Bitpie最新版app|ade

什么是ADE效应？ - 知乎

什么是ADE效应？ - 知乎首页知乎知学堂发现等你来答​切换模式登录/注册效应什么是ADE效应？关注者224被浏览1,298,428关注问题​写回答​邀请回答​好问题 22​1 条评论​分享​12 个回答默认排序小兔子不乖乖互联网的游荡者​ 关注所谓ADE效应，是指“抗体依赖增强症”。专业解释是这样的：病毒感染都是从黏附于细胞表面开始的，黏附是通过病毒表面蛋白与靶细胞上特异性受体和配体分子的相互作用来完成的。针对病毒表面蛋白的特异性抗体常常可以阻抑这一步骤，将病毒“中和”,使其失去感染细胞的能力。然而在有些情况下，抗体在病毒感染过程中却发挥相反的作用：它们协助病毒进入靶细胞，提高感染率，这一现象就是抗体依赖性增强作用。上面这个专业解释，比较绕口，我给大家来一段大白话版本的解释：简单说就是，正常情况下一个人感染了病毒之后，只要最终痊愈，人体免疫系统就会产生这个病毒的抗体。这样以后再感染病毒，人体内的抗体就可以阻抑病毒的感染，从而实现免疫。然而，在某些情况下，比如病毒发生了变异，这时候人再次感染了这个病毒后，人体原先产生的抗体，对于变异后的病毒不起作用。而且这个时候因为人体的免疫系统误以为病毒已经被“阻抑”，使得这时候人体免疫系统对病毒完全不设防。这会导致这个病人，在感染变异后的病毒，会比没有抗体的人，症状反而更严重，并且更易感染。这种时候，人体内的抗体，反而会协助变异后的病毒进入靶细胞，提高了感染率。这个现象就被称为“ADE效应”，也就是“抗体依赖增强效应”。发布于 2020-04-10 15:01​赞同 494​​45 条评论​分享​收藏​喜欢收起​彧含但当涉猎，不求甚解。​ 关注大概是这么个意思。你是一个貌美如花的大姑娘（健康细胞），隔壁老王（病毒）对你垂涎三尺，每天来砸你家门，吓得你里三层外三层给自己家上了锁（普通免疫），然后一段时间后，还请了特种兵保镖（抗体）来保护你，你给了特种兵老王的照片，特种兵看见老王就去锤他，从此老王再也无法接近你半步。于是你就放下警戒了，家里的防护网防盗门也都打开了，开始了正常生活，完全依赖特种兵保护你不受老王骚扰（免疫依赖）。可是你万万没想到啊！有一天，老王突然整容了（变异），他整成了吴彦祖（误）！特种兵照常巡逻，对着整容后的老王拿照片一看！这不对啊！这不是老王啊！于是特种兵就放老王进去了，甚至直接把老王送到你身边（帮助病毒与靶细胞结合），这下，撤去普通防护的你彻底成为了老王的盘中餐。这就是ADE编辑于 2021-05-02 19:34​赞同 380​​52 条评论​分享​收藏​喜欢

ADE效应_百度百科

什么是ADE效应，需要我们警惕 - 知乎

什么是ADE效应，需要我们警惕 - 知乎切换模式写文章登录/注册什么是ADE效应，需要我们警惕知其要者锂电本文内容引用：中国疫苗和免疫2020年12月第26卷第6期《毒病疫苗的抗体依赖增强作用及其对疫苗研究的启示》夏兰芳，王华庆（中国疾病预防控制中心免疫规划中心）一、什么是ADE效应ADE 概 念最早由Hawkes于1964年首次提出，英文全称Antibody-Dependent Enhancement的缩写，中文翻译为“抗体依赖的增强作用。当机体通过自然感染、疫苗接种、母体被动免疫可获得较高浓度的非中和抗体、低于中和浓度的中和抗体、异型病原之间的交叉免疫抗体（多为IgG抗体），当机体再次遇到该病原感染时，体内的这些抗体不能中和病原感染、提供保护作用，反而增加机体对病原易感性，或增加疾病发病程度（住院率、住院时间、疾病症状），这种现象即为ADE。翻译成通俗易懂的话就是说：通过自然感染、疫苗接种，而得到一种病毒抗体后，当再一次遇到该病毒时，体内抗体不仅不能提供保护，反而能帮助病毒绕过免疫系统，增加发病程度。二、疫苗接种与ADE人体接种某些疫苗后可出现 ADE，这些疫苗主要为上市后疫苗（麻疹灭活疫苗、重组四价登革热减毒活疫苗）或进行人体临床试验的疫苗（如呼吸道合胞病毒灭活疫苗、HIV 疫苗）；一些疫苗研究过程中，在接种试验用疫苗的动物表现出了 ADE 的症状。三、ADE 发生案例1.甲醛灭活呼吸道合胞病毒疫苗a）呼吸道合胞病毒（RSV）可引起儿童急性下呼吸道感染，是引起儿童病毒性急性下呼吸道疾病的主要原因；全球范围内，2015 年 RSV 估计引起 3 310 万 5 岁以下儿童急性下呼吸道感染，引起320 万重症病例需住院治疗，造成 59 600 名儿童死亡。b)1965-1966，美国研究者们将甲醛灭活的FI-RSV 接种到一些婴幼儿体内 。试验开始 9 个月后，RSV 感染在社区暴发流行。接种前血清学阴性的 FI-RSV 接种者，当机体再次感染 RSV 野毒株时，FI-RSV 不仅未能提供保护作用，反而引起机体产生急性下呼吸道感染严重程度（包括住院率、平均住院时间和疾病症状）显著增加。c)结局 FI-MV 于 1967 年退出市场，被更安全的减毒活疫苗所替代。2.重组四价登革热减毒活疫苗（CYD-TDV）a)登革热病毒经伊蚊传播感染人引起人体登革疾病，是一种虫媒传染病。人感染后可能无症状，也可能引起轻度发热型疾病、登革热或重症登革疾病。全球热带、亚热带国家有 39 亿人生活在登革热感染区，最新估计每年约有 3 900 万人感染登革热病毒，960 万人出现临床症状，50 万例发生重症登革疾病包括 DHF/DSS，每年造成约 2 万人死亡b)对注射疫苗临床试验受试者 3 年的安全性随访研究发现，<9 岁儿童中登革热疫苗接种者感染登革热病毒后会出现更严重的登革疾病。实验室确诊登革热住院病例风险增加，其中疫苗组比例为0.78%（38/4831），对照组比例为 0.49%（12/2406）。2-5 岁儿童风险更高，其中疫苗组比例为 0.91%（15/1 636），对照组为 0.1%（1/813）；<9 岁儿童中登革热疫苗接种组重症登革病例比例增加，为 0.24%（12/4831），对照组为 0.00%；c)结局 WHO 建议 CYD-TDV 接种前进行血清筛查，以前感染过登革热病毒的人适合接种登革热疫苗，血清抗体阴性者不适合接种；ADE效应对人类健康最大的威胁是把人类用来保护自己的盾变成了刺杀自己的矛，以己之盾，化矛攻之，这盾就是疫苗。ADE这种医学现象，所产生的问题需要引起我们的警惕。书不尽言，言不尽意。很多话想说，但是欲言又止......天佑中华！避免失联，请及时关注发布于 2022-01-05 23:25人身安全安全效应​赞同 31​​9 条评论​分享​喜欢​收藏​申请

通俗解说病毒疫苗发生的ADE效应是什么？ - 知乎

通俗解说病毒疫苗发生的ADE效应是什么？ - 知乎首发于科学历史杂谈切换模式写文章登录/注册通俗解说病毒疫苗发生的ADE效应是什么？明月清风 什么是ADE效应？ADE全称Antibody-dependent enhancement，意为抗体依赖性增强，比较通俗的解释是：病毒在感染细胞时，由于某些原因，体内已有的相关抗体会增强病毒的感染能力。换言之，经自然免疫或疫苗接种后，再次接触相关病毒时，体内产生的抗体可能会增强其感染能力，最终导致病情加重。假设人体就是一个城市，有很多城门，就是（细胞壁蛋白），城市里面还有很多拿着AK47守卫的保安，就是（免疫系统）。病毒就是想进入城市拿着刀剑抢劫杀人的强盗，这个强盗（病毒）必须有良民证才能通过城门（细胞壁蛋白）进入城市，比如人感染的感冒病毒就有进入人体细胞的良民证。如果城市里面的保安（免疫系统）认识强盗（病毒），那么毫不迟疑的会杀死进入城市的强盗。如果不认识强盗，放进去了，强盗在城市里面拿着刀剑大肆抢劫杀人，而那些不认识强盗的保安还把病毒当好人，根本不管，那我们就感冒了，生病了。直到强盗（病毒）杀的良民越来越多，报案的很多，特别是某个细胞在全家被强盗杀死前，放出一只信鸽，这信鸽的腿上拴了个布条，里面记录了强盗的信息特征，就是强盗穿着绿衣服，脸上有条一尺长的刀疤，然后保安（免疫系统）终于知道强盗（病毒）是坏人，然后保安（免疫系统）依据只要是 绿衣服有尺长刀疤的人就拿着AK47统统杀掉，毕竟拿着刀剑的强盗打不过拿AK47保安（免疫系统），这就是免疫反应。1、灭活疫苗？就是预先找个强盗（比如登革热病毒）打死了，尸体一定要完整哦，然后把所有保安叫来，看，这就是强盗，穿着红裙子，肤白貌美大长腿，唇红齿白，最重要的是有两只能迷死人的大大的蓝眼睛等等，给我牢牢记住这个人所有的特征，有红裙子，肤白貌美大长腿等第。。。以后看见就给我打死，保管没错。2、疫苗发生的ADE效应？一些意志力不坚定的保安（免疫系统）牢牢的记住了强盗尸体（比如登革热病毒）美丽的样子，可以说是永远记住在心底，这么美的人打死太可惜了，所有的保安（免疫系统）都这么想，但是没有办法，有官府命令，如果强盗（比如登革热病毒）来了，还是照样打死。但是强盗（比如登革热病毒）非常的狡猾，有个双胞胎姐妹（登革热病毒亚种），长的也是肤白貌美大长腿，唇红齿白，也有两只能迷死人的大大的蓝眼睛,但是穿着蓝裙子，首先所有的保安（免疫系统）认定她不是强盗，因为强盗是红裙子，认为她是好人。然后一些意志不坚定的保安（免疫系统）发现日夜思念的美人出现在面前，立刻拜倒在病毒双胞胎姐妹（登革热病毒亚种）的石榴裙下，保安（免疫系统）把自己的AK47交给双胞胎姐妹（登革热病毒亚种），她在城市里面用AK47大肆抢劫杀人，杀的不要太爽啊。原来城市里有些富人家用铁门，强盗（登革热病毒）用刀剑根本砍不开，进不去啊，这回，病毒双胞胎姐妹（登革热病毒亚种）用AK47轻松打碎铁门，进入原先无法进入的黄四郎家里面，大肆屠杀抢劫，真是太爽了，AK47太好用了，最终使整个城市伤亡惨重，感染者病情加重。这就是疫苗发生的ADE效应。登革热，冠状病毒都有ADE效应。 3、mRNA疫苗的原理？就是找出强盗（比如冠状病毒）的典型特征， 比如强盗会易容术，会有双胞胎姐妹，为了防止发生的ADE效应，就是防止一些意志不坚定的保安（免疫系统）被强盗（比如冠状病毒）的美色拉拢，堕落成为病毒的帮凶。强盗易容或她的双胞胎姐妹，有个天生的无法掩盖的典型特征，比如它的的典型特征，就是两只眼睛是蓝的，两只耳朵是尖的。mRNA疫苗就是找出精确的病毒的典型特征，加以识别并消灭。就是预先找个血淋漓的强盗（比如冠状病毒）的脑袋，然后把所有保安叫来，看，这就是强盗的脑袋，以后你们保安只要发现有人：不管他是不是漂亮的女人，只要两只眼睛是蓝的，两只耳朵是尖的。这人保管就是强盗装扮的，看见就给我打死，保管没错。那些意志不坚定的保安（免疫系统）因为看见的是血淋淋的脑袋，而不是漂亮的肤白貌美大长腿的病毒本人，所以这些意志不坚定的保安（免疫系统）铭记在心里的是血淋淋的脑袋，所以日后这些意志不坚定的保安（免疫系统）杀起那些入侵的肤白貌美大长腿的强盗（比如冠状病毒）是毫不怜香惜玉的。所以mRNA疫苗，没有ADE效应，有效性更高，免疫力更强，时间更持久。俗解说病毒疫苗发生的ADE效应是什么？什么是ADE效应？ADE全称Antibody-dependent enhancement，意为抗体依赖性增强，比较通俗的解释是：病毒在感染细胞时，由于某些原因，体内已有的相关抗体会增强病毒的感染能力。换言之，经自然免疫或疫苗接种后，再次接触相关病毒时，体内产生的抗体可能会增强其感染能力，最终导致病情加重。假设人体就是一个城市，有很多城门，就是（细胞壁蛋白），城市里面还有很多拿着AK47守卫的保安，就是（免疫系统）。病毒就是想进入城市拿着刀剑抢劫杀人的强盗，这个强盗（病毒）必须有良民证才能通过城门（细胞壁蛋白）进入城市，比如人感染的感冒病毒就有进入人体细胞的良民证。如果城市里面的保安（免疫系统）认识强盗（病毒），那么毫不迟疑的会杀死进入城市的强盗。如果不认识强盗，放进去了，强盗在城市里面拿着刀剑大肆抢劫杀人，而那些不认识强盗的保安还把病毒当好人，根本不管，那我们就感冒了，生病了。直到强盗（病毒）杀的良民越来越多，报案的很多，特别是某个细胞在全家被强盗杀死前，放出一只信鸽，这信鸽的腿上拴了个布条，里面记录了强盗的信息特征，就是强盗穿着绿衣服，脸上有条一尺长的刀疤，然后保安（免疫系统）终于知道强盗（病毒）是坏人，然后保安（免疫系统）依据只要是 绿衣服有尺长刀疤的人就拿着AK47统统杀掉，毕竟拿着刀剑的强盗打不过拿AK47保安（免疫系统），这就是免疫反应。1、灭活疫苗？就是预先找个强盗（比如登革热病毒）打死了，尸体一定要完整哦，然后把所有保安叫来，看，这就是强盗，穿着红裙子，肤白貌美大长腿，唇红齿白，最重要的是有两只能迷死人的大大的蓝眼睛等等，给我牢牢记住这个人所有的特征，有红裙子，肤白貌美大长腿等第。。。以后看见就给我打死，保管没错。2、疫苗发生的ADE效应？一些意志力不坚定的保安（免疫系统）牢牢的记住了强盗尸体（比如登革热病毒）美丽的样子，可以说是永远记住在心底，这么美的人打死太可惜了，所有的保安（免疫系统）都这么想，但是没有办法，有官府命令，如果强盗（比如登革热病毒）来了，还是照样打死。但是强盗（比如登革热病毒）非常的狡猾，有个双胞胎姐妹（登革热病毒亚种），长的也是肤白貌美大长腿，唇红齿白，也有两只能迷死人的大大的蓝眼睛,但是穿着蓝裙子，首先所有的保安（免疫系统）认定她不是强盗，因为强盗是红裙子，认为她是好人。然后一些意志不坚定的保安（免疫系统）发现日夜思念的美人出现在面前，立刻拜倒在病毒双胞胎姐妹（登革热病毒亚种）的石榴裙下，保安（免疫系统）把自己的AK47交给双胞胎姐妹（登革热病毒亚种），她在城市里面用AK47大肆抢劫杀人，杀的不要太爽啊。原来城市里有些富人家用铁门，强盗（登革热病毒）用刀剑根本砍不开，进不去啊，这回，病毒双胞胎姐妹（登革热病毒亚种）用AK47轻松打碎铁门，进入原先无法进入的黄四郎家里面，大肆屠杀抢劫，真是太爽了，AK47太好用了，最终使整个城市伤亡惨重，感染者病情加重。这就是疫苗发生的ADE效应。登革热，冠状病毒都有ADE效应。3、mRNA疫苗的原理？就是找出强盗（比如冠状病毒）的典型特征， 比如强盗会易容术，会有双胞胎姐妹，为了防止发生的ADE效应，就是防止一些意志不坚定的保安（免疫系统）被强盗（比如冠状病毒）的美色拉拢，堕落成为病毒的帮凶。强盗易容或她的双胞胎姐妹，有个天生的无法掩盖的典型特征，比如它的的典型特征，就是两只眼睛是蓝的，两只耳朵是尖的。mRNA疫苗就是找出精确的病毒的典型特征，加以识别并消灭。就是预先找个血淋漓的强盗（比如冠状病毒）的脑袋，然后把所有保安叫来，看，这就是强盗的脑袋，以后你们保安只要发现有人：不管他是不是漂亮的女人，只要两只眼睛是蓝的，两只耳朵是尖的。这人保管就是强盗装扮的，看见就给我打死，保管没错。那些意志不坚定的保安（免疫系统）因为看见的是血淋淋的脑袋，而不是漂亮的肤白貌美大长腿的病毒本人，所以这些意志不坚定的保安（免疫系统）铭记在心里的是血淋淋的脑袋，所以日后这些意志不坚定的保安（免疫系统）杀起那些入侵的肤白貌美大长腿的强盗（比如冠状病毒）是毫不怜香惜玉的。所以mRNA疫苗，没有ADE效应，有效性更高，免疫力更强，时间更持久。发布于 2021-02-09 11:29免疫系统生物病毒免疫​赞同 78​​26 条评论​分享​喜欢​收藏​申请转载​文章被以下专栏收录科学历史杂谈科学历

