This article refers to ‘Immunogenicity of the BNT162b2 mRNA vaccine in heart transplant recipients – a prospective cohort study’ by O. Itzhaki Ben Zadok et al., published in this issue on pages 1555–1559.

Infectious diseases are a well-known major complication after solid organ transplantation. Heart transplant (HT) patients have a high mortality rate after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, with figures of up to 25% reported.¹ Vaccines to prevent coronavirus disease 2019 (COVID-19) have shown efficacy in generating specific immune response to virus antigens and neutralizing antibodies, as well as clinical efficacy in reducing the risk and severity of symptomatic disease.^2-5 However, efficacy in the HT population is not well known, as solid organ transplant patients were excluded from clinical trials of SARS-CoV-2 mRNA vaccines. A recent study evaluated in 436 solid organ recipients the immune response to the first dose of an mRNA vaccine (BNT162b2, Pfizer-BioNTech, or mRNA-1273, Moderna)⁶ and found anti-Spike IgG antibodies in only 17% of participants after a median follow-up of 20 days. Of the 66 patients with HT, antibodies were detected in only 14%. Older age and treatment with antimetabolites were associated with a lower immune response. Also, the frequency of immune response was higher after mRNA1273 vaccine compared to BNT162b2 vaccine (69% vs. 31%, P = 0.003).⁶ Studies in kidney^{7, 8} and liver⁹ transplant patients confirm this low post-vaccine mRNA SARS-CoV-2 immune response.

In this issue of the Journal, Itzhaki Ben Zadok et al.¹⁰ report, in a prospective single-centre study in Israel, the short-term immunogenicity response following vaccination for SARS-CoV-2 with the two-dose mRNA vaccine BNT162b2, Pfizer BioNTech, in a population of 42 HT patients. Anti-spike IgG (S-IgG) antibodies were determined at two pre-specified time points; between days 21 to 26 and between 35 to 40 days after the first dose of vaccine and S-IgG value of ≥50 AU/mL or higher was considered positive. The study population was analysed in three subgroups to better characterize post-vaccine immunogenicity: Group I, seropositive antibody response after the first dose of vaccine; Group II, seropositive antibody response after either the first or second dose; and Group III, seroconversion after the second dose in non-responders to the first dose.

The percentage of patients with seropositivity for S-IgG antibodies was 15%, 49% and 32% in groups I, II and III, respectively. Analysing the baseline characteristics of the patients, according to whether they had serologic response to the two doses of the vaccine (responders, n = 18) or not (non-responders, n = 19), older patients and those with immunosuppression protocols that included antimetabolites [mycophenolate mofetil (MMF), mycophenolic acid] were associated with lower immune response. Median age (25th–75th quartiles) in responders vs. non-responders was 46 years (34–63) vs. 68 years (59–70), respectively (P = 0.03). The percentage of antimetabolite-based immunosuppression protocols was 44% in responders vs. 89% in non-responders (P = 0.011).

The efficacy of the vaccines considering COVID-19 as the main outcome was around 95% for mRNA vaccines and 70% for adenovirus vector vaccines, and efficacy against severe disease was close to 100%.^{2, 3}

The serological response to vaccines, in general, in the solid organ transplant population is poor and, furthermore, knowledge is limited and recommendations remain poorly supported by scientific evidence, due to the absence of well-defined clinical trials in this population. In a systematic review, it was observed that response varies with vaccine type, age and organ transplanted and in some vaccines the antibody titre decreases rapidly.¹¹ Regarding COVID-19 vaccines, as with other vaccines in the transplant population, it is important to know the efficacy in preventing the disease and at the same time the safety in terms of adverse reactions to the vaccine or risk of rejection.

Transplant recipients were excluded from the large clinical trials of COVID-19 vaccines so efficacy, durability and safety data in these patients are unknown. Studies of immune response following COVID-19 vaccination in solid organ transplants have been heterogeneous, both in terms of timing of post-vaccine assessment and type of response (humoral and/or T-cell), although most have focused on assessing antibody titre. Therefore, any study that measures the post-vaccination COVID-19 immune response and add knowledge is welcome.

