history of viruses essay

Module 2: Viruses

History of viruses, learning outcomes.

• Describe how viruses were first discovered and how they are detected
• Discuss three hypotheses about how viruses evolved

Viruses are noncellular parasitic entities that cannot be classified within any kingdom. They can infect organisms as diverse as bacteria, plants, and animals. In fact, viruses exist in a sort of netherworld between a living organism and a nonliving entity. Living things grow, metabolize, and reproduce. In contrast, viruses are not cellular, do not have a metabolism or grow, and cannot divide by cell division. Viruses  can  copy, or replicate themselves; however, they are entirely dependent on resources derived from their host cells to produce progeny viruses—which are assembled in their mature form. No one knows exactly when or how viruses evolved or from what ancestral source because viruses have not left a fossil record. Some virologists contend that modern viruses are a mosaic of bits and pieces of nucleic acids picked up from various sources along their respective evolutionary paths.

Figure 1. The tobacco mosaic virus (left), seen here by transmission electron microscopy, was the first virus to be discovered. The virus causes disease in tobacco and other plants, such as the orchid (right). (credit a: USDA ARS; credit b: modification of work by USDA Forest Service, Department of Plant Pathology Archive North Carolina State University; scale-bar data from Matt Russell)

Discovery and Detection

Viruses were first discovered after the development of a porcelain filter—the Chamberland-Pasteur filter—that could remove all bacteria visible in the microscope from any liquid sample. In 1886, Adolph Meyer demonstrated that a disease of tobacco plants— tobacco mosaic disease —could be transferred from a diseased plant to a healthy one via liquid plant extracts. In 1892, Dmitri Ivanowski showed that this disease could be transmitted in this way even after the Chamberland-Pasteur filter had removed all viable bacteria from the extract. Still, it was many years before it was proved that these “filterable” infectious agents were not simply very small bacteria but were a new type of very small, disease-causing particle.

Most  virions , or single virus particles, are very small, about 20 to 250 nanometers in diameter. However, some recently discovered viruses from amoebae range up to 1000 nm in diameter. With the exception of large virions, like the poxvirus and other large DNA viruses, viruses cannot be seen with a light microscope. It was not until the development of the electron microscope in the late 1930s that scientists got their first good view of the structure of the tobacco mosaic virus (TMV) (Figure 1), discussed above, and other viruses (Figure 2). The surface structure of virions can be observed by both scanning and transmission electron microscopy, whereas the internal structures of the virus can only be observed in images from a transmission electron microscope. The use of electron microscopy and other technologies has allowed for the discovery of many viruses of all types of living organisms.

Figure 2. In these transmission electron micrographs, (a) a virus is dwarfed by the bacterial cell it infects, while (b) these E. coli cells are dwarfed by cultured colon cells. (credit a: modification of work by U.S. Dept. of Energy, Office of Science, LBL, PBD; credit b: modification of work by J.P. Nataro and S. Sears, unpub. data, CDC; scale-bar data from Matt Russell)

Evolution of Viruses

Although biologists have accumulated a significant amount of knowledge about how present-day viruses evolve, much less is known about how viruses originated in the first place. When exploring the evolutionary history of most organisms, scientists can look at fossil records and similar historic evidence. However, viruses do not fossilize, so researchers can only hypothesize about viruses’ evolutionary history by investigating how today’s viruses evolve and by using biochemical and genetic information to create speculative virus histories.

While most findings agree that viruses don’t have a single common ancestor, scholars have yet to find a single hypothesis about virus origins that is fully accepted in the field—and that fully explains viruses and their characteristics. There are, however, three hypotheses that have risen as the most accepted:

• Devolution or  regressive hypothesis . This hypothesis proposes to explain the origin of viruses by suggesting that viruses evolved from free-living cells. However, many components of how this process might have occurred are a mystery.
• Escapist or progressive hypothesis . This hypothesis accounts for viruses having either an RNA or a DNA genome and suggests that viruses originated from RNA and DNA molecules that escaped from a host cell. However, this hypothesis doesn’t explain the complex capsids and other structures on virus particles.
• Self-replication hypothesis . This hypothesis posits a system of self-replication similar to that of other self-replicating molecules, likely evolving alongside the cells they rely on as hosts; studies of some plant pathogens support this hypothesis.

Another problem for those studying viral origins and evolution is their high rate of mutation, particularly the case in RNA retroviruses like HIV/AIDS.

As technology advances, scientists will develop and refine further hypotheses to explain the origin of viruses—or create new hypotheses. The emerging field called virus molecular systematics attempts to do just that through comparisons of sequenced genetic material. These researchers hope to one day better understand the origin of viruses, a discovery that could lead to advances in the treatments for the ailments they produce.

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The history of virology — the scientific study of viruses and the infections they cause – began in the closing years of the 19th century. Although Louis Pasteur and Edward Jenner developed the first vaccines to protect against viral infections, they did not know that viruses existed. The first evidence of the existence of viruses came from experiments with filters that had pores small enough to retain bacteria. In 1892, Dmitry Ivanovsky used one of these filters to show that sap from a diseased tobacco plant remained infectious to healthy tobacco plants despite having been filtered. Martinus Beijerinck called the filtered, infectious substance a "virus" and this discovery is considered to be the beginning of virology. The subsequent discovery and partial characterization of bacteriophages by Frederick Twort and Félix d'Herelle further catalyzed the field, and by the early 20th century many viruses had been discovered. In 1926, Thomas Milton Rivers defined viruses as obligate parasites. Viruses were demonstrated to be particles, rather than a fluid, by Wendell Meredith Stanley, and the invention of the electron microscope in 1931 allowed their complex structures to be visualised.

1. Pioneers

Despite his other successes, Louis Pasteur (1822–1895) was unable to find a causative agent for rabies and speculated about a pathogen too small to be detected using a microscope. [ 1 ] In 1884, the French microbiologist Charles Chamberland (1851–1931) invented a filter – known today as the Chamberland filter – that had pores smaller than bacteria. Thus, he could pass a solution containing bacteria through the filter and completely remove them from the solution. [ 2 ]

In 1876, Adolf Mayer, who directed the Agricultural Experimental Station in Wageningen was the first to show that what he called "Tobacco Mosaic Disease" was infectious, he thought that it was caused by either a toxin or a very small bacterium. Later, in 1892, the Russian biologist Dmitry Ivanovsky (1864–1920) used a Chamberland filter to study what is now known as the tobacco mosaic virus. His experiments showed that crushed leaf extracts from infected tobacco plants remain infectious after filtration. Ivanovsky suggested the infection might be caused by a toxin produced by bacteria, but did not pursue the idea. [ 3 ]

In 1898, the Dutch microbiologist Martinus Beijerinck (1851–1931), a microbiology teacher at the Agricultural School in Wageningen repeated experiments by Adolf Mayer and became convinced that filtrate contained a new form of infectious agent. [ 4 ] He observed that the agent multiplied only in cells that were dividing and he called it a contagium vivum fluidum (soluble living germ) and re-introduced the word virus . [ 3 ] Beijerinck maintained that viruses were liquid in nature, a theory later discredited by the American biochemist and virologist Wendell Meredith Stanley (1904–1971), who proved that they were in fact, particles. [ 3 ] In the same year Friedrich Loeffler (1852–1915) and Paul Frosch (1860–1928) passed the first animal virus through a similar filter and discovered the cause of foot-and-mouth disease. [ 5 ]

In 1881, Carlos Finlay (1833–1915), a Cuban physician, first conducted and published research that indicated that mosquitoes were carrying the cause of yellow fever, [ 6 ] a theory proved in 1900 by commission headed by Walter Reed (1851–1902). During 1901 and 1902, William Crawford Gorgas (1854–1920) organised the destruction of the mosquitoes' breeding habitats in Cuba, which dramatically reduced the prevalence of the disease. [ 7 ] Gorgas later organised the elimination of the mosquitoes from Panama, which allowed the Panama Canal to be opened in 1914. [ 8 ] The virus was finally isolated by Max Theiler (1899–1972) in 1932 who went on to develop a successful vaccine. [ 9 ]

By 1928 enough was known about viruses to enable the publication of Filterable Viruses , a collection of essays covering all known viruses edited by Thomas Milton Rivers (1888–1962). Rivers, a survivor of typhoid fever contracted at the age of twelve, went on to have a distinguished career in virology. In 1926, he was invited to speak at a meeting organised by the Society of American Bacteriology where he said for the first time, "Viruses appear to be obligate parasites in the sense that their reproduction is dependent on living cells." [ 10 ]

The notion that viruses were particles was not considered unnatural and fitted in nicely with the germ theory. It is assumed that Dr. J. Buist of Edinburgh was the first person to see virus particles in 1886, when he reported seeing "micrococci" in vaccine lymph, though he had probably observed clumps of vaccinia. [ 11 ] In the years that followed, as optical microscopes were improved "inclusion bodies" were seen in many virus-infected cells, but these aggregates of virus particles were still too small to reveal any detailed structure. It was not until the invention of the electron microscope in 1931 by the German engineers Ernst Ruska (1906–1988) and Max Knoll (1887–1969), [ 12 ] that virus particles, especially bacteriophages, were shown to have complex structures. The sizes of viruses determined using this new microscope fitted in well with those estimated by filtration experiments. Viruses were expected to be small, but the range of sizes came as a surprise. Some were only a little smaller than the smallest known bacteria, and the smaller viruses were of similar sizes to complex organic molecules. [ 13 ]

In 1935, Wendell Stanley examined the tobacco mosaic virus and found it was mostly made of protein. [ 14 ] In 1939, Stanley and Max Lauffer (1914) separated the virus into protein and nucleic acid, [ 15 ] which was shown by Stanley's postdoctoral fellow Hubert S. Loring to be specifically RNA. [ 16 ] The discovery of RNA in the particles was important because in 1928, Fred Griffith (c.1879–1941) provided the first evidence that its "cousin", DNA, formed genes. [ 17 ]

In Pasteur's day, and for many years after his death, the word "virus" was used to describe any cause of infectious disease. Many bacteriologists soon discovered the cause of numerous infections. However, some infections remained, many of them horrendous, for which no bacterial cause could be found. These agents were invisible and could only be grown in living animals. The discovery of viruses was the key that unlocked the door that withheld the secrets of the cause of these mysterious infections. And, although Koch's postulates could not be fulfilled for many of these infections, this did not stop the pioneer virologists from looking for viruses in infections for which no other cause could be found. [ 18 ]

2. Bacteriophages

2.1. Discovery

Bacteriophages are the viruses that infect and replicate in bacteria. They were discovered in the early 20th century, by the English bacteriologist Frederick Twort (1877–1950). [ 19 ] But before this time, in 1896, the bacteriologist Ernest Hanbury Hankin (1865–1939) reported that something in the waters of the River Ganges could kill Vibrio cholerae – the cause of cholera. The agent in the water could be passed through filters that remove bacteria but was destroyed by boiling. [ 20 ] Twort discovered the action of bacteriophages on staphylococci bacteria. He noticed that when grown on nutrient agar some colonies of the bacteria became watery or "glassy". He collected some of these watery colonies and passed them through a Chamberland filter to remove the bacteria and discovered that when the filtrate was added to fresh cultures of bacteria, they in turn became watery. [ 19 ] He proposed that the agent might be "an amoeba, an ultramicroscopic virus, a living protoplasm, or an enzyme with the power of growth". [ 20 ]

Félix d'Herelle (1873–1949) was a mainly self-taught French-Canadian microbiologist. In 1917 he discovered that "an invisible antagonist", when added to bacteria on agar, would produce areas of dead bacteria. [ 19 ] The antagonist, now known to be a bacteriophage, could pass through a Chamberland filter. He accurately diluted a suspension of these viruses and discovered that the highest dilutions (lowest virus concentrations), rather than killing all the bacteria, formed discrete areas of dead organisms. Counting these areas and multiplying by the dilution factor allowed him to calculate the number of viruses in the original suspension. [ 21 ] He realised that he had discovered a new form of virus and later coined the term "bacteriophage". [ 22 ] [ 23 ] Between 1918 and 1921 d'Herelle discovered different types of bacteriophages that could infect several other species of bacteria including Vibrio cholerae . [ 24 ] Bacteriophages were heralded as a potential treatment for diseases such as typhoid and cholera, but their promise was forgotten with the development of penicillin. [ 22 ] Since the early 1970s, bacteria have continued to develop resistance to antibiotics such as penicillin, and this has led to a renewed interest in the use of bacteriophages to treat serious infections. [ 25 ]

