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The rise of the covid-19 pandemic has led to renewed interest in the 1918-1919 influenza in search of aspects that might help us understand the current situation, but also as an opportunity to re-evaluate the serious twentieth-century health crisis in light of what we are experiencing now. In this context and with that goal, this historical reflection shows the parallels that exist and the need for a realization that our model of society is undergoing a crisis and requires profound transformation.

Seasonal influenza vaccines prevent influenza-related illnesses, hospitalizations, and deaths. However, these vaccines are not as effective as other viral vaccines, and there is clearly room for improvement. Here, we review the history of seasonal influenza vaccines, describe challenges associated with producing influenza vaccine antigens, and discuss the inherent difficulties of updating influenza vaccine strains each influenza season. We argue that seasonal influenza vaccines can be dramatically improved by modernizing antigen production processes and developing models that are better at predicting viral evolution. Resources should be specifically dedicated to improving seasonal influenza vaccines while developing entirely new vaccine platforms.

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 term "original antigenic sin" was coined approximately 60 years ago to describe the imprinting by the initial first influenza A virus infection on the antibody response to subsequent vaccination. These studies did not suggest a reduction in the response to current antigens but instead suggested anamnestic recall of antibody to earlier influenza virus strains. Then, approximately 40 years ago, it was observed that sequential influenza vaccination might lead to reduced vaccine effectiveness (VE). This conclusion was largely dismissed after an experimental study involving sequential administration of then-standard influenza vaccines. Recent observations have provided convincing evidence that reduced VE after sequential influenza vaccination is a real phenomenon. We propose that such reduction in VE be termed "negative antigenic interaction," given that there is no age cohort effect. In contrast, the potentially positive protective effect of early influenza virus infection later in life continues to be observed. It is essential that we understand better the immunologic factors underlying both original antigenic sin and negative antigenic interaction, to support development of improved influenza vaccines and vaccination strategies., (© The Author 2017. Published by Oxford University Press for the Infectious Diseases Society of America.)

This article explores the decisive role of British military medicine in shaping official approaches to the 1918 influenza pandemic. It contends that British approaches were defined through a system of military pathology, which had been established by the War Office as part of the mobilization of medicine for the First World War. Relying on the bacteriological laboratory for the identification and control of pathogenic agents, military pathology delivered therapeutic and preventive measures against a range of battlefield diseases, and military and civilian authorities trusted that it could do the same with influenza. This article traces how it shaped efforts to establish the etiology of the pandemic and to produce a general influenza vaccine. It highlights the challenges involved in both strategies. Understanding the central role of military pathology helps make sense of the nature, direction, scale, and limitations of medical mobilization against the pandemic in Britain and the authority accorded to specific medical bodies for elaborating and coordinating strategies. Crucially, it demands that we rethink the relationship between the war and pandemic as one about the social organization of medical knowledge and institutions.

The first clinical trial of an MF59(®)-adjuvanted influenza vaccine (Novartis) was conducted 20 years ago in 1992. The product that emerged (Fluad(®), Novartis) was licensed first in Italy in 1997 and is now licensed worldwide in 30 countries. US licensure is expected in the coming years. By contrast, many alternative adjuvanted vaccines have failed to progress. The key decisions that allowed MF59 to succeed in such a challenging environment are highlighted here and the lessons that were learned along the way are discussed. MF59 was connected to vaccines that did not succeed and was perceived as a 'failure' before it was a success. Importantly, it never failed for safety reasons and was always well tolerated. Even when safety issues have emerged for alternative adjuvants, careful analysis of the substantial safety database for MF59 have shown that there are no significant concerns with widespread use, even in more 'sensitive' populations.

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.

The Hong Kong Flu in the years 1968-1970 challenged both German health care systems. This article intends to analyse the patterns of reaction to the pandemic. Both German states faced the threat according to their respective ideological orientation. This applied to the two parts of Berlin - West and East - as well. In the GDR the control of influenza was centrally organized. When the pandemic passed away an influenza guiding document ("Führungsdokument") was made obligatory for the fight against the plague. In the FRG hospital treatment maintained predominance while the outpatient sector was administrated by physicians in private practice. In West- Berlin outpatient clinics were declined by the Association of Physicians ("Kassenärztliche Vereinigung"). In 1970 a first concept of surveillance was presented on the level of the state in West Germany. In the years 1968-1970 vaccinations were not common in both German states. The essay is based on the analysis of archival sources, monographs, scientific and newspaper articles., (© Georg Thieme Verlag KG Stuttgart · New York.)

