Transmission of SARS-CoV-2：High Infectivity and High Covertness

   华中科技大学同济医学院公共卫生学院团队《自然》论文“Reconstruction of the full transmission dynamics of COVID-19 in Wuhan” 揭示了新冠病毒具有两大特征：高传染性和高隐蔽性。在早期未采取干预措施的情况下，新型冠状病毒(2019-nCoV或SARS-CoV-2)的再生系数R高达3.54，传染力远高于SARS-CoV和MERS-CoV等已知的冠状病毒。2021年8月23号，波士顿大学公共卫生学院发表在JAMA Internal Medicine的研究表明，新冠患者在出现症状前2天至第3天之间传染性最强，突出了其高隐蔽性。

新冠病毒传播动力学

潜伏期（Incubation period，从感染到发病的时间）、代际间隔（Generation time，原发病例和继发病例间的感染间隔）、系列间隔（Serial interval，原发病例和继发病例的发病间隔）等关键传播参数。

新冠病毒代际间隔和序列间隔超短，中位数代际间隔只有不到3天，基本上属于所有传染病里面最快的一档；基本再生数R0高达6-9之间。流感病毒（以H3N2计）R0还不到2，中位数代际间隔3天半；而作为对比，德尔塔子代AY.4.2的R0接近10，中位数代际间隔3天。Delta平均代际间隔 2.9天，潜伏期4.4天。Omicron的代际间隔还要更短（剑桥Selby老师基于英格兰数据的测算Omicron代际间隔为2.2天）。我国2022年1月杭州疫情中，Omicron的最短代际间隔为39.1小时~41.6小时。

 为什么新冠病毒的传染性这么强？

1. 传播方式多样：呼吸道飞沫传播为主

Possible modes of transmission for SARS-CoV-2, including contact, droplet, airborne, fomite, fecal-oral, bloodborne, mother-to-child, and animal-to-human transmission. 新冠病毒的可能传播方式，包括接触、飞沫、空气传播、污染物、粪口传播、血源性传播、母婴传播和动物对人传播。（详见WHO简报： https://www.who.int/news-room/commentaries/detail/transmission-of-sars-cov-2-implications-for-infection-prevention-precautions ）

人感染 SARS-CoV-2的主要方式是通过接触携带传染性病毒的呼吸道飞沫： (1) 吸入微小的呼吸道飞沫和气溶胶颗粒；(2) 通过直接飞溅和喷雾，呼吸道飞沫和颗粒沉积在口、鼻或眼睛的暴露粘膜上；(3 ) 直接被含有病毒的呼吸道液体污染或间接接触带有病毒的表面污染的手接触粘膜。人们有可能通过接触SARS-CoV-2污染的表面或物体（污染物）而被感染，但通常认为风险较低。因此，保持社交距离、使用口罩（防护面罩、手术/外科口罩）、充足的通风以及避免拥挤的室内空间、保持良好的手部卫生和环境清洁；这些方法将减少病毒吸入和病毒在暴露的粘膜上沉积造成的传播，防止通过污染的手和物体表面造成的间接传播。

SARS-CoV-2宿主广泛：目前的证据表明，感染 SARS-CoV-2 的人类可以感染其他哺乳动物，包括狗、猫和养殖的水貂等。动物传人……

2. 建立感染所需的病毒剂量低

《Nature Medicine》论文“Safety, tolerability and viral kinetics during SARS-CoV-2 human challenge” 公布了全球首个新冠人体挑战试验的结果：36名无新冠感染史、未接种疫苗的18-29岁自愿受试者纳入试验。受试者均通过鼻腔滴液的方式吸入了10倍TCID50（半数组织培养感染剂量）（equivalent to 55 FFU, focus-forming units per milliliter）的野生型新冠毒株（带D614G突变），其中18名受试者随后确诊为阳性。(10 TCID50 是一个非常低的剂量; In human challenge studies with other respiratory viruses, such as influenza viruses and respiratory syncytial virus, inoculum doses are typically also much higher at 104–106 TCID50 because all volunteers have been exposed multiple times throughout life to those viruses, with pre-existing immunity reducing susceptibility and resulting in substantially lower peak viral loads at 103–104 copies per milliliter by PCR.) 在接种后40小时，受试者咽拭子就能够检测出核酸阳性，即存在排毒风险；而鼻拭子在58小时后才能检测出，而且咽部的病灶形成也早于鼻部。在5-6天后受试者病毒载量达到最高，此时鼻部病毒载量更高，约为109拷贝。89% 感染了病毒的人出现症状，所有感染者的症状均为轻度到中度，但病毒载量与症状严重程度之间没有定量相关性，即使在无症状感染者中病毒载量也很高。在14天后受试者仍能检出核酸，到出院时也有80%受试者检出低水平阳性，28天后仍有少部分患者检出阳性，直至90天后完全转阴。但是活病毒持续的时间相对较短，在10天左右活病毒基本被机体清除，而核酸检出一直持续到14天以后。

