新冠肺炎COVID-19中和抗体动态变化
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新型冠状病毒感染者特异性抗体动态变化特征研究进展
赵宏婷，彭质斌，杨孝坤，李志丽，任敏睿， 秦颖，孙校金，余建兴，安志杰，毛乃颖，许文波，李中杰. 新型冠状病毒感染者特异性抗体动态变化特征研究进展. 中华流行病学杂志, 2020年第41卷[网络预发表].
DOI：10.3760/cma.j.cn112338-20200809-01047
新型冠状病毒肺炎是由新型冠状病毒（新冠病毒）引起的新发传染病。新冠病毒侵入人体后，刺激免疫系统产生多种特异性抗体，来减弱或清除病原体对机体的影响。研究新冠病毒感染后人体内特异性抗体动态变化特征对于疾病认识、诊断、以及疫苗研究与防控策略制定具有重要意义。本文对国内外关于新冠病毒感染者不同类型特异性抗体产生和持续时间、抗体水平及其可能的影响因素等方面的相关研究进行归纳分析，从而增进对新冠病毒感染后机体免疫学特征的了解。
新型冠状病毒肺炎（新冠肺炎，COVID-19）是一种由新冠病毒引起的传染性疾病。据WHO 2020年7月31日统计数据显示，COVID-19已造成全球216个国家和地区约1 710万人感染，超66万人死亡［1］。COVID-19大流行对全球公共卫生系统提出了巨大挑战，由于缺乏治疗药物和疫苗，对新冠病毒感染者的早发现和早隔离仍然是目前防控疫情最有效的手段。目前，开展新冠病毒核酸检测是最常用的实验室诊断方法，检测抗新冠病毒特异性抗体可作为重要的临床辅助诊断方法。此外，抗新冠病毒特异性抗体检测在识别机体感染状态，评估人群感染水平、再感染的风险以及治疗和管理效果等方面也起着至关重要的作用。在新冠肺炎疫情发生后的半年多时间里，越来越多新冠病毒感染引起的机体体液免疫应答及其特异性抗体动态变化特征的文章发表，对其认识不断加深。本文对新冠肺炎疫情暴发以来国内外开展的感染者血清特异性抗体动态变化特征相关研究进行归纳总结（图1），同时比较了新型冠状病毒与严重急性呼吸综合征（Severe Acute Respiratory Syndrome，SARS）病毒感染所致的抗体动态变化特征（表1），希望为进一步开展新冠血清抗体相关研究提供参考。
一、新冠病毒特异性抗体的动态变化特征
1. 抗新冠病毒特异性IgM抗体动态变化特征：IgM抗体被认为是新冠病毒感染后机体最早产生的特异性抗体之一。与SARS病毒、中东呼吸综合征（middle east respiratory syndrome，MERS）病毒等冠状病毒感染类似［27-28］，多数新冠病毒感染者的血清抗体阳转发生在症状出现后第2或3周，现有研究表明新冠病毒感染确诊病例特异性IgM抗体阳转的中位时间为发病后10～12 d［11-12］。
多项研究发现，部分新冠病毒感染者（含确诊病例和无症状感染者）在发病后（或首次核酸检测阳性后）1周内就可以检测到特异性IgM抗体，阳性率约为11.1%～50.0%；发病后第2周，特异性IgM抗体水平上升达到或接近峰值状态，阳性率增加至59.7%～86.7%；自发病后第3或4周开始，特异性IgM抗体水平开始下降，但阳性率达到最高水平（约70.0%～100.0%）［2-14］。通常IgM抗体在体内维持时间较短，既往对SARS患者的研究显示，特异性IgM抗体持续时间在13周以内［15］。目前，尽管新冠病毒感染诱导的特异性IgM抗体在体内维持时间尚未能充分阐明，但现有研究显示，新冠病毒感染者在发病第4～5周后，特异性IgM抗体阳性率开始明显下降，降低10%～40%不等［4，9，14，29］。
2. 抗新冠病毒特异性IgG抗体动态变化特征：通常病原体感染机体后产生的特异性IgG抗体晚于IgM抗体。多个研究均显示，新冠病毒感染确诊病例特异性IgG抗体血清阳转的中位时间为发病后12～14 d［2，11-12，18］，几乎与特异性IgM抗体同时产生。值得注意的是，个别研究中抗新冠病毒特异性IgG抗体血清阳转的时间要早于IgM抗体，Long等［8］的研究显示，对26名新冠病毒感染确诊病例的血清抗体水平进行随访，发现其中7名感染者的抗新冠病毒特异性IgM抗体阳转早于IgG，10名感染者的抗新冠病毒特异性IgG抗体血清阳转早于IgM抗体，9名感染者的特异性IgM和IgG抗体血清阳转时间基本相同。以往对SARS的研究也曾观察到类似现象，病毒感染后特异性IgG抗体血清阳转时间比IgM抗体略早（1～3 d）或同时发生［20，30］。