2.2. Early Research 1920–1940

D'Herelle travelled widely to promote the use of bacteriophages in the treatment of bacterial infections. In 1928, he became professor of biology at Yale and founded several research institutes. [ 26 ] He was convinced that bacteriophages were viruses despite opposition from established bacteriologists such as the Nobel Prize winner Jules Bordet (1870–1961). Bordet argued that bacteriophages were not viruses but just enzymes released from "lysogenic" bacteria. He said "the invisible world of d'Herelle does not exist". [ 27 ] But in the 1930s, the proof that bacteriophages were viruses was provided by Christopher Andrewes (1896–1988) and others. They showed that these viruses differed in size and in their chemical and serological properties. In 1940, the first electron micrograph of a bacteriophage was published and this silenced sceptics who had argued that bacteriophages were relatively simple enzymes and not viruses. [ 28 ] Numerous other types of bacteriophages were quickly discovered and were shown to infect bacteria wherever they are found. Early research was interrupted by World War II. d'Herelle, despite his Canadian citizenship, was interned by the Vichy Government until the end of the war. [ 29 ]

2.3. Modern Era

Knowledge of bacteriophages increased in the 1940s following the formation of the Phage Group by scientists throughout the US. Among the members were Max Delbrück (1906–1981) who founded a course on bacteriophages at Cold Spring Harbor Laboratory. [ 25 ] Other key members of the Phage Group included Salvador Luria (1912–1991) and Alfred Hershey (1908–1997). During the 1950s, Hershey and Chase made important discoveries on the replication of DNA during their studies on a bacteriophage called T2. Together with Delbruck they were jointly awarded the 1969 Nobel Prize in Physiology or Medicine "for their discoveries concerning the replication mechanism and the genetic structure of viruses". [ 30 ] Since then, the study of bacteriophages has provided insights into the switching on and off of genes, and a useful mechanism for introducing foreign genes into bacteria and many other fundamental mechanisms of molecular biology. [ 31 ]

3. Plant Viruses

In 1882, Adolf Mayer (1843–1942) described a condition of tobacco plants, which he called "mosaic disease" ("mozaïkziekte"). The diseased plants had variegated leaves that were mottled. [ 32 ] He excluded the possibility of a fungal infection and could not detect any bacterium and speculated that a "soluble, enzyme-like infectious principle was involved". [ 33 ] He did not pursue his idea any further, and it was the filtration experiments of Ivanovsky and Beijerinck that suggested the cause was a previously unrecognised infectious agent. After tobacco mosaic was recognized as a virus disease, virus infections of many other plants were discovered. [ 33 ]

The importance of tobacco mosaic virus in the history of viruses cannot be overstated. It was the first virus to be discovered, and the first to be crystallised and its structure shown in detail. The first X-ray diffraction pictures of the crystallised virus were obtained by Bernal and Fankuchen in 1941. On the basis of her pictures, Rosalind Franklin discovered the full structure of the virus in 1955. [ 34 ] In the same year, Heinz Fraenkel-Conrat and Robley Williams showed that purified tobacco mosaic virus RNA and its coat protein can assemble by themselves to form functional viruses, suggesting that this simple mechanism was probably the means through which viruses were created within their host cells. [ 35 ]

By 1935 many plant diseases were thought to be caused by viruses. In 1922, John Kunkel Small (1869–1938) discovered that insects could act as vectors and transmit virus to plants. In the following decade many diseases of plants were shown to be caused by viruses that were carried by insects and in 1939, Francis Holmes, a pioneer in plant virology, [ 36 ] described 129 viruses that caused disease of plants. [ 37 ] Modern, intensive agriculture provides a rich environment for many plant viruses. In 1948, in Kansas, US, 7% of the wheat crop was destroyed by wheat streak mosaic virus. The virus was spread by mites called Aceria tulipae . [ 38 ]

In 1970, the Russian plant virologist Joseph Atabekov discovered that many plant viruses only infect a single species of host plant. [ 36 ] The International Committee on Taxonomy of Viruses now recognises over 900 plant viruses. [ 39 ]

4. 20th Century

By the end of the 19th century, viruses were defined in terms of their infectivity, their ability to be filtered, and their requirement for living hosts. Up until this time, viruses had only been grown in plants and animals, but in 1906, Ross Granville Harrison (1870–1959) invented a method for growing tissue in lymph, [ 40 ] and, in 1913, E Steinhardt, C Israeli, and RA Lambert used this method to grow vaccinia virus in fragments of guinea pig corneal tissue. [ 41 ] In 1928, HB and MC Maitland grew vaccinia virus in suspensions of minced hens' kidneys. [ 42 ] Their method was not widely adopted until the 1950s, when poliovirus was grown on a large scale for vaccine production. [ 43 ] In 1941–42, George Hirst (1909–94) developed assays based on haemagglutination to quantify a wide range of viruses as well as virus-specific antibodies in serum. [ 44 ] [ 45 ]

4.1. Influenza

Although the influenza virus that caused the 1918–1919 influenza pandemic was not discovered until the 1930s, the descriptions of the disease and subsequent research has proved it was to blame. [ 46 ] The pandemic killed 40–50 million people in less than a year, [ 47 ] but the proof that it was caused by a virus was not obtained until 1933. [ 48 ] Haemophilus influenzae is an opportunistic bacterium which commonly follows influenza infections; this led the eminent German bacteriologist Richard Pfeiffer (1858–1945) to incorrectly conclude that this bacterium was the cause of influenza. [ 49 ] A major breakthrough came in 1931, when the American pathologist Ernest William Goodpasture grew influenza and several other viruses in fertilised chickens' eggs. [ 50 ] Hirst identified an enzymic activity associated with the virus particle, later characterised as the neuraminidase, the first demonstration that viruses could contain enzymes. Frank Macfarlane Burnet showed in the early 1950s that the virus recombines at high frequencies, and Hirst later deduced that it has a segmented genome. [ 51 ]

4.2. Poliomyelitis

In 1949, John F. Enders (1897–1985) Thomas Weller (1915–2008), and Frederick Robbins (1916–2003) grew polio virus for the first time in cultured human embryo cells, the first virus to be grown without using solid animal tissue or eggs. Infections by poliovirus most often cause the mildest of symptoms. This was not known until the virus was isolated in cultured cells and many people were shown to have had mild infections that did not lead to poliomyelitis. But, unlike other viral infections, the incidence of polio – the rarer severe form of the infection – increased in the 20th century and reached a peak around 1952. The invention of a cell culture system for growing the virus enabled Jonas Salk (1914–1995) to make an effective polio vaccine. [ 52 ]

4.3. Epstein–Barr Virus

Denis Parsons Burkitt (1911–1993) was born in Enniskillen, County Fermanagh, Ireland. He was the first to describe a type of cancer that now bears his name Burkitt's lymphoma. This type of cancer was endemic in equatorial Africa and was the commonest malignancy of children in the early 1960s. [ 53 ] In an attempt to find a cause for the cancer, Burkitt sent cells from the tumour to Anthony Epstein (b. 1921) a British virologist, who along with Yvonne Barr and Bert Achong (1928–1996), and after many failures, discovered viruses that resembled herpes virus in the fluid that surrounded the cells. The virus was later shown to be a previously unrecognised herpes virus, which is now called Epstein–Barr virus. [ 54 ] Surprisingly, Epstein–Barr virus is a very common but relatively mild infection of Europeans. Why it can cause such a devastating illness in Africans is not fully understood, but reduced immunity to virus caused by malaria might be to blame. [ 55 ] Epstein–Barr virus is important in the history of viruses for being the first virus shown to cause cancer in humans. [ 56 ]

4.4. Late 20th and Early 21st Century

The second half of the 20th century was the golden age of virus discovery and most of the 2,000 recognised species of animal, plant, and bacterial viruses were discovered during these years. [ 57 ] [ 58 ] In 1946, bovine virus diarrhea was discovered, [ 59 ] which is still possibly the most common pathogen of cattle throughout the world [ 60 ] and in 1957, equine arterivirus was discovered. [ 61 ] In the 1950s, improvements in virus isolation and detection methods resulted in the discovery of several important human viruses including varicella zoster virus, [ 62 ] the paramyxoviruses, [ 63 ] – which include measles virus, [ 64 ] and respiratory syncytial virus [ 63 ] – and the rhinoviruses that cause the common cold. [ 65 ] In the 1960s more viruses were discovered. In 1963, the hepatitis B virus was discovered by Baruch Blumberg (b. 1925). [ 66 ] Reverse transcriptase, the key enzyme that retroviruses use to translate their RNA into DNA, was first described in 1970, independently by Howard Temin and David Baltimore (b. 1938). [ 67 ] This was important to the development of antiviral drugs – a key turning-point in the history of viral infections. [ 68 ] In 1983, Luc Montagnier (b. 1932) and his team at the Pasteur Institute in France first isolated the retrovirus now called HIV. [ 69 ] In 1989 Michael Houghton's team at Chiron Corporation discovered hepatitis C. [ 70 ] New viruses and strains of viruses were discovered in every decade of the second half of the 20th century. These discoveries have continued in the 21st century as new viral diseases such as SARS [ 71 ] and nipah virus [ 72 ] have emerged. Despite scientists' achievements over the past one hundred years, viruses continue to pose new threats and challenges. [ 73 ]

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COVID-19: Rethinking the nature of viruses

• Original Paper
• Published: 07 January 2021
• Volume 43 , article number  2 , ( 2021 )

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• Soraya de Chadarevian   ORCID: orcid.org/0000-0002-4360-7203 1 &
• Roberta Raffaetà   ORCID: orcid.org/0000-0002-0680-1613 2  

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In this brief essay, we combine biological, historical, philosophical and anthropological perspectives to ask anew the question about the nature of the virus. How should we understand Sars-CoV-2 and why does it matter? The argument we present is that the virus undermines any neat distinction between the natural and the human-made, the biological and the social. Rather, to understand the virus and the pandemic we need to understand both as intimately connected to our own social and historical condition. What started as a reflection on the nature of the virus thus turns into a reflection on the human condition as refracted in this pandemic or an anthropology of the virus.

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At the core of the pandemic we are living through, we learn, is a new coronavirus, named severe acute respiratory syndrome coronavirus 2 or, for short, SARS-CoV-2. In this short essay, we—a historian with training in biology and philosophy and an anthropologist who has thought much about microbes—aim to consider how SARS-CoV-2 can be conceived in a way that captures the pandemic in its complexity. In order to do this, we will bring into conversation the views of scientists, philosophers, anthropologists and historians who have been grappling with this question before the revelatory power of the current pandemic has exposed even more clearly the inadequacies of dominant understandings of viruses and their causal agency. Scientific knowledge, practical action and moral judgements depend on how phenomena are conceptualized and named (Bowker and Star 1999 ).

Over the last decades, scientists have learned a great deal about the molecular structure of viruses and the mechanisms by which they find their way into the host cell and use its replication machinery to produce more viruses. Scientists are exploiting this knowledge, using viruses as vectors to transport pieces of DNA into the cell for gene editing as well as to devise drugs and vaccines. Mostly, however, viruses have been studied in association with diseases (the manifest symptom of their reproduction within a host). Viruses, it seems, are only noticed when something goes wrong.

Virologist Alexander Gorbalenya, lead author on the paper that classified and named SARS-CoV-2 (Gorbalenya et al. 2020 ), has for a long time deplored the predominant association of viruses with diseases (Gorbalenya 2011 ). This perspective, together with the strong tendency not to consider viruses as living entities, has, in his view, limited scientists’ ability to appreciate the ecological role of viruses and their role in the evolution of both humans and other species.

Considering viruses simply as associated with diseases that befall us, may serve as a fertile ground for anxieties about espionage and biological warfare, as well as race-based targeting of Chinese scientists or particular populations. It also generates reactions such as considering viruses as “enemies” or something to be defeated through “war,” setting the stage for forms of preparedness simply based on culling, vaccine stockpiling, social distancing, lockdown and disinfection. These solutions are important in certain moments, but they focus only on a portion of the problem (virus-as-disease) while ignoring all the other aspects of the pandemic. Commenting on the measures taken to contain the COVID-19 pandemic in Australia, including especially the closure of its beaches, historian Warwick Anderson has observed, “The understanding of viral transmission has been reduced to a mechanical model of contact and contamination, with some alien and stigmatized groups recognized as having special proclivity for carrying and communicating the pathogen— stranger super-spreaders—on safeguarded and sacralized sites, such as the beach. The environmental, social, and cultural complexity of disease transmission, the varied and contingent configurations of spread, are erased, replaced by fear of proximity to others. Disease prevention dwindles into a purification ritual” (Anderson 2020 ).

