近日，法国巴斯德所两位病毒学大咖在《自然微生物综述》中提出了——新冠病毒的血清分型。

  https://www.nature.com/articles/s41579-022-00708-x

       奥密克戎变种表现出了和之前各种变异株明显不同的病理学、结构学和抗原特征，因此Simon-Loriere, E.和 Schwartz, O.建议将原始株和既往VOC归为血清型1，同时考虑将奥密克戎家族三大成员归为血清型2，血清分型有助于更有针对性地开展诊断、治疗和防疫。

  Omicron displays pathological, genetic, structural and antigenic features that clearly distinguish it from prior SARS-CoV-2 variants. Grouping the ancestral virus and variants as members of the original serotype 1 while considering Omicron BA.1, and probably BA.2 and BA.3, as a distinct serotype 2 should facilitate surveying the evolution of the SARS-CoV-2 pandemic and tailoring of diagnostic, treatment and prevention tools.  

   SARS-CoV-2 的血清分型将助于更好地解决 COVID-19 的诊断、治疗和疫苗接种等问题。例如， 一些快速抗原测试对 Omicron 的敏感性较低，可能是因为选择了用于检测的抗体血清型敏感性不同造成； 基于刺突的血清学检测试剂盒使用的是原始新冠病毒的抗原，对于 Omicron 变种诱导的抗体可能不太准确。 PCR 诊断试剂盒（核酸检测）也需要不断调整引物探针序列，以覆盖并识别新的新冠血清型，并可以作为基因测序的快速补充。 单克隆抗体治疗受到了 Omicron 变异的巨大影响，突出了对广谱抗冠状病毒活性的分子的需求。 疫苗制造商正在测试更新升级的疫苗，以增加引发抗体的广度，以覆盖不同的血清型，提供广泛的保护。

   Classifying SARS-CoV-2 into serotypes may help to better understand differences or solve issues observed in the diagnosis, treatment and vaccination of COVID-19. Some rapid antigenic tests are less sensitive against Omicron, probably because of the choice of the antibodies used for detection. Spike-based serology tests use antigens derived from the ancestral sequence and may also be less accurate for Omicron-elicited antibodies. PCR tests need to be continuously adapted to cover and possibly identify variants or serotypes, as a fast complement to genomic surveillance that can be leveraged for patient care. Treatments with monoclonal antibodies have been strongly affected by Omicron, highlighting the need for molecules with broad anti-coronavirus activity. Vaccine manufacturers are testing updated vaccines to enhance the breadth of the elicited antibodies, although this strategy remains under debate.

参考文献：

 Simon-Loriere, E., Schwartz, O.  Towards SARS-CoV-2 serotypes?. Nat Rev Microbiol (2022). https://doi.org/10.1038/s41579-022-00708-x  

口蹄疫病毒有7种血清型（它们之间无交叉保护反应），登革病毒有4个血清型（有一定的交叉反应），脊髓灰质炎病毒有3个血清型，麻疹病毒只有1个血清型，那么新冠病毒将来会有几种血清型呢？

   血清型的划分标准

  Serotype名词解释：   An isolate or group of isolates that are distinguished from biologically related isolates by reaction (or lack of reaction) with key serological reagents such as defined polyclonal antisera or monoclonal antibodies. 

   血清型的定义：A serotype is defined as either exhibiting no cross-reaction with others or showing a homologous/heterologous titer ratio of greater than 16 (in both directions). 

Coronavirus冠状病毒的血清分型 ：

    In some species, the Spike（S，刺突蛋白） protein is cleaved into two subunits, the N-terminal S1 fragment being slightly smaller than the C-terminal S2 sequence. The S protein is anchored in the envelope by a transmembrane region near the C-terminus of S2. The functional S protein is highly glycosylated and exists as a trimer. The bulbous outer part of the mature S protein is formed largely by S1 while the stalk is formed largely by S2, having a coiled-coil structure.  S1 is the most variable part of the S protein; some serotypes of the avian coronavirus, infectious bronchitis virus (IBV) differ from one another by 40% of S1 amino acids. S1 is the major inducer of protective immune responses. Variation in the S1 protein enables one strain of virus to avoid immunity induced by another strain of the same species.  Conventional diagnostic methods to differentiate IBV serotypes include virus isolation in specific pathogen–free (SPF) embryonated eggs followed by virus neutralization (VN) tests, hemagglutination inhibition (HI) tests, or antigen-capture enzyme-linked immunosorbent assay (ELISA) using monoclonal antibodies. However, genetic-based tests to identify IBV types have become the test of choice since the discovery that sequences in the S1 gene are correlated with different serotypes of IBV. Reverse transcription polymerase chain reaction (RT-PCR), targeting the S1 portion of the spike protein, followed by sequencing of the RT-PCR product, restriction enzyme fragment length polymorphism (RFLP), or hybridization with IBV-specific probes have been developed for differentiating serotypes and variants of the virus.