This low serological response has been seen in other solid-organ transplantation studies and with other types of mRNA vaccines. In another prospective study, also from Israel,¹² in HT patients vaccinated with two doses of the BNT162b2 vaccine, anti-receptor-binding domain IgG antibodies, after an average of 21 days after the second dose, were detected in only 18% of patients. The immunosuppressive regimen containing MMF was also associated with a lower antibody response rate. At a median follow-up of 41 days after the second dose, there were no clinical episodes of rejection, suggested by troponin leak or graft dysfunction. A study in 80 liver transplant recipients from Israel, vaccinated with two doses of BNT162b2 vaccine, the antibody response was 47.5% vs. 100% in 25 healthy controls (P < 0.001). Antibody titre was also significantly lower in this group (mean 95.41 AU/mL vs. 200.5 AU/mL in controls, P < 0.001). Older age, lower estimated glomerular filtration rate and immunosuppression medications (use of high-dose prednisone in the past 12 months, MMF and triple therapy immunosuppression) were associated with lower antibody response.⁹ A study in 205 kidney transplant recipients vaccinated with two doses of mRNA-1273 SARS-CoV-2 vaccine showed a serological response 28 days after the second dose in 48% of patients.⁸

Due to the weak response after two doses of vaccine in solid organ transplant recipients, the possibility of a third dose has been suggested, and a recent French study explored the humoral response following this strategy with the BNT162b2 vaccine.¹³ The study included 101 transplant recipients (78 renal, 12 hepatic, 8 pulmonary or cardiac, and 3 pancreatic) who were given the first two doses of vaccine spaced 1 month apart and the third dose about 2 months after the second dose. Antibody response was assessed before each dose and 4 weeks after the third dose. The prevalence of anti-SARS-CoV-2 antibodies before and after the third dose increased from 40% to 68%. Among those patients who were seronegative before the third dose, 44% were positive after the third dose and, among those patients seropositive before the third dose, all remained positive and the antibody titre increased from 32 ± 12 to 2676 ± 350 (P < 0.001). No serious adverse effects or rejection were reported, although follow-up was short.

A recent joint AST/ISHLT/ASTS statement, taking into account all the doubts and concerns that are arising in relation to studies showing a low rate of serological response to COVID-19 vaccines in transplant recipients, and on the basis that the scientific evidence is not sufficient to draw firm conclusions, and given that vaccination is critical to contain the spread of the pandemic, makes some advice on what we are learning about efficacy in organ transplant recipients. The statement strongly recommends that all solid organ transplant recipients should be vaccinated against SARS-CoV-2 to minimize risks using local approved vaccines and that booster doses are used in the context of clinical research studies. Routine antibody testing following vaccination is not recommended by the US Food and Drug Administration. Most commercial tests do not screen for neutralizing antibodies, the cut-offs for antibody detection are not necessarily the same as clinically relevant and there is no agreement on what antibody titre can be considered protective against SARS-CoV-2 infection. However, individual physicians and patients may decide that antibody testing is desirable following a discussion regarding the interpretation of the test results and the consequences/risks of acquiring COVID-19 infection.¹⁴

In summary, the immunological response to the vaccine is probably somewhat more complex than measuring antibody titre, as the T-cellular response and studies with long-term clinical follow-up are needed to assess efficacy in both preventing COVID-19 and severe disease, and safety. The issue of the third dose is a promising possibility and given the preliminary encouraging experience, deserves to be explored in future research. Also, the modification of immunosuppression, e.g. withdrawal of MMF in order to achieve a greater response, is a very controversial issue as the risk–benefit in relation to triggering rejection related to changes in immunosuppression is still unknown. Meanwhile, continued research, taking advantage of all available clinical data and evaluating immunogenicity, clinical efficacy and exploring strategies to improve vaccine response in vulnerable populations, such as HT patients, will help us to understand and control the COVID-19 pandemic.

Conflict of interest: none declared.

