LAUSR

It is perhaps a strange coincidence that in this issue of Mucosal Immunology a review entitled “Seasonal and pandemic influenza: 100 years of progress, still much to learn” is being published, while at the same time another global pandemic, this time caused by a novel coronavirus infection SARS-CoV-2, also known as Covid-19, spreads around the globe. Dunning et al. provide a comprehensive overview of current knowledge regarding seasonal influenza, with a detailed description on how the immunology of influenza has shaped the current standard of therapy and prevention. This review was written in the period before the world was confronted with the SARS-CoV-2 outbreak, which for many might feel a long time ago, though in reality is only 2–3 months in the past. We now live in a very different world where a novel virus has redefined how we experience essential elements of modern life ranging from work and education to travel and recreation. This has all arisen because of a rapidly spreading virus causing major morbidity and mortality, primarily due to severe pneumonia and development of acute respiratory distress syndrome (ARDS). Observed through the contemporary lens of covid-19, this review becomes an even more interesting and important piece of work, integrating knowledge accumulated over 100 years of research in epidemiology, global and public health, as well as evolutionary biology and immunology. These constitute the scientific rationale behind our effective current program of preventive and treatment strategies against (seasonal) influenza. It also forms a template for the knowledge, we must rapidly acquire to have similar success in controlling the novel SARS-CoV2 outbreak. The first lesson that can be distilled from this review is how difficult it still is to fully prevent seasonal influenza. With the current SARS-CoV-2 pandemic, the clock has just started to tick, and this review highlights that we need to rapidly learn about this new virus, simultaneously using our experience with previous outbreaks including influenza. The higher R0 (reproduction number) and fatality associated with this virus however emphasize the need to learn quickly. The current review starts by describing the devastating effect of the influenza pandemic that raged the globe 100 years ago, with an estimated 675,000 people dying in the USA alone. The authors highlight how the Spanish flu pandemic caused the death of a famous artist Egon Schiele and his family. Covid-19 is already exerting a similar toll. In an era of interdisciplinary endeavor, the author, cartographer and visual artist Tim Robinson has been among the early casualties of Covid-19, dying in London a few days after the death of his wife. It is worth reflecting how ironic it is that an artist defined by his connection with empty landscapes should fall victim to a pandemic for which one of our main control measures is social distancing. The review then addresses some of the key features of influenza pathogenesis. It provides a state-of-the-art resume of innate and adaptive immune responses but also highlights that important knowledge gaps remain. After 100 years of research important insights have helped us to understand how viruses evolve within the human and animal populations at geographical scale, under the selective pressure of immune responses and how differences in immune responses alter severity of disease. This knowledge has helped us to develop antiviral therapies and vaccination strategies. Yet we still face challenges identifying those patients who develop critical illness and bacterial super-infection as the authors high-light. There can also be surprises though: the author’s own data shows that patients with asthma were less likely to present with severe pulmonary or systemic disease when exposed to H1N1pdm09. When faced with a brand new virus like SARS-CoV-2 rapidly emerging in the human population, we have a much more limited knowledge base to work with, leaving us at a significant disadvantage. We rapidly must understand the origin, genetic variation and epidemiological characteristics of the new virus. This includes knowledge on mode of transmission, incubation period, window of transmission, and reproductive number, to ensure an effective public health response and to put in place appropriate infection control measures. As a consequence, most nations, supported by organizations like WHO and GOARN, have emergency response plans in place that can deal with emerging major outbreaks, including pandemic influenza and other emerging respiratory viruses (https://extranet.who.int/goarn/). In contrast to the array of data succinctly summarized by the authors on influenza, we lack comparable understanding for Covid-19. However, what we already have learned is the importance of the human angiotensin-converting enzyme 2 (hACE2) as the entry receptor for SARS-CoV-2. Based on genetic information researchers have identified that the biochemical and structural properties of SARS-CoV-2 receptor binding domain (RBD) show an even higher hACE2-binding affinity compared to SARS-CoV, which might help to explain the higher transmission rates and infectivity. The paucity of post-mortem data and the infectivity of invasive procedures such as bronchoscopies are two barriers to acquiring information, but despite many hurdles, information is rapidly accumulating. We still know little about immunity in mild disease, including correlates of effective immunity such as neutralizing antibody, though preliminary data show that antibody responses kick in early in the disease process,