多个研究发现，新冠病毒感染者特异性IgG抗体在发病后第1周的阳性率较低（3.7%～42.9%），第2周的阳性率逐渐上升到43.5%～76.0%［11，13-14］。但也有研究报告，特异性IgG抗体阳性率在第2周能达到90%以上［3］。抗新冠病毒特异性IgG抗体水平在发病后第3～4周迅速上升并达到峰值［4-7，9］，阳性率为80.0%～100.0%［9，11-14］。在第5～7周特异性IgG抗体阳性率可维持在100%左右［4，14，29］。多数研究中抗新冠病毒特异性IgG抗体水平达到的峰值高于IgM抗体［2-7，9，10］；然而也有个别研究显示抗新冠病毒特异性IgG抗体水平的峰值低于IgM抗体［11-12］，尽管两项研究均使用了同一个厂商的同一种检测试剂，但其研究结果不能排除检测试剂的影响。IgG抗体通常能维持较长时间，既往研究显示，抗SARS病毒特异性IgG抗体能在发病240 d后阳性率仍维持100%［20］，平均能维持2年左右［17］，是保护患者免于感染SARS病毒的主要抗体。然而，当前一项对新冠病毒感染者的研究中，超过90%的感染者（包括确诊病例和无症状感染者）在出院8周后（约发病2个月），特异性IgG抗体水平明显下降（下降约70%），且无症状感染者下降幅度比有症状者显著［16］，与既往对SARS患者特异性IgG抗体水平变化规律的认识完全不同。
3. 抗新冠病毒特异性IgA抗体动态变化特征：IgA抗体分布于血液和黏膜，在局部黏膜（如呼吸道上皮等）免疫中发挥重要作用［31-32］。新冠病毒感染确诊病例的特异性IgA抗体与IgM抗体类似，产生较早，阳转的中位时间为发病后11 d［18］。
多个研究发现，新冠病毒感染确诊病例发病后第1周特异性IgA抗体阳性率可以达50%以上［3，19］，第2周或第3周阳性率达到100%［3］。特异性IgA抗体水平在第3周达到高峰［2-3］，之后略微下降，但特异性IgA抗体水平持续（至少在发病后42 d内）维持较高水平，阳性率接近100%［3，18-19］。既往针对SARS的研究中，抗SARS病毒特异性IgA抗体的持续时间与IgM抗体类似，约63.6%的SARS患者在发病240 d后特异性IgA抗体消失［20］。
4. 中和抗体（neutralizing antibodies）：中和抗体是针对病毒某些表面蛋白质、抵御病毒入侵机体的一类免疫球蛋白，主要通过封闭与易感细胞受体结合的病毒抗原表位，或改变病毒表面构型，阻止病毒吸附、侵入细胞［33］。中和抗体具有抗病毒作用，是机体对抗病毒感染的有力武器，在评价病毒自然感染或疫苗接种后潜在免疫保护功效中常用作参考指标［34］。
研究发现，部分新冠病毒感染者在发病后第1～4 天可产生中和抗体，但抗体水平较低；第10～15天后（第2周）抗体水平开始显著升高，第31～40天（第5～6周）抗体水平达到峰值后维持稳定状态或略微下降［23，35-36］。既往对SARS的研究显示，中和抗体在动物模型中能够防止动物再感染，且在随访的两年内仍能检测到［21-22］。但当前一项对新冠病毒的研究中，超过60%的感染者（包括确诊病例和无症状感染者）在出院8周后（约发病2个月），中和抗体水平下降（下降约10%），且有症状感染者的中和抗体下降幅度比无症状者明显［16］。此外，虽然新冠病毒感染者多数能够产生具有抗病毒作用的中和抗体［23，36］，但也有少数重症患者在发病3周后仍无法检测出抗体，存在因无法产生抗体导致病情加重的可能［2］。
二、新冠病毒感染特异性抗体水平的影响因素
1. 病情严重程度对特异性抗体水平的影响：机体感染新冠病毒后，不同个体产生的抗体应答存在差异。基于目前的研究来看，与SARS患者相似［25］，新冠病毒感染者的抗体水平主要受病情严重程度的影响。一项研究比较了康复患者（232名）与死亡患者（32名）的抗体水平，发现死亡患者体内特异性IgM抗体水平高于康复患者；该研究同时还比较了不同临床严重程度（轻型64例，重症199例，危重症75例）患者的特异性IgM抗体水平，发现重症及危重症患者特异性IgM抗体水平高于非重症患者，特异性IgM抗体持续高水平提示可能预后不良［6］。对于IgG抗体，多数研究显示重症及危重患者的特异性IgG抗体水平高于非重症患者［7，9-10］，无症状感染者的特异性IgG抗体水平比出现症状的感染者特异性IgG抗体水平低［16］。但也有个别研究中危重患者特异性IgG抗体水平略低于轻症和重症患者［6］。特异性IgA抗体与IgM抗体和IgG抗体类似，重症患者可能高于非重症患者［3］。中和抗体水平也与病情严重程度也相关，病情越严重产生的中和抗体水平越高［23］。
2. 性别对特异性抗体水平的影响：新冠病毒感染者抗体水平还可能与性别有关，女性患者的特异性抗体水平比男性高。一项研究比较了127例男性病例与204例女性病例，发现女性在发病早期特异性IgG抗体水平高于男性患者；在重症患者中，女性特异性IgG抗体水平也高于男性［24］。有研究报道，新冠病毒感染确诊病例中男性重症比例和病死率都高于女性［37］，造成上述差异的原因尚不明确，性别间IgG抗体的差异可能是潜在的原因之一［24］。既往对SARS患者的研究也同样发现，男性患者的病死率可能比女性患者高［38］，且女性在不同病程时期里的抗体阳性率均高于男性［26］，但两者之间是否存在因果关系尚未阐明。