什么是ADE效应？一文读懂ADE效应 - 知乎

什么是ADE效应？一文读懂ADE效应 - 知乎切换模式写文章登录/注册什么是ADE效应？一文读懂ADE效应GFeL​Wanderlust先来讲一个小故事：在星际航行中，人类突然偶遇了一个外星种群。这些外星生物中有好的也有坏的，但是因为第一次遇到这种生物，人类不知道怎么判断哪些生物是好的，哪些是坏的。在与他们接触了一段时间后，人类付出了一定代价，将它们击退，而且哨兵们各自总结出了自己的一些判断外星生物好坏的观点，比如：1、肤色深绿色是坏的；2、鼻梁高挺是坏的；3、只有一只眼睛的是坏的；每个哨兵的判别标准不一样，然而事实上，粗体字的特征是充分不必要条件——也就是坏的外星生物鼻梁不一定高挺。但是有一部分哨兵，就仅仅通过鼻梁是否高挺来判断这个外星生物是否是坏的。在这些外星生物的第二次入侵中，哨兵就用这些判断方法进行判断——鼻梁低的就放入城中。然而，这一次来的外星生物大多都是鼻梁低的，因此大多都入了城。没想到，很多坏的外星生物就这样混入城中，打了人类一个措手不及，损失比第一次入侵还要严重，因为人类错误信任了坏的外星生物。这就是ADE效应。它的全称是Antigen-Dependent Enhancment. 也就是抗体依赖的增强效应。细菌病毒表面都有很多不同的蛋白质，这是它们的“特征”。在细菌病毒第一次侵入人体时，人体的免疫系统会去专门针对这些不同的蛋白质去生成不同的抗体。也就是说，一次病菌入侵结束后，人体内存在多种不同的抗体（比如：A、B两种抗体），每一种抗体的攻击对象是这个病菌表面的某一种蛋白质（比如：a、b两种蛋白质）。A抗体攻击a蛋白质，形成进攻后“残骸”A-a；B抗体攻击b蛋白质，形成进攻后“残骸”B-b。当A（或B）抗体进攻蛋白质后，其他免疫细胞会把进攻后的“残骸”吞噬，然后清理掉。因为这些免疫细胞能够识别“残骸”A-a、B-b，因而能够保证它们不会错误吞噬掉其他东西。这种病菌本身，在受到A、B两种抗体进攻后，会受到致命伤害，被沉淀，然后被吞噬、清除。这样，以后这种病菌再次入侵，人体将会有现成的抗体直接对它们攻击，故而不会再次感染，或者再次感染后症状会轻很多。然而，这种病菌有一个亲族，这个亲族的特点在于：它会受到A、B两种抗体攻击，形成“残骸”A-a、B-b。但是A抗体对它的攻击不致命！也就是说，A与病菌结合后，病菌仍然能够保持繁衍后代的能力。这样的病菌在被A进攻后形成A-a，被免疫细胞识别后吞噬，所造成的的结果就是：亲族病菌因为受到了A的攻击，形成了“残骸”A-a。但是此时病菌仍然有繁殖能力！这个“残骸”被免疫细胞识别、主动吞噬，就混入了细胞里，开始自己的繁殖过程。一般而言，病菌需要用手段主动混入细胞内开始繁殖，而在这种情况下，相当于亲族病菌被“请”入了细胞内。因此它们进入细胞、开始繁殖就会更迅速，同时免疫系统感应到“自己似乎对这个病菌有抗体A、B”，因此也就消极怠工，没有把这个亲族病菌当回事儿，完全没有及时意识到A抗体实际上已经成为了“奸细”所以患者在二次感染类似病菌后，可能出现症状加重的情况。这就是ADE现象。不过我们也不用太过担心。在现实生活中，ADE其实是不常见的。最有名的例子要数登革热了。它有好几种亚型，而其中有些亚型就恰好进化出了ADE的能力，能够被先前的抗体识别，但是不会被这个抗体沉淀掉。登革热的ADE效应因此，在二次感染登革热时，有可能会出现症状加重的现象。至于我们现有的COVID-19疫苗会不会引起ADE效应，我们下篇文章再讨论吧！发布于 2021-05-29 23:52covi 19ADE效应科普​赞同 21​​5 条评论​分享​喜欢​收藏​申请

