灭活疫苗对新冠变异病毒的中和效果
近日，由中国医学科学院流行病学微生物学研究所领导的研究团队在著名《新英格兰医学杂志》上发表通讯文章“Susceptibility of Circulating SARS-CoV-2 Variants to Neutralization”，研究了接种国药集团BBIBP-CorV灭活疫苗(Sinopharm)和北京科兴中维生物CoronaVac灭活疫苗(Sinovac)的志愿者血清，对新近出现的新冠突变毒株(主要是英国变异(B.1.1.7)和南非变异(B.1.1.351)毒株)的中和活性。该研究选取了一组34名感染新冠后5个月的康复志愿者，第二组再选取25名接种两剂国药灭活疫苗，以及25名接种两剂科兴灭活疫苗后2-3周的健康志愿者。然后抽取志愿者血液分离血清。该研究第一个实验检测了新冠康复者血清和灭活疫苗接种者血清对野生型新冠假病毒毒株(WT)中和活性，该结果发现疫苗接种志愿者的血清的中和活性与新冠感染康复者血清类似，并且略微低一些。由于新冠康复者的血清是5个月以后的样本，而疫苗接种者的血清是在接种后2-3周的样本，该时间点是抗体达到最高滴度的时期。因此，从这个结果可以得出两种灭活疫苗双剂接种后只诱导了低水平的体液免疫应答，既产生了低滴度的抗体 。此外，新冠康复者中有4个样本没有检测到中和效价。6个国药BBIBP-CorV接种者样本中没有检测到中和效价(6/25)，4个科兴CoronaVac接种者样本中没有检测到中和效价(4/25)。
此外，30份恢复期血清样本中有9份对B.1.351完全丧失中和活性。在BBIBP-CorV疫苗接种者血清样本中，尽管针对变异株的中和抗体GMT与针对野生型病毒的GMT无显著差异，但有20份血清样本对B.1.351完全或部分丧失中和活性（图1C）。
在克尔来福疫苗接种者血清样本中，研究者观察到针对B.1.1.7（0.5倍；95% CI，0.3～0.7）和B.1.351（0.3倍；95% CI，0.2～0.4）的血清中和抗体GMT明显降低。此外，大多数血清样本对B.1.351完全或部分丧失中和活性（图1D）。
本研究的结果提示，B.1.1.7对恢复期血清或疫苗接种者血清的中和活性几乎无抗性，而B.1.351对恢复期血清（2倍）和（灭活）疫苗接种者血清（2.5～3.3倍）中和活性的抗性均超过野生型病毒对血清的抗性。本研究检测的大多数疫苗接种者血清样本丧失了中和活性，这一结果与近期对恢复期血清或者mRNA或BBIBP-CorV疫苗接种者血清中和活性开展的其他研究结果一致。本研究的结果还凸显出在变异株流行地区持续监测病毒并评估疫苗保护效力的重要性。
参考文献：Susceptibility of Circulating SARS-CoV-2 Variants to Neutralization.N Engl J Med 2021; 384:2354-2356
DOI: 10.1056/NEJMc2103022
https://www.nejm.org/doi/full/10.1056/NEJMc2103022
http://nejmqianyan.cn/article/YXQYc2103022
https://nejmqianyan.cn/article/YXQYc2103022?sg=AbW1NGsHw3NxPd6F
https://www.nejm.org/doi/full/10.1056/NEJMc2103022
NEJM原文摘录：We next evaluated pseudovirus resistance to neutralization using convalescent serum obtained from 34 patients 5 months after infection with coronavirus disease 2019 (Covid-19) and serum from 50 participants obtained 2 to 3 weeks after receipt of the second dose of inactivated-virus vaccines — BBIBP-CorV (Sinopharm)1 or CoronaVac (Sinovac)2 — which were developed in China (Table S1 in the Supplementary Appendix). We first determined the serum neutralizing-antibody titer against wild-type pseudovirus and observed similar geometric mean titers (GMTs) in serum obtained from convalescent patients and from vaccinees (Figure 1A), which suggested a low antibody response after two-dose inoculation induced by BBIBP-CorV or CoronaVac.1,2 Notably, undetectable neutralization titers were seen in 4 of 34 convalescent serum samples, in 6 of 25 BBIBP-CorV serum samples, and in 4 of 25 CoronaVac serum samples.
We next assessed the neutralizing activity of convalescent serum and vaccinee serum against D614G, B.1.1.7, and B.1.351 variants as compared with wild-type pseudovirus. The convalescent serum was significantly more effective (by a factor of 2.4; 95% confidence interval , 1.9 to 3.0) in neutralizing the D614G pseudovirus, had a similar effect to that of the wild-type virus in neutralizing the B.1.1.7 variant, and was significantly less effective (by a factor of 0.5; 95% CI, 0.4 to 0.7) in neutralizing the B.1.351 pseudovirus (Figure 1B). Moreover, 9 of 30 convalescent serum samples showed complete loss of neutralizing activity against B.1.351. For the BBIBP-CorV vaccinee serum samples, although the GMTs of neutralization against the variants were not significantly different from the GMTs against the wild-type virus, 20 serum samples showed complete or partial loss of neutralization against B.1.351 (Figure 1C). For the CoronaVac vaccinee serum samples, we observed a marked decrease in the GMTs in the serum neutralization of B.1.1.7 (by a factor of 0.5; 95% CI, 0.3 to 0.7) and B.1.351 (by a factor of 0.3; 95% CI, 0.2 to 0.4). In addition, most of the serum samples showed complete or partial loss of neutralization against B.1.351 (Figure 1D).