三、问题与展望
目前，国内外已经开展了一些针对新冠病毒感染后机体特异性抗体产生的时间、持续时间及抗体水平的研究，观察到抗体产生的一些动态变化特征，但仍存在一些争议。主要体现在几个方面：首先，现有研究多提示新冠病毒感染抗体变化与患者临床严重程度密切相关［3，6-10，16，29，35］，无症状和轻症患者可能产生较低的抗体水平，但部分研究纳入的研究对象仅包括了轻型和普通型的确诊病例［2，5， 13，19，23-24］，未将无症状感染者和重症患者纳入研究范畴，而纳入的研究对象不同可能会导致研究结果产生偏倚。目前，我国COVID-19疫情处于低流行趋势，识别无症状感染者，防范社区传播尤为重要［39］，但由于受当前纳入对象和观察时限等因素所致的研究结果局限性，尚无法明确血清特异性抗体检测识别这类人群的能力［16］。其次，由于在发病后第1～2周，特异性抗体阳性率较低，抗体检测可能在发病早期对及时诊断COVID-19的意义有限，但在核酸检测为阴性的疑似病例中，抗体检测提供了弥补核酸检测漏检风险的可能［2］。另外，特异性抗体可能在COVID-19发病第3周后阳性率较高，但目前COVID-19病例发病8周后的数据非常少，尚不清楚特异性抗体持续时间。而新冠病毒特异性抗体检测试剂在人群感染率较低时，即使检测方法具有较高的特异度，也会产生大量的假阳性结果［40］。因此，血清流行病学调查（基于人群的血清抗体检测）在人群感染水平、人群免疫水平及再感染可能性等公共卫生领域问题的作用尚有待进一步探索。再者，实验室检测方法及检测试剂的准确性、一致性等可能会对研究结果带来影响，且较难评估其影响。新冠肺炎疫情发生以来，快速检测特异性IgM、IgG和总抗体等特异性抗体的检测试剂被紧急投入使用，不同的检测试剂间评价和校准的工作相对缺乏。既往研究的中和抗体也有多种检测方法，包括使用分离得到的活病毒、重组的假病毒（如水疱性口炎病毒等）进行的噬斑减少中和试验（plaque reduction neutralization test，PRNT）和微量中和试验，而不同实验室得到的中和抗体实验结果存在差异，很难进行评价和相互比较［41］。除此以外，新冠病毒与SARS病毒之间可能存在免疫交叉反应［8］，标本中可能存在的一些如类风湿因子、嗜异性抗体、补体等内源性干扰物等宿主本身内在因素以及样本采集时间等外在因素［42］都会影响抗体检测结果的准确性。此外，随着疫苗的上市使用，通过实验室方法检测到的抗体很难区分是通过自然感染获得还是因接种疫苗获得，为将来利用血清学方法辅助病例诊断带来更多的复杂性。
综上所述，当前新冠病毒感染者特异性抗体动态变化特征的研究多针对病例急性期，缺乏对抗体长期动态变化特征的认识，有必要针对不同病情严重程度的感染者和康复者开展样本量多、随访时间长的前瞻性随访，同时开展抗体检测方法和试剂的准确性和一致性评价，从而更科学、准确地认识抗体动态变化规律，更好发挥其在疾病诊断、治疗及防控中的作用。 题目：Humoral Immune Response to SARS-CoV-2 in Iceland
DOI：10.1056/NEJMoa2026116
摘要：BACKGROUND：Little is known about the nature and durability of the humoral immune response to infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).METHODS：We measured antibodies in serum samples from 30,576 persons in Iceland, using six assays (including two pan-immunoglobulin assays), and we determined that the appropriate measure of seropositivity was a positive result with both pan-Ig assays. We tested 2102 samples collected from 1237 persons up to 4 months after diagnosis by a quantitative polymerase-chain-reaction (qPCR) assay. We measured antibodies in 4222 quarantined