如果新冠产生ADE效应，是否研究新冠疫苗失去了作用？ - 知乎

如果新冠产生ADE效应，是否研究新冠疫苗失去了作用？ - 知乎首页知乎知学堂发现等你来答​切换模式登录/注册疫苗幼儿疫苗疫苗接种新型冠状病毒ADE效应如果新冠产生ADE效应，是否研究新冠疫苗失去了作用？ADE效应，简单来说就是“抗体”不能对抗变异后的病毒，反而因为变异后的病毒和原来的病毒十分相似，骗过人体的免疫系统让其无法产生作用，从而产生相对未免疫…显示全部 ​关注者513被浏览631,149关注问题​写回答​邀请回答​好问题 104​1 条评论​分享​23 个回答默认排序返朴​科普话题下的优秀答主​ 关注新冠疫苗潜在风险：ADE效应究竟有多可怕？本文要点：1、抗体依赖增强（ADE）效应主要发生在具有Fc受体的免疫细胞。许多病毒（包括冠状病毒）都发现了ADE效应的证据，主要表现是增强病毒感染能力。2、体外实验发现ADE现象，不代表一定会影响临床结果。3、提高抗体质量是减少疫苗ADE风险的关键。撰文 | Gene近来，各国的新冠疫苗研发纷纷进入三期临床阶段，新冠病毒（SARS-CoV-2） 疫苗的安全性问题再次进入公众视野。不少文章都提到，ADE效应可能是新冠疫苗的潜在风险。什么是ADE效应？ADE全称Antibody-dependent enhancement，意为抗体依赖性增强，比较通俗的解释是：病毒在感染细胞时，由于某些原因，体内已有的相关抗体会增强病毒的感染能力。换言之，经自然免疫或疫苗接种后，再次接触相关病毒时，体内产生的抗体可能会增强其感染能力，最终导致病情加重。那么，ADE在科学上是如何解释的？新冠病毒是否也存在ADE效应？我们应该怎样避免？本文将深入介绍病毒的ADE效应，希望帮助大家正确理解科学现象和科学结论。抗体依赖性增强效应的发现抗体（antibody）最早是由德国科学家贝林（Emil Adolf Von Behring）和日本科学家北里柴三郎（Kitasato Shibasaburo）共同发现的。他们发现，将感染破伤风杆菌的兔子血清注入小鼠体内，可以使小鼠免受破伤风杆菌以及破伤风毒素的侵害[1]。随后，贝林又给豚鼠注射了灭活的白喉杆菌和白喉毒素，发现豚鼠的血清也具有了抗白喉杆菌和白喉毒素的保护性[2]。因此，贝林认为免疫后的动物血清中会产生一种名为“抗毒素（antitoxin）”的保护性物质，可以与外来抗原（antigen）反应而起作用。“抗毒素”也就是后来所说的抗体，1891年，德国科学家埃尔利希（Paul Ehrlich）首次使用了“抗体”（antikörper）一词[3]。后来科学家又发现抗体主要分为五种亚型：IgA、IgD、IgE、IgG和IgM。抗原（antigen）是指病原体上能够被免疫细胞特异性识别的分子。每个抗原可以有一个或多个抗原表位。抗原表位更加细致，它是抗原分子中决定抗原特异性的化学基团。免疫细胞（或抗体）主要通过识别抗原表位来与抗原相互作用，进而引发免疫反应。（见下图）1964年，澳大利亚科学家Royle Hawkes在一次实验中意外地发现，在高度稀释的鸡抗体血清的环境中，黄病毒科的多种病毒对鸡胚成纤维细胞的感染性增强[4]。这一发现与“血清具有保护作用”的认识相矛盾，Hawkes对自己的发现产生了怀疑。3年后，Hawkes终于证实，血清确实有可能增强病毒的感染性，并进一步发现，这一现象和血清中的IgG抗体有关[5]。抗体本是机体抵抗病毒入侵的盾牌，但病毒却可以“以子之盾，化己之矛”，依靠抗体的帮助入侵细胞。这是人类首次认识到病毒的抗体依赖性增强效应，但当时Hawkes并没能解释这一现象的具体机制。现在，广义的ADE认为：一些不理想的抗体可以增强病毒感染能力，甚至协助病毒进入原先无法进入的细胞，进而导致病毒大量复制或免疫细胞应答异常，最终使感染者病情加重，导致组织病理损伤。直到 1977年，登革热领域的先驱、著名病毒学家Scott Halstead才将登革热病毒（dengue virus，DENV）在临床上引起的重症登革热和ADE联系起来——部分感染者康复之后获得了对登革热病毒的免疫力，然而一段时间后，当这些患者第二次感染登革热病毒时，病情反而比第一次更严重。登革热病毒分为不同的血清型（即病毒的亚种），实验发现，对I型、III型和IV型具有免疫力的猴子在接受II型病毒感染后，体内的登革热病毒不但没有被清除，病毒水平反而还明显高于其他猴子。Halstead进一步发现，登革热病毒在具有免疫力的猴子或人的外周血白细胞中复制得更快。基于种种证据，Halstead得出结论，ADE和白细胞有关：在有抗体的条件下，病毒可以在白细胞中大量复制[6-8]。为什么发生在白细胞？这要从病毒感染细胞的步骤说起。病毒在进入人体后，首先通过自身的膜蛋白与人体细胞表面受体结合，之后通过膜融合或细胞内吞作用进入细胞，随后释放遗传物质，进行复制装配，最后释放病毒“子代”，继续感染其他细胞。病毒入侵白细胞的过程亦不例外。Halstead解释说，ADE是由白细胞表面的Fc受体（FcR）介导发生的。在抗体的Fab段识别和结合病毒后，抗体的Fc段与白细胞（包括单核巨噬细胞、B细胞、中性粒细胞等）表面的Fc受体相互作用，使病毒粘附于白细胞表面，促进了白细胞对病毒的内吞作用，相当于“引狼入室”，增强了病毒的感染能力。这也是目前ADE发生的最主要机制。什么是抗体的Fab段和Fc段？一张图带你认识——图1. 抗体即免疫球蛋白（immunoglobulin, Ig）分子，基本结构呈“Y”字形。Y字形的两臂是识别外来抗原的关键所在，所以也称为抗原结合片段（fragment antigen binding），即Fab 段；Y字形的根部称为可结晶片段（fragment crystallizable），即Fc段，主要负责调节免疫细胞活动。另外，Fc段也与ADE有关。| 作者作图随后，著名病毒学家、香港大学公共卫生学院前院长Malik Peiris通过更详细的实验证据阐明了这一机制[9, 10]。Peiris发现，在西尼罗病毒（WNV，属于黄病毒科）感染巨噬细胞系的过程中，阻断白细胞表面的特定Fc受体与抗体Fc段的结合，就可以阻断病毒感染的ADE效应。其他研究者在登革热病毒和黄热病毒（YFV，属于黄病毒科）的实验中也得到了同样的结论[11, 12]。黄病毒科因为ADE而一时名声大噪。ADE机制不止一种1983年，马来西亚病毒学家Jane Cardosa发现了黄病毒科的另一种ADE机制。实验中，在IgM抗体存在的条件下，西尼罗病毒对淋巴瘤细胞的感染性增强。然而，像过去一样，阻断细胞表面的Fc受体，却不再有用；而如果阻断抗体Fc段与细胞表面的III型补体受体（CR3）的结合，则可以停止病毒的感染性增强作用[13]。补体（complement）是血清中一组活化后具有生物活性的蛋白质，可对特异性抗体起到补充和辅助作用，主要介导非特异性免疫和炎症反应。补体系统包括补体固有成分、补体调控成分和补体受体（CR）。这意味着，Cardosa实验中出现的ADE效应是由细胞表面的补体受体介导的。IgM抗体的Fab段识别并结合病毒后，抗体的构象改变，暴露出Fc段的补体结合位点——本来，这是为了激活补体系统，帮助抵抗病毒，然而出招便露破绽——补体系统被激活后，病毒-抗体复合物与靶细胞上的补体受体相结合，反把病毒送进了细胞内部，进一步增强了感染。这一途径独立于Fc受体介导的ADE，因为Fc受体只在免疫细胞中表达，而补体受体表达的细胞类型则相对较广[14]，病毒加剧入侵的细胞范围也更广。目前，Fc受体介导和补体受体介导是ADE最常见的两种机制。除了黄病毒科外，科学家们也相继在其他病毒科的多种病毒中都发现了ADE现象，其中机制亦不完全相同。冠状病毒中的ADE效应冠状病毒（CoV）中的ADE效应首次发现于1980年[15]。著名冠状病毒学家Niels Petersen对幼猫进行猫冠状病毒的感染实验，引发猫传染性腹膜炎（FIP）。实验中，他发现自然条件下猫传腹病毒FIPV*抗体阳性的幼猫比抗体阴性的幼猫发病时间更早，死亡也更快，也就是说对FIPV有免疫力的幼猫在被感染后，疾病反而更严重。*注：FIPV是猫冠状病毒FCoV的一种。一年后，研究者证实，预先注射抗FIPV血清或抗体（实验中称为被动免疫）的幼猫，在感染FIPV时，发病时间和死亡时间同样早于对照组的幼猫[16]。1990年，研究者给幼猫打FIPV疫苗（实验中称为主动免疫），在体内确认检测到抗体后，再用FIPV去感染这些幼猫，也得到了相同的结果[17]。至此，FIPV感染过程中的ADE现象终于广为人知。又过了两年，研究者才发现了猫冠状病毒ADE效应的机制。原来，某些抗FIPV的IgG抗体可以增强FIPV对巨噬细胞的感染能力，且该过程和 Fc受体相关[18]。此后，对FIPV 的ADE效应的研究越来越多。图2. Petersen与FIPV感染康复的小猫Tony[19]。2005年，研究人员在实验中首次发现，针对人SARS冠状病毒（SARS-CoV）的抗体可以增强另一种SARS毒株对宿主细胞的感染[20]，并且在人B细胞和巨噬细胞中，SARS病毒的ADE效应与特定类型的Fc受体（FcγRII）相关，阻断这一受体可以阻断ADE的发生[21, 22]。值得注意的是，SARS-CoV通过ADE感染巨噬细胞的过程，并非是通过单纯大量复制病毒加剧感染（图3A），而是干扰各种细胞因子信号（图3B），导致巨噬细胞在中后期负担过重，出现活化异常，炎症因子分泌增加，最终造成急性炎症和机体病理损伤[23, 24]。图3. 不理想的抗体导致冠状病毒感染加剧的两种方式。绿色代表抗体，黄色代表细胞，细胞表面突起的蓝色为Fc受体。| 改编自参考文献[25]。另一项针对MERS冠状病毒（MERS-CoV）感染的ADE的体外研究发现，有些不理想的抗体和病毒表面的刺突蛋白结合后，可以使刺突蛋白的构象发生改变，结果，不但病毒仍然可以和相应的细胞表面受体结合，同时抗体的Fc段也可以与细胞表面的Fc受体结合，反而让病毒更容易进入细胞[26]。这说明如果初次感染时诱导的抗体不够理想，也可能直接引发ADE效应。基于SARS 和MERS冠状病毒的证据以及临床研究，已有研究者合理推测，新型冠状病毒SARS-CoV-2感染也存在ADE效应[27, 28]。最近的一项体外研究（预印本）显示，SARS-CoV-2的单克隆抗体MW05可能通过Fc段与靶细胞表面的特定受体（FcγRIIB）结合，引起ADE效应，具体结果仍需进一步验证[29]。除此之外，另一项预印本研究显示，在新冠病毒感染的重症患者中，IgG抗体可能会诱导巨噬细胞产生超炎症反应，进而损坏肺内皮细胞屏障的完整性，引发微血管血栓[30]。什么是“不理想”的抗体？决定抗体是否会引起ADE的因素主要包括：抗体的特异性、滴度、亲和力以及抗体的亚型[25]。SARS 疫苗包括不同种类，针对刺突蛋白（S蛋白）的疫苗和核衣壳蛋白（N蛋白）的疫苗所选择的抗原不同，诱导出的特异性抗体也不同。在小鼠实验中，给小鼠打疫苗后， 这两类疫苗诱导出的特异性抗体滴度是相似的，随后，再让这些小鼠感染SARS-CoV，发现编码N蛋白的疫苗会诱导小鼠分泌更多的促炎症因子，小鼠体内某些白细胞的肺部渗透也相对增加，肺病理学变化相对更为严重[31]。相似地，在猴子模型中，针对SARS-CoV的刺突蛋白的不同表位的抗体，其诱导的反应也各不相同，有些可以起到很好的保护作用，有些则容易引起ADE效应[32]。抗体滴度低也容易引起ADE效应，例如在SARS或MERS冠状病毒感染过程中，如果增加抗体滴度则可以抑制ADE，并促进中和反应的发生[26, 33]。在中和反应过程中，高亲和力的抗体还会比低亲和力的抗体保护效果更好[34]。具有中和作用的抗体叫做中和性抗体。中和作用指的是抗体Fab段与相应的抗原表位结合，封阻其受体结合位点或致其构象改变，使抗原无法进入细胞。抗体的亲和力，通俗来讲是指抗体同抗原结合的牢固程度。此外，抗体的亚型不同，其Fc段调节免疫细胞的功能也各不相同：IgM能够更有效的激活补体系统，产生促炎症反应，IgG则根据细胞表面不同的Fc受体来调节免疫反应，如在SARS-CoV感染过程中，有些类型的Fc受体（FcγRIIa和FcγRIIb）可以介导ADE发生，有些（FcγRI 和FcγRIIIa）则不能[33]。进一步的，同一类型的Fc受体的不同剪接体（isoform），引发的ADE效应也不尽相同[35]。疫苗研发如何避免ADE？在新冠疫苗的研发过程中，减少ADE风险的关键在于提高抗体的质量，主要包括抗原表位与佐剂的选择。抗原表位的选择尤其重要。此前SARS疫苗的开发过程中，在小鼠或猴子身上，有些疫苗一定程度上可以引发ADE效应，或引起由嗜酸性粒细胞介导的免疫病理学变化[20, 23, 36]。究其原因，可能是疫苗中起主要贡献的优势抗原表位诱导出的抗体质量（主要是滴度）不理想。 所谓佐剂，就是预先或与抗原同时注射的物质。佐剂可以有效增强机体对抗原的免疫应答，也可以改变免疫反应类型。研究显示，在老年小鼠中，铝佐剂增强的灭活SARS疫苗可以诱导出高滴度的抗体，但却是不理想的抗体亚型。此外，不适当的佐剂还会改变免疫反应类型，进而影响免疫应答过程，引起肺病理学变化[36]。除此之外，疫苗的接种途径也会影响其作用。针对同一种SARS 疫苗，分别经鼻腔途径或肌肉途径接种，再经病毒感染后，前一种途径的接种者出现的肺部病理学变化更少[37]。另外也有研究显示，利用生物手段为疫苗颗粒表面包装一层外壳，例如在登革热疫苗颗粒表面包装磷酸钙矿化外壳，可以在不影响其保护效果的同时，有效避免ADE现象的发生[38]。从ADE的发生机制入手，也能为疫苗研发“避雷”。既然大部分ADE效应是由细胞表面 Fc受体介导发生的，那么封阻细胞表面的特定Fc受体，则可以防止病毒-抗体复合物与Fc受体结合，进而阻止ADE效应[39]。要想实现这一过程，针对Fc受体的特异性抗体，或抑制结合过程的小分子抑制剂都是不错的选择，前者可以作为免疫抑制剂使用[40,41]。例如，临床上对重症COVID-19患者使用静脉注射免疫球蛋白，可以改善患者症状[42, 43]，但大范围是否安全有效还需进一步研究。总之，通过封阻病毒-抗体复合物与Fc受体结合也是一种阻止ADE发生的手段，但是除了Fc受体外，ADE仍可以通过前述其他途径，如补体介导发生。因此，在开发疫苗时，不但要保证诱导出高质量的中和抗体，最重要的是还要尽量选择可以诱导强细胞免疫的疫苗。实际上，机体清除病毒也依赖于细胞免疫，因为中和抗体只能对细胞外的病毒起作用，对于进入细胞内的“漏网之鱼”往往无能为力。病毒在细胞内会将其蛋白信息表达在感染的细胞表面，而杀伤性T细胞能够识别这些信息，从而发动攻击，将病毒与其感染的细胞共同杀灭。同样重要的是，初次免疫（即疫苗接种）除了诱导出抗体外，还会产生记忆细胞。疫苗诱导的细胞免疫越强，激活的杀伤性T细胞就越多，转化的记忆性T细胞就越多，这样一来，在下次病毒感染时，免疫细胞行使功能的速度也就越快，从而有效地减少ADE的发生。因此，疫苗的种类选择也至关重要。结 语新冠疫苗研发至今，已公布的多项动物结果和临床试验结果均未出现明确的ADE证据。但是基于SARS疫苗和MERS疫苗的经验，笔者认为，在极个别新冠病毒单克隆抗体中发现ADE效应的确证，大概率只是时间问题。虽然前文写到，已有研究初步表明新冠病毒的某些单克隆抗体在体外可能存在ADE效应，但目前证据仍不充分。更需要注意的是，体外实验与体内情况往往有较大差距，离临床表现更是相去甚远。机体经抗原免疫后，会出现针对多个表位的多克隆抗体反应，即便单个抗体具有ADE效应，也难以影响血清的中和性。单克隆抗体是由单一B细胞克隆产生的、仅针对某一特定抗原表位的抗体。相应的，多克隆抗体是针对多种抗原表位的不同抗体。另外，除了疫苗以外，开发单克隆抗体、制备抗体药物也是一种不错的选择。单克隆抗体具有分子精度，易于通过基因工程学编辑，如仅使用抗体的Fab段、或使用工程学对抗体的Fc段进行改造（如引入突变），都可以显著提高安全性[44]。目前，世界各地的科研团队正在开发的新冠疫苗已有百种，其中至少30种已进入临床试验阶段（中国有10种），最快的已经开展临床III期，其余还有多种正在动物模型上开展试验[45]。同时，单克隆抗体的开发竞赛也正如火如荼。笔者认为，ADE不会成为新冠疫苗开发过程中的障碍。参考文献[1] Behring E, Kitasato S. 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High- Dose Intravenous Immunoglobulin as a Therapeutic Option for Deteriorating Patients With Coronavirus Disease 2019. Open Forum Infectious Diseases 2020;7.[43] Shao Z., et al. Clinical efficacy of intravenous immunoglobulin therapy in critical patients with COVID-19: A multicenter retrospective cohort study. medRxiv. Posted April 20, 2020.[44.] 57. Amanat F, Krammer F. SARS-CoV-2 Vaccines: Status Report. Immunity. 2020 Apr 14;52(4):583-589.[45] Le TT., et al. Evolution of the COVID-19 vaccine development landscape. Nat Rev Drug Discov. 2020 Sep 4. doi: 10.1038/d41573-020-00151-8.发布于 2020-09-16 13:13​赞同 654​​91 条评论​分享​收藏​喜欢收起​biokiwi​生物学话题下的优秀答主​ 关注我们系统地给大家梳理一下抗体和 ADE 效应，并讨论ADE 效应是否会阻碍 COVID-19 疫苗的研发，最后介绍一下不同疫苗的研发思路。走近抗体在开始介绍ADE之前，我们有必要先简单介绍下抗体。抗体（antibody）是一种特殊的免疫球蛋白（immunoglobulin），共分为五大类，各自具有不同的免疫学功能（图 1)。关于不同类别抗体及其功能的内容繁多，大家如感兴趣，我们可以在日后的文章中一一介绍；但本篇我们只把目光聚焦在与 ADE 效应关系最密切的 IgG 抗体上。图 1免疫B细胞合成并分泌的IgG （Immunoglobulin G ），是血循环中最常见的一类抗体，大约占血清抗体的75%。IgG由两条重链（Heavy Chain）和两条轻链（Light Chain），共四个亚基组成（图 2）。其中两条重链组成 “Y” 字型结构，两条轻链与重链共价连接。“Y” 字结构的上面两臂是抗原结合区域（Fab），该区域与抗原结合部分的氨基酸序列是高度可变的，这也是不同抗体可以识别不同的病原体（比如病毒）的结构基础。“Y”字结构的下端是由两条重链组成的可结晶区（Fc），其氨基酸序列较为保守，主要的功能是招募免疫细胞（如吞噬细胞），激发免疫反应。图 2在保护机体对抗病毒入侵的过程中，IgG 抗体主要执行以下几点功能：通过直接与病毒特异性结合，阻止其入侵细胞，IgG可以起到中和的作用（即作为中和抗体）；对于已经感染细胞的病毒，IgG会结合其在靶细胞表面呈现的抗原，做好标记，招募吞噬细胞清理门户；IgG还能激活补体、结合免疫细胞，引发免疫应答；IgG可以穿过胎盘屏障，从母体被动传输给胎儿，实现天然被动免疫。ADE 效应是什么？Antibody-dependent enhancement (ADE)，直译过来即“抗体依赖增强”。也就是说，抗体在ADE 的整个病理学发展过程中至关重要。目前发现的 ADE 效应，主要是由 IgG 抗体导致，也有一小部分是由 IgM 抗体所引起（为了方便表述，下面统称抗体）。图 3在病毒造成的疾病中，主要存在两大类 ADE 效应机制。第一类是抗体导致的病毒感染力增强，表现为病毒的感染率上升、复制增多；甚至会因为抗体的存在，病毒可以感染一些原本无法被感染的免疫细胞（图 3a）。这一过程来源于抗体的 Fc 区域与免疫细胞上的 Fc 受体的结合作用。具体来说，抗体一端的Fab 区域结合了病毒，另一端的Fc 区域结合了免疫细胞（如单核细胞和巨噬细胞）表面的 Fc 受体，病毒因此就黏附在免疫细胞表面。然后因为 Fc-Fc 受体结合的影响，免疫细胞的内吞作用加强，抗体就像病毒的“特洛伊木马”一样把病毒簇拥进了细胞内部，之后病毒也就开足马力在细胞里开始复制。这类 ADE 的代表就是登革热病毒（黄病毒科 黄病毒属）所引起的登革热 （图 4）。科学研究发现，感染过不同登革热病毒亚型的病人，在面对其他亚型病毒侵染时会表现出 ADE 效应。这很可能是因为不同亚型的病毒虽然可以与抗体结合，但是因为结合效果较差，没有起到中和抗体的作用，且又得到了与免疫细胞结合的机会。登革热的 ADE 效应不仅加重了自然感染患者的病情，还使得最近一项登革热的疫苗试验宣告失败。图 4第二类 ADE 效应机制是抗体导致的免疫过激反应。造成过激行为的并非“外人”，而是过度的 Fc 介导的免疫细胞功能，以及抗体依赖的免疫复合物的形成 （图 3b）。病理上表现为病症加重，包括检测到的免疫病理学和炎症标识物水平升高。RSV （呼吸道合胞病毒）和Measles （麻疹）病毒所导致的肺炎便是典型的病例（图 3b）。非中和抗体和抗原会形成免疫复合物，并沉积于气道中；随之而来的是大量被分泌的炎症因子和被招募的免疫细胞，进而又激活了补体途径。最终在过度的炎症作用下，虽然病毒的清除工作开展顺利，但是肺部组织的损伤也加重了。值得注意的是，两种 ADE 机制都可能由非中和抗体（non-neutralizing antibodies），或者低于保护作用滴度的中和抗体引发。而这也就为疫苗的研发工作敲响了警钟：为避免 ADE 效应，疫苗最好是只会让人体生成高于保护作用滴度的中和抗体；否则产生非中和抗体和低滴度中和抗体的疫苗都存在 ADE 效应的风险。COVID-19 感染中存在 ADE 效应吗？先说一下答案，没有决定性的证据表明存在。那么这个担忧是从何而来的呢？主要是因为临床上观察到的一个现象，SARS 和 COVID-19 病患体内的抗体滴度与病情的严重程度以及死亡率呈正相关。但是这并不能表明抗体会导致 ADE 效应进而加重病情，上述关系可能只是因为病情严重的患者体内病毒载量较高，因此会产生相应较多的抗体。还有一些二次感染病例也导致了人们对于 ADE 效应的担忧。例如《柳叶刀》的《传染病》子刊报道了美国内华达州一男子二次感染了 SARS-CoV-2，第二次感染的病情比第一次还要严重。对此的解释其实不止 ADE 一种，可能性更大的原因包括”暴露于更大量的病毒“，以及”二次感染的病毒更具有毒性”。并且目前 COVID-19 的治愈患者数千万，二次感染的案例非常罕见，个例并不具有普遍性。图 5. 美国内华达州的二次感染病例的时间轴虽然体外实验发现了 SARS 与 MERS 会在细胞水平通过感染巨噬细胞引发 ADE 效应，但是动物模型的研究并不能给出明确的免疫病理学证据来证明 ADE 效应存在于在机体层面。而导致 COVID-19 的 SARS- CoV -2 是否会感染巨噬细胞并进行复制都还尚不明确，更别提体内存在ADE 的证据了。图 3. 前面我们介绍过ADE，我决定“一图多用”，帮助大家再回忆一下此外，人体内可能存在因为其他低致病性冠状病毒感染所产生的抗体，这些抗体有和新感染的 SARS-CoV-2 交叉结合的可能, 而这种“不好”的结合并不能起到中和的作用。我们前面提到过，低浓度、非中和抗体是有导致 ADE 的风险的。所以理论上来说，这也是一个 ADE 效应的来源，不过依然没有证据来证明这个猜测。接种 COVID-19 疫苗会导致 ADE 效应吗？虽然机体自身产生的抗体引发 ADE 效应的可能性很小，我们依然不能忽视疫苗的潜在风险。在 SARS 疫苗早期筛选的动物实验中，确实观察到过 ADE 效应的存在。但是更多的实验结果表明，那些可以引发针对 S 蛋白（病毒进入细胞所依赖的途径之一）中和抗体的疫苗，能够可靠地保护实验动物免受病毒的侵袭，并且没有感染或病情加重的迹象。这给了 COVID-19 疫苗研发提供了策略上的启示，研究人员也应该筛选是那些可以引发高浓度中和抗体的疫苗，这些疫苗的成功机会大，ADE 风险低。举例来说，只呈递 S 蛋白亚基的疫苗，理论上来说引发 ADE 效应的风险是会更低的。图 6. SARS-CoV-2 S 蛋白结构灭活疫苗被认为在理论上有比较高的引发 ADE 风险，因为可能呈递引发非中和抗体的抗原。二十世纪六十年代发生过灭活的 RSV（呼吸道合胞病毒）疫苗导致了儿童接种者的致命性感染的案例。后续研究发现，因为使用了福尔马林进行的灭活，所以 RSV 表面抗原的构型发生了改变，引发的抗体在遇到真正的 RSV 病毒时没有起到中和抗体的作用，反倒是形成了免疫复合物（参见前文提到过的第二种 ADE 机制）。不过即使是有“前科”，生命学科的实力已经今非昔比了，加之人类对于灭活疫苗的研发也是最具经验的，所以可以在很大程度上避免 ADE 的风险。近期对于 COVID-19 灭活疫苗的调查发现，进入临床阶段的灭活疫苗并非具有先天劣势。中国主攻的几个灭活疫苗项目，目前已经进入到了三期临床。相比于担忧灭活疫苗会不会有 ADE 的风险，更应该关注非抗体依赖的 ERD 效应的风险。ADE 属于 ERD（enhanced respiratory disease） 中的一类。ERD 效应也是 SARS 和 COVID-19 高致病性的一大原因，病患往往是因为过激的免疫反应而非病毒的复制而病情严重。目前已知有些 SARS 疫苗会引发 T 细胞主导的 ERD 效应，不过适当的疫苗辅剂的选择可以极大地缓解这个问题（辅剂选择对于避免 ADE 效应也十分重要）。另外，好的动物模型可以帮助研究者筛选合适的疫苗进入到临床阶段。恒河猴是常用的动物模型，但是近来研究发现叙利亚仓鼠的免疫系统和人类更为相似，可能是更好的选项。图 7.叙利亚仓鼠也可以作为宠物饲养总之，无论是担忧哪种风险，疫苗研发都需要经历实践的检验。二期和三期临床就是很好的检验手段，特别是参与者广泛的三期临床，可以提供大量的数据，便于研究者发掘出潜在的风险因素。抗体治疗与康复患者血浆治疗这次 COVID-19 疫情为一些酝酿已久的新技术提供了大展身手的机会，比如利用单克隆、或者多克隆抗体（鸡尾酒疗法）进行治疗。众所周知，特朗普先生在出现了COVID-19 的症状后，立刻注射了 Regeneron 公司的多克隆抗体，而且使用了人体试验中的最高剂量。从结果上来说确实很快就控制住了病情，体现了这一疗法的极大潜力。衷心希望这个疗法可以快速普及，让所有人都体验到总统级的医疗待遇。图 8. 特朗普先生接受多克隆抗体治疗抗体不仅可以直接用于治疗，还可以用于预防感染。原理其实和疫苗类似，只不过是通过直接注射中和抗体的方式（特朗普先生因为使用了最高剂量进行治疗，其体内的抗体滴度甚至可以保护他在一段时间内免受新感染的威胁）。说到这肯定又会有人担忧 ADE 的问题了。这些用于临床的抗体都是千挑万选的，安全性和有效性都大可放心。而且抗体还可以通过进一步的生物工程学手段去除掉 Fc 区域。（请回看我们上一篇文章）理论上来说没有了Fc 区域，抗体无法与免疫细胞结合，就不存在 ADE 的风险了。抗体疗法虽然新颖，但是普及度不高；利用康复患者捐献的血浆进行治疗这一“古老”的方法却广为应用。异体捐献本身就有免疫排斥的风险，加之可能存在的 ADE 效应，血浆疗法在使用时需要倍加小心。好在有研究调查了大量血浆疗法的病例，目前来看这一疗法至少是安全的，并且对大部分患者有效。多路并进的 COVID-19 疫苗研发目前较为领先的疫苗主要是四大类：灭活疫苗、重组蛋白疫苗、病毒载体疫苗和核酸疫苗。下面简单介绍下各种疫苗（研发）的优势和劣势。图 9. 四大疫苗研发途径1.灭活疫苗灭活疫苗是最为传统和经典的疫苗研发路径，虽然有引发 ADE 的“前科”，但是我们也要看到成功的灭活疫苗案例数不胜数。我国常用的乙肝疫苗、脊灰灭活疫苗、乙脑灭活疫苗、百白破疫苗等都是灭活疫苗。其优点是制备方法简单快速，可以作为应对急性疾病传播通常采用的手段。缺点是相对而言，接种剂量大、免疫期短、免疫途径单一，还有潜在的 ADE 风险。2.重组蛋白疫苗以 COVID-19 疫苗研发为例，只将 S 蛋白亚基注射入人体，让免疫系统识别这个目标蛋白，然后产生相对应的中和抗体。因为只是将蛋白质注射入人体，相比于减活和灭活疫苗来说更加的安全。重组蛋白质疫苗过往有较为成功案例，比如乙型肝炎表面抗原疫苗。所以这条研发途径也比较好走通，生产经验也相对丰富。但是值得注意的是，重组蛋白疫苗依赖一个合适的表达系统，不同的表达系统会有不同的翻译后修饰，以及蛋白质折叠构型，这些都会影响抗原的免疫激活效率。3.病毒载体疫苗将 S 蛋白亚基整合入无害的腺病毒载体，或者减毒的流感病毒载体。该类疫苗注射入人体后就会表达 S 蛋白，从而让免疫系统识别。牛津大学团队和我国的陈薇团队在腺病毒载体疫苗的研发上较为领先，之前都有比较成功的腺病毒载体疫苗研发经验。从牛津大学已经公布的三期临床数据来看，虽然保护效力不如预期（相比于美国的两个 mRNA 疫苗来说），但是最高效率 90%、综合效率 70.4% 已经是很合格的疫苗产品了。而且相比于核酸疫苗，腺病毒载体疫苗的储存和运输条件都比较容易实现，更有助于全球抗疫。腺病毒载体疫苗的一个缺陷是，因为绝大多数人都曾感染过腺病毒，所以可能存在抗体中和新注射的疫苗的情况，从而降低免疫效力。十一月份，陈薇院士与康希诺生物合作新冠疫苗在墨西哥开展三期临床试验，希望他们尽快传来捷报。减毒流感载体疫苗的报道虽然较少，但是鉴于 SARS-CoV-2 可能长期与人类共存，将两种疫苗结合起来将会是一种非常高效的预防途径。4.核酸疫苗将编码 S 蛋白的 DNA 或 mRNA片段注射入人体，利用人体细胞来表达 S 蛋白。与病毒载体疫苗的区别在于，该类疫苗不需要病毒作为载体来帮助表达。理论上这种疫苗的研制流程较为简单，安全性也是最高的。但是未有先例，到底哪里是“坑”，有哪些“坑”还有待探索。而且辉瑞与biontech 联合研发的 mRNA 疫苗需要 -70℃ 低温保存，这在美国都不好实现，更别提第三世界国家了。不过，美国另一款由莫德纳公司研发的 mRNA 疫苗需要的保存温度为 -20 ℃，这就比较容易实现了。两款 mRNA 疫苗的保存条件相差如此之大，可能是因为采用了不同的“包裹”技术，这提醒我们疫苗研发是一个综合科研能力的比拼，不光是比拼特异性抗原的表达。另外，这两款疫苗的保护效率都超过了 90 %，甚至达到了 95 %！这是前所未有的成就，新技术再一次在疫情中大展身手。“大人，时代变了。”结语笔者认为，不应对灭活疫苗带有“偏见”，也不要过分“神话”腺病毒载体疫苗和核酸疫苗。要科学地看待疫苗的效果，无论是哪种疫苗，经得起临床的检验，能有效地保护人体免受病毒感染的就是好疫苗！希望在疫苗的助力下，全球疫情可以尽快得到控制！参考资料：Lee W S, Wheatley A K, Kent S J, et al. Antibody-dependent enhancement and SARS-CoV-2 vaccines and therapies[J]. Nature microbiology, 2020, 5(10): 1185-1191.Gao Q, Bao L, Mao H, et al. Development of an inactivated vaccine candidate for SARS-CoV-2[J]. Science, 2020.Haynes B F, Corey L, Fernandes P, et al. Prospects for a safe COVID-19 vaccine[J]. Science translational medicine, 2020, 12(568).Tillett R L, Sevinsky J R, Hartley P D, et al. Genomic evidence for reinfection with SARS-CoV-2: a case study[J]. The Lancet Infectious Diseases, 2020.发布于 2020-12-07 20:18​赞同 184​​28 条评论​分享​收藏​喜欢

