The G2P2 virology consortium: keeping pace with SARS-CoV-2 variants, providing evidence to vaccine policy, and building agility for the next pandemic

自从2019年中国从一次人畜共患病事件中崛起以来，SARS-CoV-2关注变种(VOC)通过突变和选择进化，阿尔法、德尔塔和奥美康在全球范围内依次占据主导地位，而其他地区主导的VOC如南非的贝塔和南美的伽马。VOCs独立于早期病毒(武汉)进化，而不是按顺序从一个病毒进化到另一个病毒，这可能意味着不同的优势路径，因为每个VOC都被一种更适合的VOC取代，以推动新的感染浪潮。这种进化模式可以通过免疫逃逸与人类宿主的适应性变化相结合来解释，从而在人类体内实现更有效的复制和传播。有效疫苗的部署大大降低了与COVID19相关的住院率、发病率和死亡率，但即使在接种疫苗/受感染的人群中，高感染率仍然存在，从而为病毒的进一步进化和新型VOCs的产生提供了机会。事实上，在SARS-CoV-2上观察到的结果与之前在其他季节性呼吸道感染中所做的工作是一致的，表明免疫反应可以减轻第二次感染的症状，但在抑制再次感染和抑制继续传播方面效果较差。Omicron VOC代表着第一次重大的抗原性转变，Spike的&gt；30突变使病毒对疫苗接种和/或先前感染诱导的抗体的中和敏感性显著降低。重要的是，为了逃避人类免疫而进行的Spike适应与增加体外和体内复制以及降低对人类和动物模型的致病性有关(尽管免疫记忆可能也是导致人类Omicron致病性降低的原因)。自从第一个Omicron分离物BA.1出现以来，又有更多的Omicron亚型进化，产生了一系列亚系，BA.1-5，现在的BQ.1.1和XBB，它们共同循环和重组，从而获得更多的适应性突变。这些突变增强了复制、传播和逃避宿主适应性免疫和先天免疫的能力。总而言之，SARS-CoV-2在向地方性转变过程中不断发生的序列多样化和进化，加上个人和人群水平上适应性免疫的不可避免地减弱，提出了未来VOCs的致病性和传播性可能增加的非常真实的可能性，从而增加了疾病负担，并加剧了全球卫生系统的压力。事实上，截至2023年1月，有超过11,000人因COVID19而住院。在为新的VOC的出现做准备的过程中，我们的联盟将通力合作：1)在新的变种出现时，对它们进行快速风险评估，以增加传播和致病作用；2)定义和机械地剖析VOC携带的、支持表型变化的病毒序列特征/模式。这些数据将有助于在出现令人担忧的突变星座时提供早期预警，并为针对新的VOCs的科学和公共卫生对策提供信息，为旨在加强疫苗接种计划和/或改进疫苗本身的政策提供科学证据。

Since arising in China from a single zoonotic event in 2019, SARS-CoV-2 variants of concern (VOCs) have evolved through mutation and selection with Alpha, Delta, and Omicron becoming sequentially dominant worldwide, contrasting with other VOCs that have been regionally dominant e.g., Beta in South Africa and Gamma in South America. VOCs have evolved independently from the early virus (Wuhan), rather than sequentially from one to another, potentially implying differing pathways to dominance as each VOC has been replaced by a "fitter" VOC to drive new waves of infection. This pattern of evolution can be explained by immune escape combining with adaptive changes to the human host to confer more efficient replication and transmission in humans. The deployment of effective vaccines has significantly reduced COVID19 associated hospitalisation, morbidity and mortality, yet high infection rates persist even in vaccinated/infected populations thus providing the opportunity for further viral evolution and the genesis of novel VOCs. Indeed, what is being observed with SARS-CoV-2 is consistent with previous work in other seasonal respiratory infections, showing that immune responses reduce symptoms from a second infection but are less effective at suppressing re-infection and inhibiting onward transmission.The Omicron VOC represents the first substantial antigenic shift, with >30 mutations in Spike rendering the virus markedly less sensitive to neutralisation by antibodies induced by vaccination and/or prior infection. Importantly, Spike adaptation to escape human immunity was linked to increased replication in vitro and in vivo, and reduced pathogenicity in humans as well as animal models (though immune memory also presumably contributes to reduced Omicron pathogenicity in humans). Since the emergence of the first Omicron isolate, BA.1, further Omicron subvariants have evolved, yielding a series of sub-lineages, BA.1-5, and now BQ.1.1 and XBB, that co-circulate and recombine thus acquiring additional adaptive mutations. These mutations have enhanced replication, transmission and escape from the host adaptive and innate immunity. In sum, the ongoing sequence diversification and evolution of SARS-CoV-2 as it transitions to endemicity, together with the inevitable waning of adaptive immunity at the level of individuals and populations, raise the very real possibility that the pathogenicity and transmissibility of future VOCs may increase, thus increasing disease burden and intensifying the pressures on health systems globally. Indeed, as of Jan 2023, there were over 11,000 hospitalisations due to COVID19. In preparing for the emergence of a new VOC, our consortium will work collaboratively to: 1) rapidly risk-assess new variants as they arise for increased transmission and pathogenesis; and 2) define and mechanistically dissect the viral sequence signatures/ patterns that are carried by VOCs and that underpin phenotypic changes. These data will help provide early warning as constellations of mutations of concern arise, and inform the scientific and public health responses to novel VOCs, providing scientific evidence to policy aimed to for example intensify vaccination programmes and/or refine the vaccines themselves.