persons who had been exposed to SARS-CoV-2 and in 23,452 persons not known to have been exposed. RESULTS：Of the 1797 persons who had recovered from SARS-CoV-2 infection, 1107 of the 1215 who were tested (91.1%) were seropositive; antiviral antibody titers assayed by two pan-Ig assays increased during 2 months after diagnosis by qPCR and remained on a plateau for the remainder of the study. Of quarantined persons, 2.3% were seropositive; of those with unknown exposure, 0.3% were positive. We estimate that 0.9% of Icelanders were infected with SARS-CoV-2 and that the infection was fatal in 0.3%. We also estimate that 56% of all SARS-CoV-2 infections in Iceland had been diagnosed with qPCR, 14% had occurred in quarantined persons who had not been tested with qPCR (or who had not received a positive result, if tested), and 30% had occurred in persons outside quarantine and not tested with qPCR. CONCLUSIONS：Our results indicate that antiviral antibodies against SARS-CoV-2 did not decline within 4 months after diagnosis. We estimate that the risk of death from infection was 0.3% and that 44% of persons infected with SARS-CoV-2 in Iceland were not diagnosed by qPCR. 目前有限的数据表明，SARS-CoV-2可诱导一定程度的免疫。到目前为止，只有一份通过病毒基因测序证实的4个月内再次感染的明确报告，以及在一项小型研究中，恒河猴似乎可免受再次感染。尽管现在还处于早期阶段，而且这种免疫可能不会持续很长时间，但这对于研制出有效疫苗的前景来说是个好消息，研制出的疫苗在理想情况下应该能产生某种免疫反应，从而保护人体免受再次感染。
CD8+ T细胞、CD4+ T细胞和B细胞在清除大多数病毒感染中发挥着重要作用，康复后产生的T细胞和B细胞记忆在保护宿主在再次接触时免受严重疾病中起着至关重要的作用。然而，迄今为止，大多数有效疫苗的成功在很大程度上取决于产生强效和持久的抗体反应， 通过记忆B细胞和长寿浆细胞的活化，它们源源不断地供应高亲和力抗体。这些抗体在血液中和粘膜表面上流通和检查，即使在微小的浓度下也能结合并中和病毒。
虽然基于抗体的免疫力受到了很多关注，但越来越多的证据表明，T细胞在消除COVID-19中发挥了重要作用，但是SARS-CoV-2是否会产生长期的记忆T细胞反应，以及这些反应是否对持久的免疫力很重要仍不清楚。这些问题很重要，这是因为疫苗在诱发CD8+ T细胞反应方面通常不太有效。
近期，有两项独立的研究探讨了针对SARS-CoV-2的长期免疫的形成。Kaneko人等报道了严重的SARS-CoV-2感染会减弱生发中心反应，这可能会抑制长期抗体反应的产生。他们着手确定了之前报道的SARS-CoV-2短期体液反应的根本原因，其中体液反应持续时间较短也是导致人类严重感染的SARS-CoV和MERS-CoV等相关冠状病毒的特征。对于SARS-CoV感染，这被认为是由于缺乏生发中心反应造成的。生发中心是抗原激活的B细胞从一种称为滤泡辅助T细胞（TFH）的特定CD4+ T细胞亚群获得帮助后形成的短暂存在的微解剖环境。在生发中心内，B细胞经历了克隆扩增（clonal expansion）和亲和力成熟，并得到TFH细胞的进一步帮助，分化为记忆B细胞或长寿浆细胞。
