫原性和安全性,为制定新型冠状病毒疫苗的加强免疫策略提供科学依据。 方法 采用开放性试验设计,筛选入组360例已接种两剂新冠病毒灭活疫苗3～4个月、6～8个月、11～13个月的18周岁及以上研究对象并接种1剂重组新型冠状病毒疫苗(CHO细胞)。采集所有研究对象研究用疫苗接种前、接种后14 d血样,用于体液免疫检测,收集研究用疫苗接种后1个月内的所有不良事件。 结果 本研究入组360例研究对象,按研究对象加强免疫与基础免疫间隔时间分3组(A组91～120 d,B组181～240 d,C组331～390 d),各组120例,无研究对象脱落。三组年龄均值分别为38.13、40.22和45.73岁,各组间年龄差异有统计学意义(F=13.516,P＜0.001),A、B组差异无统计学意义(P=0.168),C组和A、B组间差异均有统计学意义(P＜0.001)。三组 IgG GMC(几何平均浓度)免疫前分别为4.81、4.23、2.12 AU/ml,差异有统计学意义(F=10.054,P＜0.001),C组和A、B组间差异均有统计学意义(P＜0.001),A、B组间差异无统计学意义(P=0.520);三组免疫后 IgG GMC 分别为106.69、124.05、80.04 AU/ml,差异无统计学意义(F=2.028,P=0.133)。三组 IgG 抗体阳转率分别为84.17%、87.50%、79.17%,差异无统计学意义(χ²=3.081,P=0.214)。免疫前血清针对Delta变异株和原型株不同组别的中和抗体滴度比较,三组原型株中和抗体GMT(几何平均滴度)为1∶2.18、1∶2.18、1∶2.19,差异无统计学意义(F=0.011,P=0.990);三组Delta变异株中和抗体GMT为1∶2.09、1∶2.17、1∶2.16,差异无统计学意义(F=0.378,P=0.686)。免疫后血清三组原型株中和抗体 GMT为1∶31.09、1∶34.90、1∶21.98,差异无统计学意义(F=2.262,P=0.106);三组Delta变异株中和抗体GMT为1∶61.46、1∶77.44、1∶43.71,差异无统计学意义(F=2.105,P=0.123)。序贯加强免疫后血清对新型冠状病毒Delta变异株和原型株的中和抗体阳转率分别达到82.78%、83.33%。三组 SARS-CoV-2原型株中和抗体阳转率分别为86.67%、87.50%、75.83%,差异有统计学意义(χ²=7.320,P=0.026),其中C组低于A组和B组;三组 SARS-CoV-2 Delta变异株中和抗体阳转率分别为87.50%、84.17%、76.67%,差异无统计学意义(χ²=5.183,P=0.075)。发生不良事件人数为124人,不良事件总体发生率为34.44%。各组发生率分别为35.83%、40.83%和26.67%,差异无统计学意义(χ²=5.487,P=0.064),所有研究对象出现的不良事件以接种部位不良事件为主,主要表现为疫苗接种部位疼痛(23.89%);全身不良事件主要表现为疲劳/乏力(6.94%),未发生与疫苗接种有关的SAEs。结论 接种两剂新型冠状病毒灭活疫苗后序贯加强免疫重组新型冠状病毒疫苗(CHO细胞)具有良好的免疫原性和安全性。较长间隔期的免疫前IgG和免疫后原型株中和抗体阳转率较低,不同间隔期的免疫后IgG 、Delta变异株和原型株中和抗体水平比较差异均无统计学意义,建议基础免疫后6~8个月为最佳的接种间隔。

Immunogenicity and safety of recombinant novel coronavirus vaccine (CHO cell) after two doses of inactivated SARS-CoV-2 vaccine in healthy adults

Objective To evaluate the immunogenicity and safety of recombinant novel coronavirus vaccine (CHO cell) after sequential immunization in population inoculated with two doses of inactivated SARS-CoV-2 vaccine so as to provide a scientific basis for formulating the enhanced immunization strategy of the SARS-CoV-2 vaccine. Methods Open experimental design was used to screen 360 subjects aged 18 and above who had been inoculated with two doses of new coronavirus inactivated vaccine for 3-4 months, 6-8 months, 11-13 months and one dose of recombinant novel coronavirus vaccine (CHO cell). Blood samples of all subjects before and 14 days after vaccination were collected for humoral immunity test, and all adverse events within one month after vaccination were collected. Results In this study, 360 subjects were divided into three groups according to the interval between fundamental immunity and booster (group A 91-120 days, group B 181-240 days, group C 331-390), 120 cases in each group, and no subject was dropped off. The mean age of the three groups was 38.13, 40.22 and 45.73 years, respectively, and the age difference among the groups was statistically significant (F=13.516, P<0.001). There was no significant difference between groups A and B (P=0.168), but the difference between groups C and A, B was statistically significant (both P<0.001). The IgG geometric mean concentration (GMC) of the three groups before booster immunization was 4.81 AU/ml, 4.23 AU/ml and 2.12 AU/ml, respectively, showing statistically significant differences (F=10.054, P<0.001). The differences between groups C and A, B were statistically