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A century ago, nonpharmaceutical interventions such as school closings, restrictions on large gatherings, and isolation and quarantine were the centerpiece of the response to the Spanish Flu. Yet, even though its cause was unknown and the science of vaccine development was in its infancy, considerable enthusiasm also existed for using vaccines to prevent its spread. This desire far exceeded the scientific knowledge and technological capabilities of the time. Beginning in the early 1930s, however, advances in virology and influenza vaccine development reshaped the relative priority given to biomedical approaches in epidemic response over traditional public health activities. Today, the large-scale implementation of nonpharmaceutical interventions akin to the response to the Spanish Flu would face enormous legal, ethical, and political challenges, but the enthusiasm for vaccines and other biomedical interventions that was emerging in 1918 has flourished. The Spanish Flu functioned as an inflection point in the history of epidemic responses, a critical moment in the long transition from approaches dominated by traditional public health activities to those in which biomedical interventions are viewed as the most potent and promising tools in the epidemic response arsenal.

This year marks the 100th anniversary of the deadliest event in human history. In 1918-1919, pandemic influenza appeared nearly simultaneously around the globe and caused extraordinary mortality (an estimated 50-100 million deaths) associated with unexpected clinical and epidemiological features. The descendants of the 1918 virus remain today; as endemic influenza viruses, they cause significant mortality each year. Although the ability to predict influenza pandemics remains no better than it was a century ago, numerous scientific advances provide an important head start in limiting severe disease and death from both current and future influenza viruses: identification and substantial characterization of the natural history and pathogenesis of the 1918 causative virus itself, as well as hundreds of its viral descendants; development of moderately effective vaccines; improved diagnosis and treatment of influenza-associated pneumonia; and effective prevention and control measures. Remaining challenges include development of vaccines eliciting significantly broader protection (against antigenically different influenza viruses) that can prevent or significantly downregulate viral replication; more complete characterization of natural history and pathogenesis emphasizing the protective role of mucosal immunity; and biomarkers of impending influenza-associated pneumonia.

Four influenza pandemics, starting with the historic 1918 pandemic, have killed thousands of people around the world. Vaccination, still the most important means of preventing influenza, is currently recommended yearly for all people age 6 months and older, with a goal of vaccinating 80% of all Americans and 90% of at-risk populations. Neuraminidase inhibitors are underused, and a new drug with a different mechanism of action, baloxavir marboxil, is expected to be approved soon in the United States., (Copyright © 2018 Cleveland Clinic.)

The 1918 influenza pandemic spread rapidly around the globe, leading to high mortality and social disruption. The countermeasures available to mitigate the pandemic were limited and relied on nonpharmaceutical interventions. Over the past 100 years, improvements in medical care, influenza vaccines, antiviral medications, community mitigation efforts, diagnosis, and communications have improved pandemic response. A number of gaps remain, including vaccines that are more rapidly manufactured, antiviral drugs that are more effective and available, and better respiratory protective devices.

Vaccination against influenza represents our most effective form of prevention. Historical approaches toward vaccine creation and production have yielded highly effective vaccines that are safe and immunogenic. Despite their effectiveness, these historical approaches do not allow for the incorporation of changes into the vaccine in a timely manner. In 2013, a recombinant protein-based vaccine that induces immunity toward the influenza virus hemagglutinin was approved for use in the USA. This vaccine represents the first approved vaccine formulation that does not require an influenza virus intermediate for production. This review presents a brief history of influenza vaccines, with insight into the potential future application of vaccines generated using recombinant technology.

The Center for Human Immunology, Autoimmunity, and Inflammation (CHI) is an exciting initiative of the NIH intramural program begun in 2009. It is uniquely trans-NIH in support (multiple institutes) and leadership (senior scientists from several institutes who donate their time). Its goal is an in-depth assessment of the human immune system using high-throughput multiplex technologies for examination of immune cells and their products, the genome, gene expression, and epigenetic modulation obtained from individuals both before and after interventions, adding information from in-depth clinical phenotyping, and then applying advanced biostatistical and computer modeling methods for mining these diverse data. The aim is to develop a comprehensive picture of the human "immunome" in health and disease, elucidate common pathogenic pathways in various diseases, identify and validate biomarkers that predict disease progression and responses to new interventions, and identify potential targets for new therapeutic modalities. Challenges, opportunities, and progress are detailed., (Published 2013. This article is a U.S. Government work and is in the public domain in the USA.)