Kaneko等人研究了SARS-CoV-2感染者生发中心内的B细胞反应。他们对死后胸腔淋巴结和脾脏进行了广泛的组织学评估。就像在SARS-CoV中发现的那样，他们发现在COVID-19的急性期也基本上没有生发中心。在缺乏生发中心的同时，也没有表达BCL6的B细胞或TFH细胞，而这些细胞对生发中心的产生是不可或缺的。此外，通过原位分析CD4+ T细胞组成，他们发现表达TBET的T细胞的富集伴随着TNF-α的增加。
Kaneko等人推测，过多的TNF-α通过阻断TFH细胞分化和促进TH1反应，抑制了COVID-19患者中生发中心反应的形成。已有肿瘤坏死因子（TNF）介导的生发中心阻断的先例在鼠埃立克体（Ehrlichia muris）感染（一种细胞内细菌性疾病）以及重症疟疾中报道过。在这两种感染模型中，TNF-α阻断可以恢复生发中心反应。虽然TNF-α是体内生发中心反应不可缺少的，但这可通过它在淋巴细胞发育和建立次级淋巴器官结构中的作用加以解释。因此，Kaneko及其同事们的研究结果表明，在严重的COVID-19感染中，TNF-α阻断不仅可以防止过度炎症，而且还可以使得长效的源自生发中心的抗体反应产生。
总的来说，他们的数据表明，生发中心反应的缺乏可能是COVID-19患者中观察到的多变的、通常是低水平的和短暂的抗体反应的原因。尽管如此，鉴于他们所有的分析都是使用从致命的COVID-19病例中获得的组织进行的，生发中心是否在平均较轻的COVID-19感染中也被清除仍然是未知数。短暂的B细胞抗体反应有可能是胸腺不依赖性B细胞激活的结果。尽管他们将AID+ B细胞的存在解释为T:B细胞强劲相互作用的标志，但胸腺不依赖性反应也可以是同种型转换的，是短暂存在的，并且可由包被在病毒衣壳上的高度重复性表位诱导，或由与病毒核酸结合的Toll样受体的激活诱导。
在另一项研究中，Sekine及其同事们对不同疾病严重程度和处于不同感染阶段的COVID-19患者的T细胞免疫进行了广泛描述。他们在大多数康复者中发现SARS-CoV-2特异性记忆T细胞，包括无症状病例和抗体反应无法检测到的病例。
在急性感染的COVID-19患者中，T细胞显示出一种活化表型，而康复期患者则拥有SARS-CoV-2特异性CD8+ T细胞，它们的表型让人联想到早期分化的记忆T细胞。这些细胞表达的TCF-1表明它们可能具有类似干细胞的表型，这使得它们有能力在再次感染时分化成多个效应T细胞亚群。因此，如果这些记忆T细胞产生TFH细胞，第二次接触SARS-CoV-2可能会引发有效的生发中心反应。
有趣的是，SARS-CoV-2特异性记忆T细胞在暴露于这种病毒的血清阴性健康人（确诊病例的亲属）中检测到，这表明无症状感染。值得注意的是，尽管只有60%的病例是血清阳性的，但是93%的 “暴露无症状（exposed asymptomatic）”的人对SARS-CoV-2产生了可检测的T细胞反应。这表明无症状感染可能比目前的数据所显示的更为普遍，而仅仅通过抗体检测进行免疫监测可能会低估感染率或人群免疫力。大多数康复患者中存在SARS-CoV-2特异性T细胞是一个有希望的迹象，表明感染可能会产生免疫力，但是这些T细胞是否能提供免于再次感染的保护还有待检验。
在2019年年中收集的一小部分样本（即未暴露的个体）也显示出SARS-CoV2反应性记忆T细胞，这并非完全出乎意料。目前有4种已知的冠状病毒毒株在人群中季节性地传播，并且人们已经记录了这些病毒毒株之间存在广泛的T细胞交叉反应性。携带交叉反应性T细胞的未暴露个体可能会受到保护，免受严重疾病的侵害，但这些细胞的存在是否会对保护性免疫的产生带来负面影响还有待检验。
根据这些结果，可以很容易推测，尽管COVID-19感染诱导的最佳保护性免疫可能依赖于记忆T细胞和源自生发中心的长寿浆细胞的产生，但单独的任何一种反应都可能在一定程度上免受严重疾病的侵害。有大量的证据表明，免疫系统的冗余性和多样性确保了在某一免疫分支受损的情况下对感染的保护水平。在无症状感染期间，即使在没有可检测到的抗体反应的情况下，也能发现强效的记忆CD8+ T细胞和CD4+ T细胞反应，这增加了科学家们对SARS CoV-2感染后产生保护性免疫的希望。然而，强效的记忆CD8+ T细胞反应可能难以通过接种疫苗来重现，而接种疫苗可能更多地依赖于强效高亲和力中和抗体的诱导。 Patel, Manish M., et al. "Change in Antibodies to SARS-CoV-2 Over 60 Days Among Health Care Personnel in Nashville, Tennessee." JAMA.
https://jamanetwork.com/journals/jama/fullarticle/2770928