抗体依赖增强作用（ADE）免疫学基础和抗体疫苗开发的提示|ADE|免疫学|抗体|疫苗|细胞|病毒|-健康界

抗体依赖增强作用（ADE）免疫学基础和抗体疫苗开发的提示|ADE|免疫学|抗体|疫苗|细胞|病毒|-健康界

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抗体依赖增强作用（ADE）免疫学基础和抗体疫苗开发的提示

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COVID-19病人血清治疗，临床研究未显示增进疾病，提示无ADE。这是SARS-CoV-2和SARS-CoV的区别。

最近ADE又吵的火热了，再发给大家看看什么是ADE。

抗体依赖的增强作用（Antibody- dependent enhancement，ADE) 是病毒感染后（疫苗接种类似），产生的抗体为非中和或弱中和作用，此类抗体促进病毒进入和感染宿主细胞，导致传染性和毒力增强。1973年Halstead等科学家在登革热感染中描述了ADE，认为主要机理是结合病毒的抗体，其IgG Fc段和细胞表面FcγRs交联，形成多聚体，并通过胞吞内化，病毒借机进入细胞内，复制，增殖，产生感染。FcγR及其功能FcγR分类及免疫细胞表达其中FcγRIIb、胞内段为ITIM（immunoreceptor tyrosine inhibitory motif，免疫受体酪氨酸抑制基序），FcγRIIIb不含胞内段。其余FcγR均为ITAM（immunoreceptor tyrosine activating motif，免疫受体酪氨酸激活基序）。B细胞只表达FcγRIIb（参与生发中心高亲和力抗体产生)，T细胞不表达 FcγR。FcγR信号通路①FcγR被IgG免疫复合物交联②ITAM磷酸化，激酶SYKSRCPKC激活③钙离子内流④Actin重排，吞噬IgG免疫复合物⑤转录激活⑥细胞因子和趋化因子释放功能脱颗粒颗粒细胞（中性粒，碱性粒细胞，酸性粒细胞）在活化后，产生活性氧（reactive oxygen species，ROS）活性氮（reactive nitrogen species，RNS），产生细胞毒性，抗微生物感染。另外，钙离子内流，也会出发脱颗粒（ 丝氨酸蛋白酶，白三烯，抗菌活性蛋白质，如溶菌酶和乳铁蛋白，以及抗菌肽，如α防御素等）。NK细胞也类似，激活后，释放穿孔素和颗粒酶等，产生抗病毒活性。吞噬及抗原递呈FcγR被交联激活后，DC细胞，单核细胞，巨噬细胞诱导IgG调理素作用，吞噬病毒和感染的细胞（病毒在其中复制），称之为抗体依赖的细胞胞吞作用（antibody- dependent cellular phagocytosis. ADCP）。ADE一些研究显示：体内非中和抗体，可能会导致ADE。登革热ADEADE最早的报道来自于登革热。在预先感染登革热后，产生的非中和抗体，在再次感染登革热时，不但不能起到保护作用，而且会引起ADE，促进病毒感染（文献4）。ADE其实也是借助了抗体介导的胞吞作用（ADCP），其中FcγRIIa和FcγRIIIa其促进作用，FcγRIIb起抑制作用。通过胞吞进入细胞的病毒，在吞噬体低pH环境下，包膜蛋白结构变化，促进病毒融合和感染。通过这种方式，病毒可以进入没有病毒受体的细胞，如髓系细胞，上皮，内皮细胞等。ADE此后在HIV，埃博拉，流感等都有报道。冠状病毒ADE在SARS-CoV，MERS-CoV都有ADE的报道，主要通过FcγRIIb介导。抗Spike蛋白抗体，灭活疫苗，以及感染病人血清，在体外模型，及小鼠，非人灵长类动物都有ADE的报道，但是据此不能预测病人体内的情况。SARS-CoV-2在SARS-CoV-2（COVID-19致病病毒）灭活疫苗和中和抗体，临床前研究数据（来自于小鼠，大鼠，非人灵长类等），显示保护作用，没有发现ADE（文献12，13，14）。但是人FcγR和模型动物还是有很大区别的，因而临床前数据不能完全预测人体情况。虽然人源化FcγR小鼠已经开始使用，但是其结果也不能完全模拟人体。COVID-19病人血清治疗，临床研究未显示增进疾病，提示无ADE。这是SARS-CoV-2和SARS-CoV的区别（文献16）。未来抗体及疫苗研发提示主要参考文献Halstead, S. B., Chow, J. & Marchette, N. J. Immunologic enhancement of dengue virus replication. Nat. New Biol. 243, 24–25 (1973).Halstead, S. B., Shotwell, H. & Casals, J. Studies on the pathogenesis of dengue infection in monkeys. II. Clinical laboratory responses to heterologous infection. J. Infect. Dis. 128, 15–22 (1973).Stylianos Bournazos et al，The role of IgG Fc receptors in antibody-dependent enhancement，Nat Rev Immunol. 2020 Aug 11:1-11Katzelnick, L. C. et al. Antibody- dependent enhancement of severe dengue disease in humans. Science 358, 929–932 (2017).Thulin, N. K. et al. Maternal anti- dengue IgG fucosylation predicts susceptibility to dengue disease in infants. Cell Rep. 31, 107642 (2020).Gotoff, R. et al. Primary influenza A virus infection induces cross- reactive antibodies that enhance uptake of virus into Fc receptor- bearing cells. J. Infect. Dis. 169, 200–203 (1994).Laurence, J., Saunders, A., Early, E. & Salmon, J. E. Human immunodeficiency virus infection of monocytes: relationship to Fc- γ receptors and antibody- dependent viral enhancement. Immunology 70, 338–343 (1990).Kuzmina, N. A. et al. Antibody- dependent enhancement of Ebola virus infection by human antibodies isolated from survivors. Cell Rep. 24, 1802–1815 (2018).Wan, Y. et al. Molecular mechanism for antibody dependent enhancement of coronavirus entry. J. Virol. 94, e02015–e02019 (2020).Kam, Y. W. et al. Antibodies against trimeric S glycoprotein protect hamsters against SARS- CoV challenge despite their capacity to mediate FcγRII- dependent entry into B cells in vitro. Vaccine 25, 729–740 (2007).Wang, Q. et al. Immunodominant SARS coronavirus epitopes in humans elicited both enhancing and neutralizing effects on infection in non- human primates. ACS Infect. Dis. 2, 361–376 (2016).Gao, Q. et al. Rapid development of an inactivated vaccine candidate for SARS- CoV-2. Science 369, 77–81 (2020).Rogers, T. F. et al. Isolation of potent SARS- CoV-2 neutralizing antibodies and protection from disease in a small animal model. Science https://doi.org/ 10.1126/science.abc7520 (2020).Cleary, S. J. et al. Animal models of mechanisms of SARS- CoV-2 infection and COVID-19 pathology. Br. J. Pharmacol. https://doi.org/10.1111/bph.15143 (2020).Smith, P., DiLillo, D. J., Bournazos, S., Li, F. & Ravetch, J. V. Mouse model recapitulating human Fcγ receptor structural and functional diversity. Proc. Natl Acad. Sci. USA 109, 6181–6186 (2012).Joyner, M. et al. Early safety indicators of COVID-19 convalescent plasma in 5,000 patients. J. Clin. Invest. https://doi.org/10.1101/2020.05.12.20099879 (2020).

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Antibody-dependent enhancement and SARS-CoV-2 vaccines and therapies | Nature Microbiology

Antibody-dependent enhancement and SARS-CoV-2 vaccines and therapies | Nature Microbiology

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perspectives

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Antibody-dependent enhancement and SARS-CoV-2 vaccines and therapies

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Perspective

Published: 09 September 2020

Antibody-dependent enhancement and SARS-CoV-2 vaccines and therapies

Wen Shi Lee 

ORCID: orcid.org/0000-0001-7285-40541, Adam K. Wheatley 

ORCID: orcid.org/0000-0002-5593-93871,2, Stephen J. Kent 

ORCID: orcid.org/0000-0002-8539-48911,2,3 & …Brandon J. DeKosky 

ORCID: orcid.org/0000-0001-6406-08364,5,6 Show authors

Nature Microbiology

volume 5, pages 1185–1191 (2020)Cite this article

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Applied immunologyInfectious diseases

AbstractAntibody-based drugs and vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are being expedited through preclinical and clinical development. Data from the study of SARS-CoV and other respiratory viruses suggest that anti-SARS-CoV-2 antibodies could exacerbate COVID-19 through antibody-dependent enhancement (ADE). Previous respiratory syncytial virus and dengue virus vaccine studies revealed human clinical safety risks related to ADE, resulting in failed vaccine trials. Here, we describe key ADE mechanisms and discuss mitigation strategies for SARS-CoV-2 vaccines and therapies in development. We also outline recently published data to evaluate the risks and opportunities for antibody-based protection against SARS-CoV-2.

