Abstract The control of re-occurring pandemic pathogens requires understanding the origins of new pandemic variants and the factors that drive their global spread. This is especially important for GII.4 norovirus, where vaccines under development offer promise to prevent hundreds of millions of annual gastroenteritis cases. Previous studies have hypothesized that new GII.4 pandemic viruses arise when previously circulating pandemic or pre-pandemic variants undergo substitutions in antigenic regions that enable evasion of host population immunity, as described by conventional models of antigenic drift. In contrast, we show here that the acquisition of new genetic and antigenic characteristics cannot be the proximal driver of new pandemics. Pandemic GII.4 viruses diversify and spread over wide geographical areas over several years prior to simultaneous pandemic emergence of multiple lineages, indicating that the necessary sequence changes must have occurred before diversification, years prior to pandemic emergence. We confirm this result through serological assays of reconstructed ancestral virus capsids, demonstrating that by 2003, the ancestral 2012 pandemic strain had already acquired the antigenic characteristics that allowed it to evade prevailing population immunity against the previous 2009 pandemic variant. These results provide strong evidence that viral genetic changes are necessary but not sufficient for GII.4 pandemic spread. Instead, we suggest that it is changes in host population immunity that enable pandemic spread of an antigenically preadapted GII.4 variant. These results indicate that predicting future GII.4 pandemic variants will require surveillance of currently unsampled reservoir populations. Furthermore, a broadly acting GII.4 vaccine will be critical to prevent future pandemics.

中文翻译：

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大流行 GII.4 诺如病毒在出现前几年在未取样的病毒库中的预适应

摘要 控制再次发生的大流行病原体需要了解新的大流行变种的起源以及推动其全球传播的因素。这对于 GII.4 诺如病毒尤为重要，正在开发的疫苗有望预防每年数亿例胃肠炎病例。先前的研究假设，当先前流行的大流行或大流行前的变体在能够逃避宿主群体免疫的抗原区域进行替换时，会出现新的 GII.4 大流行病毒，如抗原漂移的常规模型所述。相比之下，我们在这里表明，获得新的遗传和抗原特征不能成为新流行病的近端驱动因素。大流行 GII。4 种病毒在多个谱系同时出现大流行之前的几年内多样化并在广泛的地理区域传播，这表明必要的序列变化必须在多样化之前发生，在大流行出现之前的几年。我们通过对重建的祖先病毒衣壳的血清学检测证实了这一结果，证明到 2003 年，祖先的 2012 年大流行毒株已经获得了使其能够逃避针对先前 2009 年大流行变体的普遍人群免疫的抗原特征。这些结果提供了强有力的证据，证明病毒基因改变对于 GII.4 大流行的传播是必要的，但还不够。相反，我们认为宿主群体免疫的变化使抗原预适应的 GII.4 变体能够大范围传播。这些结果表明，预测未来的 GII.4 大流行变体将需要监测当前未采样的水库种群。此外，具有广泛作用的 GII.4 疫苗对于预防未来的大流行至关重要。