The COVID‐19 pandemic, caused by SARS‐CoV‐2, has resulted in more than a million deaths and tens of millions of infections globally. As we approach the first anniversary of its characterization, it is timely to consider the developments, and persistent limitations, in our understanding of this pathogen. In this special edition of Clinical and Experimental Immunology, we present five reviews and research papers on crucial aspects of COVID‐19.

The causes of COVID‐19 severity, and possible routes to limit severity, are a major topic of immunological research. It is becoming increasingly apparent that while disease is initiated by viral infection, the immune response itself may become pathogenic in later phases of disease. The presence of autoantibodies against type‐I interferons (IFNs) has recently been associated with COVID‐19 severity [1], demonstrating the importance of this arm of anti‐viral immunity in limiting disease. Type‐I IFNs are induced by the signalling of innate immune pattern recognition receptors (PRRs), and many viruses have evolved mechanisms to suppress PRR signalling. This virally mediated suppression of innate immunity has also been documented for SARS‐CoV‐2, as reviewed in this edition by Amor et al. [2]. Robust early innate immune responses probably contribute to early viral clearance, or the restriction of disease to asymptomatic or paucisymptomatic manifestations. By contrast, Amor et al. also discuss how elements of the innate immune system such as the activation of coagulation and complement may contribute to disease progression. Given the strong association between COVID‐19 severity and age [3], ‘inflammaging’, may also contribute to disease through the dysfunction of early innate immune viral recognition and the propensity to initiate pathological inflammatory responses [2].

COVID‐19 severity can be attenuated through the use of dexamethasone in patients with severe disease, demonstrating the role of steroid‐sensitive inflammation in COVID‐19 severity [4]. Numerous other therapeutics are being tested for their ability to attenuate COVID‐19, including the COVACTA trial of the anti‐interleukin (IL)‐6 receptor monoclonal antibody tocilizumab [5] and granulocyte–macrophage colony‐stimulating factor (GM‐CSF) neutralizing monoclonal antibodies [6]. In addition to these immunomodulatory therapeutic agents, prophylactic immunomodulation may offer some benefit in limiting COVID‐19 severity. Vaccination against Mycobacterium tuberculosis using the bacillus Calmette–Guérin (BCG) vaccine has been studied in many settings as a possible trigger of ‘off‐target’ effects that protect against non‐mycobacterial pathogens, and has been considered for its possible role in combating COVID‐19 [7]. In this edition, Aksu et al. retrospectively studied the records of patients hospitalized with COVID‐19 to determine their disease severity and BCG vaccine history [8]. Using multivariate analysis, age and socio‐economic status were determined to be independent risk factors for severe disease, in line with other studies [3, 9]. By contrast, BCG vaccine history was not associated with disease severity in this analysis. While this may indicate that BCG vaccine history is not a major determinant of COVID‐19 severity, the relatively small size of this data set (n = 123 hospitalized patients) may require confirmation in larger‐scale population studies.

The humoral immune response to SARS‐CoV‐2 may be a crucial determinant of viral clearance and could act as a correlate of protection following natural infection or vaccine‐mediated immune responses. Additionally, antibody testing is essential for understanding the rate of infection in the population through the use of public health serosurveillance, and therefore accurately determining populations at risk of severe disease and the absolute case fatality rate. As such, studies of the nature, scale and longevity of the antibody response to SARS‐CoV‐2 are essential. In this issue, Huang et al. monitored the immunoglobulin (Ig)G, IgM and IgA responses in longitudinal serum samples from 43 COVID‐19 patients using a recombinant Spike‐protein‐based capture immunoassay [10]. This demonstrated that the scale of these antibody responses increased with disease severity, in agreement with other reports, and were largely well correlated between immunoglobulin isotypes. Furthermore, Huang et al. demonstrate that IgA, which has been relatively understudied thus far, may be detectable relatively early in the process of COVID‐19, potentially offering a better serological marker of infection than other isotypes. This work highlights the urgent need for improved understanding of the serological response to SARS‐CoV‐2, for both diagnostic testing and public health serosurveillance studies.