      Information on the complexity of CoV serotypes is crucial for predictions on whether antibodies against a previous CoV infection or a specific vaccine may protect from reinfection, which has important implications for vaccine design and neutralizing antibody therapy. Antigenic variability in the S protein, the major target of neutralizing antibodies, is extremely low between different MERS-CoV strains (Drosten et al., 2015). A recent serological study using infectious MERS-CoV isolates collected from patients in Saudi Arabia in 2014 showed no significant differences in serum neutralization, indicating that all these isolates belong to the same serotype (Muth et al., 2015). Based on these data, it seems likely that the S genes of all currently circulating MERS-CoVs are interchangeable in candidate vaccine formulations. The potential relevance of neutralizing antibodies directed against other envelope proteins remains to be studied. （by L. Enjuanes, S. Zuñiga, C. Castaño-Rodriguez, J. Gutierrez-Alvarez, J. Canton, I. Sola）

      Amongst group 2 coronaviruses sequence variation is also greater in S1 than S2, a C-terminal region of S1 being hypervariable. Indeed, this region is deleted in variants of MHV. Avian infectious bronchitis virus (IBV), a chicken Gammacoronavirus, is a major poultry pathogen, and is probably endemic in all regions with intensive poultry production. Since IBV was fi rst described in 1936, many serotypes and variants of IBV have been isolated worldwide. Most IBV serotypes differ from each other by 20 to 25% of S1 amino acids. However, some serotypes differ by 50% of S1 amino acids. The differences between the S1 proteins undoubtedly have a selective advantage; generally speaking, the immunity induced by inoculation with one serotype protects poorly against infection with heterologous serotypes. Differences of as few as 2 to 3% of S1 amino acid residues can result in a change in serotype, defined as lack of cross-neutralization using convalescent sera. These few differences may contribute to diminished cross-protection in challenge experiments in chickens. Crossprotection between them often being poor. Consequently IBV vaccines have been developed with several serotypes (by Dave Cavanagh).

     Recombination of coronaviruses appears to be a process of significant importance in the wild. Its occurrence has been shown to contribute to the natural evolution of IBV. This highly contagious virus comprises many different serotypes, and new ones emerge regularly, with the result that these viruses escape from host immunity and cause new outbreaks. Although many of the new variants arise by genetic drift as a result of subtle mutations in the spike protein (S) gene, similar to the changes that lead to antigenic drift in influenza viruses, new serotypes apparently also originate from genetic exchange of S gene sequences between different viruses through homologous RNA recombination (Kusters et al. 1990; Cavanagh et al. 1990; Wang et al. 1993; Jia et al. 1995).

     Feline coronavirus (FCoV) is composed of nucleocapsid (N) proteins, membrane (M) proteins, and spike (S) proteins. FCoV has been classified into serotypes I and II according to the amino acid sequence of its S protein and antibody neutralization. Both serotypes consist of two biotypes: feline infectious peritonitis virus (FIPV) and feline enteric coronavirus (FECV). FECV infection is asymptomatic in cats, whereas FIPV infection causes lethal disease: FIP (by Tomomi Takano and Tsutomu Hohdatsu). Efforts to make effective vaccines against infectious peritonitis caused by FCoV have been ongoing for many years. A phenomenon that has militated against their widespread application has been that of antibody dependent enhancement (ADE) of disease. That is, antibodies induced by a first infection or vaccination may enhance the disease caused by a subsequent infection. Infection of cats by FCoV usually results in an infection confined largely to the digestive tract. In some cases the virus disseminates to other organs, leading to fatal infectious peritonitis. This dissemination is facilitated by macrophages. It is believed that uptake of FCoV by macrophages is enhanced when the virus has immunoglobulins, induced by a prior infection or vaccination, on its surface; the Fc moiety of the immunoglobulin attaches the virus-antibody complex to the surface of the macrophage (by Dave Cavanagh). 

 RBD is the most variable part of the coronavirus genome!

https://elifesciences.org/articles/51230 

进化病毒学大佬Bloom认为这篇Elife的论文被低估了。

  Sequence analysis has shown that the three receptor binding loops of HCoV-229E are the most variable region in the entire viral genome. Indeed, loop variation has led to the emergence of six RBD classes whose viruses have successively replaced each other in the human population over the past 50 years (Wong et al., 2017). 

参考文献：

Li, Zhijie et al. “The human coronavirus HCoV-229E S-protein structure and receptor binding.” eLife vol. 8 e51230. 25 Oct. 2019, doi:10.7554/eLife.51230