Dynamic Changes of Antibodies to SARS-CoV-2 in COVID-19 Patients at Early Stage of Outbreak
https://link.springer.com/article/10.1007/s12250-020-00268-5
The coronavirus disease 2019 (COVID-19), caused by SARS-CoV-2, has spread around the world with high mortality. To diagnose promptly and accurately is the vital step to effectively control its pandemic. Dynamic characteristics of SARS-CoV-2-specific antibodies which are important for diagnosis of infection have not been fully demonstrated. In this retrospective, single-center, observational study, we enrolled the initial 131 confirmed cases of COVID-19 at Jin-Yin-Tan Hospital who had at least one-time antibody tested during their hospitalization. The dynamic changes of IgM and IgG antibodies to SARS-CoV-2 nucleocapsid protein in 226 serum samples were detected by ELISA. The sensitivities of IgM and IgG ELISA detection were analyzed. Result showed that the sensitivity of the IgG ELISA detection (92.5%) was significantly higher than that of the IgM (70.8%) (P < 0.001). The meantimes of seroconversion for IgM and IgG were 6 days and 3 days, respectively. The IgM and IgG antibody levels peaked at around 18 days and 23 days, and then IgM fell to below the baseline level at about day 36, whereas IgG maintained at a relatively high level. In conclusion, antibodies should be detected to aid in diagnosis of COVID-19 infection. IgG could be a sensitive indicator for retrospective diagnosis and contact tracing, while IgM could be an indicator of early infection. Waning of SARS-CoV-2 RBD antibodies in longitudinal convalescent plasma samples within four months after symptom onset
https://pubmed.ncbi.nlm.nih.gov/33001206/
Antibody responses against SARS‐CoV‐2 in COVID‐19 patients
https://onlinelibrary.wiley.com/doi/full/10.1002/jmv.26241
Seow, J., Graham, C., Merrick, B. et al. Longitudinal observation and decline of neutralizing antibody responses in the three months following SARS-CoV-2 infection in humans. Nat Microbiol 5, 1598–1607 (2020).
