Flu: TrailMap-One Health

世界与以往一样接近出现由H5N1流感病毒引起的流感大流行。这是一种致命的禽流感病毒，目前的菌株被称为进化枝2.3.4.4b，现在已经传播到五大洲，这在地理上是前所未有的。这种病毒杀死野鸟和家禽。这种病毒似乎还具有额外的环境适应性，因为它在冬季以外通常不会出现禽流感的地区熬过了夏季。更令人担忧的是，吃过死鸟尸体的野生哺乳动物也被感染了，往往会造成致命的后果。在英国，包括狐狸和水獭，在美洲，包括海狮和其他海洋哺乳动物。到目前为止，只有11人被报告感染，但这种病毒现在已经进入了养殖或驯养的动物，包括西班牙的养殖水貂、芬兰的养殖狐狸和波兰的猫。与野生食腐动物或海洋哺乳动物相比，人类与这些动物之间的接触要多得多、更频繁，因此，接触携带病毒的动物导致更多人类感染或“溢出”的可能性增加了。在人口层面上，我们也面临着这种禽流感变异并引发流行病甚至新的大流行的风险。以往所有流感大流行都起源于最初在野鸟中传播的病毒。大多数禽流感病毒，包括这一种，不能立即引起新的大流行，因为它们不适合在人的呼吸道中有效复制或通过空气传播，即使它们可以感染人类。上个世纪的大流行性流感病毒有时在感染猪等中间家畜哺乳动物并发生变异后传染给人类。在这样的时刻，各国政府面临着真正困难的决定，即为某一特定菌株的大流行准备投入多少时间和金钱。我们应该储备抗病毒药物和匹配的疫苗，并投资于个人防护装备，还是静观事态发展？在21世纪初，一种不同的H5N1毒株引起了公共卫生关注，但从未获得转化为大流行病毒的适应性突变。这个有什么不同吗？2005年，该病毒在外溢事件中导致约50%的感染者死亡。因为到目前为止，很少有人被目前的进化支23.3.4 b H5N1毒株感染，我们不知道这种病毒对人类有多危险，也不知道大流行会有多严重。为了回答这些问题，我们需要将新病毒与以前的毒株进行比较，评估中间动物宿主的易感性，并了解该病毒在分子水平上进一步适应人类的障碍。我们建议作为一个联合体，采取多管齐下的方法，深入评估目前的2.3.4.4b进化支H5N1禽流感病毒对人类的溢出感染和大流行的可能性。当代病毒将与21世纪初的病毒进行比较，并与1968年和2009年导致人类大流行的其他流感病毒进行比较。我们将使用最先进的方法来研究病毒/宿主分子相互作用，并定义这些相互作用如何随着2.3.4.4b进化枝病毒的不同分离株和不同宿主物种而变化。我们将考虑病毒与儿童和成人呼吸道的相互作用，以了解谁最有可能被病毒感染和传播，以及谁最有可能患病。我们将采用建模方法为监测提供信息，询问病毒最有可能在何处以及如何感染可作为中间宿主的哺乳动物。如果病毒确实跨物种传播，我们将开发系统，通过该系统可以评估抗病毒药物或疫苗等缓解措施。

The world is as close as ever to the emergence of an influenza pandemic caused by an H5N1 influenza virus. This is a deadly bird flu virus and the current strain, known as clade 2.3.4.4b, has now spread across 5 continents, a geographically unprecedented distribution. The virus kills wild birds as well as poultry. The virus also appears to have additional environmental resilience in that it has survived over the summer in regions where bird flu does not normally persist outside of winter. More worryingly, wild mammals that have scavenged dead bird carcasses have been infected, often with fatal consequence. In the UK this includes foxes and otters, in the Americas, sea lions and other marine mammals. So far, only 11 people have been reported infected, but the virus has now found its way into farmed or domesticated animals including farmed mink in Spain, farmed foxes in Finland and cats in Poland. There is much higher and more frequent contact between humans and these animals compared to the wild scavengers or marine mammals, so the likelihood of more human infections, or 'spillovers', from exposure to an animal carrying the virus has increased. At the population level, we are also at risk that this bird flu mutates and gives rise to an epidemic or even a new pandemic. All previous influenza pandemics have originated from viruses that originally circulated in wild birds. Most avian influenza viruses, including this one, cannot immediately cause a new pandemic because they are not adapted for efficient replication in the human airway or for transmission through the air, even if they can infect humans. The pandemic influenza viruses of the last century have sometimes reached humans after infecting and mutating in an intermediate domestic mammal such as pigs. At times like this governments are faced with truly difficult decisions about how much time and money to invest in pandemic preparation for a particular strain. Should we stockpile antivirals and matched vaccines and invest in PPE, or wait and see what develops? In the early 2000s a different strain of H5N1 caused public health concern but never acquired the adaptive mutations to transform into a pandemic virus. Is this one any different? The virus in 2005 killed around 50% of the people it infected during spillover events. Because so few people have been infected as of yet by the current clade 2.3.3.4b H5N1 strain we don't really know how dangerous this virus is for humans and how severe a pandemic would be. To answer these questions, we need to compare the new virus to previous strains, to assess the susceptibility of intermediate animal hosts, and to understand the barriers for this virus to acquire further adaptation to humans at the molecular level. We propose to work as a consortium and take a multipronged approach to risk assess in depth the current clade 2.3.4.4b H5N1 avian influenza viruses for human spillover infection and pandemic potential. The contemporary viruses will be compared with those of the early 2000s, and with other influenza viruses that did cause human pandemics in 1968 and 2009. We will use state of the art approaches to study virus/host molecular interactions, and define how these vary with different isolates of the clade 2.3.4.4b virus and between different host species. We will consider the interactions the virus makes with the human airway from children and adults, to understand who is most likely to be infected by and transmit the virus and who is most at risk of disease. We will incorporate modelling approaches to inform surveillance, asking where and how the virus is most likely to infect mammals that could serve as intermediate hosts. We will develop systems by which mitigations such as antiviral drugs or vaccines could be assessed, if the virus were indeed to jump species.