A fourth dose of the mRNA-1273 SARS-CoV-2 vaccine improves serum neutralization against the Delta variant in kidney transplant recipients.
A fourth dose of the mRNA-1273 SARS-CoV-2 vaccine improves serum neutralization against the Delta variant in kidney transplant recipients.
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DOI：
10.1016/j.kint.2022.02.011
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发表时间：
2022-05
影响因子：
19.6
通讯作者：
Caillard S
中科院分区：
文献类型：
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作者：
Benotmane I;Bruel T;Planas D;Fafi-Kremer S;Schwartz O;Caillard S
结果67例肾移植受者（中位年龄56.6岁;四分位距[IQR] 47-64.6岁; n= 41 [61.2%]男性）在3剂mRNA-1273疫苗后显示出弱的体液应答，并接受了第4剂（补充方法）。这些患者均无COVID-19病史并显示抗核衣壳抗体。从移植到第四剂的中位间隔为6.1年（IQR 2.2-11.4年）。至于免疫抑制治疗，97%的研究患者接受钙调磷酸酶抑制剂治疗，82%接受吗替麦考酚酯治疗，76%接受类固醇治疗，18%接受雷帕霉素哺乳动物靶点抑制剂治疗（表1）。第三次和第四次给药之间的中位间隔为68天（IQR 63-82天）。在第四剂后，中值抗RBD滴度从13个结合抗体单位（BAU）/ml（IQR 2.6- 66.3BAU/ml）显著增加（P< 0.0001）至112.5BAU/ml（IQR 13.5-260 BAU/ml）（图la）。平行地，中值抑制稀释50（ID 50）滴度从< 7.5（IQR< 7.5-15.1）显著增加（P= 0.0001）至47.1（IQR< 7.5-284.2）。尽管在第四次注射前只有16%的患者（n= 11）携带针对Delta毒株的中和抗体，但之后这一百分比上升至66%（n= 44）（图1 B）。第三次给药后未检出中和抗体的患者在第四次给药后中和能力增加的可能性较小（中位倍数变化1.1 [IQR 1-7.5] vs. 6.3 [IQR 2-15.9]; P= 0.01）。在第三剂后血清阴性的9名患者中，仅1名显示出强烈的抗RBD IgG应答（> 143 BAU/ml），2名能够在第四剂后中和Delta变体。此外，81%在第三次注射后免疫应答较弱的患者在第四次注射后显示出较强的抗RBD IgG应答。值得注意的是，其中63.8%的人能够在第四次给药后中和Delta变体。有趣的是，接受他克莫司、吗替麦考酚酯和类固醇联合治疗的患者显示出较低的中和ID 50滴度（中位ID 50滴度25.6 vs. 140.6; P= 0.01）。针对Delta变体的中和ID 50滴度与抗RBD滴度正相关（Pearson r2 = 0.54; P< 0.0001;图Ic）。一旦第4次给药后抗RBD滴度超过143 BAU/ml，检测中和活性的特异性、灵敏度、阳性预测值和阴性预测值分别为92.9%、74.3%、93.6%和72.2%。在第四次给药后，未观察到主要不良事件和移植物排斥。一名患者在第四次注射后缺乏中和活性（ID 50滴度< 7.5），在接受第四剂后19天出现了由Delta变异体引起的症状性COVID-19。
ResultsSixty-seven kidney transplant recipients (median age 56.6 years; interquartile range [IQR] 47–64.6 years; n= 41 [61.2%] men) showed a weak humoral response after 3 doses of the mRNA-1273 vaccine and received a fourth dose (Supplementary Methods). None of these patients had a history of COVID-19 and displayed anti–nucleocapsid antibodies. The median interval from transplantation to the fourth dose was 6.1 years (IQR 2.2–11.4 years). As for immunosuppressive therapy, 97% of the study patients were being treated with calcineurin inhibitors, 82% with mycophenolate mofetil, 76% with steroids, and 18% with mammalian target of rapamycin inhibitors (Table 1). The median interval between the third and fourth doses was 68 days (IQR 63–82 days). After the fourth dose, the median anti-RBD titer increased significantly (P< 0.0001) from 13 binding antibody units (BAUs)/ml (IQR 2.6–66.3 BAUs/ml) to 112.5 BAUs/ml (IQR 13.5–260 BAUs/ml)(Figure 1 a). In parallel, median inhibitory dilution 50 (ID 50) titers increased significantly (P= 0.0001) from< 7.5 (IQR< 7.5–15.1) to 47.1 (IQR< 7.5–284.2). Although only 16% of patients (n= 11) harbored neutralizing antibodies against the Delta strain before the fourth injection, this percentage raised to 66%(n= 44) afterward (Figure 1 b). Patients with undetectable neutralizing antibodies after the third dose were less likely to have their neutralizing capacity increased after the fourth dose (median fold change 1.1 [IQR 1–7.5] vs. 6.3 [IQR 2–15.9]; P= 0.01). Of the 9 patients who were seronegative after the third dose, only 1 displayed a strong anti-RBD IgG response (> 143 BAUs/ml) and 2 were able to neutralize the Delta variant after the fourth dose. Additionally, 81% of patients with a weak immune response after the third dose displayed a strong anti-RBD IgG response after the fourth injection. Notably, 63.8% of them were able to neutralize the Delta variant after the fourth dose. Interestingly, patients under combined therapy with tacrolimus, mycophenolate mofetil, and steroids displayed lower neutralizing ID 50 titers (median ID 50 titers 25.6 vs. 140.6; P= 0.01). Neutralizing ID 50 titers against the Delta variant were positively correlated with anti-RBD titers (Pearson r 2= 0.54; P< 0.0001; Figure 1 c). Once the anti-RBD titer exceeded 143 BAUs/ml after the fourth dose, the specificity, sensitivity, positive predictive value, and negative predictive value for detecting neutralizing activity were 92.9%, 74.3%, 93.6%, and 72.2%, respectively. Neither major adverse events nor graft rejections were observed after the fourth dose. One patient, who lacked neutralizing activity after the fourth injection (ID 50 titer< 7.5), developed symptomatic COVID-19 caused by the Delta variant 19 days after receiving the fourth dose.
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影响因子：
13.8
作者：
Kamar N;Abravanel F;Marion O;Romieu-Mourez R;Couat C;Del Bello A;Izopet J
通讯作者：
Izopet J
DOI：
10.1056/nejmoa2108891
发表时间：
2021-08-12
期刊：
The New England journal of medicine
影响因子：
--
作者：
Lopez Bernal J;Andrews N;Gower C;Gallagher E;Simmons R;Thelwall S;Stowe J;Tessier E;Groves N;Dabrera G;Myers R;Campbell CNJ;Amirthalingam G;Edmunds M;Zambon M;Brown KE;Hopkins S;Chand M;Ramsay M
通讯作者：
Ramsay M
影响因子：
64.8
作者：
Planas, Delphine;Veyer, David;Schwartz, Olivier
通讯作者：
Schwartz, Olivier
影响因子：
82.9
作者：
Khoury, David S.;Cromer, Deborah;Davenport, Miles P.
通讯作者：
Davenport, Miles P.