Aging is associated with a decline in immune function (immunosenescence) that leads to progressive deterioration in both innate and adaptive immune functions. These changes contribute to the subsequent increased risk for infectious diseases and their sequelae. Vaccination is the most effective and inexpensive public health strategy for prevention of infection, despite the decreased efficacy of vaccines in older adults due to immunosenescence. The rapid rise in the older adult population globally represents a great challenge for vaccination programs. This article first addresses the status of innate and adaptive immune functions in aging and then focuses on influenza vaccine. The development history of influenza vaccines, current status, and potential strategies to improve the immunogenicity and vaccine effectiveness in older adults are discussed.

Since the isolation of influenza virus in 1933, a great deal of work was carried out in order to develop influenza vaccines and improve these fundamental tools of prevention in terms of production, quality control, safety and tolerability, and immunogenicity. The paper summarizes the cornerstones of the continuous evolution of influenza vaccines and the most recent and promising developments in this field.

The influenza pandemic of 1918-1919 dramatically altered biomedical knowledge of the disease. At its onset, the foundation of scientific knowledge was information collected during the previous major pandemic of 1889-1890. The work of Otto Leichtenstern, first published in 1896, described the major epidemiological and pathological features of pandemic influenza and was cited extensively over the next two decades. Richard Pfeiffer announced in 1892 and 1893 that he had discovered influenza's cause. Pfeiffer's bacillus (Bacillus influenzae) was a major focus of attention and some controversy between 1892 and 1920. The role this organism or these organisms played in influenza dominated medical discussion during the great pandemic. Many vaccines were developed and used during the 1918-1919 pandemic. The medical literature was full of contradictory claims of their success; there was apparently no consensus on how to judge the reported results of these vaccine trials. The result of the vaccine controversy was both a further waning of confidence in Pfeiffer's bacillus as the agent of influenza and the emergence of an early set of criteria for valid vaccine trials.

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.

Against the background of the renewed interest aroused in recent years by the influenza pandemic of 1918-1919, and the leading role now played by research analysing the process of innovation in medicine, this paper assesses the role played by serums and vaccines - the new resources of the medical science of the time 0 in the fight against the influenza outbreak of 1918-1919. The paper highlights the dependence on combined scientific, social, economic and professional factors, and also shows the main consequences arising from the fine-tuning and implementation of these therapeutic and prophylactic resources.

Fears of a potential pandemic due to A(H5N1) viruses have focussed new attention on our current vaccines, their shortcomings, and concerns regarding global vaccine supply in a pandemic. The bulk of current vaccines are inactivated split virus vaccines produced from egg-grown virus and have only modest improvements compared with those first introduced over 60 years ago. Splitting, which was introduced some years ago to reduce reactogenicity, also reduces the immunogenicity of vaccines in immunologically naïve recipients. The A(H5N1) viruses have been found poorly immunogenic and present other challenges for vaccine producers which further exacerbate an already limited global production capacity. There have been some recent improvements in vaccine production methods and improvements to immunogenicity by the development of new adjuvants, however, these still fall short of providing timely supplies of vaccine for all in the face of a pandemic. New approaches to influenza vaccines which might fulfil the demands of a pandemic situation are under evaluation, however, these remain some distance from clinical reality and face significant regulatory hurdles.

The article "Pandemic influenza in Korea with special references to its etiology," published in JAMA in April, 1919 by Dr. Frank William Schofield, is a valuable material reflecting the influenza pandemic situation in 1918 in Korea. It contains the case reports of influenza infected patients and the results of the bacteriological experiments. Dr. Schofield worked as a bacteriology professor in Severance Union Medical College in Seoul from 1916 to 1920. His academic activities are lesser-known than the role of contributor of Korean independent movement. However, he was a remarkable veterinarian and scientist. According to Dr. Schofield, the number of Influenza infected population in Korea in 1918 was supposed to be 4,000,000 to 8,000,000, which corresponds with other resources (6.7 per 1,000 in Gangwon province). Considering the cases which were not registered as influenza infection by misdiagnosis of pneumonia complication the sum should be higher. However, the estimated crude influenza death rate from the reports by the Japanese colonial government was only 2.38 (per 1,000). Dr. Schofield and his colleague tried to culture "Pfeiffer Bacillus" from the sputum and blood specimens of patients showing typical influenza symptoms. The bacterium was mistakenly considered as the influenza agent till the virological nature of influenza was discovered in the 1930s. From the results of his study he seemed to agree that "filterable virus" was the influenza agent and the secondary infection of the bacillus caused respiratory symptoms. He also reported on the influenza vaccination during the epidemics. Dr. Schofield's article confirms that the damage caused by the influenza outbreak in Korea was as great as in other Asian countries or even worse. It also gives information about the researches and education on the etiology and vaccination of influenza based on the germ theory in the medical colleges in Korea, which adopted the western medical educational system in the early 20th century.