本文引用了 O. Itzhaki Ben Zadok等人在本期第 1555-1559 页上发表的“BNT162b2 mRNA 疫苗在心脏移植受者中的免疫原性——一项前瞻性队列研究”。

传染病是众所周知的实体器官移植后的主要并发症。心脏移植 (HT) 患者在感染严重急性呼吸综合征冠状病毒 2 (SARS-CoV-2) 后死亡率很高，据报道这一数字高达 25%。¹预防 2019 年冠状病毒病 (COVID-19) 的疫苗已显示出对病毒抗原产生特异性免疫反应和中和抗体的功效，以及降低症状性疾病风险和严重程度的临床功效。^2-5然而，在 HT 人群中的疗效尚不清楚，因为实体器官移植患者被排除在 SARS-CoV-2 mRNA 疫苗的临床试验之外。最近的一项研究评估了 436 名实体器官接受者对第一剂 mRNA 疫苗（BNT162b2，Pfizer-BioNTech，或 mRNA-1273，Moderna）⁶的免疫反应，发现只有 17% 的参与者在接受中位随访 20 天。在 66 名 HT 患者中，仅 14% 检测到抗体。年龄较大和使用抗代谢物治疗与较低的免疫反应有关。此外，与 BNT162b2 疫苗相比，mRNA1273 疫苗后的免疫反应频率更高（69% 对 31%，P  = 0.003）。⁶研究肾脏^7、8和肝脏⁹名移植患者证实了这种低疫苗后 mRNA SARS-CoV-2 免疫反应。

在本期杂志中，Itzhaki Ben Zadok等人。¹⁰报告，在以色列的一项前瞻性单中心研究中，在 42 名 HT 患者中使用两剂 mRNA 疫苗 BNT162b2、辉瑞 BioNTech 接种 SARS-CoV-2 后的短期免疫原性反应。在两个预先指定的时间点测定抗尖峰 IgG (S-IgG) 抗体；在第一次接种疫苗后的第 21 至 26 天和 35 至 40 天之间，S-IgG 值≥50 AU/mL 或更高被认为是阳性的。研究人群在三个亚组中进行了分析，以更好地表征疫苗接种后的免疫原性： I 组，第一剂疫苗后的血清阳性抗体反应；第 II 组，第一剂或第二剂后的血清阳性抗体反应；第 III 组，无应答者在第二剂后血清转化为第一剂。

在 I、II 和 III 组中，S-IgG 抗体血清阳性的患者百分比分别为 15%、49% 和 32%。分析患者的基线特征，根据他们是否对两剂疫苗（应答者，n  = 18）或没有（无应答者，n  = 19）、老年患者和免疫抑制方案（包括抗代谢物 [霉酚酸酯 (MMF)、霉酚酸] 与较低的免疫反应有关。响应者与非响应者的中位年龄（第 25-75 个四分位数）分别为 46 岁（34-63）和 68 岁（59-70）（P  = 0.03）。基于抗代谢物的免疫抑制方案的百分比在应答者中为 44%，而在无应答者中为 89%（P = 0.011)。

以 COVID-19 为主要结果的疫苗对 mRNA 疫苗的有效性约为 95%，对腺病毒载体疫苗的有效性约为 70%，对严重疾病的有效性接近 100%。^2、3

一般来说，实体器官移植人群对疫苗的血清学反应很差，此外，由于缺乏在该人群中明确定义的临床试验，知识有限，科学证据支持的建议仍然很少。在一项系统评价中，观察到反应因疫苗类型、年龄和移植器官而异，并且在某些疫苗中抗体滴度迅速下降。¹¹关于 COVID-19 疫苗，与移植人群中的其他疫苗一样，重要的是要了解预防疾病的功效，同时了解疫苗的不良反应或排斥风险方面的安全性。

移植受者被排除在 COVID-19 疫苗的大型临床试验之外，因此这些患者的疗效、耐久性和安全性数据尚不清楚。实体器官移植中 COVID-19 疫苗接种后的免疫反应研究在疫苗后评估时间和反应类型（体液和/或 T 细胞）方面存在异质性，尽管大多数都集中在评估抗体滴度。因此，欢迎任何测量疫苗接种后 COVID-19 免疫反应并增加知识的研究。

