A number of studies have emphasized the weak humoral response to COVID-19 m-RNA vaccination in hemodialysis patients and kidney transplant recipients naïve to SARS-CoV-2.^{1, 2} Firket et al.³ recently reported in this journal that kidney transplant recipients previously infected with SARS-CoV-2 develop similar levels of anti-S1/S2 IgG titers compared with healthy controls following of BNT162b2 mRNA vaccination, suggesting that natural infection may prime the immune system for optimal antibody response to COVID-19 mRNA vaccination.

We would like to report on a larger prospective observational study of the antibody response to the BNT162B2 mRNA vaccine (intramuscular injection of 30 µg mRNA on day 0 and day 21) in hemodialysis patients, kidney transplant recipients and healthy adults controls, naïve or previously infected with SARS-CoV-2, as documented by PCR or serology (IRB-approved studies, CTA 2021-000412-28 and CTA 2021-000461-33). Healthy adult controls were staff from nursing homes.⁴ SARS-CoV-2 receptor-binding domain (RBD)-specific IgG titers were measured by ELISA (Wantai Bio-Pharm) before and 21, 28, and 49 days after administration of the first vaccine dose.

The mean duration of dialysis and mean interval since transplantation were 47 and 122 months, respectively. In these patients, the mean time between COVID-19 and vaccination was 170 ± 16 days. Most COVID-19 were mild, except in 12 patients who required oxygenotherapy, 3 of them were critically ill. Patients received hydroxychloroquine (n = 3), dexamethasone (n = 3), and convalescent plasma therapy (n = 1, 224 days before vaccination). Transplant recipients received steroids (80%), antimetabolite immunosuppressants (78%), anticalcineurin (76%), and mTOR inhibitors (30%). There was no rejection episode during the year before vaccination.

Lower levels of RBD IgG were detected in SARS-CoV-2 naive hemodialysis patients and kidney transplant recipients as compared to healthy adults (Figure 1). In contrast, levels of RBD IgG levels were high and similar in hemodialysis patients, kidney transplant recipients, and adult controls previously infected with SARS-CoV-2, already after a single dose of mRNA vaccine. No serious adverse event was observed in any of the study groups.

Our results are in line with previously published studies describing weak immune responses to vaccine in COVID-19-naïve transplanted or hemodialysis patients.^1-3 More importantly, they indicate that the immune suppression of hemodialysis patients and kidney transplant recipients does not reduce the antibody response to mRNA vaccination following priming by natural infection, confirming the observation of Firket et al. in a smaller cohort of kidney transplanted patients.³ Immunity to SARS-CoV-2 induced by the combination of natural infection and vaccination has been named hybrid immunity in healthy adults.⁵ Although the mechanism underlying hybrid immunity remains to be investigated, this process likely depends on the induction of memory B cells and CD4+ T cells by natural infection, leading to up to 100 times higher antibody titers following vaccination. One limitation of our study is that it does not include assessment of cell-mediated immunity. The observation that hybrid immunity can be induced in immunocompromised patients opens an important opportunity for the rational development of vaccines in this vulnerable population. It also provides reassurance that kidney transplant recipients and hemodialysis patients acquire robust immunity if they survive COVID-19.

许多研究强调了血液透析患者和未感染过 SARS-CoV-2 的肾移植受者对 COVID-19 m-RNA 疫苗接种的体液反应较弱。^1、2 Firket 等人。³最近在该杂志上报道说，与 BNT162b2 mRNA 疫苗接种后的健康对照相比，先前感染 SARS-CoV-2 的肾移植受者产生了相似水平的抗 S1/S2 IgG 滴度，这表明自然感染可能使免疫系统达到最佳状态对 COVID-19 mRNA 疫苗接种的抗体反应。

我们想报告一项更大规模的前瞻性观察研究，该研究涉及血液透析患者、肾移植受者和健康成人对照、未感染或以前感染过的 BNT162B2 mRNA 疫苗（在第 0 天和第 21 天肌内注射 30 µg mRNA）的抗体反应与 SARS-CoV-2，如 PCR 或血清学所记录（IRB 批准的研究，CTA 2021-000412-28 和 CTA 2021-000461-33）。健康成人对照是来自疗养院的工作人员。⁴ SARS-CoV-2 受体结合域 (RBD) 特异性 IgG 滴度在接种第一剂疫苗之前和接种第一剂疫苗后 21、28 和 49 天通过 ELISA（万泰生物制药）进行测量。

透析的平均持续时间和移植后的平均间隔时间分别为 47 个月和 122 个月。在这些患者中，COVID-19 和接种疫苗之间的平均时间为 170 ± 16 天。大多数 COVID-19 是轻度的，除了 12 名需要氧疗的患者外，其中 3 名病情危重。患者接受了羟氯喹（n  = 3）、地塞米松（n  = 3）和恢复期血浆疗法（n  = 1，接种前 224 天）。移植受者接受类固醇 (80%)、抗代谢免疫抑制剂 (78%)、抗钙调神经磷酸酶 (76%) 和 mTOR 抑制剂 (30%)。接种前一年没有发生排异反应。

与健康成人相比，在未接受过 SARS-CoV-2 血液透析的患者和肾移植受者中检测到的 RBD IgG 水平较低（图 1）。相比之下，血液透析患者、肾移植受者和先前感染过 SARS-CoV-2 的成人对照组的 RBD IgG 水平较高且相似，并且已经接种了单剂 mRNA 疫苗。在任何研究组中均未观察到严重不良事件。

我们的结果与之前发表的研究一致，这些研究描述了未接受过 COVID-19 移植或血液透析的患者对疫苗的免疫反应较弱。^1-3更重要的是，它们表明血液透析患者和肾移植受者的免疫抑制不会降低自然感染引发后对 mRNA 疫苗接种的抗体反应，证实了 Firket 等人的观察。在较小的肾移植患者队列中。³由自然感染和疫苗接种相结合诱导的对 SARS-CoV-2 的免疫被称为健康成人的混合免疫。^5个尽管混合免疫的潜在机制仍有待研究，但这一过程可能取决于通过自然感染诱导记忆 B 细胞和 CD4+ T 细胞，从而导致接种疫苗后抗体滴度高达 100 倍。我们研究的一个局限性是它不包括对细胞介导免疫的评估。可以在免疫功能低下的患者中诱导混合免疫的观察结果为在这一脆弱人群中合理开发疫苗提供了重要机会。它还提供了保证，即肾移植受者和血液透析患者如果在 COVID-19 中存活下来，将获得强大的免疫力。