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.

Influenza viruses are remarkably adept at surviving in the human population over a long timescale. The human influenza A virus continues to thrive even among populations with widespread access to vaccines, and continues to be a major cause of morbidity and mortality. The virus mutates from year to year, making the existing vaccines ineffective on a regular basis, and requiring that new strains be chosen for a new vaccine. Less-frequent major changes, known as antigenic shift, create new strains against which the human population has little protective immunity, thereby causing worldwide pandemics. The most recent pandemics include the 1918 'Spanish' flu, one of the most deadly outbreaks in recorded history, which killed 30-50 million people worldwide, the 1957 'Asian' flu, and the 1968 'Hong Kong' flu. Motivated by the need for a better understanding of influenza evolution, we have developed flexible protocols that make it possible to apply large-scale sequencing techniques to the highly variable influenza genome. Here we report the results of sequencing 209 complete genomes of the human influenza A virus, encompassing a total of 2,821,103 nucleotides. In addition to increasing markedly the number of publicly available, complete influenza virus genomes, we have discovered several anomalies in these first 209 genomes that demonstrate the dynamic nature of influenza transmission and evolution. This new, large-scale sequencing effort promises to provide a more comprehensive picture of the evolution of influenza viruses and of their pattern of transmission through human and animal populations. All data from this project are being deposited, without delay, in public archives.

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.

Pandemic influenza presents special problems for vaccine development. There must be a balance between rapid availability of vaccine and the safeguards to ensure safety, quality and efficacy of vaccine. Vaccine was developed for the pandemics of 1957, 1968, 1977 and for the pandemic alert of 1976. This experience is compared with that gained in developing vaccines for a possible H5N1 pandemic in 1997-1998. Our ability to mass produce influenza vaccines against a pandemic threat was well illustrated by the production of over 150 million doses of 'swine flu' vaccine in the USA within a 3 month period in 1976. However, there is cause for concern that the lead time to begin vaccine production is likely to be about 7-8 months. Attempts to reduce this time should receive urgent attention. Immunogenicity of vaccines in pandemic situations is compared over the period 1968-1998. A consistent feature of the vaccine trials is the demonstration that one conventional 15 microg haemagglutinin dose of vaccine is not sufficiently immunogenic in naive individuals. Much larger doses or two lower doses are needed to induce satisfactory immunity. There is some evidence that whole-virus vaccines are more immunogenic than split or subunit vaccines, but this needs substantiating by further studies. H5 vaccines appeared to be particularly poor immunogens and there is evidence that an adjuvant may be needed. Prospects for improving the development of pandemic vaccines are discussed.

In reviewing 50 years of personal research on influenza, I have journeyed, literally and figuratively, from an army camp epidemic in Fort Monmouth NJ in 1947 to a (literal and figurative) Valhalla, where I now conduct my research. Having entered the field as a physician, I have always sought practical applications of my work, yet in every instance, such applications have led me to seek further answers in basic research as new questions arose. I entered the area of influenza virus genetics by the back door through an interest in the effects of corticosteroid hormones on viral replication, used the genetic approach in analyzing the morphological variation of the virus and, in so doing, exploited the finding of a linkage of high-yield growth to spherical morphology. Today, all influenza vaccine viruses are high-yield genetic reassortants. Subsequent study of reassortant viruses facilitated the identification and isolation of the two major antigens of the virus in antigenic hybrids and showed their differing functions in the induction of immunity. In turn, a new approach to influenza vaccination has been discovered and is presently under clinical investigation.

Scholars have argued that the beginning of virology can be dated from the end of the 19th century: the discovery that some infectious agents could pass through ultrafilters produced a criterium to distinguish ultrafilterable viruses from infectious agents that are not filterable, e.g. bacteria. A filterable agent, claimed to be the cause of human influenza, was isolated in 1933. It will be argued in this paper, however, that the influence of a bacteriological paradigm on influenza research in the first half of the twentieth century was very powerful. Until the late 1940s influenza viruses were studied as infectious entities which, although filterable, were conceived of as analogous to bacteria. It was assumed that filterable viruses which infected animals were a kind of ultrabacteria. According to the bacteriological paradigm the assumed dependence of the filterable viruses on living cells was easy to account for. The second half of the 1940s saw the 'modern concept of virus' begin to be applied to the influenza viruses. Influenza vaccinations in 1946 did not appear to provide protection, from which it was concluded that the influenza virus is very variable. Furthermore, in 1946 and 1947 experimental studies were published, which indicated that the influenza virus may go through an eclipse during its multiplication: it disappears as an infectious agent. Viewed from this perspective, it was only by the second half of the 1940s that research on the influenza virus became emancipated from the bacteriological paradigm.