It is widely considered that an effective vaccine against SARS‐CoV‐2 will be required to enable the lifting of social and workplace restriction imposed due to COVID‐19. Here, Tregoning et al. provide a timely and thorough summary of vaccine approaches in development and in clinical trials for SARS‐CoV‐2 [11]. There are currently > 200 vaccines in development and 39 clinical trials ongoing globally, after less than 1 year since the first identification of SARS‐CoV‐2. This rate of global vaccine development is unprecedented, reflecting the urgency of this task. It is humbling to consider how much slower this response might have been without the global co‐ordination of vaccine efforts and the early implementation of key technologies such as whole viral genome sequencing, which greatly expedited these efforts [12]. Some SARS‐CoV‐2 vaccine candidates utilize platform technologies common with many other vaccines, including inactivated virions, viral protein or peptide vaccines or attenuated viruses. Other approaches, such as vectored vaccines (e.g. the Oxford/AstraZeneca candidate ChAdOx1 nCoV‐19 [13]) and self‐amplifying RNA vaccines (e.g. self‐amplifying RNA encoding pre‐fusion stabilized Spike protein [14]), are more novel approaches to human vaccination. In addition to the immunogenicity, safety and efficacy of these vaccines, a crucial consideration is the ability to produce each vaccine candidate at the scale required for global immunization. As discussed by Tregoning et al., this potential bottleneck in vaccine manufacture and deployment are important considerations for the probable global success of each candidate, as safety and efficacy data become available. These considerations are also crucial for preparedness against future pandemics. COVID‐19 has highlighted the pressing need for vaccine platforms that can rapidly adapt to novel pathogens and be produced on a scale suitable for global immunization. Support for such basic scientific work in the future could greatly expedite vaccine delivery in the face of novel pathogens.

Vaccines against SARS‐CoV‐2 may need to be selectively given to at‐risk populations, including older adults and patients with diabetes [9], especially if the availability of vaccine doses is limited. Our understanding of which comorbidities might be associated with greater COVID‐19 severity has developed substantially. One early consideration was the risk presented by the use of immunomodulatory therapies for autoimmune diseases and cancer. As presented in this issue by Baker et al., depletion of B cells using anti‐CD20 antibodies has been regarded as a potential aggravating factor that could enhance COVID‐19 severity [15]. While data do not currently support this increase in severity, the possible impact upon antibody responses to infection, and the immunity generated by natural infection or vaccination, has yet to be determined. Baker et al. usefully extract information on the role of one anti‐CD20 therapy, ocrelizumab, in inhibiting vaccine responses, measured by generation of specific antibodies. This provides further evidence that anti‐CD20 therapies, and possibly other therapies that inhibit the adaptive immune system, might limit vaccine immunogenicity. This issue is likely to become an important consideration if natural or vaccine‐induced immunity is dependent upon an antibody response, or may be of lesser significance if immunity is largely mediated by cytotoxic cells. The risks and benefits in temporarily pausing immunomodulatory therapies on the response to SARS‐CoV‐2 vaccines will require careful consideration as these vaccines emerge, and our understanding of COVID‐19 severity in these patient populations evolves.

After nearly a year of research on SARS‐CoV‐2, great strides have been made in our understanding and ability to combat this pathogen. However, with many vaccine efficacy studies and therapeutic trials still under way, it is as important as ever that we continue to develop our understanding of this disease. Rationally designed therapeutic and prophylactic interventions, benefiting from the wealth of basic and translational research now available, may yet make major impacts on this pandemic.