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MainThe emergence and rapid global spread of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), the causative agent of coronavirus disease 2019 (COVID-19), has resulted in substantial global morbidity and mortality along with widespread social and economic disruption. SARS-CoV-2 is a betacoronavirus closely related to SARS-CoV (with ~80% sequence identity), which caused the SARS outbreak in 2002. Its next closest human coronavirus relative is Middle East respiratory syndrome-related coronavirus (MERS-CoV; ~54% sequence identity), which caused Middle East respiratory syndrome in 2012 (refs. 1,2). SARS-CoV-2 is also genetically related to other endemic human coronaviruses that cause milder infections: HCoV-HKU1 (~52% sequence identity), HCoV-OC43 (~51%), HCoV-NL63 (~49%) and HCoV-229E (~48%)1. SARS-CoV-2 is even more closely related to coronaviruses identified in horseshoe bats, suggesting that horseshoe bats are the primary animal reservoir with a possible intermediate transmission event in pangolins3.Cellular entry of SARS-CoV-2 is mediated by the binding of the viral spike (S) protein to its cellular receptor, angiotensin-converting enzyme 2 (ACE2)4,5. Other host entry factors have been identified, including neuropilin-1 (refs. 6,7) and TMPRSS2, a transmembrane serine protease involved in S protein maturation4. The SARS-CoV-2 S protein consists of the S1 subunit, which contains the receptor binding domain (RBD), and the S2 subunit, which mediates membrane fusion for viral entry8. A major goal of vaccine and therapeutic development is to generate antibodies that prevent the entry of SARS-CoV-2 into cells by blocking either ACE2–RBD binding interactions or S-mediated membrane fusion.One potential hurdle for antibody-based vaccines and therapeutics is the risk of exacerbating COVID-19 severity via antibody-dependent enhancement (ADE). ADE can increase the severity of multiple viral infections, including other respiratory viruses such as respiratory syncytial virus (RSV)9,10 and measles11,12. ADE in respiratory infections is included in a broader category named enhanced respiratory disease (ERD), which also includes non-antibody-based mechanisms such as cytokine cascades and cell-mediated immunopathology (Box 1). ADE caused by enhanced viral replication has been observed for other viruses that infect macrophages, including dengue virus13,14 and feline infectious peritonitis virus (FIPV)15. Furthermore, ADE and ERD has been reported for SARS-CoV and MERS-CoV both in vitro and in vivo. The extent to which ADE contributes to COVID-19 immunopathology is being actively investigated.In this Perspective, we discuss the possible mechanisms of ADE in SARS-CoV-2 and outline several risk mitigation principles for vaccines and therapeutics. We also highlight which types of studies are likely to reveal the relevance of ADE in COVID-19 disease pathology and examine how the emerging data might influence clinical interventions.Box 1 ADE and ERDERDERD describes severe clinical presentations of respiratory viral infections associated with medical interventions (especially vaccines). Similar clinical presentations can occur as a result of natural infections, and so ERD is detected during preclinical and clinical trials by comparing the distribution of disease severities between the intervention and placebo study arms. ERD can be associated with a broad range of molecular mechanisms, including FcR-dependent antibody activity and complement activation (that is, ADE), but also to other antibody-independent mechanisms such as tissue cell death, cytokine release and/or local immune cell activation.ADEADE can be broadly categorized into two different types based on the molecular mechanisms involved:ADE via enhanced infection. Higher infection rates of target cells occur in an antibody-dependent manner mediated by Fc–FcR interactions. ADE via enhanced infection is commonly measured using in vitro assays detecting the antibody-dependent infection of cells expressing FcγRIIa, such as monocytes and macrophages. The link between in vitro ADE assay results and clinical relevance is often implied, rather than directly observed. Dengue virus represents the best documented example of clinical ADE via enhanced infection.ADE via enhanced immune activation. Enhanced disease and immunopathology are caused by excessive Fc-mediated effector functions and immune complex formation in an antibody-dependent manner. The antibodies associated with enhanced disease are often non-neutralizing. ADE of this type is usually examined in vivo by detecting exacerbated disease symptoms, including immunopathology and inflammatory markers, and is most clearly associated with respiratory viral infections. RSV and measles are well-documented examples of ADE caused by enhanced immune activation.ERD and ADE (of the second type described above) are often identified by clinical data, including symptom prevalence and disease severity, rather than by the specific molecular mechanisms that drive severe disease. The presence of complex feedback loops between different arms of the immune system makes it very difficult (although not impossible) to conclusively determine molecular mechanisms of ADE and ERD in human and animal studies, even if the clinical data supporting ADE and ERD are quite clear. Many different measurements and assays are used to track ADE and ERD, which can vary based on the specific virus, preclinical and/or clinical protocols, biological samples collected and in vitro techniques used.Respiratory ADE is a specific subset of ERD.Mechanisms of ADEADE has been documented to occur through two distinct mechanisms in viral infections: by enhanced antibody-mediated virus uptake into Fc gamma receptor IIa (FcγRIIa)-expressing phagocytic cells leading to increased viral infection and replication, or by excessive antibody Fc-mediated effector functions or immune complex formation causing enhanced inflammation and immunopathology (Fig. 1, Box 1). Both ADE pathways can occur when non-neutralizing antibodies or antibodies at sub-neutralizing levels bind to viral antigens without blocking or clearing infection. ADE can be measured in several ways, including in vitro assays (which are most common for the first mechanism involving FcγRIIa-mediated enhancement of infection in phagocytes), immunopathology or lung pathology. ADE via FcγRIIa-mediated endocytosis into phagocytic cells can be observed in vitro and has been extensively studied for macrophage-tropic viruses, including dengue virus in humans16 and FIPV in cats15. In this mechanism, non-neutralizing antibodies bind to the viral surface and traffic virions directly to macrophages, which then internalize the virions and become productively infected. Since many antibodies against different dengue serotypes are cross-reactive but non-neutralizing, secondary infections with heterologous strains can result in increased viral replication and more severe disease, leading to major safety risks as reported in a recent dengue vaccine trial13,14. In other vaccine studies, cats immunized against the FIPV S protein or passively infused with anti-FIPV antibodies had lower survival rates when challenged with FIPV compared to control groups17. Non-neutralizing antibodies, or antibodies at sub-neutralizing levels, enhanced entry into alveolar and peritoneal macrophages18, which were thought to disseminate infection and worsen disease outcome19.Fig. 1: Two main ADE mechanisms in viral disease.a, For macrophage-tropic viruses such as dengue virus and FIPV, non-neutralizing or sub-neutralizing antibodies cause increased viral infection of monocytes or macrophages via FcγRIIa-mediated endocytosis, resulting in more severe disease. b, For non-macrophage-tropic respiratory viruses such as RSV and measles, non-neutralizing antibodies can form immune complexes with viral antigens inside airway tissues, resulting in the secretion of pro-inflammatory cytokines, immune cell recruitment and activation of the complement cascade within lung tissue. The ensuing inflammation can lead to airway obstruction and can cause acute respiratory distress syndrome in severe cases. COVID-19 immunopathology studies are still ongoing and the latest available data suggest that human macrophage infection by SARS-CoV-2 is unproductive. Existing evidence suggests that immune complex formation, complement deposition and local immune activation present the most likely ADE mechanisms in COVID-19 immunopathology. Figure created using BioRender.com.Full size imageIn the second described ADE mechanism that is best exemplified by respiratory pathogens, Fc-mediated antibody effector functions can enhance respiratory disease by initiating a powerful immune cascade that results in observable lung pathology20,21. Fc-mediated activation of local and circulating innate immune cells such as monocytes, macrophages, neutrophils, dendritic cells and natural killer cells can lead to dysregulated immune activation despite their potential effectiveness at clearing virus-infected cells and debris. For non-macrophage tropic respiratory viruses such as RSV and measles, non-neutralizing antibodies have been shown to induce ADE and ERD by forming immune complexes that deposit into airway tissues and activate cytokine and complement pathways, resulting in inflammation, airway obstruction and, in severe cases, leading to acute respiratory distress syndrome10,11,22,23. These prior observations of ADE with RSV and measles have many similarities to known COVID-19 clinical presentations. For example, over-activation of the complement cascade has been shown to contribute to inflammatory lung injury in COVID-19 and SARS24,25. Two recent studies found that S- and RBD-specific immunoglobulin G (IgG) antibodies in patients with COVID-19 have lower levels of fucosylation within their Fc domains26,27—a phenotype linked to higher affinity for FcγRIIIa, an activating Fc receptor (FcR) that mediates antibody-dependent cellular cytotoxicity. While this higher affinity can be beneficial in some cases via more vigorous FcγRIIIa-mediated effector functions28,29, non-neutralizing IgG antibodies against dengue virus that were afucosylated were associated with more severe disease outcomes30. Larsen et al. further show that S-specific IgG in patients with both COVID-19 and acute respiratory distress syndrome had lower levels of fucosylation compared to patients who had asymptomatic or mild infections26. Whether the lower levels of fucosylation of SARS-CoV-2-specific antibodies directly contributed to COVID-19 immunopathology remains to be determined.Importantly, SARS-CoV-2 has not been shown to productively infect macrophages31,32. Thus, available data suggest that the most probable ADE mechanism relevant to COVID-19 pathology is the formation of antibody–antigen immune complexes that leads to excessive activation of the immune cascade in lung tissue (Fig. 1).Evidence of ADE in coronavirus infections in vitroWhile ADE has been well documented in vitro for a number of viruses, including human immunodeficiency virus (HIV)33,34, Ebola35,36, influenza37 and flaviviruses38, the relevance of in vitro ADE for human coronaviruses remains less clear. Several studies have shown increased uptake of SARS-CoV and MERS-CoV virions into FcR-expressing monocytes or macrophages in vitro32,39,40,41,42. Yip et al. found enhanced uptake of SARS-CoV and S-expressing pseudoviruses into monocyte-derived macrophages mediated by FcγRIIa and anti-S serum antibodies32. Similarly, Wan et al. showed that a neutralizing monoclonal antibody (mAb) against the RBD of MERS-CoV increased the uptake of virions into macrophages and various cell lines transfected with FcγRIIa39. However, the fact that antigen-specific antibodies drive phagocytic uptake is unsurprising, as monocytes and macrophages can mediate antibody-dependent phagocytosis via FcγRIIa for viral clearance, including for influenza43. Importantly, macrophages in infected mice contributed to antibody-mediated clearance of SARS-CoV44. While MERS-CoV has been found to productively infect macrophages45, SARS-CoV infection of macrophages is abortive and does not alter the pro-inflammatory cytokine gene expression profile after antibody-dependent uptake41,42. Findings to date argue against macrophages as productive hosts of SARS-CoV-2 infection31,32.ADE in human coronavirus infectionsNo definitive role for ADE in human coronavirus diseases has been established. Concerns were first raised for ADE in patients with SARS when seroconversion and neutralizing antibody responses were found to correlate with clinical severity and mortality46. A similar finding in patients with COVID-19 was reported, with higher antibody titres against SARS-CoV-2 being associated with more severe disease47. One simple hypothesis is that greater antibody titres in severe COVID-19 cases result from higher and more prolonged antigen exposure due to higher viral loads48,49. However, a recent study showed that viral shedding in the upper respiratory tract was indistinguishable between patients with asymptomatic and symptomatic COVID-19 (ref. 50). Symptomatic patients showed higher anti-SARS-CoV-2 antibody titres and cleared the virus from the upper respiratory tract more quickly, contradicting a simpler hypothesis that antibody titres are simply caused by higher viral loads. Other studies showed that anti-SARS-CoV-2 T-cell responses could be found at high levels in mild and asymptomatic infections51,52. Taken together, the data suggest that strong T-cell responses can be found in patients with a broad range of clinical presentations, whereas strong antibody titres are more closely linked to severe COVID-19. One important caveat is that viral shedding was measured in the upper respiratory tract rather than in the lower respiratory tract50. The lower respiratory tract is likely more important for severe COVID-19 lung pathology, and it is unclear how closely SARS-CoV-2 viral shedding in the upper and lower respiratory tracts correlate throughout the disease course.Beyond the host response to new SARS-CoV-2 infections, the potential of pre-existing antibodies against other human coronavirus strains to mediate ADE in patients with COVID-19 is another possible concern53. Antibodies elicited by coronavirus strains endemic in human populations (such as HKU1, OC43, NL63 and 229E) could theoretically mediate ADE by facilitating cross-reactive recognition of SARS-CoV-2 in the absence of viral neutralization. Preliminary data show that antibodies from SARS-CoV-2-naïve donors who had high reactivity to seasonal human coronavirus strains were found to have low levels of cross-reactivity against the nucleocapsid and S2 subunit of SARS-CoV-2 (ref. 54). Whether such cross-reactive antibodies can contribute to clinical ADE of SARS-COV-2 remains to be addressed.Risk of ERD for SARS-CoV-2 vaccinesSafety concerns for SARS-CoV-2 vaccines were initially fuelled by mouse studies that showed enhanced immunopathology, or ERD, in animals vaccinated with SARS-CoV following viral challenge55,56,57,58. The observed immunopathology was associated with Th2-cell-biased responses55 and was largely against the nucleocapsid protein56,58. Importantly, immunopathology was not observed in challenged mice following the passive transfer of nucleocapsid-specific immune serum56, confirming that the enhanced disease could not be replicated using the serum volumes transferred. Similar studies using inactivated whole-virus or viral-vector-based vaccines for SARS-CoV or MERS-CoV resulted in immunopathology following viral challenge59,60,61, which were linked to Th2-cytokine-biased responses55 and/or excessive lung eosinophilic infiltration57. Rational adjuvant selection ensures that Th1-cell-biased responses can markedly reduce these vaccine-associated ERD risks. Candidate SARS-CoV vaccines formulated with either alum, CpG or Advax (a delta inulin-based adjuvant) found that while the Th2-biased responses associated with alum drove lung eosinophilic immunopathology in mice, protection without immunopathology and a more balanced Th1/Th2 response were induced by Advax62. Hashem et al. showed that mice vaccinated with an adenovirus 5 viral vector expressing MERS-CoV S1 exhibited pulmonary pathology following viral challenge, despite conferring protection. Importantly, the inclusion of CD40L as a molecular adjuvant boosted Th1 responses and prevented the vaccine-related immunopathology63.Should it occur, ERD caused by human vaccines will first be observed in larger phase II and/or phase III efficacy trials that have sufficient infection events for statistical comparisons between the immunized and placebo control study arms. Safety profiles of COVID-19 vaccines should be closely monitored in real time during human efficacy trials, especially for vaccine modalities that may have a higher theoretical potential to cause immunopathology (such as inactivated whole-virus formulations or viral vectors)64,65.Risk of ADE for SARS-CoV-2 vaccinesEvidence for vaccine-induced ADE in animal models of SARS-CoV is conflicting, and raises potential safety concerns. Liu et al. found that while macaques immunized with a modified vaccinia Ankara viral vector expressing the SARS-CoV S protein had reduced viral replication after challenge, anti-S IgG also enhanced pulmonary infiltration of inflammatory macrophages and resulted in more severe lung injury compared to unvaccinated animals66. They further showed that the presence of anti-S IgG prior to viral clearance skewed the wound-healing response of macrophages into a pro-inflammatory response. In another study, Wang et al. immunized macaques with four B-cell peptide epitopes of the SARS-CoV S protein and demonstrated that while three peptides elicited antibodies that protected macaques from viral challenge, one of the peptide vaccines induced antibodies that enhanced infection in vitro and resulted in more severe lung pathology in vivo67.In contrast, to determine whether low titres of neutralizing antibodies could enhance infection in vivo, Luo et al. challenged rhesus macaques with SARS-CoV nine weeks post-immunization with an inactivated vaccine, when neutralizing antibody titres had waned below protective levels68. While most immunized macaques became infected following viral challenge, they had lower viral titres compared to placebo controls and did not show higher levels of lung pathology. Similarly, Qin et al. showed that an inactivated SARS-CoV vaccine protected cynomolgus macaques from viral challenge and did not result in enhanced lung immunopathology, even in macaques with low neutralizing antibody titres69. A study in hamsters demonstrated that despite enhanced in vitro viral entry into B cells via FcγRII, animals vaccinated with the recombinant SARS-CoV S protein were protected and did not show enhanced lung pathology following viral challenge70.SARS-CoV immunization studies in animal models have thus produced results that vary greatly in terms of protective efficacy, immunopathology and potential ADE, depending on the vaccine strategy employed. Despite this, vaccines that elicit neutralizing antibodies against the S protein reliably protect animals from SARS-CoV challenge without evidence of enhancement of infection or disease71,72,73. These data suggest that human immunization strategies for SARS-CoV-2 that elicit high neutralizing antibody titres have a high chance of success with minimal risk of ADE. For example, subunit vaccines that can elicit S-specific neutralizing antibodies should present lower ADE risks (especially against S stabilized in the prefusion conformation, to reduce the presentation of non-neutralizing epitopes8). These modern immunogen design approaches should reduce potential immunopathology associated with non-neutralizing antibodies.Vaccines with a high theoretical risk of inducing pathologic ADE or ERD include inactivated viral vaccines, which may contain non-neutralizing antigen targets and/or the S protein in non-neutralizing conformations, providing a multitude of non-protective targets for antibodies that could drive additional inflammation via the well-described mechanisms observed for other respiratory pathogens. However, it is encouraging that a recent assessment of an inactivated SARS-CoV-2 vaccine elicited strong neutralizing antibodies in mice, rats and rhesus macaques, and provided dose-dependent protection without evidence of enhanced pathology in rhesus macaques74. Going forward, increased vaccine studies in the Syrian hamster model may provide critical preclinical data, as the Syrian hamster appears to replicate human COVID-19 immunopathology more closely than rhesus macaque models75.ADE and recombinant antibody interventionsThe discovery of mAbs against the SARS-CoV-2 S protein is progressing rapidly. Recent advances in B-cell screening and antibody discovery have enabled the rapid isolation of potent SARS-CoV-2 neutralizing antibodies from convalescent human donors76,77 and immunized animal models78, and through re-engineering previously identified SARS-CoV antibodies79. Many more potently neutralizing antibodies will be identified in the coming weeks and months, and several human clinical trials are ongoing in July 2020. Human trials will comprise both prophylactic and therapeutic uses, both for single mAbs and cocktails. Some human clinical trials are also incorporating FcR knockout mutations to further reduce ADE risks80. Preclinical data suggest a low risk of ADE for potently neutralizing mAbs at doses substantially above the threshold for neutralization, which protected mice and Syrian hamsters against SARS-CoV-2 challenge without enhancement of infection or disease81,82. ADE risks could increase in the time period where mAb concentrations have waned below a threshold for protection (which is analogous to the historical mother–infant data that provided important clinical evidence for ADE in dengue83). The sub-protective concentration range will likely occur several weeks or months following mAb administration, when much of the initial drug dose has cleared the body. Notably, Syrian hamsters given low doses of an RBD-specific neutralizing mAb prior to challenge with SARS-CoV-2 showed a trend for greater weight loss than control animals82, though differences were not statistically significant and the low-dose animals had lower viral loads in the lung compared to control animals. Non-neutralizing mAbs against SARS-CoV-2 could also be administered before or after infection in a hamster model to determine whether non-neutralizing antibodies enhance disease. Passive transfer of mAbs at various time points after infection (for example, in the presence of high viral loads during peak infection) could also address the question of whether immune complex formation and deposition results in the enhancement of disease and lung immunopathology. If ADE of neutralizing or non-neutralizing mAbs is a concern, the Fc portion of these antibodies could be engineered with mutations that abrogate FcR binding80. Animal studies can help to inform whether Fc-mediated effector functions are crucial in preventing, treating or worsening SARS-CoV-2 infection, in a similar way to previous studies of influenza A and B infection in mice84,85 and simian-HIV infection in macaques86,87. An important caveat for testing human mAbs in animal models is that human antibody Fc regions may not interact with animal FcRs in the same way as human FcRs88. Whenever possible, antibodies used for preclinical ADE studies will require species-matched Fc regions to appropriately model Fc effector function.ADE and convalescent plasma interventionsConvalescent plasma (CP) therapy has been used to treat patients with severe disease during many viral outbreaks in the absence of effective antiviral therapeutics. It can offer a rapid solution for therapies until molecularly defined drug products can be discovered, evaluated and produced at scale. While there is a theoretical risk that CP antibodies could enhance disease via ADE, case reports in SARS-CoV and MERS-CoV outbreaks showed that CP therapy was safe and was associated with improved clinical outcomes89,90. One of the largest studies during the SARS outbreak reported the treatment of 80 patients with SARS in Hong Kong91. While there was no placebo control group, no CP-associated adverse effects were detected and there was a higher discharge rate among patients treated earlier in infection. Several small studies of individuals with severe COVID-19 disease and a study of 5,000 patients with COVID-19 have shown that CP therapy appears safe and may improve disease outcomes92,93,94,95,96, although the benefits appear to be mild97. However, it is difficult to determine whether CP therapy contributed to recovery as most studies to date were uncontrolled and many patients were also treated with other drugs, including antivirals and corticosteroids. The potential benefits of CP therapy in patients with severe COVID-19 is also unclear, as patients with severe disease may have already developed high antibody titres against SARS-CoV-2 (refs. 47,98). CP has been suggested for prophylactic use in high-risk populations, including people with underlying risk factors, frontline healthcare workers and people with exposure to confirmed COVID-19 cases99. CP for prophylactic use may pose an even lower ADE risk compared to its therapeutic use, as there is a lower antigenic load associated with early viral transmission compared to established respiratory infection. As we highlighted above with recombinant mAbs, and as shown in historical dengue virus mother–infant data, the theoretical risk of ADE in CP prophylaxis is highest in the weeks following transfusion, when antibody serum neutralization titres fall to sub-protective levels. ADE risks in CP studies will be more difficult to quantify than in recombinant mAb studies because the precise CP composition varies widely across treated patients and treatment protocols, especially in CP studies that are performed as one-to-one patient–recipient protocols without plasma pooling.To mitigate potential ADE risks in CP therapy and prophylaxis, plasma donors could be pre-screened for high neutralization titres. Anti-S or anti-RBD antibodies could also be purified from donated CP to enrich for neutralizing antibodies and to avoid the risks of ADE caused by non-neutralizing antibodies against other SARS-CoV-2 antigens. Passive infusion studies in animal models are helping to clarify CP risks in a well-controlled environment, both for prophylactic and therapeutic use. Key animal studies (especially in Syrian hamsters, and ideally with hamster-derived CP for matched antibody Fc regions) and human clinical safety and efficacy results for CP are now emerging contemporaneously. These preclinical and clinical data will be helpful to deconvolute the risk profiles for ADE versus other known severe adverse events that can occur with human CP, including transfusion-related acute lung injury96,100.ConclusionADE has been observed in SARS, MERS and other human respiratory virus infections including RSV and measles, which suggests a real risk of ADE for SARS-CoV-2 vaccines and antibody-based interventions. However, clinical data has not yet fully established a role for ADE in human COVID-19 pathology. Steps to reduce the risks of ADE from immunotherapies include the induction or delivery of high doses of potent neutralizing antibodies, rather than lower concentrations of non-neutralizing antibodies that would be more likely to cause ADE.Going forwards, it will be crucial to evaluate animal and clinical datasets for signs of ADE, and to balance ADE-related safety risks against intervention efficacy if clinical ADE is observed. Ongoing animal and human clinical studies will provide important insights into the mechanisms of ADE in COVID-19. Such evidence is sorely needed to ensure product safety in the large-scale medical interventions that are likely required to reduce the global burden of COVID-19.