这种低血清学反应已在其他实体器官移植研究和其他类型的 mRNA 疫苗中看到。在同样来自以色列的另一项前瞻性研究中，^{12 名}HT 患者接种了两剂 BNT162b2 疫苗，在第二剂后平均 21 天后，只有 18% 的患者检测到抗受体结合域 IgG 抗体. 含有 MMF 的免疫抑制方案也与较低的抗体反应率相关。在第二次给药后 41 天的中位随访中，没有出现临床排斥反应，这表明肌钙蛋白渗漏或移植物功能障碍。一项对来自以色列的 80 名肝移植受者进行的一项研究，接种了两剂 BNT162b2 疫苗，25 名健康对照者的抗体反应分别为 47.5% 和 100%（P < 0.001)。该组的抗体滴度也显着降低（平均为 95.41 AU/mL，对照组为 200.5 AU/mL，P  < 0.001）。年龄较大、估计肾小球滤过率较低和免疫抑制药物（过去 12 个月内使用大剂量强的松、MMF 和三联疗法免疫抑制）与较低的抗体反应相关。⁹一项针对 205 名接受两剂 mRNA-1273 SARS-CoV-2 疫苗接种的肾移植受者的研究显示，48% 的患者在第二剂接种后 28 天出现血清学反应。⁸

由于实体器官移植受者在接种两剂疫苗后反应较弱，因此提出了第三剂接种的可能性，最近法国的一项研究探讨了采用 BNT162b2 疫苗这一策略后的体液反应。¹³该研究包括 101 名移植受者（78 名肾移植受者、12 名肝移植受者、8 名肺或心脏移植受者，以及 3 名胰腺移植受者），他们在间隔 1 个月的时间接种了前两剂疫苗，在第二剂后约 2 个月接种了第三剂。在每次给药前和第三次给药后 4 周评估抗体反应。第三次给药前后抗 SARS-CoV-2 抗体的流行率从 40% 增加到 68%。在第三剂前血清阴性的患者中，44% 在第三剂后呈阳性，在第三剂前血清阳性的患者中，均保持阳性，抗体滴度从 32 ± 12 增加到 2676 ± 350 ( P  < 0.001 ）。尽管随访时间很短，但没有报告严重的不良反应或排斥反应。

最近的 AST/ISHLT/ASTS 联合声明，考虑到与研究显示移植受者对 COVID-19 疫苗的血清学反应率低相关的所有疑虑和担忧，并基于科学证据不足以得出确切的结论，并且鉴于疫苗接种对于遏制大流行的传播至关重要，因此对我们正在了解的器官移植受者的疗效提出了一些建议。该声明强烈建议所有实体器官移植受者都应接种 SARS-CoV-2 疫苗，以尽量减少使用当地批准的疫苗的风险，并在临床研究的背景下使用加强剂量。美国食品和药物管理局不建议在接种疫苗后进行常规抗体检测。大多数商业测试不筛选中和抗体，抗体检测的临界值不一定与临床相关，并且对于什么抗体滴度可以被视为对 SARS-CoV-2 感染具有保护作用也没有达成一致。但是，个别医生和患者可能会在讨论有关检测结果的解释和感染 COVID-19 的后果/风险后决定是否需要进行抗体检测。¹⁴

总之，对疫苗的免疫反应可能比测量抗体滴度更复杂，因为需要 T 细胞反应和长期临床随访研究来评估预防 COVID-19 和严重疾病的功效，和安全。第三剂的问题是一个很有希望的可能性，鉴于初步的令人鼓舞的经验，值得在未来的研究中进行探索。此外，免疫抑制的修改，例如为了获得更大的反应而停用 MMF，是一个非常有争议的问题，因为与触发与免疫抑制变化相关的排斥相关的风险-收益仍然未知。同时，继续研究，利用所有可用的临床数据并评估免疫原性，

利益冲突：没有声明。