Against this “mechanical model of contact and contamination” and the limited understanding of viruses it implies, Gorbalenya reminds us that the vast biological diversity of viruses is yet to be discovered and that most viruses are harmless. As he points out, all organisms, including humans, are infected by viruses and there is no escape from this situation as infection is one of the driving forces of evolution (Gorbalenya 2011 ). Other scientists have also emphasized the key role of viruses for evolution (Koonin and Dolja 2013 ; Villarreal 2004 ), a role confirmed by the fact that nearly half of the human genome derives from genes acquired from other species, with viruses most likely acting as mediators (Cordaux and Batzer 2009 ).

Philosophers of science who adopt a system-biological approach to biology, and the biology of microorganisms in particular, or highlight processes rather than structures, share a similar view while complicating the distinction between life/non-life in viruses (Soyer and O’Malley 2013 ; O’Malley et al. 2015 ). As Stephan Guttinger and John Dupré have argued, viruses “are not living things certainly, but they are stages of living processes” (Guttinger and Dupré 2016 ). Similarly, social anthropologist Celia Lowe has described viruses as dynamic and interacting processes, as “clouds” rather than entities in their own right (Lowe 2010 ).

These approaches resonate with anthropologist David Napier’s understanding of viruses and infectious diseases although he includes more explicitly the sociocultural dimension in his considerations. Like Gorbalenya, he rejects the notion that viruses “attack” us. Yet departing from Gorbalenya, he believes military metaphors stem from considering viruses as living entities with their own agency (Napier 2020 ). Rejecting this notion and specifically commenting on the COVID-19 pandemic, Napier notes, “Science … has led us to believe that viruses invade us, which they don’t. … Proliferation is a social matter…. Our inability to involve social science seriously in responding to COVID-19 and how it makes specific populations vulnerable…has altered the epidemic landscape profoundly” (Napier 2020 ). Historian Andy Horowitz concurs when he writes, “The history that scholars will name ‘the COVID-19 pandemic’ ultimately will have as much to do with the social world the virus encounters as it does with the virus itself” (Horowitz 2020 ). That these considerations always again turn around the apparently intractable question whether viruses should be considered as living or non-living entities speaks to the key role the distinction between life and non-life plays in late neoliberal narratives and configurations, a distinction grounding new forms of human and non-human marginalization and exploitation (Povinelli 2016 ).

Multispecies approaches in anthropology tries to challenge both anthropocentric and neoliberal ontological perspectives, by analyzing contact situations in specific settings not only from a human perspective but also from the perspective of other species (Kirksey and Helmreich 2010 ). Building on such a framework, Eben Kirksey describes COVID-19 as a “multispecies assemblage” to highlight the adaptive transformations of the virus in interactions with other life forms. He includes specifically the political, economic and ecological life world of humans that often threatens the viruses’ original habitat and sets the stage for the passage of viruses from animal to human hosts (Kirksey 2020 ; van Dooren 2020 ).

Nevertheless, COVID-19 is not a big event from an evolutionary point of view, but it is a huge problem for humans because it dramatically interacts with and disturbs human social practices. This is because SARS-CoV-2 is us, too (Napier 2020 ). Karen Barad proposes the term “intra-action” instead of “interaction” exactly to highlight the fact that agencies (in this case the virus and humans) are not distinguished before their encounter but arise from it (Barad 2007 ). SARS-CoV-2 is neither natural/biological nor human-made/cultural: humans are the main vectors for its proliferation and this makes the virus always and already both natural and human made. Some scientists are trying to analyze such complexity by aggregating a huge number of heterogeneous data sets about the pandemic (Capua and Rasetti 2020 ). The success of such projects, we contend, will depend on how well the data can model the specific and diverse settings where the intra-action occurs.

Therefore, to answer our question—how can we conceive of the virus in a way that captures the pandemic in its complexity—it will not suffice to simply combine biological and social approaches. Rather, to understand the virus and the pandemic we need to understand the social and biological world as inextricably connected. The more we will take into consideration the dynamic interactions of humans and other species in specific historical settings, the more we could gain useful and promising insights on how to live humanly in a pandemic and more-than-human world, marked by different degrees of exposure and vulnerabilities. What started as a reflection on the nature of the virus thus turns into a reflection on the social life of humans and its entanglement with the viral world or an anthropology of the virus.

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Acknowledgements

We wish to thank the conveners and participants of the Corona Multispecies Reading Group for providing a generative multidisciplinary forum to think about the virus and the pandemic.

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Department of History and Institute for Society and Genetics, University of California Los Angeles, Los Angeles, USA

Soraya de Chadarevian

Department of Cultural Heritage, Alma Mater University of Bologna, Via degli Ariani, 1, Ravenna, Italy

Roberta Raffaetà

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de Chadarevian, S., Raffaetà, R. COVID-19: Rethinking the nature of viruses. HPLS 43 , 2 (2021). https://doi.org/10.1007/s40656-020-00361-8

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History of Virus

Table of Contents

What are Viruses?

Are viruses alive, the progressive hypothesis, the regressive hypothesis, the virus-first hypothesis, pioneers of virology.

Viruses are small infectious agents that can divide only inside a host cell such as plants, animals or bacteria. Because they can be grown in-vitro and require a cell machinery to divide, they are also known as genetic parasites.

They are a diverse group of organisms that include viruses that have RNA genome (poliovirus), DNA genome (herpesvirus), double stranded genetic material (smallpox) or single stranded genetic material (influenza virus). Their replication models and structures are equally diverse. However, viruses do have some common features, such as very small size (<200 nm), their ability to replicate only within host cells and absence of ribosomes.

It is a controversial and open-ended question that still has no answer. Living organisms possess certain properties such as, their ability to grow, reproduce, respond to stimuli, carry out metabolic processes and maintain homeostasis.

On checking if viruses fit in this criteria, it was observed that, viruses do reproduce within host cells and cause infectious diseases but they do not carry out metabolic processes. They also do not have ribosomes , hence cannot replicate on their own.

In conclusion, many scientists believe them to be living while many believe them to be non-living.

Where did the virus come from? To answer this question, three hypotheses were put forward. Let us look at them one by one.

This hypothesis states that viruses originated in a progressive manner. The viruses were thought to be composed of mobile genetic elements. Mobile genetic elements are pieces of the genome that have the ability to move, i.e., they can exit from one cell and enter another.

This origin theory can be linked to retrotransposons which are a common occurrence in eukaryotes. Retrotransposons are also mobile genetic elements that copy-paste themselves into different locations by converting RNA back to DNA using reverse transcription. These mobile genetic elements may have been the basis of the origin of viruses.

This hypothesis states that the viruses may have originated in a regressive or reduced manner. It was believed that certain bacteria that are obligate parasites may have evolved from free-living ancestors. It was then deduced that viruses might have evolved from complex free-living organisms that lost their genetic information over time and adopted a parasitic mode of life.

The descendants of these complex free-living organisms first became symbiotic in nature. Slowly over time, one organism became more dependent on the other and the relationship became parasitic in nature. This led to the loss of essential genes in the organism and it became unable to replicate independently.

Both the progressive and regressive theories assumed that viruses originated from pre-existing cells. In the virus-first hypothesis it was questioned that what if viruses existed first? It was postulated that viruses existed as self-replicating units in the previous times.

There is no specific conclusion to the above postulated hypotheses. The possibility of viruses arising from progressive manner or regressive manner is large. Perhaps, the third hypothesis about viruses being the first ones to originate also has intriguing implications. It could be that viruses arose multiple times through multiple mechanisms or they originated by a method which we are still to discover.

Louis Pasteur, a French microbiologist speculated the existence of a submicroscopic organism/particle when he couldn’t find the causative agent for rabies. Charles Chamberland, a fellow scientist of Louis Pasteur then invented a filter, known as the Chamberland filter in 1884 that consisted of pores smaller than the size of bacteria.

Adolf Eduard Mayer, a German chemist, published his work showing the mosaic disease of tobacco. He showed that the disease could be transferred from an infected plant to a healthy plant by rubbing the liquid extract and thought it to be a bacterial disease. Dmitri Ivanovski, a Russian botanist then used the Chamberland filter for the first time to demonstrate that the leaf extract of plants infected with the tobacco mosaic disease remained infectious even after filtration.

In 1898, Martinus Beijerinck, a Dutch botanist repeated the experiments of Adolf Mayer and came to a conclusion that the disease was caused by a new form of an infectious agent. He observed that the agent only multiplied in living cells and called it contagium vivum fluidum (soluble liquid germ) and named it as virus. He was convinced that the agent has a liquid and soluble nature. Ivanovsky and Beijerinck’s work was published as “One Hundred Years of Virology” in 1992 to honour their work.

In 1898, two German scientists Friedrich Loeffler and Paul Frosch, discovered the second virus Foot and mouth disease virus (FMDV). They are believed to be the true discoverers of the virus as they concluded that the virus was a particle, not a soluble liquid. Yellow fever virus was the first human virus to be discovered.

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COVID-19 Pandemic

By: History.com Editors

Updated: March 11, 2024 | Original: April 25, 2023

The outbreak of the infectious respiratory disease known as COVID-19 triggered one of the deadliest pandemics in modern history. COVID-19 claimed nearly 7 million lives worldwide. In the United States, deaths from COVID-19 exceeded 1.1 million, nearly twice the American death toll from the 1918 flu pandemic . The COVID-19 pandemic also took a heavy toll economically, politically and psychologically, revealing deep divisions in the way that Americans viewed the role of government in a public health crisis, particularly vaccine mandates. While the United States downgraded its “national emergency” status over the pandemic on May 11, 2023, the full effects of the COVID-19 pandemic will reverberate for decades.

A New Virus Breaks Out in Wuhan, China

In December 2019, the China office of the World Health Organization (WHO) received news of an isolated outbreak of a pneumonia-like virus in the city of Wuhan. The virus caused high fevers and shortness of breath, and the cases seemed connected to the Huanan Seafood Wholesale Market in Wuhan, which was closed by an emergency order on January 1, 2020.

After testing samples of the unknown virus, the WHO identified it as a novel type of coronavirus similar to the deadly SARS virus that swept through Asia from 2002-2004. The WHO named this new strain SARS-CoV-2 (Severe Acute Respiratory Syndrome Coronavirus 2). The first Chinese victim of SARS-CoV-2 died on January 11, 2020.

Where, exactly, the novel virus originated has been hotly debated. There are two leading theories. One is that the virus jumped from animals to humans, possibly carried by infected animals sold at the Wuhan market in late 2019. A second theory claims the virus escaped from the Wuhan Institute of Virology, a research lab that was studying coronaviruses. U.S. intelligence agencies maintain that both origin stories are “plausible.”

The First COVID-19 Cases in America

The WHO hoped that the virus outbreak would be contained to Wuhan, but by mid-January 2020, infections were reported in Thailand, Japan and Korea, all from people who had traveled to China.

On January 18, 2020, a 35-year-old man checked into an urgent care center near Seattle, Washington. He had just returned from Wuhan and was experiencing a fever, nausea and vomiting. On January 21, he was identified as the first American infected with SARS-CoV-2.

In reality, dozens of Americans had contracted SARS-CoV-2 weeks earlier, but doctors didn’t think to test for a new type of virus. One of those unknowingly infected patients died on February 6, 2020, but her death wasn’t confirmed as the first American casualty until April 21.

On February 11, 2020, the WHO released a new name for the disease causing the deadly outbreak: Coronavirus Disease 2019 or COVID-19. By mid-March 2020, all 50 U.S. states had reported at least one positive case of COVID-19, and nearly all of the new infections were caused by “community spread,” not by people who contracted the disease while traveling abroad. 

At the same time, COVID-19 had spread to 114 countries worldwide, killing more than 4,000 people and infecting hundreds of thousands more. On March 11, the WHO made it official and declared COVID-19 a pandemic.

The World Shuts Down

Pandemics are expected in a globally interconnected world, so emergency plans were in place. In the United States, health officials at the Centers for Disease Control and Prevention (CDC) and the National Institutes of Health (NIH) set in motion a national response plan developed for flu pandemics.