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Download referencesAcknowledgementsThis work was supported by the Victorian government, Australian Research Council Centre of Excellence in Convergent Bio-Nano Science and Technology (S.J.K.), an Australian National Health and Medical Research Council (NHMRC) programme grant no. 1149990 (S.J.K.), NHMRC project grant no. 1162760 (A.K.W.), NHMRC fellowships to S.J.K. and A.K.W., the United States National Institutes of Health grant nos. 1DP5OD023118 and R21AI143407 (B.J.D.), the COVID-19 Fast Grants programme (B.J.D.) and the Jack Ma Foundation (B.J.D.).Author informationAuthors and AffiliationsDepartment of Microbiology and Immunology, University of Melbourne at the Peter Doherty Institute for Infection and Immunity, Melbourne, Victoria, AustraliaWen Shi Lee, Adam K. Wheatley & Stephen J. KentARC Centre for Excellence in Convergent Bio-Nano Science and Technology, University of Melbourne, Parkville, Victoria, AustraliaAdam K. Wheatley & Stephen J. KentMelbourne Sexual Health Centre and Department of Infectious Diseases, Alfred Hospital and Central Clinical School, Monash University, Melbourne, Victoria, AustraliaStephen J. KentDepartment of Pharmaceutical Chemistry, The University of Kansas, Lawrence, KS, USABrandon J. DeKoskyDepartment of Chemical Engineering, The University of Kansas, Lawrence, KS, USABrandon J. DeKoskyBioengineering Graduate Program, The University of Kansas, Lawrence, KS, USABrandon J. DeKoskyAuthorsWen Shi LeeView author publicationsYou can also search for this author in

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PubMed Google ScholarContributionsW.S.L., A.K.W., S.J.K. and B.J.D. drafted the manuscript, edited the draft and prepared the final manuscript, which was approved by all co-authors.Corresponding authorsCorrespondence to

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Nat Microbiol 5, 1185–1191 (2020). https://doi.org/10.1038/s41564-020-00789-5Download citationReceived: 16 May 2020Accepted: 20 August 2020Published: 09 September 2020Issue Date: October 2020DOI: https://doi.org/10.1038/s41564-020-00789-5Share this articleAnyone you share the following link with will be able to read this content:Get shareable linkSorry, a shareable link is not currently available for this article.Copy to clipboard

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A perspective on potential antibody-dependent enhancement of SARS-CoV-2

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Perspective

Published: 13 July 2020

A perspective on potential antibody-dependent enhancement of SARS-CoV-2

Ann M. Arvin1,2, Katja Fink1,3, Michael A. Schmid1,3, Andrea Cathcart1, Roberto Spreafico1, Colin Havenar-Daughton 

ORCID: orcid.org/0000-0002-2880-39271, Antonio Lanzavecchia1,3, Davide Corti 

ORCID: orcid.org/0000-0002-5797-13641,3 & …Herbert W. Virgin 

ORCID: orcid.org/0000-0001-8580-76281,4 Show authors

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volume 584, pages 353–363 (2020)Cite this article

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Humoral immunitySARS-CoV-2Vaccines

AbstractAntibody-dependent enhancement (ADE) of disease is a general concern for the development of vaccines and antibody therapies because the mechanisms that underlie antibody protection against any virus have a theoretical potential to amplify the infection or trigger harmful immunopathology. This possibility requires careful consideration at this critical point in the pandemic of coronavirus disease 2019 (COVID-19), which is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Here we review observations relevant to the risks of ADE of disease, and their potential implications for SARS-CoV-2 infection. At present, there are no known clinical findings, immunological assays or biomarkers that can differentiate any severe viral infection from immune-enhanced disease, whether by measuring antibodies, T cells or intrinsic host responses. In vitro systems and animal models do not predict the risk of ADE of disease, in part because protective and potentially detrimental antibody-mediated mechanisms are the same and designing animal models depends on understanding how antiviral host responses may become harmful in humans. The implications of our lack of knowledge are twofold. First, comprehensive studies are urgently needed to define clinical correlates of protective immunity against SARS-CoV-2. Second, because ADE of disease cannot be reliably predicted after either vaccination or treatment with antibodies—regardless of what virus is the causative agent—it will be essential to depend on careful analysis of safety in humans as immune interventions for COVID-19 move forward.

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MainThe benefit of passive antibodies in ameliorating infectious diseases was recognized during the 1918 influenza pandemic1. Since then, hyperimmune globulin has been widely used as pre- and post-exposure prophylaxis for hepatitis A, hepatitis B, chickenpox, rabies and other indications for decades without evidence of ADE of disease2 (see Box 1 for definition of terms). The detection of antibodies has also been a reliable marker of the effectiveness of the many licensed human vaccines3. The antiviral activity of antibodies is now known to be mediated by the inhibition of entry of infectious viral particles into host cells (neutralization) and by the effector functions of antibodies as they recruit other components of the immune response. Neutralizing antibodies are directed against viral entry proteins that bind to cell surface receptors, either by targeting viral proteins that are required for fusion or by inhibiting fusion after attachment4,5,6 (Fig. 1). Antibodies can cross-neutralize related viruses when the entry proteins of the viruses share epitopes—the part of a protein to which the antibody attaches. Antibodies also eliminate viruses through effector functions triggered by simultaneous binding of the antigen-binding fragment (Fab) regions of immunoglobulin G (IgG) to viral proteins on the surfaces of viruses or infected cells, and of the fragment crystallizable (Fc) portion of the antibody to Fc gamma receptors (FcγRs) that are expressed by immune cells7,8 (Fig. 2). Antibodies that mediate FcγR- and complement-dependent effector functions may or may not have neutralizing activity, can recognize other viral proteins that are not involved in host-cell entry and can be protective in vivo independent of any Fab-mediated viral inhibition9,10. Recent advances in FcR biology have identified four activating FcγRs (FcγRI, FcγRIIa, FcγRIIc and FcγRIIIa) and one inhibitory FcγR (FcγRIIb) that have various Fc ligand specificities and cell-signalling motifs10. The neonatal Fc receptor (FcRn) has been described to support antibody recycling and B and T cell immunity through dendritic cell endocytosis of immune complexes11,12. Natural killer cells recognize IgG–viral protein complexes on infected cells via FcγRs to mediate antibody-dependent cytotoxicity, and myeloid cells use these interactions to clear opsonized virions and virus-infected cells by antibody-dependent cellular phagocytosis (Fig. 2). The complement pathway is also activated by Fc binding to the complement component C1q, resulting in the opsonization of viruses or infected cells and the recruitment of myeloid cells. Antibody effector functions also contribute to antiviral T-cell-mediated immunity in vivo13. Notably, new knowledge about Fc effector functions has led to improved passive-antibody therapies through Fc modifications that reduce or enhance interactions with FcγRs, lengthen the half-life of the antibody and potentially enhance antigen presentation to T cells, providing what is termed a vaccinal effect8,11,14.Fig. 1: Neutralization of viruses by functions of the IgG Fab fragment.Mechanisms of antibody-mediated neutralization of viruses by functions of the IgG Fab fragment that block binding to cell surface receptors and inhibit infectivity by aggregating viral particles and inhibiting steps in the viral life cycle, such as fusion. Binding of antibodies with certain properties may enable changes in the viral entry protein that accelerate fusion.Full size imageAlthough their importance for protection is indisputable, the concern about ADE of disease arises from the possibility that antibodies present at the time of infection may increase the severity of an illness. The enhancement of disease by antibody-dependent mechanisms has been described clinically in children given formalin-inactivated respiratory syncytial virus (RSV) or measles vaccines in the 1960s, and in dengue haemorrhagic fever due to secondary infection with a heterologous dengue serotype15,16,17,18,19,20,21. For example, antibodies may enable viral entry into FcγR-bearing cells, bypassing specific receptor-mediated entry; this is typically followed by degradation of the virus, but could amplify infection if progeny virions can be produced. Although cytokine release triggered by interactions between the virus, antibody and FcγR is also highly beneficial—owing to direct antiviral effects and the recruitment of immune cells—tissue damage initiated by viral infection may be exacerbated22.While recognizing that other mechanisms of immune enhancement may occur, the purpose of this Perspective is to review clinical experiences, in vitro analyses and animal models relevant to understanding the potential risks of antibody-dependent mechanisms and their implications for the development of the vaccines and antibodies that will be essential to stop the COVID-19 pandemic. Our objective is to evaluate the hypothesis that antibody-mediated enhancement is a consequence of low-affinity antibodies that bind to viral entry proteins but have limited or no neutralizing activity; antibodies that were elicited by infection with or vaccination against a closely related serotype, termed ‘cross-reactive’ antibodies; or suboptimal titres of otherwise potently neutralizing antibodies. We assess whether there are experimental approaches that are capable of reliably predicting ADE of disease in humans and conclude that this is not the case.Box 1