由 SARS-CoV-2 引起的 COVID-19 大流行已导致全球超过一百万人死亡和数千万人感染。当我们接近其特征描述一周年之际，是时候考虑我们对这种病原体的理解的进展和持续的局限性了。在本期《临床和实验免疫学》特别版中，我们提出了有关 COVID-19 关键方面的五篇评论和研究论文。

COVID-19 严重程度的原因以及限制严重程度的可能途径是免疫学研究的一个主要主题。越来越明显的是，虽然疾病是由病毒感染引发的，但免疫反应本身可能在疾病的后期阶段变得致病。最近，针对 I 型干扰素 (IFN) 的自身抗体的存在与 COVID-19 的严重程度相关[ 1 ]，这证明了这一抗病毒免疫在限制疾病方面的重要性。 I 型干扰素是由先天免疫模式识别受体 (PRR) 信号传导诱导的，许多病毒已经进化出抑制 PRR 信号传导的机制。正如 Amor等人在本版中所评论的那样，这种病毒介导的先天免疫抑制也已在 SARS-CoV-2 中得到记录。 [ 2 ]。强大的早期先天免疫反应可能有助于早期病毒清除，或将疾病限制为无症状或少症状表现。相比之下，阿莫尔等人。还讨论了先天免疫系统的要素（例如凝血和补体的激活）如何促进疾病进展。鉴于 COVID-19 严重程度与年龄之间的密切相关性 [ 3 ]，“炎症”也可能通过早期先天免疫病毒识别功能障碍和引发病理性炎症反应的倾向而导致疾病 [ 2 ]。

通过对重症患者使用地塞米松可以减轻 COVID-19 的严重程度，这证明了类固醇敏感性炎症在 COVID-19 严重程度中的作用[ 4 ]。许多其他疗法正在测试其减弱 COVID-19 的能力，包括抗白细胞介素 (IL)-6 受体单克隆抗体托珠单抗 [ 5 ] 和粒细胞-巨噬细胞集落刺激因子 (GM-CSF) 中和的 COVACTA 试验单克隆抗体[ 6 ]。除了这些免疫调节治疗药物外，预防性免疫调节可能在限制 COVID-19 严重程度方面提供一些益处。使用卡介苗 (BCG) 疫苗进行结核分枝杆菌疫苗接种已在许多环境中进行了研究，认为它可能触发“脱靶”效应，以预防非分枝杆菌病原体，并被认为在对抗新冠肺炎方面可能发挥作用‐19 [ 7 ]。在这个版本中，阿克苏等人。回顾性研究了因 COVID-19 住院的患者的记录，以确定他们的疾病严重程度和卡介苗疫苗史 [ 8 ]。使用多变量分析，年龄和社会经济状况被确定为严重疾病的独立危险因素，与其他研究一致[ 3, 9 ]。相比之下，在本次分析中，卡介苗接种史与疾病严重程度无关。虽然这可能表明 BCG 疫苗接种史并不是 COVID-19 严重程度的主要决定因素，但该数据集规模相对较小（ n = 123 名住院患者），可能需要在更大规模的人群研究中进行确认。

针对 SARS-CoV-2 的体液免疫反应可能是病毒清除的关键决定因素，并且可能与自然感染或疫苗介导的免疫反应后的保护相关。此外，抗体检测对于通过公共卫生血清监测了解人群的感染率至关重要，从而准确确定面临严重疾病风险的人群和绝对病死率。因此，研究 SARS-CoV-2 抗体反应的性质、规模和寿命至关重要。在本期中，黄等人。使用基于重组 Spike 蛋白的捕获免疫测定法监测了 43 名 COVID-19 患者的纵向血清样本中的免疫球蛋白 (Ig)G、IgM 和 IgA 反应 [ 10 ]。这表明这些抗体反应的规模随着疾病的严重程度而增加，与其他报告一致，并且在免疫球蛋白同种型之间很大程度上具有良好的相关性。此外，黄等人。证明迄今为止研究相对较少的 IgA 可能在 COVID-19 的过程中相对较早地被检测到，可能提供比其他同种型更好的感染血清学标记。这项工作强调了诊断测试和公共卫生血清监测研究中迫切需要加深对 SARS-CoV-2 血清学反应的了解。