Our findings suggest that B.1.1.7 showed little resistance to the neutralizing activity of convalescent or vaccinee serum, whereas B.1.351 showed more resistance to the neutralization of both convalescent serum (by a factor of 2) and vaccinee serum (by a factor of 2.5 to 3.3) than the wild-type virus. Most of the vaccinee serum samples that were tested lost neutralizing activity, a finding that was consistent with the results of other recent studies of neutralization by convalescent serum or serum obtained from recipients of messenger RNA or BBIBP-CorV vaccines.3-5 Our findings also highlight the importance of sustained viral monitoring and evaluation of the protective efficacy of vaccines in areas where variants are circulating.
Guo-Lin Wang, Ph.D.
Beijing Institute of Microbiology and Epidemiology, Beijing, China
Zhuang-Ye Wang, B.Med.
Dezhou Center for Disease Control and Prevention, Dezhou, China
Li-Jun Duan, B.Sc.
Beijing Institute of Microbiology and Epidemiology, Beijing, China
Qing-Chuan Meng, B.Med.
Ningjin County Community Health Service Center, Dezhou, China
Ming-Dong Jiang, M.Med.
Jing Cao, M.Med.
Dezhou Center for Disease Control and Prevention, Dezhou, China
Lin Yao, B.Med.
Ka-Li Zhu, B.Med.
Wu-Chun Cao, Ph.D.
Mai-Juan Ma, Ph.D.
Beijing Institute of Microbiology and Epidemiology, Beijing, China 北大生物医学前沿创新中心谢晓亮团队揭示不同类型新冠疫苗对突变株体液免疫应答情况
2021年5月21日，北京大学，首都医科大学及中国食品药品监督管理局等多单位合作，谢晓亮，曹云龙，秦成峰，王佑春，冯英梅及肖俊宇共同通讯在Cell Research 在线发表题为“Humoral immune response to circulating SARS-CoV-2 variants elicited by inactivated and RBD-subunit vaccines”的研究论文，该研究报告了对循环SARS-CoV-2变体（例如501Y.V2（B.1.351））的血浆和由CoronaVac（灭活疫苗），ZF2001（RBD亚单位疫苗）和自然感染引起的中和抗体（NAb）的体液免疫反应。
在本研究中，谢晓亮团队利用高通量单细胞测序、冷冻电镜、病毒中和实验等多种技术手段解析了新冠病毒灭活疫苗（科兴）和RBD亚单位重组蛋白疫苗（智飞）接种者以及新冠感染康复者的血浆和诱导的中和抗体对于目前流行新冠突变株（例如南非株）的应答情况。
谢晓亮团队利用高通量单细胞测序，从两种类型疫苗的接种者和康复者外周血的记忆B细胞中筛选并表达出831个抗刺突蛋白抗体，并从中筛选出86个对新冠病毒野生型具有高中和活性的抗体。假病毒中和测试实验显示，超过一半的抗RBD中和抗体对K417N/E484K/N501Y突变组合的中和活性大幅下降。高分辨率冷冻电镜结构显示，引起中和抗体活性大幅降低的原因是E484K突变导致的电荷反转。
与中和抗体实验结果类似，康复者和灭活疫苗接种者的血浆对南非突变株均表现出中和活性下降的趋势。假病毒和真病毒中和实验结果显示，相比于普通流行株，新冠感染康复者和灭活疫苗接种者的血浆针对南非株的中和活性下降4倍左右。其原因主要是由E484K/N501Y和242-244Δ突变引起，且这两个区域的突变对血浆中和活性的削弱程度可叠加。而RBD亚单位重组蛋白疫苗的血浆中和活性在真病毒和假病毒中只下降2倍左右，表明RBD亚单位重组蛋白疫苗接种者血浆对南非株的耐受性优于康复者血浆。其主要原因是由于其诱导的抗RBD中和抗体具有丰富的多样性，且不受NTD突变的影响。
此研究还发现，与标准的RBD重组蛋白亚基疫苗三剂免疫（第0天/30天/60天）相比，第三剂和第二剂重组蛋白疫苗免疫之间的接种间隙延长（第0天/30天/140天）会产生更强中和活性的抗体，对南非突变株具有更强的耐受性。这些结果表明，如果未来新冠突变株大流行，特别是对于携带能改变NTD抗原热点蛋白构象突变的病毒株，注射第三剂RBD重组蛋白疫苗来加强免疫或是一种优化方案。
原文链接：https://www.nature.com/articles/s41422-021-00514-9
来源：北京大学生物医学前沿创新中心，北京大学新闻网
参考文献 ：Cao, Y., Yisimayi, A., Bai, Y. et al. Humoral immune response to circulating SARS-CoV-2 variants elicited by inactivated and RBD-subunit vaccines. Cell Res 31, 732–741 (2021). https://doi.org/10.1038/s41422-021-00514-9
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