State by state and city by city, government officials took emergency measures to encourage “ social distancing ,” one of the many new terms that became part of the COVID-19 vocabulary. Travel was restricted. Schools and churches were closed. With the exception of “essential workers,” all offices and businesses were shuttered. By early April 2020, more than 316 million Americans were under a shelter-in-place or stay-at-home order.

With more than 1,000 deaths and nearly 100,000 cases, it was clear by April 2020 that COVID-19 was highly contagious and virulent. What wasn’t clear, even to public health officials, was how individuals could best protect themselves from COVID-19. In the early weeks of the outbreak, the CDC discouraged people from buying face masks, because officials feared a shortage of masks for doctors and hospital workers.

By April 2020, the CDC revised its recommendations, encouraging people to wear masks in public, to socially distance and to wash hands frequently. President Donald Trump undercut the CDC recommendations by emphasizing that masking was voluntary and vowing not to wear a mask himself. This was just the beginning of the political divisions that hobbled the COVID-19 response in America.

Global Financial Markets Collapse

In the early months of the COVID-19 pandemic, with billions of people worldwide out of work, stuck at home, and fretting over shortages of essential items like toilet paper , global financial markets went into a tailspin.

In the United States, share prices on the New York Stock Exchange plummeted so quickly that the exchange had to shut down trading three separate times. The Dow Jones Industrial Average eventually lost 37 percent of its value, and the S&P 500 was down 34 percent.

Business closures and stay-at-home orders gutted the U.S. economy. The unemployment rate skyrocketed, particularly in the service sector (restaurant and other retail workers). By May 2020, the U.S. unemployment rate reached 14.7 percent, the highest jobless rate since the Great Depression . 

All across America, households felt the pinch of lost jobs and lower wages. Food insecurity reached a peak by December 2020 with 30 million American adults—a full 14 percent—reporting that their families didn’t get enough to eat in the past week.

The economic effects of the COVID-19 pandemic, like its health effects, weren’t experienced equally. Black, Hispanic and Native Americans suffered from unemployment and food insecurity at significantly higher rates than white Americans. 

Congress tried to avoid a complete economic collapse by authorizing a series of COVID-19 relief packages in 2020 and 2021, which included direct stimulus checks for all American families.

The Race for a Vaccine

A new vaccine typically takes 10 to 15 years to develop and test, but the world couldn’t wait that long for a COVID-19 vaccine. The U.S. Department of Health and Human Services (HHS) under the Trump administration launched “ Operation Warp Speed ,” a public-private partnership which provided billions of dollars in upfront funding to pharmaceutical companies to rapidly develop vaccines and conduct clinical trials.

The first clinical trial for a COVID-19 vaccine was announced on March 16, 2020, only days after the WHO officially classified COVID-19 as a pandemic. The vaccines developed by Moderna and Pfizer were the first ever to employ messenger RNA, a breakthrough technology. After large-scale clinical trials, both vaccines were found to be greater than 95 percent effective against infection with COVID-19.

A nurse from New York officially became the first American to receive a COVID-19 vaccine on December 14, 2020. Ten days later, more than 1 million vaccines had been administered, starting with healthcare workers and elderly residents of nursing homes. As the months rolled on, vaccine availability was expanded to all American adults, and then to teenagers and all school-age children.

By the end of the pandemic in early 2023, more than 670 million doses of COVID-19 vaccines had been administered in the United States at a rate of 203 doses per 100 people. Approximately 80 percent of the U.S. population received at least one COVID-19 shot, but vaccination rates were markedly lower among Black, Hispanic and Native Americans.

COVID-19 Deaths Heaviest Among Elderly and People of Color

In America, the COVID-19 pandemic impacted everyone’s lives, but those who died from the disease were far more likely to be older and people of color.

Of the more than 1.1 million COVID deaths in the United States, 75 percent were individuals who were 65 or older. A full 93 percent of American COVID-19 victims were 50 or older. Throughout the emergence of COVID-19 variants and the vaccine rollouts, older Americans remained the most at-risk for being hospitalized and ultimately dying from the disease.

Black, Hispanic and Native Americans were also at a statistically higher risk of developing life-threatening COVID-19 systems and succumbing to the disease. For example, Black and Hispanic Americans were twice as likely to be hospitalized from COVID-19 than white Americans. The COVID-19 pandemic shined light on the health disparities between racial and ethnic groups driven by systemic racism and lower access to healthcare.

Mental health also worsened during the COVID-19 pandemic. The anxiety of contracting the disease, and the stresses of being unemployed or confined at home, led to unprecedented numbers of Americans reporting feelings of depression and suicidal ideation.

A Time of Social & Political Upheaval

In the United States, the three long years of the COVID-19 pandemic paralleled a time of heightened political contention and social upheaval.

When George Floyd was killed by Minneapolis police on May 25, 2020, it sparked nationwide protests against police brutality and energized the Black Lives Matter movement. Because so many Americans were out of work or home from school due to COVID-19 shutdowns, unprecedented numbers of people from all walks of life took to the streets to demand reforms.

Instead of banding together to slow the spread of the disease, Americans became sharply divided along political lines in their opinions of masking requirements, vaccines and social distancing.

By March 2024, in signs that the pandemic was waning, the CDC issued new guidelines for people who were recovering from COVID-19. The agency said those infected with the virus no longer needed to remain isolated for five days after symptoms. And on March 10, 2024, the Johns Hopkins Coronavirus Resource Center stopped collecting data for its highly referenced COVID-19 dashboard.

Still, an estimated 17 percent of U.S. adults reported having experienced symptoms of long COVID, according to the Household Pulse Survey. The medical community is still working to understand the causes behind long COVID, which can afflict a patient for weeks, months or even years.

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“CDC Museum COVID Timeline.” Centers for Disease Control and Prevention . “Coronavirus: Timeline.” U.S. Department of Defense . “COVID-19 and Related Vaccine Development and Research.” Mayo Clinic . “COVID-19 Cases and Deaths by Race/Ethnicity: Current Data and Changes Over Time.” Kaiser Family Foundation . “Number of COVID-19 Deaths in the U.S. by Age.” Statista . “The Pandemic Deepened Fault Lines in American Society.” Scientific American . “Tracking the COVID-19 Economy’s Effects on Food, Housing, and Employment Hardships.” Center on Budget and Policy Priorities . “U.S. Confirmed Country’s First Case of COVID-19 3 Years Ago.” CNN .

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Bombs and viruses: The shadowy history of Israel’s attacks on Iranian soil

From cyberattacks and assassinations to drone strikes, Israel-linked plots have targeted Iran and its nuclear programme for years.

Israel’s leaders have signalled that they are weighing their options on how to respond to Iran’s attack early Sunday morning, when Tehran targeted its archenemy with more than 300 missiles and drones .

Iran’s attack, which followed  an Israeli strike last week on the Iranian consulate in Damascus, Syria, that killed 13 people was historic: It was the first time Tehran had directly targeted Israeli soil, despite decades of hostility. Until Sunday, many of Iran’s allies in the so-called axis of resistance — especially the Palestinian group Hamas, the Lebanese group Hezbollah, Yemen’s Houthis and armed groups in Iraq and Syria — were the ones who launched missiles and drones at Israel.

But if Israel were to hit back militarily inside Iran, it wouldn’t be the first time. Far from it.

For years, Israel has focused on one target within Iran in particular: the country’s nuclear programme. Israel has long accused Iran of clandestinely building a nuclear bomb that could threaten its existence — and has publicly, and frequently, spoken of its diplomatic and intelligence-driven efforts to derail those alleged efforts. Iran denies that it has had a military nuclear programme, while arguing that it has the right to access civil nuclear energy.

As Israel prepares its response, here’s a look at the range of attacks in Iran — from drone strikes and cyberattacks to assassinations of scientists and the theft of secrets — that Israel has either accepted it was behind or is accused of having orchestrated.

Assassinations of Iranian scientists

• January 2010 : A physics professor at Tehran University, Masoud Ali-Mohammadi , was killed through a remote-controlled bomb planted in his motorcycle. Iranian state media claimed that the US and Israel were behind the attack. The Iranian government described Ali-Mohammadi as a nuclear scientist.
• November 2010 : A professor at the nuclear engineering faculty at Shahid Beheshti University in Tehran, Majid Shahriari , was killed in a car explosion on his way to work. His wife was also wounded. The president of Iran at the time, Mahmoud Ahmadinejad, blamed the United States and Israel for the attacks.
• January 2012 : Mostafa Ahmadi Roshan , a chemical engineering graduate, was killed by a bomb placed on his car by a motorcyclist in Tehran. Iran blamed Israel and the US for the attack and said Ahmadi Roshan was a nuclear scientist who supervised a department at Iran’s primary uranium enrichment facility, in the city of Natanz.
• November 2020 :Prominent nuclear scientist Mohsen Fakhrizadeh was killed in a roadside attack outside Tehran. Western and Israeli intelligence had long suspected that Fakhrizadeh was the father of an Iranian nuclear weapons programme. He was sanctioned by the United Nations in 2007 and the US in 2008.
• May 2022 : Colonel Hassan Sayyad Khodaei of the Islamic Revolutionary Guard Corps (IRGC) was shot five times outside of his home in Tehran. Majid Mirahmadi, a member of Iran’s Supreme National Security Council, alleged the assassination was “definitely the work of Israel”.

Israel’s cyberattacks on Iran

• June 2010 :The Stuxnet virus was found in computers at the nuclear plant in Iran’s Bushehr city, and it spread from there to other facilities. As many as 30,000 computers across at least 14 facilities were impacted by September 2010. At least 1,000 out of 9,000 centrifuges in Iran’s Natanz enrichment facility were destroyed, according to an estimate by the Institute for Science and International Security. Upon investigation, Iran blamed Israel and the US for the virus attack.
• April 2011 : A virus called Stars was discovered by the Iranian cyberdefence agency which said the malware was designed to infiltrate and damage Iran’s nuclear facilities. The virus mimicked official government files and inflicted “minor damage” on computer systems, according to Gholamreza Jalali, the head of Iran’s Passive Defense Organization. Iran blamed Israel and the US.
• November 2011 : Iran said it discovered a new virus called Duqu, based on Stuxnet. Experts said Duqu was intended to gather data for future cyberattacks. The Iranian government announced it was checking computers at main nuclear sites. The Duqu spyware was widely believed by experts to have been linked to Israel.
• April 2012 : Iran blamed the US and Israel for malware called Wiper, which erased the hard drives of computers owned by the Ministry of Petroleum and the National Iranian Oil Company.
• May 2012 : Iran announced that a virus called Flame had tried to steal government data from government computers. The Washington Post reported that Israel and the US had used it to collect intelligence. Then-Israeli Vice Prime Minister Moshe Yaalon did not confirm the nation’s involvement but acknowledged that Israel would use all means to “harm the Iranian nuclear system”.
• October 2018 : The Iranian government said that it had blocked an invasion by a new generation of Stuxnet, blaming Israel for the attack.
• October 2021 : A cyberattack hit the system that allows Iranians to use government-issued cards to purchase fuel at a subsidised rate, affecting all 4,300 petrol stations in Iran. Consumers had to either pay the regular price, more than double the subsidised one, or wait for stations to reconnect to the central distribution system. Iran blamed Israel and the US.
• May 2020 : A cyberattack impacted computers that control maritime traffic at Shahid Rajaee port on Iran’s southern coast in the Gulf, creating a hold-up of ships that waited to dock. The Washington Post quoted US officials as saying that Israel was behind the attack, though Israel did not claim responsibility.

Israel’s drone strikes and raids on Iran

• January 2018 : Mossad agents raided a secure Tehran facility, stealing classified nuclear archives. In April 2018, Israeli Prime Minister Benjamin Netanyahu announced that Israel discovered 100,000 “secret files that prove” Iran lied about never having a nuclear weapons programme.
• February 2022 : Former Israeli Prime Minister Naftali Bennett admitted in an op-ed published in The Wall Street Journal in December 2023, that Israel carried out an attack on an unmanned aerial vehicle, and assassinated a senior IRGC commander in February of the previous year.
• May 2022 : Explosives-laden quadcopter suicide drones hit the Parchin military complex southeast of Tehran, killing an engineer and damaging a building where drones had been developed by the Ministry of Defence and Armed Forces. IRGC Commander Hossein Salami pledged retaliation against unspecified “enemies”.
• January 2023 : Several suicide drones struck a military facility in central Isfahan, but they were thwarted and caused no damage. While Iran did not immediately place blame for the attacks, Iran’s UN envoy, Amir Saeid Iravani, wrote a letter to the UN chief saying that “primary investigation suggested Israel was responsible”.
• February 2024 : A natural gas pipeline in Iran was attacked. Iran’s Oil Minister Javad Owji alleged that the “explosion of the gas pipeline was an Israeli plot”.