2. 高隐蔽性：潜伏期（Incubation Periods）具有传染性

The period after infection but before the signs of disease are apparent is called the incubation period.

Virus     Incubation period (days)

Influenza virus: 1–2

Rhinovirus: 1–3

Ebola virus: 2–21

Herpes simplex: 5–8

SARS-CoV-2: 5–7

Infectious period defines the time during which an individual is shedding virus that can be transmitted to others. Often, but not always, this coincides with signs of sickness. In some cases, such as ebolavirus, virus is not shed until symptoms appear. In others, such as varicella-zoster virus and measles virus, the host may be infectious for some period (days, even a week or more) before symptoms are evident.

SARS-CoV-2感染者出现症状前就具备传染性，且无症状者可作为传染源。

Furthermore, asymptomatic individuals and people with mild symptoms may carry large amounts of virus in the upper respiratory tract, thus contributing to the rapid spread of SARS-CoV-2.

3. 病毒复制速度快（病毒滴度/载量高）, 感染者的排毒量大

奥密克戎变异株在人支气管中的复制速度比德尔塔变异株快70倍，而在人肺组织中的复制速度比德尔塔变异株慢10倍。研究发现奥密克戎变异株没有增加人群初发感染的风险，甚至降低人群的初发感染风险；但其增加了重复感染的风险。奥密克戎变异株还拥有强大的免疫逃逸能力。奥密克戎变异株更倾向于感染人的上呼吸道，感染病例以轻型和无症状为主（轻型和无症状约占91.9%，其中轻型占82.2%）。

  感染者的排毒量…   

4. 病毒在环境中的稳定性强（环境因素）

SARS-CoV-2在气溶胶中的稳定性…

在多孔表面上，不同的研究表明在几分钟到几小时内无法检测出活病毒;而在无孔表面上，可以在数天到数周内检测到活病毒。与非多孔表面相比，多孔表面上的 SARS-CoV-2相对更快的灭活可能归因于孔隙内的毛细作用和更快的气溶胶液滴蒸发。来自表面存活研究的数据表明，在典型的室内环境条件下，在不锈钢、塑料和玻璃等常见无孔表面上，预计在 3 天（72 小时）内，传染性 SARS-CoV-2 和其他冠状病毒减少 99% 。然而，多孔和无孔表面的实验条件不一定反映真实世界的条件，例如初始病毒量（例如，呼吸道飞沫中的病毒载量）、通风和不断变化的环境条件等（https://www.cdc.gov/coronavirus/2019-ncov/more/science-and-research/surface-transmission.html ）。

来自日本京都府立医科大学的一项最新研究表明，新冠病毒的变异毒株比大流行早期的原始毒株在塑料和皮肤表面存活的时间要长得多。在对塑料表面进行了一系列实验室测试后，研究人员发现，新冠病毒原始毒株和阿尔法、贝塔、伽玛和德尔塔变异毒株的存活时间分别为56小时、191.3小时、156.6小时、59.3小时和114小时。对于奥密克戎变种而言，它可以在塑料表面存活193.5小时，相当于8天；是原始株的4倍。