https://doi.org/10.1038/s41564-020-00813-8 Defining the features and duration of antibody responses to SARS-CoV-2 infection associated with disease severity and outcome
https://immunology.sciencemag.org/content/5/54/eabe0240
Science Immunology07 Dec 2020:
Vol. 5, Issue 54, eabe0240
DOI: 10.1126/sciimmunol.abe0240
Abstract
SARS-CoV-2-specific antibodies, particularly those preventing viral spike receptor binding domain (RBD) interaction with host angiotensin-converting enzyme 2 (ACE2) receptor, can neutralize the virus. It is, however, unknown which features of the serological response may affect clinical outcomes of COVID-19 patients. We analyzed 983 longitudinal plasma samples from 79 hospitalized COVID-19 patients and 175 SARS-CoV-2-infected outpatients and asymptomatic individuals. Within this cohort, 25 patients died of their illness. Higher ratios of IgG antibodies targeting S1 or RBD domains of spike compared to nucleocapsid antigen were seen in outpatients who had mild illness versus severely ill patients. Plasma antibody increases correlated with decreases in viral RNAemia, but antibody responses in acute illness were insufficient to predict inpatient outcomes. Pseudovirus neutralization assays and a scalable ELISA measuring antibodies blocking RBD-ACE2 interaction were well correlated with patient IgG titers to RBD. Outpatient and asymptomatic individuals’ SARS-CoV-2 antibodies, including IgG, progressively decreased during observation up to five months post-infection. A longitudinal study of SARS-CoV-2-infected patients reveals a high correlation between neutralizing antibodies and COVID-19 severity
https://www.nature.com/articles/s41423-020-00588-2
Abstract
Understanding the immune responses elicited by SARS-CoV-2 infection is critical in terms of protection against reinfection and, thus, for public health policy and vaccine development for COVID-19. In this study, using either live SARS-CoV-2 particles or retroviruses pseudotyped with the SARS-CoV-2 S viral surface protein (Spike), we studied the neutralizing antibody (nAb) response in serum samples from a cohort of 140 SARS-CoV-2 qPCR-confirmed infections, including patients with mild symptoms and also more severe forms, including those that required intensive care. We show that nAb titers correlated strongly with disease severity and with anti-spike IgG levels. Indeed, patients from intensive care units exhibited high nAb titers; conversely, patients with milder disease symptoms had heterogeneous nAb titers, and asymptomatic or exclusive outpatient-care patients had no or low nAbs. We found that nAb activity in SARS-CoV-2-infected patients displayed a relatively rapid decline after recovery compared to individuals infected with other coronaviruses. Moreover, we found an absence of cross-neutralization between endemic coronaviruses and SARS-CoV-2, indicating that previous infection by human coronaviruses may not generate protective nAbs against SARS-CoV-2. Finally, we found that the D614G mutation in the spike protein, which has recently been identified as the current major variant in Europe, does not allow neutralization escape. Altogether, our results contribute to our understanding of the immune correlates of SARS-CoV-2-induced disease, and rapid evaluation of the role of the humoral response in the pathogenesis of SARS-CoV-2 is warranted.
Legros, V., Denolly, S., Vogrig, M. et al. A longitudinal study of SARS-CoV-2-infected patients reveals a high correlation between neutralizing antibodies and COVID-19 severity. Cell Mol Immunol (2021).
Peng, P., Hu, J., Deng, Hj. et al. Changes in the humoral immunity response in SARS-CoV-2 convalescent patients over 8 months. Cell Mol Immunol (2021). https://doi.org/10.1038/s41423-020-00605-4
https://www.nature.com/articles/s41423-020-00605-4
Longitudinal analysis of humoral immunity against SARS-CoV-2 Spike in convalescent individuals up to 8 months post-symptom onset
https://www.biorxiv.org/content/10.1101/2021.01.25.428097v1
Humoral responses in naive or SARS-CoV-2 experienced individuals vaccinated with an inactivated vaccine
https://www.nature.com/articles/s41421-021-00311-z
RE: Why there is a second wave in India?