Current H5N1 Bird Flu Situation in Dairy Cows

Domestic Summary

Global summary, risk to humans.

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Dairy Herds Affected

CDC systems that monitor national, state, and local level influenza data are being used during the current avian influenza A(H5N1) situation. These systems show no indicators of unusual influenza activity in people, including avian influenza A(H5N1).

A multi-state outbreak of HPAI A(H5N1) bird flu in dairy cows  was first reported on March 25, 2024. This is the first time that these bird flu viruses were found in cattle. CDC confirmed one human HPAI A(H5N1) infection  that had exposure to dairy cattle in Texas that were presumed to be infected with the virus. While thought to be rare, this exposure to HPAI A(H5N1) bird flu virus is the first instance of likely mammal to human transmission.

In the United States, since 2022, USDA APHIS has reported HPAI A(H5N1) virus detections  in more than 200 mammals .

While rare, mammals can be infected with highly pathogenic avian influenza (HPAI) A(H5N1) (“H5N1 bird flu”) viruses. Reports of these sporadic infections in mammals have occurred globally amid widespread outbreaks of bird flu infections in wild birds and poultry.

Mammals can be infected with H5N1 bird flu viruses when they eat infected birds, poultry, or other animals and/or if they are exposed to environments contaminated with virus. Spread of H5N1 bird flu viruses from mammal to mammal is thought to be rare, but possible.

Globally, sporadic HPAI A(H5N1) virus infections in mammals have been reported across the continents of Asia, North America, South America, and Europe. More information about the global impact of avian influenza can be found here: Avian Influenza – WOAH – World Organisation for Animal Health.

Specifically, recent HPAI A(H5N1) infections in mammals have been detected in sea lions in Peru and Chile, sea elephants in Argentina, and foxes in Canada, France, and other countries. A list of significant HPAI outbreaks, including in mammals, can be found here: Highlights in the History of Avian Influenza (Bird Flu) Timeline – 2020-2024.

The wide geographic spread of HPAI A(H5N1) viruses in wild birds, poultry, and some other mammals, including in cows, could create additional opportunities for people to be exposed to these viruses. Therefore, there could be an increase in sporadic human infections resulting from bird and animal exposures, even if the risk of these viruses spreading from birds to people has not increased. CDC believes the current risk to the general public from bird flu viruses is low. People who have job-related or recreational exposure to infected birds or animals, including cows, are at greater risk of contracting HPAI A(H5N1) virus. CDC has recommendations related to testing, treatment of HPAI A(H5N1) infection and prevention of exposure to these viruses: Highly Pathogenic Avian Influenza A(H5N1) Virus in Animals: Interim Recommendations for Prevention, Monitoring, and Public Health Investigations .

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• Questions and Answers Regarding Milk Safety During Highly Pathogenic Avian Influenza (HPAI) Outbreaks
• Questions and Answers Regarding the Safety of Eggs During Highly Pathogenic Avian Influenza Outbreaks

In recent years, HPAI H5N1 infections have been detected in mammals including but not limited to wild or feral animals such as foxes, bears, and seals; stray or domestic animals such as cats and dogs; farm animals, such as goats, cows, and mink, and zoo animals such as tigers and leopards. A timeline, which includes mammalian detections of bird flu, can be found here: Highlights in the History of Avian Influenza (Bird Flu) Timeline – 2020-2024

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Shadow War Between Iran and Israel: A Timeline

A recent round of strikes has brought the conflict more clearly into the open and raised fears of a broader war.

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By Cassandra Vinograd

• April 19, 2024

For decades, Israel and Iran have fought a shadow war across the Middle East , trading attacks by land, sea, air and in cyberspace. A recent round of strikes — mainly an aerial barrage by Iran against Israel last weekend — has brought the conflict more clearly into the open and raised fears of a broader war.

A retaliatory Israeli strike on an Iranian air base on Friday, however, appeared limited in scope, and analysts said it suggested an effort to pull back from the dangerous cycle and potentially move the war back into the shadows.

Here is a recent history of the conflict:

August 2019: An Israeli airstrike killed two Iranian-trained militants in Syria, a drone set off a blast near a Hezbollah office in Lebanon and an airstrike in Qaim, Iraq, killed a commander of an Iran-backed Iraqi militia. Israel accused Iran at the time of trying to establish an overland arms-supply line through Iraq and northern Syria to Lebanon, and analysts said the strikes were aimed at stopping Iran and signaling to its proxies that Israel would not tolerate a fleet of smart missiles on its borders.

January 2020: Israel greeted with satisfaction the assassination of Maj. Gen. Qassim Suleimani , the commander of the foreign-facing arm of Iran’s Islamic Revolutionary Guards Corps, in an American drone strike in Baghdad.

Iran hit back by attacking two bases in Iraq that housed American troops with a barrage of missiles, wounding about 100 U.S. military personnel .

2021-22: In July 2021, an oil tanker managed by an Israeli-owned shipping company was attacked off the coast of Oman, killing two crew members, according to the company and three Israeli officials. Two of the officials said that the attack appeared to have been carried out by Iranian drones.

Iran did not explicitly claim or deny responsibility, but a state-owned television channel described the episode as a response to an Israeli strike in Syria.

In November 2021, Israel killed Iran’s top nuclear scientist, Mohsen Fakhrizadeh , and followed up with the assassination of a Revolutionary Guards commander, Col. Sayad Khodayee , in May 2022.

December 2023: After Israel’s bombardment of Gaza began in response to the Oct. 7 Hamas-led assault, Iranian-backed militias stepped up their own attacks . And late last year, Iran accused Israel of killing a high-level military figure, Brig. Gen. Sayyed Razi Mousavi , in a missile strike in Syria.

A senior adviser to the Revolutionary Guards, General Mousavi was described as having been a close associate of General Suleimani and was said to have helped oversee the shipment of arms to Hezbollah. Israel, adopting its customary stance, declined to comment directly on whether it was behind General Mousavi’s death.

January 2024: An explosion in a suburb of Beirut, Lebanon, killed Saleh al-Arouri , a Hamas leader, along with two commanders from that group’s armed wing, the first assassination of a top Hamas official outside the West Bank and Gaza in recent years. Officials from Hamas, Lebanon and the United States ascribed the blast to Israel , which did not publicly confirm involvement.

Hezbollah, which receives major support from Iran, stepped up its assaults on Israel after Mr. al-Arouri’s death. Israel’s military hit back at Hezbollah in Lebanon, killing several of the group’s commanders .

March: An Israeli drone strike hit a car in southern Lebanon, killing at least one person. Israel’s military said it had killed the deputy commander of Hezbollah’s rocket and missile unit. Hezbollah acknowledged the death of a man, Ali Abdulhassan Naim, but did not provide further details.

The same day, airstrikes killed soldiers near Aleppo, northern Syria, in what appeared to be one of the heaviest Israeli attacks in the country in years. The strikes killed 36 Syrian soldiers, seven Hezbollah fighters and a Syrian from a pro-Iran militia, according to the Syrian Observatory for Human Rights, a British-based group that tracks Syria’s civil war.

Israel’s military did not claim responsibility. But the country’s defense minister, Yoav Gallant, wrote on social media, “We will pursue Hezbollah every place it operates and we will expand the pressure and the pace of the attacks.”

April: A strike on an Iranian Embassy building in Damascus on April 1 killed three top Iranian commanders and four officers. Iran blamed Israel and vowed to hit back forcefully.

Two weeks later, Tehran launched a barrage of more than 300 drones and missiles at Israel, an unexpectedly large-scale attack , although nearly all the weapons were shot down by Israel and allies. Israel said for days it would respond, before a strike on Friday hit a military air base near the central Iranian city of Isfahan.

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Virals: an Essay on VIRUSES: The History and Threats of Viruses in Human Life. © H. J. Spencer [23Sep.2021] 9,300 words (15 pages).

This essay is designed to investigate the mystery of the virus: the smallest form of organic material that is able to replicate itself by following a parasitic approach that needs an external, living cell. As it is quite unable to metabolize nutrients, it is not considered to be alive. This essay will share some little known facts about viruses and help to dispel some dangerous myths that evolved about them and the vaccines used against them. Since 1892 when scientists started to investigate these objects, they have been confronted with the primary mystery: what are viruses? How do they survive on their endless quest from host to host? This essay will concentrate on the virulent viruses: those that cause a major threat to humanity; we will focus on the Big Three: smallpox, polio and influenza. The influenza story becomes central because it illustrates the false assumptions that have been made in the past with earlier false alarms, such as the Swine Flu panic of 1976 and the even larger false assumptions about the 'Great Spanish Flu Pandemic' of 1918-1920, where most deaths were due to deadly bacteria. The present covid panic seems to be a reflection of the 1976 Swine Flu panic. Several other viruses are examined (like Hepatitis B and the Herpes family: Herpes Simplex and Epstein-Barr) as they illustrate the successful vaccines used to defeat them; interestingly, this has NOT been used here in the current Covid Panic. This study of viruses has increased my respect for the variety of nature, no matter what its scale but a better understanding of how they function will help us react to their ongoing threats. Knowing their structure, is only the first step in understanding what is going on: processes are more significant than structure (relationships are key to knowledge; not just identifying-and naming-objects). Although written for an educated audience (but not virologists) there is much here of interest to non-scientists to show HOW real virology is done (slowly: one discovery at a time). I hope this great story will appeal to many.

Related Papers

Encyclopedia of Virology - 4th Edition

Neeraja Sankaran

Carolina Mendeiro

Mohamed Ali

Golden Meteorite Press

Austin A Mardon , Yi Yang Fei , Chitrini Tandon , Christina Nguyen , Noah Varghese , Grace Nzovwa Zulu-Sitima

Viruses in humans can be traced back to the 1900s. Smallpox and measles are the oldest, and as of 2012, 219 virus species affecting humans were identified. Among them are Yellow fever, influenza, Zika, Polio, Human Immunodeficiency Virus (HIV), Ebola and Corona virus, which was discovered in 2019. Viruses were discovered over a period of time through rigorous processes which continue to be utilized with the application of new knowledge, which makes new findings modify and rediscover their inevitability. What in the World are Viruses? Each chapter in this book helps the reader sift through individual themes of well-researched and articulated articles for easy understanding written to contribute towards building on existing knowledge on viruses. The impact of viruses on humans cannot be ignored, especially in this era where the world is grappling with the effects of Corona Virus that has claimed many lives worldwide. The impact of virus outbreaks on a macro scale in society has been felt globally with disruptions of economies and livelihoods. Against this background, this publication explores the importance of studying viruses, particularly their effect on individuals. A chapter in the book looks at how a virus affects society, unearthing how a pandemic affects the global supply chain, how easily hospitals can become overwhelmed, the economic impact of viruses, and the positive impact that viruses have on society. Effects make the issue of viruses of utmost importance to study. Researching on viruses has improved knowledge to find solutions through vaccines' discovery, identifying preventive measures to eradicate the danger that viruses present to humans. Anti-viral treatments are available in the world today as a solution to fight against viruses. With this, many lives have been saved as people continue to access treatment. Although controversies surrounding viruses exist, they do not deter research on viruses from continuing. Information contained in this publication will add value to your knowledge base; this is why you should take time to read and enjoy the book.

Emerging and Reemerging Viral Pathogens

Moulay Mustapha Ennaji

Bishnupriya Ghosh

Judy Diamond

Mike Collier

In 2011, I was invited by Dr. Shirley Wheeler to make new work for a multi-media exhibition at St. John&#39;s College, Oxford University, based around the theme Virus. The brief for this project was broad and flexible. The exhibition aimed to engage the public with the science of viruses through a variety of creative approaches - approaches informed by some aspect, understanding or inspiration gained from the scientific knowledge pertaining to viruses. The exhibition provided insights, challenges and perspectives that help to lead people to a new or different comprehension of this field of science. It took a fresh look at this area of science through the eyes of contemporary artists and designers and was deliberately multidisciplinary with two, three dimensional and interactive work. For my work, I decided to take the theme of the decline of the bumblebee - a decline caused by the spread of viruses - a spread which can, to some extent, be contained if the bee population is healthy -...