The history of the 1957/58 Asian flu in Germany is systematically presented for the first time. The focus is on flu vaccination, which is discussed as a yardstick of the perception of the pandemic. International expertise on influenza virology was predominantly based in Anglo-Saxon countries. German microbiologists issued no clear recommendation for preventative vaccination until 1960. Instead, quinine was relied upon as the traditional medicinal prophylaxis. Antibiotics were more frequently administered. In East Germany, little fuss was made over the Asian flu. In line with the authorities' social hygiene orientation, vaccination was accepted as a matter of principle. In the Federal Republic and West Berlin, the population rejected the vaccination largely. It was seen as a scandal that many employees were on sick leave because of the flu, thus adversely affecting the economy.

Bacterial vaccines of various sorts were widely used for both preventive and therapeutic purposes during the great influenza pandemic of 1918-19. Some were derived exclusively from the Pfeiffer's bacillus, the presumed cause of influenza, while others contained one or more other organisms found in the lungs of victims. Although initially most reports of the use of these vaccines claimed that they prevented influenza or pneumonia, the results were inconsistent and sometimes contradictory. During the course of the debates over the efficacy of these vaccines, it became clear that the medical profession had no consensus on what constituted a proper vaccine trial. Even among those who asserted that clinical impression was not enough, there was no agreement on how a trial ought to be conducted. The American Public Health Association, through its Working Program on Influenza, sought to establish standards for the profession. The standards the APHA set in December 1918 guided American vaccine trials for a quarter century.

The availability of immunogenic, licensed H5N1 vaccines and the anticipated development of vaccines against "swine" influenza A(H1N1) have stimulated debate about the possible use of these vaccines for protection of those exposed to potential pandemic influenza viruses and for immunization or "priming" of populations in the so-called "prepandemic" (interpandemic) era. However, the safety of such vaccines is a critical issue in policy development for wide-scale application of vaccines in the interpandemic period. For example, wide-scale interpandemic use of H5N1 vaccines could lead to millions of persons receiving vaccines of uncertain efficacy potentially associated with rare severe adverse events and against a virus that may not cause a pandemic. Here, we first review aspects of the 1976 National Influenza Immunization Programme against "swine flu" and its well-documented association with Guillain-Barré syndrome as a case study illustration of a suspected vaccine-associated severe adverse event in a mass interpandemic immunization setting. This case study is especially timely, given the recent spread of a novel influenza A(H1N1) virus in humans in Mexico and beyond. Following this, we examine available safety data from clinical trials of H5N1 vaccines and briefly discuss how vaccine safety could be monitored in a postmarketing surveillance setting.

Influenza experts have been trying for a long time to convince other scientists, the public health community, and the general population that preparations for a pandemic should be a priority. But it was not until the highly pathogenic H5N1 avian strain emerged, causing a great epizootic and infecting and killing people exposed to infected birds, that research on this topic exploded. Below I discuss some truly phenomenal advances that have emerged from this newfound interest in pandemic influenza, to show that, yes, we are doing enough.

This article describes the sustained effort by American researchers between the mid-1930s and the mid-1950s to develop an effective influenza vaccine. From almost the beginning of this project, researchers succeeded in protecting laboratory animals from lethal influenza infection, and they believed that success with humans would follow quickly. Yet although they succeeded in producing a vaccine that proved effective in field trials in 1943 and 1945, that same vaccine failed to offer any protection in 1947. This vaccine failure forced researchers to reconsider the growing evidence of antigenic variation and challenged the model of the virus that had been taken for granted.

In 1976, 2 recruits at Fort Dix, New Jersey, had an influenza like illness. Isolates of virus taken from them included A/New Jersey/76 (Hsw1n1), a strain similar to the virus believed at the time to be the cause of the 1918 pandemic, commonly known as swine flu. Serologic studies at Fort Dix suggested that >200 soldiers had been infected and that person-to-person transmission had occurred. We review the process by which these events led to the public health decision to mass-vaccinate the American public against the virus and the subsequent events that led to the program's cancellation. Observations of policy and implementation success and failures are presented that could help guide decisions regarding avian influenza.

Two examples-the "swine flu affair" in 1976 and the emergence of HIV in the blood supply in the early 1980s-illustrate the difficulties of decision-making in public health. Both cases illustrate trade-offs between product risks and public health benefits, especially with regard to uncertainty in estimates of product risks, public health risks, and the benefits of prevention. The cases also illustrate the tendency of public health policy makers to go all the way or do nothing at all, rather than consider intermediate options that can be adapted as new information emerges. This review suggests three lessons for public health policy makers: (1) be open and honest about scientific uncertainty; (2) communicate with the public, even when the facts are not clear; and (3) consider intermediate, adaptable policy options, such as obtaining more information, thus reducing uncertainty, and building in decision points to reconsider initial policies. Underlying all of these lessons is the need to commission studies to resolve important uncertainties and increase the information base for public communication, and to review regulations and other policy options in the light of the new data that emerge.