 DefinitionsADE of disease: Enhancement of disease severity in an infected person or animal when an antibody against a pathogen—whether acquired by an earlier infection, vaccination or passive transfer—worsens its virulence by a mechanism that is shown to be antibody-dependent.Vaccine enhancement of disease: Enhancement of disease severity in an infected person or animal that had been vaccinated against the pathogen compared to unvaccinated controls. This results from deleterious T cell responses or ADE of disease and is usually difficult to link to one or the other.Neither ADE of disease nor vaccine enhancement of disease have established, objective clinical signs or biomarkers that can be used to distinguish these events from severe disease caused by the pathogen. Carefully controlled human studies of sufficient size enable the detection of an increased frequency of severe cases in cohorts given passive antibodies or vaccines compared to the control group, and atypical manifestations of infection can be identified should they occur.Mechanisms of antibody-mediated protection and the potential for ADE of infectionThe essential benefits of antibodies are mediated by several well-defined mechanisms that also have the potential for ADE of infection. Protection as well as ADE of infection can be observed in various assays of virus–cell interactions. An observation of ADE of infection in vitro does not predict ADE of disease in humans or animals.Virus entry: Antibodies block viruses by interfering with their binding to receptors on host cells or inhibiting changes in the viral protein needed for entry.Virus binding and internalization: Antibodies bind viruses to cells of the immune system via Fcγ receptors on the cell surface and internalization of viruses typically results in their degradation.Instead of protection, ADE of infection may occur if antibody binding improves the capacity of the viral protein to enable entry of the virus into its target cell, or if the virus has the capacity to evade destruction and produce more viruses after Fcγ receptor-mediated entry.Cytokine release: Antibodies that bind viruses and Fcγ receptors on cells of the immune system trigger the release of cytokines that inhibit viral spread and recruit other immune cells to eliminate infected cells. Although a part of the normal protective immune response, this can result in ADE of disease if excessive.Complement activation: Antibodies binding to virus or viral proteins on host cells may activate the complement cascade, a series of plasma proteins that together have a role in protective immunity through multiple mechanisms. Formation of large complexes of antibodies and viral proteins (antigens) can lead to immune complex deposition that activates complement. When excessive, antibody-dependent activation of complement may result in tissue damage and potential ADE of disease.Antibody-mediated mechanisms in the development of memory immunity: Antibodies bound to viruses or viral proteins can be taken up Fcγ receptors into immune system cells that process the antigens for activation and expansion of B cells and T cells. These mechanisms, which are critical for the establishment of memory immunity against future encounters with the virus, balance the potential risk of amplification of infection after viral uptake by some immune system cells.Principles for assessing potential ADE of diseaseThe use of ADE to denote enhanced severity of disease must be rigorously differentiated from ADE of infection—that is, from the binding, uptake and replication of the virus, cytokine release or other activities of antibodies detected in vitro. The first principle is that an antibody-dependent effect in vitro does not represent or predict ADE of disease without proof of a role for the antibody in the pathogenesis of a more severe clinical outcome. A second principle is that animal models for the evaluation of human polyclonal antibodies or monoclonal antibodies (mAbs) should be judged with caution because FcRs that are engaged by IgGs are species-specific23,24, as is complement activation. Antibodies can have very different properties in animals that are not predictive of those in the human host, because the effector functions of antibodies are altered by species-specific interactions between the antibody and immune cells. Animals may also develop antibodies against a therapeutic antibody that limit its effectiveness, or cause immunopathology. In addition, the pathogenesis of a model virus strain in animals does not fully reflect human infection because most viruses are highly species-specific. These differences may falsely support either protective or immunopathological effects of vaccines and antibodies. A third principle is that the nature of the antibody response depends on the form of the viral protein that is recognized by the immune system, thus determining what epitopes are presented. Protective and non-protective antibodies can be elicited to different forms of the same protein. A fourth principle is that mechanisms of pathogenesis in the human host differ substantially among viruses, or even between strains of a particular virus. Therefore, findings regarding the effects of passive antibodies or vaccine-induced immunity on outcomes cannot be extrapolated with confidence from one viral pathogen to another.Observations about RSV, influenza and dengueAs background for considering the risks of ADE of disease caused by SARS-CoV-2, it is important to closely examine clinical circumstances relevant to the hypothesis that antibodies predispose to ADE of disease by amplifying infection or through damaging inflammatory responses. We focus on the clinical experiences with RSV, influenza and dengue to demonstrate the complexities of predicting from in vitro assays or animal models whether passively transferred or vaccine-induced antibodies will cause ADE of disease, and of differentiating ADE from a severe illness that is unrelated to pre-existing antibodies.RSVIn a study of RSV in children under the age of 2 years, there were more cases requiring hospitalization for RSV-related bronchiolitis or pneumonia—especially in those aged between 6 and 11 months—in children who were immunized with a formalin-inactivated (FI)-RSV vaccine (10/101) than in children who were not immunized with FI-RSV (control cases; 2/173)25. This was also observed in a second study (18/23 hospitalizations of immunized children, with two deaths, compared with 1/21 control cases)16 and in two smaller studies17,26. This condition has been termed vaccine-associated enhanced respiratory disease. Later studies showed that the ratio of fusion protein (F) binding antibodies to neutralizing antibodies was higher in the sera of 36 vaccinated compared to 24 naturally infected children, suggesting that non-neutralizing antibodies to an abnormal F-protein conformation may have been a predisposing factor27. Complement activation, detected by the presence of C4d in the lungs of the two fatal cases, suggested that antibody–F protein immune complexes led to more severe disease28. However, C4d deposition can result from the lectin-binding pathway as well as from the classical pathway, and C4 can be produced by epithelial cells and activated by tissue proteases29. Whether harmful RSV-specific T cells were induced was not determined: although lymphocyte transformation frequencies were higher, this early method did not differentiate antigen-specific responses from secondary cytokine stimulation or from CD4 and CD8 T cell responses, although CD4 T cell proliferation is more likely30. Importantly, the FI-RSV clinical experience did not establish that vaccine-enhanced disease was antibody-dependent31. Subsequently, in animal studies, the production of low-avidity antibodies due to insufficient Toll-like-receptor signalling and lack of antibody maturation, and the formation of immune complexes have been implicated. However, a definitive antibody-mediated mechanism of enhancement has not been documented32, and models have also identified Th2-skewing of the T cell response and lung eosinophilia with challenge after FI-RSV, raising the possibility that T cells contribute to vaccine-induced enhancement of RSV disease31,33.Experience with RSV also includes more than 20 years of successful prophylaxis of high-risk infants with palivizumab, a mAb directed against pre- and post-fusion F protein34. Importantly, this experience challenges a role for low neutralizing-antibody titres in the ADE of lung disease, because RSV morbidity does not increase as titres decrease. Further, if suboptimal neutralization were a factor, the failure of suptavumab—caused by F protein drift in RSV B strains—would be associated with ADE of disease; however, infections in such cases were not more severe35. Clinical trials of an RSV mAb that has an extended half-life have shown a reduction in hospitalizations of around 80%, again supporting the concept that such treatments provide protection without a secondary risk from declining titres36. mAbs against RSV have been consistently safe, even as the neutralizing capacity diminishes after administration.InfluenzaInfluenza is instructive when considering the hypothesis that cross-reactive antibodies predispose to ADE of disease, because almost all humans contain antibodies that are not fully protective against antigenically drifted strains that emerge year after year. Instead, pre-existing immunity typically provides some protection against a second viral strain of the same subtype. Antibodies against neuraminidase and against the stem or head regions of haemagglutinin also correlate with protection37. When an H1N1 strain with a haemagglutinin shift emerged in the 2009 H1N1 pandemic, some epidemiological studies linked a greater incidence of medically treated illness to previous vaccination against influenza, whereas others did not38,39,40,41. One report correlated cross-reactive, low-avidity and poorly neutralizing antibodies with risk in middle-aged people—the demographic with a higher prevalence of severe 2009 H1N142. Immunopathology and C4d were reported in the lungs of six fatal cases in this age group, indicating that antibody-dependent complement activation through immune-complex formation may have been a contributing factor. However, as noted above, other mechanisms lead to C4d deposition, and lung T lymphocytosis attributed to T cell epitopes shared by 2009 H1N1 and earlier H1N1 strains was also observed, raising the possibility that T cells played a part. Another study correlated pre-existing antibodies that mediated infected cell lysis by complement activation with protection against H1N1 in children43. In a porcine model, enhanced pulmonary disease was observed after vaccination with an inactivated influenza H1N2 strain followed by heterologous H1N1 challenge44. The animals had non-neutralizing antibodies that bound haemagglutinin in the stem region, but did not block the binding of haemagglutinin to its cell receptor and accelerated fusion in vitro by a Fab-dependent mechanism (Fig. 1). Lung pathology was also observed in mice treated with a mAb that induced a conformational change in haemagglutinin that facilitated fusion45. Such a mechanism was postulated to have potential clinical relevance when the infecting influenza virus has undergone antigenic shift and the infection boosts non-neutralizing haemagglutinin-stem-binding antibodies without a neutralizing antibody response. The likelihood of these circumstances occurring is unclear. Further, human influenza vaccines are not known to elicit immunodominant antibodies with this property. Importantly, as noted above, stem antibodies correlate both with resistance to infection and to severe disease in humans, indicating that this interesting mechanism is not predictive of disease causation for stem-specific antibodies37. In addition, mAbs can be screened to avoid fusion-enhancing properties, and fusion is not intrinsically accelerated by low titres of neutralizing antibodies. Notably, infants benefit from immunization from six months of age, despite their limited capacity to produce affinity-matured, high-avidity antibodies. Overall, widespread annual surveillance of influenza does not reveal ADE of disease, even though cross-reactive strains and vaccine mismatches are common.Fig. 2: Antibody effector functions of the IgG Fc fragment.Antibody effector functions are mediated by binding of the IgG Fc domain to FcγRs on myeloid cells or to components of the complement system. These activities occur when the antibody binds the target virus protein either on virions or on infected cells. a, Viral particles are internalized and degraded and local cytokine release recruits immune cells. b, If cells are permissive, progeny virions could be produced. When virus–antibody complexes are taken up by the cell, a detrimental cytokine response may be generated. c, Binding of the IgG Fc fragment to C1q leads the activation of complement components C3, C3a and C5a and of the complement membrane attack complex (MAC) that disrupts membranes. C3 and C5a facilitate phagocytosis by myeloid cells. C3a and C5a are anaphylatoxins that attract inflammatory cells, which can secrete cytokines that enhance antiviral immunity but could be detrimental if produced in excess. d, e, The IgG Fc domain binds to multiple types of FcγRs on myeloid cells to trigger effector functions. The specific consequences of this interaction are dependent on the FcγR that is involved and are not detailed here. d, Antibody-dependent phagocytosis by macrophages and dendritic cells. e, Antibody-dependent cytotoxicity mediated by natural killer (NK) cells. f, Antibody-mediated antigen presentation after the uptake of virus or virus-infected cells by phagocytic cells leads to the activation of antiviral T cells.Full size imageDengueThere are four viral serotypes of dengue that circulate in endemic areas19. Although severe dengue haemorrhagic fever and shock syndrome occurs during primary infection, possible ADE of disease has been associated with poorly neutralizing cross-reactive antibodies against a heterologous dengue serotype. Taking into account the difficulty of classification due to the overlapping signs of severe infection and ADE of disease, clinical experience indicates that ADE of disease does occur, but is rare in endemic areas (36/6,684 participants; around 0.5%) and is correlated with a narrow range of low pre-existing antibody titres (1:21–1:80)20. In the same study, high antibody titres were found to be protective. The challenge of predicting how to avoid such a rare immune-enhancing situation against the background of protection conferred by dengue neutralizing antibodies implies that it will be equally difficult for SARS-CoV-2.When considering conditions that may result in ADE of disease, it is important to emphasize that dengue differs from other viruses because it targets monocytes, macrophages and dendritic cells and can produce progeny virus in these cells, which abundantly express both viral entry receptors and FcγRs. ADE of infection can be demonstrated in vitro with FcγR-expressing cells—typically with cross-reactive antibodies that have low or no neutralizing activity, have low affinity, or target non-protective epitopes, or if a narrow range of antibody and infectious virus concentrations is tested46,47. The mechanism of ADE of disease associated with dengue therefore depends on three factors: the circulation of multiple strains of a virus that have variable antigenicity, a virus that is capable of replication in FcγR-expressing myeloid cells and sequential infection of the same person with these different viral serotypes. Despite these pre-disposing conditions and the fact that dengue is an increasingly common infectious disease, severe dengue disease is rare.The role of pre-existing immunity has also been a concern for the quadrivalent live attenuated dengue vaccine (Dengvaxia), because higher hospitalization rates were observed among vaccine recipients who were initially seronegative—especially children aged between two and eight years48. Other explanations for this outcome include poor efficacy against serotypes 1–3, or the failure to induce cell-mediated immunity because T cells primarily recognize non-structural proteins that are not present in the chimeric vaccine. Importantly, the cause of death in 14 fatal cases of dengue could not be determined by the WHO (World Health Organization) Global Advisory Committee on Vaccine Safety, because a failure of vaccine protection could not be distinguished from immune enhancement by clinical or laboratory criteria49. This experience underscores how difficult it is to predict the potential for vaccine-induced antibodies or a therapeutic antibody to enhance the severity of disease, because other mechanisms of pathogenesis that result in severe disease are potentially involved—even for the well-studied case of dengue.In other assessments of the risks and benefits of cross-reactive antibodies, infection with Zika—which, as with dengue, is a flavivirus—was less common in individuals who had previously been infected with dengue50. In addition, the presence of cross-reactive antibodies has been associated with improved efficacy, as measured by the responses to a yellow fever vaccine in recipients who had received a Japanese encephalitis vaccine47, and by association of the effectiveness of Dengvaxia with seropositivity for dengue at the time of immunization51.In summary, these clinical experiences with RSV, influenza and dengue provide strong evidence that the circumstances that are proposed to lead to ADE of disease—including low affinity or cross-reactive antibodies with limited or no neutralizing activity or suboptimal titres—are very rarely implicated as the cause of severe viral infection in the human host. Furthermore, clinical signs, immunological assays or biomarkers that can differentiate severe viral infection from a viral infection enhanced by an immune mechanism have not been established49,52.Assessing the risk of ADE of disease with SARS-CoV-2Given the complexities described above, it is sobering to take on the challenge of predicting ADE of disease caused by SARS-CoV-2. Here we consider whether clinical circumstances point to a role for antibodies with poor or no neutralizing activity in severe COVID-19, incorporating relevant experience from disease caused by the common human coronaviruses, as well as by severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome-related coronavirus (MERS-CoV).Infection by SARS-CoV-2 is initiated by the binding of its fusion protein, the spike (S) protein, to the entry receptor, angiotensin-converting enzyme 2 (ACE2)53,54,55. Other receptors for SARS-CoV-2, such as CD147, have also been reported56. ACE2 is expressed on alveolar type II pneumocytes, airway epithelial cells, nasal tract goblet cells and ciliated cells, as well as on intestinal and other non-respiratory tract cells, as assessed by RNA expression57. On most such cells, ACE2 seems to be expressed at low levels; however, it can be upregulated by interferons58, which could theoretically promote infection if the virus overcomes interferon-induced barriers. FcγRIIa and FcγRIIIa were detected in alveolar, bronchial and nasal-cavity epithelial cells by single-cell RNA sequencing, but both fractions of positive cells and levels of expression per cell were considerably lower than for resident myeloid and natural killer cells59,60. The moderate prevalence of both ACE2 and FcγRs results in poor co-occurrence, although this might be underestimated because of the dropout effect in single-cell transcriptomics. Co-expression of ACE2 and FcγRs therefore seems to be limited, which would mitigate against antibody-enhanced disease caused by SARS-CoV-2 via the dual-receptor mechanism proposed in dengue infection.When considering potential detrimental effects of antibodies, the presence or absence of cross-reactive antibodies against other human coronavirus (HCoV) strains has not been linked to whether SARS-CoV-2 infection is more severe, mild or asymptomatic, although antibodies that recognized the SARS-CoV-2 S2 subunit were detected in 12 out of 95 uninfected individuals61. In two reports, 30–50% of SARS-CoV-2 seronegative or unexposed individuals had CD4 T cells that recognized the SARS-CoV-2 S protein62,63. Previous infection with HCoV-HKU1 and HCoV-OC43 betacoronaviruses, or HCoV-NL63 and HCoV-229E alphacoronaviruses, is not known to predispose to more severe infection with the related virus from the same lineage64,65,66,67. Conversely, the endemic nature of coronavirus infections indicates that infection in the presence of low levels of antibodies is common, providing a theoretical opportunity for ADE of disease—although these illnesses are mild—and suggesting that cross-protection may be transient68. It is of interest that neither low neutralizing-antibody titres nor heterologous virus challenge were associated with enhanced disease in human studies of HCoV-229E64,65. Although HCoV-NL63 also uses the ACE2 entry receptor, the receptor-binding domain (RBD) of HCoV-NL63 is structurally very different from that of SARS-CoV-2, which would limit antibody cross-reactivity.Antibodies to the S proteins of SARS-CoV and SARS-CoV-2—and, to a much lesser extent, MERS-CoV—can cross-react, and both high-potency neutralizing antibodies that also mediate antibody-dependent cytotoxicity and antibody-dependent cellular phagocytosis69, as well as non-neutralizing antibodies, can be elicited against conserved S epitopes70,71. However, the limited spread of SARS-CoV and MERS-CoV means that it is not feasible to assess whether there is any ADE of disease due to SARS-CoV-2 attributable to cross-reactive antibodies72. A finding that pre-existing antibodies for other coronaviruses correlate with the low incidence of symptomatic SARS-CoV-2 infection in children would support protection rather than a risk of disease enhancement73. To answer this question, the broad application of serological assays that quantify antibodies to virus-specific and cross-reactive epitopes of human coronaviruses in relation to the outcomes of natural infection and of vaccine and antibody trials is required.The administration of passive antibodies could also reveal whether antibodies predispose to ADE of disease. In small studies, patients infected with SARS or MERS received polyclonal antibodies without apparent worsening of their illness74,75,76,77, and from a meta-analysis it was concluded that early treatment with plasma from patients that had recovered from SARS-CoV infection correlated with a better outcome76. In 10 patients with severe COVID-19 that were given plasma with neutralizing titres greater than 1:640 (200 ml) at a median of 16.5 days after disease onset, viraemia was no longer detected and clinical parameters improved within 3 days78. Similar findings were reported for 5 severely ill patients treated with plasma with neutralizing titres greater than 1:4079; however, another study found no difference in outcome between 52 treated and 51 untreated patients80. The evidence that COVID-19 does not worsen after treatment with plasma from convalescent patients has been substantially reinforced by a study of 20,000 patients who were severely ill with the disease, showing an adverse event incidence of 1–3%81. If further substantiated, these findings will markedly diminish the concern that clinically relevant amplification of infection, release of immunopathogenic cytokines or immune-complex deposition in the presence of a high viral load is mediated by SARS-CoV-2 antibody-dependent mechanisms82,83.High-dose intravenous polyclonal IgG (IVIg)—which is used to treat systemic lupus erythematosus (SLE), idiopathic thrombocytopenia and Kawasaki syndrome84—is thought to exert its beneficial effects through the activation of FcγR inhibitory signalling. Because severe COVID-19 could reflect immune dysregulation, a benefit and/or lack of adverse effects in patients receiving plasma from convalescent individuals might reflect the suppression of inflammation induced by IgG, rather than supporting the conclusion that passive antibodies do not trigger ADE of disease through Fab- or Fc-dependent mechanisms. However, the dose of IgG administered to patients with SLE (2 g per kg over 5 days)85 is much higher than the dose received from convalescent plasma, based on the expected IgG concentrations in plasma (around 500–800 mg per 100 ml) and the amount of convalescent plasma received (200 ml)78,79. Assuming a concentration of 1,600 mg per 200 ml, the IgG levels after receiving convalescent plasma (1.6 g per 80 kg) would be approximately 100-fold less than after receiving IVIg (160 g per 80 kg). It is therefore unlikely that the immunomodulatory effects of polyclonal non-antigen-specific IgG dampened possible manifestations of enhanced illness.Clinically, infections with SARS-CoV, MERS-CoV and SARS-CoV-2 are often biphasic, with more severe respiratory symptoms developing after a week or more and, in some patients, in association with the release of pro-inflammatory cytokines. This pattern has led to the hypothesis that an emerging immune response—including low-avidity, poorly neutralizing antibodies—could exacerbate the disease. However, reports that relate antibody titres to disease progression involve relatively few patients86,87,88, and are confounded by the higher levels of antigen seen in severe infections that are predicted to drive a stronger immune response or a heightened innate inflammatory response. One report of three cases of fatal SARS-CoV infection reported that high neutralizing anti-S antibodies and a prominent CD163+ monocyte/macrophage pulmonary infiltrate of cells were associated with reduced expression of TGF-β and CD206+, which are proposed to be markers of macrophages with beneficial functions89. However, quantitative analysis of these changes and evidence of an antibody-mediated pathology that is dependent on these cells were not reported. A recent meta-analysis found no relationship between the kinetics of antibody responses to SARS-CoV, MERS-CoV or SARS-CoV-2 and clinical outcomes90. At present, there is no evidence that ADE of disease is a factor in the severity of COVID-19. Instead, lung pathology is characterized by diffuse alveolar damage, pneumocyte desquamation, hyaline membranes, neutrophil or macrophage alveolar infiltrates and viral infection of epithelial cells and type II pneumocytes91. Further, if instances of ADE of disease occur at all, the experience with dengue suggests that this or other types of immune enhancement will be rare and will occur under highly specific conditions. The aetiology of the inflammatory, Kawasaki-like syndrome that has been associated with SARS-CoV-2 infection in children is unknown, but has not been associated with antibody responses so far92.In summary, current clinical experience is insufficient to implicate a role for ADE of disease, or immune enhancement by any other mechanism, in the severity of COVID-19 (Table 1). Prospective studies that relate the kinetics and burden of infection and the host response—including the magnitude, antigen-specificity and molecular mechanisms of action of antibodies, antibody classes and T cell subpopulations—to clinical outcomes are needed to define the characteristics of a beneficial compared with a failed or a potentially detrimental host response to SARS-CoV-2 infection. Although it will probably continue to be difficult to prove that ADE of disease is occurring, or to predict when it might occur, it should be possible to identify correlates of protection that can inform immune-based approaches to the COVID-19 pandemic.Effects of antibodies on SARS-CoV and MERS-CoVIn vitro studies of the effects of antibodies on viral infection have been used extensively to seek correlates or predictors of ADE of disease (Table 1). These efforts are complicated by the fact that the same antibody mechanisms that are often proposed to result in ADE of infection are responsible for protection from viral disease in vivo. Although infection was most often blocked by anti-S antibodies, several reports have shown antibody-dependent uptake of SARS-CoV or SARS-CoV S-pseudoviruses that was mediated by binding of the Fab component to the virus and the Fc component to FcγR on the target cell (Fig. 2) using in vitro methods93,94,95,96,97,98. Importantly, viral uptake did not result in productive infection. An antibody that binds the S protein and mimics receptor-mediated entry to facilitate viral uptake has been described for MERS-CoV99, but not for SARS-CoV or SARS-CoV-2. Although SARS-CoV and SARS-CoV-2 do not infect myeloid cells100,101,102,103, the productive infection of macrophages by MERS-CoV has been reported, albeit at low levels104. It is notable that higher production of immune-cell-attracting chemokines was observed in myeloid cells infected by MERS-CoV but not in cells exposed to SARS-CoV, suggesting that productive infection has a greater effect on this response104. The biology of the interactions of coronaviruses with cells expressing FcγRs is therefore very different from the targeting of FcγR-expressing myeloid cells by the dengue viruses. Conversely, in vitro methods can reliably define the properties of mAbs or of vaccine-induced antibodies—including their epitope specificity, binding affinity and avidity, and maturation as well as any potential to enhance fusion, together with their capacities for neutralization and antiviral Fc-dependent effector functions (Fig. 2).Antibody effects in coronavirus-infected animalsSmall-animal modelsSeveral mouse, rat and other small-animal models of SARS-CoV infection have used passive-antibody administration or immunization to investigate whether pre-existing antibodies protect against or enhance disease. Although vaccine enhancement of disease in these models could occur through other mechanisms, such studies can directly assess the protective or enhancing properties of passive antibodies (Table 1).In the ferret model of SARS-CoV infection, a human mAb was found to protect the animals from infection105; however, modified vaccinia Ankara expressing S protein (MVA-S) was not protective and liver inflammation was noted in this model106. Pre- and post-exposure administration of a mAb against MERS-CoV protected mice from challenge, as assessed by lung viral load, lung pathology and weight loss107. Three mAbs against SARS-CoV, given at a high dose before challenge, protected young and old mice against lung viral spread and inflammation, but had no effect when given after infection108. Low doses were less protective, but no ADE of disease was observed. A caveat is that human mAbs were tested in the context of mouse FcγRs; however, this can be addressed using human FcgR transgenic animals109. Both previous infection and passive transfer of mouse neutralizing antibodies partially protected 4–6-week-old mice against secondary infection with SARS-CoV110, and no ADE of disease was observed despite low neutralizing titres. In another mouse study111, passive transfer of SARS-CoV-immune serum was found to mediate protection by Fc-dependent monocyte effector function through antibody-dependent cellular phagocytosis; however, natural killer cells, antibody-dependent cytotoxicity or complement-antibody complexes did not contribute to protection. In a mouse model of vaccination, which used SARS-CoV in which the E protein had been deleted as a live attenuated vaccine, induction of antibodies and T cell immunity and protection against lethal viral challenge was observed in mice from three age groups112. By contrast, enhanced disease was observed in mice that were immunized with formalin- or ultraviolet-inactivated SARS-CoV. Whereas younger mice were protected, older mice developed pulmonary pathology with an eosinophil infiltrate; this suggests a detrimental Th2 response related to age, rather than ADE of disease113. In some models, cellular immunopathology might be linked to Th17-mediated activation of eosinophils114. In another report, mice given formalin- or ultraviolet-inactivated SARS-CoV or other vaccine formulations developed neutralizing antibodies and were protected from challenge, but also developed eosinophilic pulmonary infiltrates115. This type of immunopathology has not been reported in fatal human coronavirus infections.Small-animal studies of SARS-CoV-2 infection are being reported rapidly. Neutralizing antibodies to SARS-CoV-2 were induced by immunizing rats with the RBD of the S protein and adjuvant94. In vitro evaluation of the potential for enhanced uptake of SARS-CoV-2 using HEK293T cells expressing rat FcγRI in the presence or absence of ACE2 expression showed neutralization but no enhancement of viral entry. Mice that were given an mRNA vaccine expressing pre-fusion SARS-CoV-2 S protein developed neutralizing antibodies and S-protein-specific CD8 T cell responses that were protective against lung infection without evidence of immunopathology116, and neutralizing mAbs against the RBD of the S protein of SARS-CoV-2 reduced lung infection and cytokine release117.Passive transfer of a neutralizing antibody protected Syrian hamsters against high-dose SARS-CoV-2, as demonstrated by maintained weight and low lung viral titres118. Similarly, hamsters immunized with recombinant SARS-CoV S protein trimer developed neutralizing antibodies and were protected against challenge119. Whereas serum from vaccinated hamsters mediated FcγRIIb-dependent enhancement of SARS-CoV entry into B cell lines, virus replication was abortive in vitro and viral load and lung pathology were not increased in vaccinated animals98. These data underscore that enhancement of viral entry into cells in vitro does not predict negative consequences in vivo, further highlighting the important gap between in vitro findings and the causes of ADE of disease in vivo.Unlike SARS-CoV, MERS-CoV and SARS-CoV-2, feline infectious peritonitis virus is an alphacoronavirus that, as with dengue, has tropism for macrophages. Infection with this virus has been shown to be enhanced by pre-existing antibodies, especially those against the same strain120.Non-human primate modelsIn non-human primates (NHPs), infection with SARS-CoV, MERS-CoV or SARS-CoV-2 results in viral spread to multiple tissues, including lungs121,122,123. Rhesus macaques that were administered a high inoculum of SARS-CoV-2 by nasal, tracheal, ocular and oral routes had increased temperatures and respiratory rates for 1 day, and reduced appetite and dehydration for 9–16 days122. Macaques that were euthanized at 3 days and 21 days had multifocal lung lesions, with alveolar septal thickening due to oedema and fibrin, small to moderate numbers of macrophages, a few neutrophils, minimal type II pneumocyte hyperplasia and some perivascular lymphocyte cuffing. SARS-CoV-2 viral proteins were detected in a few type I and type II pneumocytes, and alveolar macrophages and virions were found in type I pneumocytes. Although these foci of lung pathology have some similarities to those observed in human infection91, NHPs develop minimal or no signs of respiratory or systemic betacoronavirus disease.After the outbreaks of SARS-CoV and MERS-CoV disease, NHPs were used in the evaluation of several vaccine and antibody interventions (Supplementary Table 1). In one study, FI-SARS-CoV reduced viraemia and protected against lung pathology in rhesus macaques124, whereas in another study macaques given FI-SARS-CoV developed macrophage and lymphocytic infiltrates and alveolar oedema with fibrin deposition after challenge, indicating the difficulties of establishing consistent NHP models125. Synthetic peptide vaccines have also been prepared using sera from convalescent patients to define immunodominant epitopes of SARS-CoV S protein125. The vaccines were found to reduce pathology after SARS-CoV challenge unless the S protein of the vaccine included amino acids 597−603, suggesting an epitope-specific basis for the induction of lung pathology. However, these peptide constructs would not be expected to fully mimic antibody or T cell responses that would be elicited to the intact S protein.Two studies have reported the immunization of rhesus macaques with MVA expressing SARS-CoV S protein or an MVA control. In the first report, three out of four immunized macaques had no detectable shedding or enhanced lung infection 7 days after challenge126. In the second report, immunization elicited polyclonal anti-S antibodies with neutralizing activity and reduced infection in three out of eight macaques after challenge89. However, although the challenge inoculum was the same as in the first study, areas of diffuse alveolar damage were detected in six out of eight vaccinated macaques compared with one out of eight control animals euthanized at 7 days, as well as at 35 days. Immunization with MVA-S was associated with an accumulation of monocytes and macrophages, and with the detection of activated alveolar macrophages that produced pro-inflammatory MCP-1 and IL-8, which were were not observed in control animals. In a second cohort that was given polyclonal IgG from vaccinated macaques or control animals, loss of TGF-β and increased IL-6 production by activated pulmonary macrophages was observed in macaques that were pre-treated with anti-S IgG, and lung pathology was described as skewed towards immunopathological inflammation. However, it was not stated whether the histopathology was focal or widespread in the lungs, and immunopathology was not associated with impaired respiratory function in macaques evaluated for 21 days (passive anti-S) or for 35 days (MVA-S). Although differences in macrophage markers were associated with changes in the lungs, a causal relationship between anti-S antibodies and an antibody-dependent macrophage-mediated mechanism of more severe pathological changes was not explored, and whether MVA-S might have generated non-neutralizing antibodies that enhanced lung pathology was not assessed. It will therefore be important to define the epitope specificity and serum neutralization activity in these animal models, and potential T cell mechanisms will need to be excluded before enhanced immunopathology can be attributed to antibody mechanisms.The second study reporting immunization of rhesus macaques with MVA-S89 also described in vitro experiments using sera from patients who had recovered from SARS-CoV infection. However, only one out of eight sera samples elicited enhanced cytokine production by human macrophages in vitro. Because IL-8 production by macrophages treated with one of the serum samples was lower in the presence of FcγR-blocking antibody (no control serum), it was concluded that blocking FcγRs might be necessary to reduce lung damage caused by SARS-CoV. However, the finding was not confirmed with sera from other severe cases of SARS, and is subject to the caveat that in vitro studies cannot be taken as evidence of ADE of disease.In contrast to the immunopathology observed after immunization with MVA-S, other studies of SARS-CoV have suggested a protective effect of vaccine-induced antibodies. Using a purified SARS-CoV-infected cell lysate as a vaccine, cynomolgus macaques were protected from challenge, and low neutralizing antibody titres were not associated with ADE of disease127. Further, African green monkeys with pre-existing antibody and/or T cells after primary SARS-CoV infection were protected from homologous re-challenge as assessed by lung virus titres, although the pulmonary inflammatory response was not different from that of primary infection128.In additional studies, rhesus macaques immunized with a chimpanzee adenovirus (ChAdOx1 MERS) expressing MERS-CoV S protein, a recombinant S-RBD protein or a synthetic MERS-CoV S DNA vaccine, had decreased infection and no enhanced lung pathology upon challenge129,130,131.The potential for immune enhancement of SARS-CoV-2 infection by antibody-dependent or other mechanisms has been assessed by infection and re-challenge of rhesus macaques. Out of two rhesus macaques that were re-challenged 28 days after initial infection—when neutralizing antibody titres were low (1:8–1:16)—neither exhibited viral shedding and one had no lung pathology. Immunity to SARS-CoV-2 in nine rhesus macaques—including the presence of neutralizing antibodies, antibody-mediated effector functions and antiviral CD4 and CD8 T cells—was associated with protection upon re-challenge at 35 days123. When vaccines were tested, rhesus macaques immunized with purified β-propriolactone-inactivated SARS-CoV-2 in alum showed complete or partial protection against high-inoculum SARS-CoV-2 challenge, and histopathological analyses of lungs and other organs at 29 days showed no evidence of ADE of disease compared with control macaques132. A large study involving 35 rhesus macaques, which were given prototype DNA vaccines expressing either full-length SARS-CoV-2 S protein or components of this protein, found that protection was correlated with the presence of neutralizing antibodies—and, notably, with Fc-dependent antibody effector functions—and there were no adverse outcomes after challenge133.In studies of neutralizing mAbs (Supplementary Table 1), viral titres and lung pathology after nasal challenge were reduced in rhesus macaques that were administered a mAb directed against a proteolytic cleavage site in the SARS-CoV S protein that is required for host-cell entry134. Macaques given mAbs against MERS-CoV showed less pulmonary involvement and no worsening of disease with challenge135. The prophylactic administration of mAbs against MERS-CoV to marmosets one day before challenge was associated with reduced lung pathology compared with the administration of control mAbs136,137,138; mAbs were found to be protective when administered 2–12 h after challenge but not when given 1 day after challenge137,138. These animal studies of coronavirus infections parallel the observation that the passive transfer of mAbs against RSV that have selected properties can be protective, whereas a particular vaccine formulation (FI-RSV) that is directed to the same viral protein can enhance disease.In summary, in most animal models—including NHPs—vaccination or the administration of passive mAbs have demonstrated protection against challenge with SARS-CoV, MERS-CoV or SARS-CoV-2, although reports on SARS-CoV-2 are limited. However, studies of an FI-SARS-CoV vaccine, one of two studies of an MVA vaccine expressing SARS-CoV S protein, and vaccination with one S-derived peptide showed enhanced lung pathology in NHPs. Thus, there are limited data to indicate that immune responses that include antibodies (and probably also T cells) induced by some vaccine formulations may be associated with more extensive lung pathology compared with infection alone, whereas the transfer of mAbs with specific properties have, so far, provided protection in animals (Supplementary Table  1).Table 1 Information provided by and limitations of approaches for the assessment of antibody-mediated protection against SARS-CoV-2 and the potential for antibody-dependent enhancement of diseaseFull size tableOverall, the lack of a link between clinical measures of disease severity in NHPs and the experimental conditions associated with exacerbated lung pathology is a limitation to their utility in predicting the risks of ADE associated with passive-antibody or vaccine interventions in humans. So far, the models do not emulate the severe respiratory disease observed in COVID-19. Evaluation of T cell responses will also be needed to draw conclusions regarding mechanisms if immunopathology is observed. For example, a strong T cell response has been described as ameliorating ADE of disease in a dengue model139 and animal studies have suggested an aberrant T cell response to FI-RSV vaccination33,114. Quantitative assessments of the extent of lung involvement, and histopathological scoring of the characteristics and severity of lesions using validated markers of infected cells, patterns of cell-subtype infection and quantification of infiltrating immune cells will be also be necessary before these models can be used to better understand either protective immunity or immune enhancement—whether mediated by antibodies, T cells, intrinsic responses or a combination of factors. A critical point is that the identification of correlates of protection in humans will be necessary to understand how studies in small- and large-animal models can be designed to support or question the benefits of particular immune interventions for SARS-CoV-2 infection.ConclusionsIt is clear that after many years, and considerable attention, the understanding of ADE of disease after either vaccination or administration of antiviral antibodies is insufficient to confidently predict that a given immune intervention for a viral infection will have negative outcomes in humans. Despite the importance that such information would have in the COVID-19 pandemic, in vitro assays do not predict ADE of disease. Most animal models of vaccines and antibody interventions show protection, whereas those that suggest potential ADE of disease are not definitive and the precise mechanisms have not been defined. Although ADE is a concern, it is also clear that antibodies are a fundamentally important component of protective immunity to all of the pathogens discussed here, and that their protective effects depend both on the binding of viral proteins by their Fab fragments and on the effector functions conferred by their Fc fragments. Even when vaccine formulations such as formalin inactivation have shown disease enhancement, neutralizing antibodies with optimized properties have been protective. Further, the potential mechanisms of ADE of disease are probably virus-specific and, importantly, clinical markers do not differentiate severe infection from immune enhancement. Additional mechanism-focused studies are needed to determine whether small-animal and NHP models of virus infection, including for SARS-CoV-2, can predict the probable benefits or risks of vaccines or passive-antibody interventions in humans. Optimizing these models must be informed by understanding the correlates of protection against SARS-CoV-2 in natural human infection and as vaccines and antibodies are evaluated in humans. Such mechanistic and in vivo studies across viral pathogens are essential so that we are better prepared to face future pandemics. In the meantime, it will be necessary to directly test safety and define correlates of protection conferred by vaccines and antibodies against SARS-CoV-2 and other viral pathogens in human clinical trials.