Acta Virologica

Junior Rodas

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Institute of Medicine (US) Forum on Microbial Threats; Knobler SL, Mack A, Mahmoud A, et al., editors. The Threat of Pandemic Influenza: Are We Ready? Workshop Summary. Washington (DC): National Academies Press (US); 2005.

The Threat of Pandemic Influenza: Are We Ready? Workshop Summary.

• Hardcopy Version at National Academies Press

1 The Story of Influenza

In the early 20th century, science was sufficiently sophisticated to anticipate that influenza, which had twice reached pandemic proportions in the late 19th century, would recur, but was largely powerless to blunt the devastating impact of the 1918 (H1N1) pandemic. Since then, mankind has gained several advantages against the disease: experience of three better characterized pandemics (1918, 1957, and 1968); knowledge of influenza viruses; capacity to design and manufacture vaccines and antiviral drugs to forestall (if not prevent) infection; and molecular technology that may one day pinpoint the viral components that produce virulence, and thereby identify targets for more effective vaccines and drugs.

Yet the world is vulnerable to the next pandemic, perhaps even more than in 1918, when the pace and frequency of global travel was considerably less than today. As the contributors to this chapter demonstrate, there is still much to be learned from past pandemics that can strengthen defenses against future threats. The chapter begins with a review of the events of 1918, the lessons they offer, and the historical and scientific questions they raise. It describes the epidemiology and symptomology of that deadly viral strain, limited efforts toward prevention and treatment, and the resulting social disruption and its exacerbation by the actions of public officials and the media.

The chapter continues with an account of molecular studies underway to determine the origin of the 1918 virus and the source(s) of its exceptional virulence. Clues are being sought by examining viruses preserved in frozen and fixed tissues of victims of the 1918 flu. Characterization of five of the eight RNA segments of the 1918 influenza virus indicates that it was the common ancestor of both subsequent human and swine H1N1 lineages, and experiments testing models of virulence using reverse genetics approaches with 1918 influenza genes have begun in hopes of identifying genetic features that confer virulence in humans.

In a parallel effort, subsequently described, epidemiologists are analyzing death records and serological data to better understand patterns of transmission, morbidity, and mortality in past influenza pandemics. Such findings could inform planning for public health interventions to reduce the incidence of severe outcomes in future pandemics. In particular, these studies reveal a signature change in excess mortality from the elderly to younger age groups, a “pandemic age shift,” that occurred with each of the three pandemics of the 20th century. If such a shift could be recognized in incipient pandemics, it might allow sufficient time for the production and distribution of vaccine and antiviral drugs before the worst pandemic impact occurs.

• 1918 REVISITED: LESSONS AND SUGGESTIONS FOR FURTHER INQUIRY

John M. Barry

Distinguished Visiting Scholar

Center for Bioenvironmental Research at Tulane and Xavier Universities

The 1918–1919 influenza pandemic killed more people in absolute numbers than any other disease outbreak in history. A contemporary estimate put the death toll at 21 million, a figure that persists in the media today, but understates the real number. Epidemiologists and scientists have revised that figure several times since then. Each and every revision has been upward. Frank Macfarlane Burnet, who won his Nobel Prize for immunology but who spent most of his life studying influenza, estimated the death toll as probably 50 million, and possibly as high as 100 million. A 2002 epidemiologic study also estimates the deaths at between 50 and 100 million ( Johnson and Mueller, 2002 ).

The world population in 1918 was only 28 percent of today's population. Adjusting for population, a comparable toll today would be 175 to 350 million. By comparison, at this writing AIDS has killed approximately 24 million, and an estimated 40 million more people are infected with the virus.

A letter from a physician at one U.S. Army camp to a colleague puts a more human face on those numbers:

These men start with what appears to be an ordinary attack of LaGrippe or Influenza, and when brought to the Hosp. they very rapidly develop the most vicious type of Pneumonia that has ever been seen … and a few hours later you can begin to see the Cyanosis extending from their ears and spreading all over the face, until it is hard to distinguish the colored men from the white. It is only a matter of a few hours then until death comes…. It is horrible. One can stand it to see one, two or twenty men die, but to see these poor devils dropping like flies…. We have been averaging about 100 deaths per day…. Pneumonia means in about all cases death…. We have lost an outrageous number of Nurses and Drs. It takes special trains to carry away the dead. For several days there were no coffins and the bodies piled up something fierce…. It beats any sight they ever had in France after a battle. An extra long barracks has been vacated for the use of the Morgue, and it would make any man sit up and take notice to walk down the long lines of dead soldiers all dressed and laid out in double rows…. Good By old Pal, God be with you till we meet again ( Grist, 1979 ).

That letter reflected a typical experience in American Army cantonments. The civilian experience was not much better.

In preparing for another pandemic, it is useful to examine events of 1918 for lessons, warnings, and areas for further inquiry.

The Virus Itself

The pandemic in 1918 was hardly the first influenza pandemic, nor was it the only lethal one. Throughout history, there have been influenza pandemics, some of which may have rivaled 1918's lethality. A partial listing of particularly violent outbreaks likely to have been influenza include one in 1510 when a pandemic believed to come from Africa “attacked at once and raged all over Europe not missing a family and scarce a person” ( Beveridge, 1977 ). In 1580, another pandemic started in Asia, then spread to Africa, Europe, and even America (despite the fact that it took 6 weeks to cross the ocean). It was so fierce “that in the space of six weeks it afflicted almost all the nations of Europe, of whom hardly the twentieth person was free of the disease” and some Spanish cities were “nearly entirely depopulated by the disease” ( Beveridge, 1977 ). In 1688, influenza struck England, Ireland, and Virginia; in all these places “the people dyed … as in a plague” ( Duffy, 1953 ). A mutated or new virus continued to plague Europe and America again in 1693 and Massachusetts in 1699. “The sickness extended to almost all families. Few or none escaped, and many dyed especially in Boston, and some dyed in a strange or unusual manner, in some families all were sick together, in some towns almost all were sick so that it was a time of disease” ( Pettit, 1976 ). In London in 1847 and 1848, more people died from influenza than from the terrible cholera epidemic of 1832. In 1889 and 1890, a great and violent worldwide pandemic struck again ( Beveridge, 1977 ).

But 1918 seems to have been particularly violent. It began mildly, with a spring wave. In fact, it was so mild that some physicians wonder if this disease actually was influenza. Typically, several Italian doctors argued in separate journal articles that this “febrile disease now widely prevalent in Italy [is] not influenza” ( Policlinico, 1918 ). British doctors echoed that conclusion; a Lancet article in July 1918 argued that the spring epidemic was not influenza because the symptoms, though similar to influenza, were “of very short duration and so far absent of relapses or complications” ( Little et al., 1918 ).

Within a few weeks of that Lancet article appearing, a second pandemic wave swept around the world. It also initially caused investigators to doubt that the disease was influenza—but this time because it was so virulent. It was followed by a third wave in 1919, and significant disease also struck in 1920. (Victims of the first wave enjoyed significant resistance to the second and third waves, offering compelling evidence that all were caused by the same virus. It is worth noting that the 1889–1890 pandemic also came in waves, but the third wave seemed to be the most lethal.)

The 1918 virus, especially in its second wave, was not only virulent and lethal, but extraordinarily violent. It created a range of symptoms rarely seen with the disease. After H5N1 first appeared in 1997, pathologists reported some findings “not previously described with influenza” ( To et al., 2001 ). In fact, investigators in 1918 described every pathological change seen with H5N1 and more ( Jordon, 1927 : 266–268).

Symptoms in 1918 were so unusual that initially influenza was misdiagnosed as dengue, cholera, or typhoid. One observer wrote, “One of the most striking of the complications was hemorrhage from mucous membranes, especially from the nose, stomach, and intestine. Bleeding from the ears and petechial hemorrhages in the skin also occurred” ( Ireland, 1928 : 57). A German investigator recorded “hemorrhages occurring in different parts of the interior of the eye” with great frequency ( Thomson and Thomson, 1934b ). An American pathologist noted: “Fifty cases of subconjunctival hemorrhage were counted. Twelve had a true hemotypsis, bright red blood with no admixture of mucus…. Three cases had intestinal hemorrhage” ( Ireland, 1928 : 13). The New York City Health Department's chief pathologist said, “Cases with intense pain look and act like cases of dengue … hemorrhage from nose or bronchi … paresis or paralysis of either cerebral or spinal origin … impairment of motion may be severe or mild, permanent or temporary … physical and mental depression. Intense and protracted prostration led to hysteria, melancholia, and insanity with suicidal intent” ( Jordon, 1927 : 265).

The 1918 virus also targeted young adults. In South African cities, those between the ages of 20 and 40 accounted for 60 percent of the deaths ( Katzenellenbogen, 1988 ). In Chicago the deaths among those aged 20 to 40 nearly quintupled deaths of those aged 41 to 60 ( Van Hartesveldt, 1992 ). A Swiss physician “saw no severe case in anyone over 50.” 1 In the “registration area” of the United States—those states and cities that kept reliable statistics—the single greatest number of deaths occurred in the cohort aged 25 to 29, the second greatest in those aged 30 to 34, and the third in those aged 20 to 24. More people died in each one of those 5-year groups than the total deaths among all those over age 60, and the combined deaths of those aged 20 to 34 more than doubled the deaths of all those over 50 ( U.S. Bureau of the Census, 1921 ). The single group most likely to die if infected were pregnant women. In 13 studies of hospitalized pregnant women during the 1918 pandemic, the death rate ranged from 23 to 71 percent ( Jordon, 1927 : 273). Of the pregnant women who survived, 26 percent lost the child ( Harris, 1919 ). (As far back as 1557, people connected influenza with miscarriage and the death of pregnant women.)

The case mortality rate varied widely. An overall figure is impossible to obtain, or even estimate reliably, because no solid information about total cases exists. In U.S. Army camps where reasonably reliable statistics were kept, case mortality often exceeded 5 percent, and in some circumstances exceeded 10 percent. In the British Army in India, case mortality for white troops was 9.6 percent, for Indian troops 21.9 percent.

In isolated human populations, the virus killed at even higher rates. In the Fiji islands, it killed 14 percent of the entire population in 16 days. In Labrador and Alaska, it killed at least one-third of the entire native population ( Jordan, 1927 ; Rice, 1988 ).

But perhaps most disturbing and most relevant for today is the fact that a significant minority—and in some subgroups of the population a majority—of deaths came directly from the virus, not from secondary bacterial pneumonias.

In 1918, pathologists were intimately familiar with the condition of lungs of victims of bacterial pneumonia at autopsy. But the viral pneumonias caused by the influenza pandemic were so violent that many investigators said the only lungs they had seen that resembled them were from victims of poison gas.

Then, the Army called them “atypical pneumonias.” Today we would call this atypical pneumonia Acute Respiratory Distress Syndrome (ARDS). The Army's pneumonia board judged that “more than half” of all the deaths among soldiers came from this atypical pneumonia ( Ireland, 1928 ).

One cannot extrapolate from this directly to the civilian population. Army figures represent a special case both in terms of demographics and environment, including overcrowded barracks.

Even so, the fact that ARDS likely caused more than half the deaths among young adults sends a warning. ARDS mortality rates today range from 40 to 60 percent, even with support in modern intensive care units (ICUs). In a pandemic, ICUs would be quickly overwhelmed, representing a major challenge for public health planners.

Treatment and Prevention in 1918

Physicians tried everything they knew, everything they had ever heard of, from the ancient art of bleeding patients, to administering oxygen, to developing new vaccines and sera (chiefly against what we now call Hemophilus influenzae—a name derived from the fact that it was originally considered the etiological agent—and several types of pneumococci). Only one therapeutic measure, transfusing blood from recovered patients to new victims, showed any hint of success.

George Whipple, later a Nobel laureate, studied numerous vaccines and sera and found them “without therapeutic benefit.” But of some vaccines he said, “The statistical evidence, so far as it goes, indicates a probability … [of] some prophylactic value.” 2 Some bacterial vaccines may have prevented particular secondary pneumonias.

Meanwhile, the public used home remedies of every description. None showed any evidence of effect.