5. 病毒刺突蛋白与受体亲和力高，组织嗜性广，变异快

Science杂志上一篇题为“Cryo-EM Structure of the 2019-nCoV Spike in the Prefusion Conformation”的研究论文中，来自美国德克萨斯大学和国家过敏和传染病研究所的研究人员通过联合研究利用冷冻电镜技术解析了新型冠状病毒刺突蛋白（Spike, S）的结构，深入研究后，研究者发现，新冠病毒S蛋白与宿主细胞ACE2之间的亲和力是SARS-CoV-1的10-20倍。Variants bearing D164G and N501Y mutation infect human ACE2 cell lines more efficiently than wild-type virus. Moreover, progeny virus has increased expression of S protein, the S protein has a higher rate of binding to ACE2, and that in vivo viral loads may be higher for this variant. 奥密克戎变异株RBD与人类ACE2受体的结合亲和力，大约比最早的贝塔属原始株高2.4倍。

病毒组织嗜性较广…

变异快… (逃逸中和能力强) 

6. 人群普遍易感（宿主因素）

新冠病毒有多种机制可以抑制或逃逸宿主的固有免疫应答，特别是干扰素应答。宿主针对新冠病毒的中和抗体保护衰减快，重复感染频繁。疫苗接种或自然感染后，尽管存在免疫记忆，但是仍然会再次感染（防重症，防不住感染？）。 

      SARS-CoV-2 has an enhanced rate of transmission compared to the 2002 SARS-CoV. This is due to several characteristics, both of the virus (i.e., SARS-CoV-2) and its associated disease (i.e., COVID-19). For instance, active virus can remain viable on some surfaces for up to 9 days and in the indoor air for several hours, thus increasing the chances of exposure [37]（稳定性强）. Likewise, differences in the severity and onset of symptoms of COVID-19 compared to SARS may lead to increased contact with infected individuals. For example, during the SARS-CoV epidemic of 2002, mortality rates were nearly twice that currently observed for COVID-19 pandemic (9.6% vs. 5.4%, respectively) [10], [12], and infected individuals exhibited clear symptoms of respiratory distress almost immediately [38], [39], [40]. In contrast, people infected with SARS-CoV-2 may not show signs of infection or illness for a week or longer, despite being contagious and shedding virus [41]（隐蔽性强，出现症状前就具备传染性，且无症状者亦可作为传染源）. Furthermore, asymptomatic individuals and people with mild symptoms may carry large amounts of virus in the upper respiratory tract, thus contributing to the rapid spread of SARS-CoV-2. In fact, in some situations, even after symptoms disappear, SARS-CoV-2-infected individuals may be shedding virus. In addition, re-infection may occur in specific cases, especially given that human coronaviruses are well equipped to subvert host immunity（免疫逃逸强，易变异，再感染普遍）. For instance, the emergence of new variants of the virus that are more contagious and may carry an increased risk of death, such as the South African variant (B.1.351), the UK variant (B.1.1.7), the Indian variant (B.1.617.2, also commonly known as the delta variant), or the Brazil/Japan variant (P.1), suggest that SARS-CoV-2 is rapidly evolving mechanisms to increase contagiousness and subvert existing immune defenses [42], [43].

   参考文献：Meyerowitz EA, Richterman A, Gandhi RT, Sax PE. Transmission of SARS-CoV-2: A Review of Viral, Host, and Environmental Factors. Ann Intern Med. 2021 Jan; 174(1):69-79. doi: 10.7326/M20-5008. Epub 2020 Sep 17. 

SARS-CoV-1 (2002-2003年“非典”病原体)

Host cell receptor can determine whether inter species transmission of an emerging virus can occur or not, but many other cellular factors as the innate immune response, and metabolic characteristics of the host cell that may abort or facilitate the viral spread may have a role [42].

    Contact with respiratory secretions was a significant risk factor for SARS transmission [43]. Exposure to body fluids of healthcare workers’ eyes and mucous membranes was noticed to increase the risk of transmission [44]. Contaminated faeces proved to be important in at least one major community outbreak, Amoy Gardens in Hong Kong, in which over 300 patients were infected within the period of a few days [45].

The physical stability of SARS-CoV allowed transmission of SARS-CoV by indirect contact with contaminated environment. SARS-CoV can survive in the environment for 72– 20 hours [46, 47] and the infectivity is remained for up to 6 days on a dried surface [48] while the respiratory specimens can be infectious for over 7 days at room temperature and SARS –CoV can survive for 4 days in diarrheal stool samples with an alkaline pH [49]. Both the proximity and duration of contact with SARS patients may be associated with a higher risk of viral transmission [50, 51].