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Download referencesAcknowledgementsThe authors thank D. Ma for her contributions to preparing this review.Author informationAuthors and AffiliationsVir Biotechnology, San Francisco, CA, USAAnn M. Arvin, Katja Fink, Michael A. Schmid, Andrea Cathcart, Roberto Spreafico, Colin Havenar-Daughton, Antonio Lanzavecchia, Davide Corti & Herbert W. VirginStanford University School of Medicine, Stanford, CA, USAAnn M. ArvinHumabs Biomed SA, a subsidiary of Vir Biotechnology, Bellinzona, SwitzerlandKatja Fink, Michael A. Schmid, Antonio Lanzavecchia & Davide CortiWashington University School of Medicine, Saint Louis, MO, USAHerbert W. VirginAuthorsAnn M. ArvinView author publicationsYou can also search for this author in

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PubMed Google ScholarContributionsA.M.A. and H.W.V. drafted the manuscript, K.F., M.A.S., A.C., R.S., C.H.-D., A.L. and D.C. edited the draft, and A.M.A. and H.W.V. prepared the final manuscript, which was reviewed and approved by all authors.Corresponding authorsCorrespondence to

Ann M. Arvin or Herbert W. Virgin.Ethics declarations

Competing interests

The authors of this manuscript are employees of, or have other affiliations with, Vir Biotechnology. Vir had to choose how to proceed with mAbs to treat or prevent COVID-19 disease in the light of the evidence surrounding the possibility of ADE as detailed in this review. This review reflects the result of the team of authors carefully reviewing the literature to assess these choices and is provided as a service to the community. Vir has elected to test human mAbs with Fc activity preserved or enhanced, based on the lack of consistent evidence for ADE of disease noted above and evidence that the protective activities and potency of antibodies often involves antibody effector functions. We could have elected to take forward mAbs engineered to lack effector function, and so our antibody-related clinical programmes for SARS-CoV-2 could have moved forward regardless of the outcome of our review. A.M.A.’s contributions were part of her personal outside consulting arrangement with Vir Biotechnology and were not associated with Stanford University.

Additional informationPeer review information Nature thanks James Crowe, Gary Nabel and Stanley Perlman for their contribution to the peer review of this work.Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.Supplementary informationSupplementary Table 1| Summary of studies of SARS-CoV, MERS-CoV and SARS-CoV-2 in non-human primates.Rights and permissionsReprints and permissionsAbout this articleCite this articleArvin, A.M., Fink, K., Schmid, M.A. et al. A perspective on potential antibody-dependent enhancement of SARS-CoV-2.

Nature 584, 353–363 (2020). https://doi.org/10.1038/s41586-020-2538-8Download citationReceived: 15 May 2020Accepted: 06 July 2020Published: 13 July 2020Issue Date: 20 August 2020DOI: https://doi.org/10.1038/s41586-020-2538-8Share this articleAnyone you share the following link with will be able to read this content:Get shareable linkSorry, a shareable link is not currently available for this article.Copy to clipboard

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什么是「抗体依赖的增强作用」，为什么只有一部分病毒有？ - 知乎

什么是「抗体依赖的增强作用」，为什么只有一部分病毒有？ - 知乎首页知乎知学堂发现等你来答​切换模式登录/注册生物病毒病毒传播免疫系统病毒学寨卡病毒（Zika virus）什么是「抗体依赖的增强作用」，为什么只有一部分病毒有？抗体依赖的增强作用 Antibody-dependent enhancemen 指一些次优的抗体（一般为可结合病毒的非中和抗体）与病毒结合后，抗体的F…显示全部 ​关注者6被浏览11,110关注问题​写回答​邀请回答​好问题 3​添加评论​分享​1 个回答默认排序知乎用户略知病毒1、首先说一下ADE吧，某些疫苗免疫或者病毒感染后预存的抗体不仅不可以提供保护作用反而使病情加重的现象。在呼吸道粘膜感染的疫苗（如呼吸道合胞病毒疫苗、麻疹疫苗）、登革疫苗，与新冠病毒同种的严重急性呼吸道综合征冠状病毒、中东呼吸综合征冠状病毒疫苗研发过程也有ADE。2、产生ADE的原因如下图：以冠状病毒为例，正常的有中和活性的抗体可以和病毒的囊膜蛋白（S）结合（图a），因此阻断了S与细胞受体ACE2的结合导致病毒不能侵入细胞复制，从而起到了保护作用。低中和活性或者非中和抗体与S蛋白结合后，抗体的Fc结构域会和巨噬细胞或者某些单核细胞表面表达的Fc受体结合促进了病毒进入细胞，这样病毒就可以大量复制产生ADE现象。3、值得注意的是低中和活性或者非中和抗体也可能导致促炎性细胞因子的释放，导致炎性细胞因子风暴而使病情加重。机制和2相似。4、ADE产生的机制主要是发生在入侵阶段，也就是病毒蛋白与细胞受体相互作用的阶段，这个阶段被一些病毒特异性抗体干扰了结果导致病毒复制增加或者是严重免疫损伤。至于为什么只有部分病毒存在这种现象，主要与病毒的入侵方式和靶细胞相关。详细解释可以看参考文献1、Iwasaki, A., & Yang, Y. (2020). The potential danger of suboptimal antibody responses in COVID-19.Nature reviews. Immunology,20(6), 339–341. https://doi.org/10.1038/s41577-020-0321-62、侯婉婷, 呼钰. 抗体依赖性感染增强作用与新型冠状病毒肺炎防治[J]. 国际免疫学杂志, 2020, 43(04):362-365.发布于 2021-03-17 16:19​赞同 16​​添加评论​分享​收藏​喜欢收起​​