Some nonmedical interventions did succeed. Total isolation, cutting a community off from the outside world, did work if done early enough. Gunnison, Colorado, a town that was a rail center and was large enough to have a college, succeeded in isolating itself. So did Fairbanks, Alaska. American Samoa escaped without a single case, while a few miles away in Western Samoa, 22 percent of the entire population died.

More interestingly—and perhaps importantly—an Army study found that isolating both individual victims and entire commands that contained infected soldiers “failed when and where [these measures] were carelessly applied,” but “did some good … when and where they were rigidly carried out” (Soper, undated draft report).

Even if isolation only slowed the virus, it had some value. One of the more interesting epidemiologic findings in 1918 was that the later in the second wave someone got sick, the less likely he or she was to die, and the more mild the illness was likely to be.

This was true in terms of how late in the second wave the virus struck a given area, and, more curiously, it was also true within an area. That is, cities struck later tended to suffer less, and individuals in a given city struck later also tended to suffer less. Thus west coast American cities, hit later, had lower death rates than east coast cities, and Australia, which was not hit by the second wave until 1919, had the lowest death rate of any developed country.

Again, more curiously, someone who got sick 4 days into an outbreak in one place was more likely to develop a viral pneumonia that progressed to ARDS than someone who got sick 4 weeks into the outbreak in the same place. They were also more likely to develop a secondary bacterial pneumonia, and to die from it.

The best data on this comes from the U.S. Army. Of the Army's 20 largest cantonments, in the first five affected, roughly 20 percent of all soldiers with influenza developed pneumonia. Of those, 37.3 percent died ( Soper, 1918 ; undated draft report).

In the last five camps affected—on average 3 weeks later—only 7.1 percent of influenza victims developed pneumonia. Only 17.8 percent of the soldiers who developed pneumonia died ( Soper, 1918 ).

Inside each camp the same trend held true. Soldiers struck down early died at much higher rates than soldiers in the same camp struck down late.

Similarly, the first cities struck—Boston, Baltimore, Pittsburgh, Philadelphia, Louisville, New York, New Orleans, and smaller cities hit at the same time—all suffered grievously. But in those same places, the people struck by influenza later in the epidemic were not becoming as ill, and were not dying at the same rate, as those struck in the first 2 to 3 weeks.

Cities struck later in the epidemic also usually had lower mortality rates. One of the most careful epidemiologic studies of the epidemic was conducted in Connecticut. The investigator noted that “one factor that appeared to affect the mortality rate was proximity in time to the original outbreak at New London, the point at which the disease was first introduced into Connecticut…. The virus was most virulent or most readily communicable when it first reached the state, and thereafter became generally attenuated” (Thompson and Thompson, 1934a: 215).

The same pattern held true throughout the country and the world. It was not a rigid predictor. The virus was never completely consistent. But places hit later tended to suffer less.

One obvious hypothesis that might explain this phenomenon is that medical care improved as health care workers learned how to cope with the disease. But this hypothesis collapses upon examination. In a given city, as the epidemic proceeded, medical care disintegrated. Doctors and nurses were overworked and sick themselves, and victims—possibly even a majority of victims—received no care at all late in an epidemic.

Even in Army camps, where one could expect communication between physicians from one camp to the next, there seemed to be no improvements in medical care that could account for the different mortality rates. A distinguished investigator specifically looked for evidence of improved care or better preventive measures in Army camps and found none.

A second obvious explanatory hypothesis, that the most vulnerable people were struck first, also fails. For that hypothesis to be true, Americans on the east coast had to have been more vulnerable than those on the west coast, and Americans and western Europeans had to have been more vulnerable than Australians.

But another hypothesis, although entirely speculative, may be worth exploring. If one steps back and looks at the entire United States, it seems that people across the country infected with the virus in September and early to mid-October suffered the most severe attacks. Those infected later, in whatever part of the country they were, suffered less.

At the peak of the pandemic, then, the virus seemed to still be mutating rapidly, virtually with each passage through humans, and it was mutating toward a less lethal form.

We do know that after a mild spring wave, after a certain number of passages through humans, a lethal virus evolved. Possibly after additional passages it became less virulent. This makes sense particularly if the virus was immature when it erupted in September, if it entered the human population only a few months before the lethal wave.

This hypothesis may suggest some areas for investigation.

Social Disruption and Public Health Lessons

In the United States, national and local government and public health authorities badly mishandled the epidemic, offering a useful case study.

The context is important. Every country engaged in World War I tried to control public perception. To avoid hurting morale, even in the nonlethal first wave the press in countries fighting in the war did not mention the outbreak. (But Spain was not at war and its press wrote about it, so the pandemic became known as the Spanish flu).

The United States was no different. In 1917 California Senator Hiram Johnson made the since-famous observation that “The first casualty when war comes is truth.” The U.S. government passed a law that made it punishable by 20 years in jail to “utter, print, write or publish any disloyal, profane, scurrilous, or abusive language about the government of the United States.”

One could go to jail for cursing or criticizing the government, even if what one said was true. A Congressman was jailed. Simultaneously, the government mounted a massive propaganda effort. An architect of that effort said, “Truth and falsehood are arbitrary terms…. There is nothing in experience to tell us that one is always preferable to the other…. The force of an idea lies in its inspirational value. It matters very little if it is true or false” ( Vaughn, 1980 ).

The combination of rigid control and disregard for truth had dangerous consequences. Focusing on the shortest term, local officials almost universally told half-truths or outright lies to avoid damaging morale and the war effort. They were assisted—not challenged—by the press, which although not censored in a technical sense cooperated fully with the government's propaganda machine.

Routinely, as influenza approached a city or town—one could watch it march from place to place—local officials initially told the public not to worry, that public health officials would prevent the disease from striking them. When influenza first appeared, officials routinely insisted at first it was only ordinary influenza, not the Spanish flu. As the epidemic exploded, officials almost daily assured the public that the worst was over.

This pattern repeated itself again and again. Chicago offers one example: Its public health commissioner said he'd do “nothing to interfere with the morale of the community…. It is our duty to keep the people from fear. Worry kills more people than the epidemic” ( Robertson, 1918 ).

That idea—“Fear kills more than the disease”—became a mantra nationally and in city after city. As Literary Digest, one of the largest circulation periodicals in the country, advised, “Fear is our first enemy” ( Van Hartesveldt, 1992 ).

In Philadelphia, when the public health commissioner closed all schools, houses of worship, theaters, and other public gathering places, one newspaper went so far as to say that this order was “not a public health measure” and reiterated that “there is no cause for panic or alarm.”

But as people heard these reassurances, they could see neighbors, friends, and spouses dying horrible deaths.

In Chicago, the Cook County Hospital mortality rate of all influenza admissions—not just those who developed pneumonia—was 39.8 percent ( Keeton and Cusman, 1918 ). In Philadelphia, bodies remained uncollected in homes for days, until eventually open trucks and even horse-drawn carts were sent down city streets and people were told to bring out the dead. The bodies were stacked without coffins and buried in cemeteries in mass graves dug by steam shovels.

This horrific disconnect between reassurances and reality destroyed the credibility of those in authority. People felt they had no one to turn to, no one to rely on, no one to trust.

Ultimately society depends on trust. Without it, society began to come apart. Normally in 1918 America, when someone was ill, neighbors helped. That did not happen during the pandemic. Typically, the head of one city's volunteer effort, frustrated after repeated pleas for help yielded nothing, turned bitter and contemptuous:

Hundreds of women who are content to sit back had delightful dreams of themselves in the roles of angels of mercy, had the unfathomable vanity to imagine that they were capable of great sacrifice. Nothing seems to rouse them now. They have been told that there are families in which every member is ill, in which the children are actually starving because there is no one to give them food. The death rate is so high and they still hold back. 3

That attitude persisted outside of cities as well. In rural Kentucky, the Red Cross reported “people starving to death not from lack of food but because the well were panic stricken and would not go near the sick” ( An Account of the Influenza Epidemic, 1919 ).

As the pressure from the virus continued, an internal Red Cross report concluded, “A fear and panic of the influenza, akin to the terror of the Middle Ages regarding the Black Plague, [has] been prevalent in many parts of the country” ( The Mobilization of the American National Red Cross, 1920 ). Similarly, Victor Vaughan, a sober scientist not given to overstatement, worried, “If the epidemic continues its mathematical rate of acceleration, civilization could easily … disappear … from the face of the earth within a matter of a few more weeks” ( Collier, 1974 ).

Of course, the disease generated fear independent of anything officials did or did not do, but the false reassurances given by the authorities and the media systematically destroyed trust. That magnified the fear and turned it into panic and terror.

It is worth noting that this terror, at least in paralyzing form, did not seem to materialize in the few places where authorities told the truth.

One lesson is clear from this experience: In handling any crisis, it is absolutely crucial to retain credibility. Giving false reassurance is the worst thing one can do. If I may speculate, let me suggest that almost as bad as outright lying is holding information so closely that people think officials know more than they say.

The Site of Origin

It is very possible that we will never know with certainty where the 1918 virus crossed into man. In the 1920s and 1930s, outstanding investigators in several countries launched massive reviews of evidence searching for the site of origin. They could not definitively answer the question. But they were unanimous in believing that no known outbreak in China could, as one investigator said, “be reasonably regarded as the true forerunner” of the epidemic.

They considered the most likely sites of origin to be France and the United States, and most agreed with Macfarlane Burnet, who concluded that the evidence was “strongly suggestive” that the 1918 influenza pandemic began in the United States, and that its spread was “intimately related to war conditions and especially the arrival of American troops in France” ( Burnet and Clark, 1942 ).

My own research also makes me think that the United States was the most likely site of origin. The unearthing of previously unknown epidemiologic evidence has led me to advance my own hypothesis that the pandemic began in rural Kansas and traveled with draftees to what is now Fort Riley.

But whether the pandemic began in France or the United States is not really important. What does matter is that the pandemic most likely did not begin in Asia.

This has important implications for modern surveillance efforts. Although Asia's population density and the close proximity of humans and animals there makes the region particularly dangerous, the evidence of 1918—confirmed by the H7N7 outbreak in Europe of 2003—demonstrates the need for surveillance worldwide.

Something else should be addressed regarding surveillance. A physician now active in public health who received his medical degree in Honduras in 1986 says that he and his colleagues were taught that there was no difference between a cold and influenza. He believes physicians in Central America and possibly elsewhere in the world routinely ignore influenza. Clearly, if we are to have an adequate surveillance system, physicians need to be alert to the disease.

Outstanding laboratory investigators have made enormous progress over the years in understanding the virus and developing effective antiviral drugs as well as new technologies to make vaccines. But one area remains in which investigators have lagged behind—in applying modern insights and statistical methods to old data.

To use an analogy, a similar situation is found in the flooding of the Sacramento River, one of the few rivers in the country where flood control is the direct responsibility of the U.S. Army Corps of Engineers. The Corps has as powerful computers as anyone, but in a recent 10-year period, the Sacramento River experienced a 100-year flood three times, devastating parts of California—despite the fact that each time the Corps raised the standard for a 100-year flood. The point is not that the river exceeded the 100-year level three times in 10 years. Random chance could account for that. The point is that it did so even though the Corps changed the definition of a 100-year flood. A senior Corps official confessed that the Corps simply did not have enough data to know what a 100-year flood was.

We may be in a similar situation with influenza. We have had only three pandemics in the 20th century. That is not a good base on which to build models. Indeed, the Centers for Disease Control and Prevention's model of what would happen in the United States should another pandemic strike predicts that the most likely death toll would fall between 89,000 and 207,000. Yet the actual death tolls of two of the three pandemics fell well outside the predicted range. Adjusted for population, 1968 deaths were somewhat fewer than the best case scenario, and 1918 nearly 800 percent worse than the worst case. (In 1918, antibiotics would likely have lessened this gap, but the increased population of those with impaired immune systems would somewhat balance that benefit, and increase deaths.)

In addition, we have not taken advantage of the data that we do have. Several presentations at this conference demonstrate that fact—some on the plus side, by deriving findings of value by reviewing records from 1918, but also on the negative side, by making certain assumptions about 1918 that conflict with actual data.

A careful review of old data would also prove valuable. Studying 1889 (and enough data can be found, possibly from earlier pandemics as well), 1918, 1957, and 1968 might tell us whether each followed the same patterns, which in turn could help us to devise strategies for the use of antivirals and vaccines.