Prajjval Pratap Singh, Scientist,
Cytogenetics laboratory, Banaras Hindu University, Varanasi, India-221005
Other Contributors:
Gyaneshwer Chaubey, Molecular Anthropologist
(10 April 2021)
Why there is a second wave in India?
Prajjval Pratap Singh1, Gyaneshwer Chaubey1 and BHU Serosurveillance Consortium
1 Cytogenetics laboratory, Department of Zoology, Banaras Hindu University, Varanasi, India-221005
Dear Editor,
Buss et al. 1 have found >50% of seroprevalence among populations of Manaus. Brazil. This study has added a ray of hope to achieve herd immunity. However, we have taken a case of Indian city with >40% of seroprevalence, and shown here that the achieving herd immunity by infection is more hypothetical than real in case of SARS-CoV-2.
The recent steep rise of new cases in India have added a major concern 2. In the light of recent serosurveys in India, it was clear that many of the previous hotspots are saturated with approximately 50% of the seropositive individuals 3,4. With the recent explosion in cases, it has been seen that, most of the new hotspots are least affected, however, old hotspots do have substantial number of cases. Such rapid expansion of COVID-19 cases in India has raised an uncertainty on the existence of antibody among large number of individuals.
To investigate the key reason behind the second wave in India, we have revisited the people who have already shown seroprevalence in our previous survey 4. In addition with that, we have also included ten symptomatic individuals who have been tested with RT-PCR and their antibodies have been positive previously.
In this study, we have retested 100 people with the antibody kit CoviscreenTM from district Varanasi of India. Surprisingly, only seven individuals out of 100 showed seropositivity, suggesting that majority of individuals have lost their antibody within 3-6 months (Fig. 1). The frequency of seroprevalence significantly (p<0.0001) reduced from 0.409 (95% CI 0.362-0.457) to 0.07 (95% CI 0.035-0.068). Nevertheless, reports on other regions of world have also shown variable time estimates about the presence of antibodies after the infection 5–9.
Thus, here we explain the major reason for the second wave in India which is likely due to diminished antibody level from large number of seroprevalent population. One of the major driving component of this resurgence was due to broken wall of immunity landscape, formed during first wave of infection. However, it is less likely for a person to be critical in case of reinfection 10. This should significantly reduce the case fatality ratio in the second wave.
References
1. Buss, L. F. et al. Three-quarters attack rate of SARS-CoV-2 in the Brazilian Amazon during a largely unmitigated epidemic. Science 371, 288–292 (2021).
2. Coronavirus in India: Latest Map and Case Count. https://www.covid19india.org.
3. Murhekar, M. V. et al. SARS-CoV-2 antibody seroprevalence in India, August–September, 2020: findings from the second nationwide household serosurvey. Lancet Glob. Health 9, e257–e266 (2021).
4. Singh, P. P. et al. Estimation of real-infection and immunity against SARS-CoV-2 in Indian populations. medRxiv (2021).
5. Crawford, K. H. et al. Dynamics of neutralizing antibody titers in the months after severe acute respiratory syndrome coronavirus 2 infection. J. Infect. Dis. 223, 197–205 (2021).
6. Hueston, L. et al. The antibody response to SARS-CoV-2 infection. in Open forum infectious diseases vol. 7 ofaa387 (Oxford University Press US, 2020).
7. L’Huillier, A. G. et al. Antibody persistence in the first 6 months following SARS-CoV-2 infection among hospital workers: a prospective longitudinal study. Clin. Microbiol. Infect. (2021).
8. Pradenas, E. et al. Stable neutralizing antibody levels 6 months after mild and severe COVID-19 episodes. Med (2021).
9. Wang, K. et al. Longitudinal dynamics of the neutralizing antibody response to SARS-CoV-2 infection. Clin. Infect. Dis. (2020).
10. Abu-Raddad, L. J. et al. SARS-CoV-2 reinfection in a cohort of 43,000 antibody-positive individuals followed for up to 35 weeks. medRxiv (2021).
https://science.sciencemag.org/content/re-why-there-second-wave-india
https://science.sciencemag.org/content/371/6526/288/tab-e-letters
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