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

自2019年在中国由单一人畜共患病事件产生以来，SARS-CoV-2关注变体（VOCs）通过突变和选择进化，α、δ和欧米克隆在全球范围内依次占据主导地位，与南非的Beta和南美的Gamma等区域性主导VOCs形成对比。挥发性有机化合物是独立于早期病毒（武汉）进化而来的，而不是依次从一种挥发性有机化合物进化到另一种，这可能意味着不同的主导途径，因为每种挥发性有机化合物都被一种“更适合”的挥发性有机化合物取代，从而引发新的感染浪潮。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，从而使人类更有效地复制和传播。有效疫苗的部署大大降低了与covid - 19相关的住院率、发病率和死亡率，但即使在接种疫苗/感染人群中，高感染率仍然存在，从而为病毒的进一步进化和新型挥发性有机化合物的产生提供了机会。事实上，在SARS-CoV-2中观察到的情况与之前在其他季节性呼吸道感染中的研究一致，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进一步传播方面效果较差。Omicron VOC代表了第一个实质性的抗原转移，Spike的bbbb30突变使病毒对疫苗接种和/或先前感染诱导的抗体的中和明显不敏感。重要的是，逃避人类免疫的刺突适应与体外和体内复制的增加有关，并降低了人类和动物模型的致病性（尽管免疫记忆也可能有助于降低人类的组粒致病性）。自第一个Omicron分离物BA.1出现以来，进一步的Omicron亚变体已经进化，产生了一系列的亚谱系，BA.1-5，以及现在的BQ.1.1和XBB，它们共同循环和重组，从而获得额外的适应性突变。这些突变增强了宿主适应性免疫和先天免疫的复制、传播和逃逸。总之，SARS-CoV-2在向地方性转变过程中持续的序列多样化和进化，以及个体和人群层面不可避免的适应性免疫减弱，提高了未来voc的致病性和传播性可能增加的真实可能性，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，因covid - 19住院的人数超过1.1万人。在为新挥发性有机化合物的出现做准备时，我们的联盟将共同努力：1)快速评估新变异的风险，因为它们会增加传播和发病机制；2)定义和机械剖析由VOCs携带并支持表型变化的病毒序列特征/模式。这些数据将有助于在引起关注的一系列突变出现时提供早期预警，并为针对新型挥发性有机化合物的科学和公共卫生对策提供信息，为旨在加强疫苗接种规划和/或改进疫苗本身等政策提供科学证据。

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rather than sequentially from one to another, potentially implying differing pathways to dominance as each VOC has been replaced by a "fitter" VOC to drive new waves of infection.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.