人们普遍认为，需要一种针对 SARS-CoV-2 的有效疫苗，才能解除因 COVID-19 施加的社会和工作场所限制。在这里，特雷戈宁等人。及时、全面地总结了 SARS-CoV-2 疫苗开发和临床试验的方法[ 11 ]。自首次发现 SARS-CoV-2 以来不到一年，目前全球有超过 200 种疫苗正在开发中，39 项临床试验正在进行中。全球疫苗研发的速度是前所未有的，反映出这项任务的紧迫性。如果没有疫苗工作的全球协调以及全病毒基因组测序等关键技术的早期实施，这种反应可能会慢得多，这令人感到羞愧，这大大加快了这些工作[ 12 ]。一些 SARS-CoV-2 候选疫苗利用了许多其他疫苗常见的平台技术，包括灭活病毒颗粒、病毒蛋白或肽疫苗或减毒病毒。其他方法，例如载体疫苗（例如牛津/阿斯利康候选 ChAdOx1 nCoV-19 [ 13 ]）和自扩增 RNA 疫苗（例如编码融合前稳定刺突蛋白的自扩增 RNA [ 14 ]），是更新颖的方法用于人类疫苗接种。除了这些疫苗的免疫原性、安全性和有效性之外，一个重要的考虑因素是能够以全球免疫所需的规模生产每种候选疫苗。正如 Tregoning等人所讨论的，随着安全性和有效性数据的获得，疫苗生产和部署中的这一潜在瓶颈是每个候选疫苗可能在全球取得成功的重要考虑因素。 这些考虑因素对于防范未来流行病也至关重要。 COVID-19 凸显了对能够快速适应新型病原体并以适合全球免疫的规模生产的疫苗平台的迫切需求。未来对此类基础科学工作的支持可以大大加快面对新型病原体的疫苗交付。

可能需要有选择地向高危人群接种针对 SARS-CoV-2 的疫苗，包括老年人和糖尿病患者 [ 9 ]，特别是在疫苗剂量有限的情况下。我们对哪些合并症可能与 COVID-19 严重程度更高相关的认识已经有了很大的发展。一个早期的考虑因素是使用免疫调节疗法治疗自身免疫性疾病和癌症所带来的风险。正如 Baker等人在本期中提出的，使用抗 CD20 抗体消耗 B 细胞被认为是一个潜在的加重因素，可能会增强 COVID-19 的严重程度 [ 15 ]。虽然目前的数据并不支持这种严重程度的增加，但对抗体对感染的反应以及自然感染或疫苗接种产生的免疫力的可能影响尚未确定。贝克等人。有效地提取了有关一种抗 CD20 疗法 ocrelizumab 在抑制疫苗反应中的作用的信息，通过产生特异性抗体来衡量。这提供了进一步的证据，表明抗 CD20 疗法以及可能的其他抑制适应性免疫系统的疗法可能会限制疫苗的免疫原性。如果自然或疫苗诱导的免疫依赖于抗体反应，这个问题可能会成为一个重要的考虑因素，或者如果免疫主要由细胞毒性细胞介导，则可能不太重要。随着这些疫苗的出现，以及我们对这些患者群体中 COVID-19 严重程度的了解的不断发展，需要仔细考虑暂时停止针对 SARS-CoV-2 疫苗的免疫调节疗法的风险和益处。

经过近一年对 SARS-CoV-2 的研究，我们对这种病原体的认识和对抗能力取得了长足的进步。然而，由于许多疫苗功效研究和治疗试验仍在进行中，我们继续加深对这种疾病的了解与以往一样重要。受益于现有丰富的基础和转化研究，合理设计的治疗和预防干预措施可能会对这一流行病产生重大影响。