significant (both P<0.001), but no statistically significant difference was found between groups A and B (P=0.520). The IgG GMC of the three groups after booster were 106.69 AU/ml, 124.05 AU/ml and 80.04 AU/ml, respectively, with no statistically significant difference (F=2.028, P=0.133). The positive conversion rates of IgG antibody in the three groups were 84.17%, 87.50% and 79.17%, respectively, and the difference was not statistically significant (χ²=3.081, P=0.214). Before booster immunization, the geometric mean titers (GMTs) of neutralizing antibodies in serumagainst prototype strains in the three groups were 1:2.18, 1:2.18 and 1:2.19, respectively, showing no statistically significant difference (F=0.011, P=0.990). The GMTs of neutralizing antibodies against delta mutant strains in the three groups were 1:2.09, 1:2.17 and 1:2.16, respectively, without statistically significant difference (F=0.378, P=0.686). After boosterimmunization, the GMTs of neutralizing antibodies in serum against prototype strains in the three groups were 1:31.09, 1:34.90 and 1: 21.98, respectively, without statistically significant difference (F=2.262, P=0.106). The GMTs of neutralizing antibodies against delta mutant strains in the three groups were 1:61.46, 1:77.44 and 1:43.71, respectively, showing no statisticallysignificant difference (F=2.105, P=0.123). After sequential immunization, the positive conversion rates of neutralizing antibodies in serum against delta mutant and prototype strains of new coronavirus reached 82.78% and 83.33%, respectively. The positive conversion rates of neutralizing antibody of SARS-CoV-2 prototype strains in the three groups were 86.67%, 87.50% and 75.83%, respectively, the difference was statistically significant (χ²=7.320, P=0.026), among which group C was lower than that in group A and group B. The positive conversion rate of neutralizing antibodies against SARS-CoV-2 delta variants in the three groups was 87.50%, 84.17% and 76.67%, respectively, with no significant difference (χ²=5.183, P=0.075). The number of adverse events was 124, and the overall incidence rate of adverse events was 34.44%. The incidence rates of adverse events in groups A, B and C were 35.83%, 40.83% and 26.67%, respectively, without statistically significant difference (χ²=5.487, P=0.064). The major adverse event found in all subjects occurred on vaccination site, with 23.89% of local pain. General adverse events mainly presented with fatigue or lacking of strength(6.94 %). No serious adverse events (SAEs) related to vaccination occurred. Conclusion After inoculation of two doses of inactivated SARS-CoV-2 vaccine, a sequential booster with recombinant novel coronavirus vaccine (CHO cell) has good immunogenicity and safety. The antibody level of IgG before booster immunization and the seroconversion rate of neutralizing antibody against prototype strains after booster immunization were lower in group of longer interval between fundamental immunization and booster immunization. There was no significant difference in theneutralizing antibody levels of IgG, delta mutant and prototype strains among different intervals. Six to eight months is recommended as an optimal interval of booster after fundamental immunization.