The Next Pandemic

Virtually every expert on influenza believes another pandemic is nearly inevitable, that it will kill millions of people, and that it could kill tens of millions—and a virus like 1918, or H5N1, might kill a hundred million or more—and that it could cause economic and social disruption on a massive scale. This disruption itself could kill as well.

Given those facts, every laboratory investigator and every public health official involved with the disease has two tasks: first, to do his or her work, and second, to make political leaders aware of the risk. The preparedness effort needs resources. Only the political process can allocate them.

• CHASING THE ELUSIVE 1918 VIRUS: PREPARING FOR THE FUTURE BY EXAMINING THE PAST

Jeffery K. Taubenberger 4

Department of Molecular Pathology

Armed Forces Institute of Pathology

Introduction

Influenza A viruses are negative strand RNA viruses of the genus Orthomyxoviridae . They continually circulate in humans in yearly epidemics (mainly in the winter in temperate climates) and antigenically novel virus strains emerge sporadically as pandemic viruses ( Cox and Subbarao, 2000 ). In the United States, influenza is estimated to kill 30,000 people in an average year ( Simonsen et al., 2000 ; Thompson et al., 2003 ). Every few years, a more severe influenza epidemic occurs, causing a boost in the annual number of deaths past the average, with 10,000 to 15,000 additional deaths. Occasionally, and unpredictably, influenza sweeps the world, infecting 20 to 40 percent of the population in a single year. In these pandemic years, the numbers of deaths can be dramatically above average. In 1957–1958, a pandemic was estimated to cause 66,000 excess deaths in the United States ( Simonsen et al., 1998 ). In 1918, the worst pandemic in recorded history was associated with approximately 675,000 total deaths in the United States ( U.S. Department of Commerce, 1976 ) and killed at least 40 million people worldwide ( Crosby, 1989 ; Patterson and Pyle, 1991 ; Johnson and Mueller, 2002 ).

Influenza A viruses constantly evolve by the mechanisms of antigenic drift and shift ( Webster et al., 1992 ). Consequently they should be considered emerging infectious disease agents, perhaps “continually” emerging pathogens. The importance of predicting the emergence of new circulating influenza virus strains for subsequent annual vaccine development cannot be underestimated ( Gensheimer et al., 1999 ). Pandemic influenza viruses have emerged three times in this century: in 1918 (“Spanish” influenza, H1N1), in 1957 (“Asian” influenza, H2N2), and in 1968 (“Hong Kong” influenza, H3N2) ( Cox and Subbarao, 2000 ; Webby and Webster, 2003 ). Recent circulation of highly pathogenic avian H5N1 viruses in Asia from 1997 to 2004 has caused a small number of human deaths ( Claas et al., 1998 ; Subbarao et al., 1998 ; Tran et al., 2004 ; Peiris et al., 2004 ). How and when novel influenza viruses emerge as pandemic virus strains and how they cause disease is still not understood.

Studying the extent to which the 1918 influenza was like other pandemics may help us to understand how pandemic influenzas emerge and cause disease in general. On the other hand, if we determine what made the 1918 influenza different from other pandemics, we may use the lessons of 1918 to predict the magnitude of public health risks a new pandemic virus might pose.

Origin of Pandemic Influenza Viruses

The predominant natural reservoir of influenza viruses is thought to be wild waterfowl ( Webster et al., 1992 ). Periodically, genetic material from avian virus strains is transferred to virus strains infectious to humans by a process called reassortment. Human influenza virus strains with recently acquired avian surface and internal protein-encoding RNA segments were responsible for the pandemic influenza outbreaks in 1957 and 1968 ( Scholtissek et al., 1978a ; Kawaoka et al., 1989 ). The change in the hemagglutinin subtype or the hemagglutinin (HA) and the neuraminidase (NA) subtype is referred to as antigenic shift. Because pigs can be infected with both avian and human virus strains, and various reassortants have been isolated from pigs, they have been proposed as an intermediary in this process ( Scholtissek, 1994 ; Ludwig et al., 1995 ). Until recently there was only limited evidence that a wholly avian influenza virus could directly infect humans, but in 1997 18 people were infected with avian H5N1 influenza viruses in Hong Kong, and 6 died of complications after infection ( Claas et al., 1998 ; Subbarao et al., 1998 ; Scholtissek, 1994 ; Ludwig et al., 1995 ). Although these viruses were very poorly transmissible or non-transmissible ( Claas et al., 1998 ; Subbarao et al., 1998 ; Scholtissek, 1994 ; Ludwig et al., 1995 ; Katz et al., 1999 ), their isolation from infected patients indicates that humans can be infected with wholly avian influenza virus strains. In 2003–2004, H5N1 outbreaks in poultry have become widespread in Asia ( Tran et al., 2004 ), and at least 32 people have died of complications of infection in Vietnam and Thailand ( World Health Organization, 2004 ). In 2003, a highly pathogenic H7N7 outbreak occurred in poultry farms in The Netherlands. This virus caused infections (predominantly conjunctivitis) in 86 poultry handlers and 3 secondary contacts. One of the infected individuals died of pneumonia ( Fouchier et al., 2004 ; Koopmans et al., 2004 ; World Health Organization, 2004 ). In 2004, an H7N3 influenza outbreak in poultry in Canada also resulted in the infection of a single individual ( World Health Organization, 2004 ), and a patient in New York was reported to be sick following infection with an H7N2 virus ( Lipsman, 2004 ). Therefore, it may not be necessary to invoke swine as the intermediary in the formation of a pandemic virus strain because reassortment between an avian and a human influenza virus could take place directly in humans.

While reassortment involving genes encoding surface proteins appears to be a critical event for the production of a pandemic virus, a significant amount of data exists to suggest that influenza viruses must also acquire specific adaptations to spread and replicate efficiently in a new host. Among other features, there must be functional HA receptor binding and interaction between viral and host proteins ( Weis et al., 1988 ). Defining the minimal adaptive changes needed to allow a reassortant virus to function in humans is essential to understanding how pandemic viruses emerge.

Once a new virus strain has acquired the changes that allow it to spread in humans, virulence is affected by the presence of novel surface protein(s) that allow the virus to infect an immunologically naïve population ( Kilbourne, 1977 ). This was the case in 1957 and 1968 and was almost certainly the case in 1918. While immunological novelty may explain much of the virulence of the 1918 influenza, it is likely that additional genetic features contributed to its exceptional lethality. Unfortunately not enough is known about how genetic features of influenza viruses affect virulence. The degree of illness caused by a particular virus strain, or virulence, is complex and involves host factors like immune status, and viral factors like host adaptation, transmissibility, tissue tropism, or viral replication efficiency. The genetic basis for each of these features is not yet fully characterized, but is most likely polygenic in nature ( Kilbourne, 1977 ).

Prior to the analyses on the 1918 virus described in this review, only two pandemic influenza virus strains were available for molecular analysis: the H2N2 virus strain from 1957 and the H3N2 virus strain from 1968. The 1957 pandemic resulted from the emergence of a reassortant influenza virus in which both HA and NA had been replaced by gene segment closely related to those in avian virus strains ( Scholtissek et al., 1978b ; Schafer et al., 1993 ; Webster et al., 1995 ). The 1968 pandemic followed with the emergence of a virus strain in which the H2 subtype HA gene was exchanged with an avian-derived H3 HA RNA segment ( Scholtissek et al., 1978b ; Webster et al., 1995 ), while retaining the N2 gene derived in 1957. More recently it has been shown that the PB1 gene was replaced in both the 1957 and the 1968 pandemic virus strains, also with a likely avian derivation in both cases ( Kawaoka et al., 1989 ). The remaining five RNA segments encoding the PA, PB2, nucleoprotein, matrix and non-structural proteins, all were preserved from the H1N1 virus strains circulating before 1957. These segments were likely the direct descendants of the genes present in the 1918 virus. Because only the 1957 and 1968 influenza pandemic virus strains have been available for sequence analysis, it is not clear what changes are necessary for the emergence of a virus strain with pandemic potential. Sequence analysis of the 1918 influenza virus allows us potentially to address the genetic basis of virulence and human adaptation.

Historical Background

The influenza pandemic of 1918 was exceptional in both breadth and depth. Outbreaks of the disease swept not only North America and Europe, but also spread as far as the Alaskan wilderness and the most remote islands of the Pacific. It has been estimated that one-third of the world's population may have been clinically infected during the pandemic ( Frost, 1920 ; Burnet and Clark, 1942 ). The disease was also exceptionally severe, with mortality rates among the infected of more than 2.5 percent, compared to less than 0.1 percent in other influenza epidemics ( Marks and Beatty, 1976 ; Rosenau and Last, 1980 ). Total mortality attributable to the 1918 pandemic was probably around 40 million ( Crosby, 1989 ; Johnson and Mueller, 2002 ; Patterson and Pyle, 1991 ).

Unlike most subsequent influenza virus strains that have developed in Asia, the “first wave” or “spring wave” of the 1918 pandemic seemingly arose in the United States in March 1918 ( Barry, 2004 ; Crosby, 1989 ; Jordan, 1927 ). However, the near simultaneous appearance of influenza in March–April 1918 in North America, Europe, and Asia makes definitive assignment of a geographic point of origin difficult ( Jordan, 1927 ). It is possible that a mutation or reassortment occurred in the late summer of 1918, resulting in significantly enhanced virulence. The main wave of the global pandemic, the “fall wave” or “second wave,” occurred in September–November 1918. In many places, there was yet another severe wave of influenza in early 1919 ( Jordan, 1927 ).

Three extensive outbreaks of influenza within 1 year is unusual, and may point to unique features of the 1918 virus that could be revealed in its sequence. Interpandemic influenza outbreaks generally occur in a single annual wave in the late winter. The severity of annual outbreaks is affected by antigenic drift, with an antigenically modified virus strain emerging every 2 to 3 years. Even in pandemic influenza, while the normal late winter seasonality may be violated, the successive occurrence of distinct waves within a year is unusual. The 1890 pandemic began in the late spring of 1889 and took several months to spread throughout the world, peaking in northern Europe and the United States late in 1889 or early 1890. The second wave peaked in spring 1891 (over a year after the first wave) and the third wave in early 1892 ( Jordan, 1927 ). As in 1918, subsequent waves seemed to produce more severe illness so that the peak mortality was reached in the third wave of the pandemic. The three waves, however, were spread over more than 3 years, in contrast to less than 1 year in 1918. It is unclear what gave the 1918 virus this unusual ability to generate repeated waves of illness. Perhaps the surface proteins of the virus drifted more rapidly than other influenza virus strains, or perhaps the virus had an unusually effective mechanism for evading the human immune system.

The influenza epidemic of 1918 killed an estimated 675,000 Americans, including 43,000 servicemen mobilized for World War I ( Crosby, 1989 ). The impact was so profound as to depress average life expectancy in the United States by more than 10 years ( Grove and Hetzel, 1968 ) ( Figure 1-1 ) and may have played a significant role in ending the World War I conflict ( Crosby, 1989 ; Ludendorff, 1919 ).

Life expectancy in the United States, 1900–1960, showing the impact of the 1918 influenza pandemic. SOURCES: U.S. Department of Commerce (1976); Grove and Hetzel (1968); Linder and Grove (1943).

Many individuals who died during the pandemic succumbed to secondary bacterial pneumonia ( Jordan, 1927 ; LeCount, 1919 ; Wolbach, 1919 ) because no antibiotics were available in 1918. However, a subset died rapidly after the onset of symptoms often with either massive acute pulmonary hemorrhage or pulmonary edema, often in less than 5 days ( LeCount, 1919 ; Winternitz et al., 1920 ; Wolbach, 1919 ). In the hundreds of autopsies performed in 1918, the primary pathologic findings were confined to the respiratory tree and death was due to pneumonia and respiratory failure ( Winternitz et al., 1920 ). These findings are consistent with infection by a well-adapted influenza virus capable of rapid replication throughout the entire respiratory tree ( Reid and Taubenberger, 1999 ; Taubenberger et al., 2000 ). There was no clinical or pathological evidence for systemic circulation of the virus ( Winternitz et al., 1920 ).

Furthermore, in the 1918 pandemic most deaths occurred among young adults, a group that usually has a very low death rate from influenza. Influenza and pneumonia death rates for 15- to 34-year-olds were more than 20 times higher in 1918 than in previous years ( Linder and Grove, 1943 ; Simonsen et al., 1998 ) ( Figure 1-2 ). The 1918 pandemic is also unique among influenza pandemics in that absolute risk of influenza mortality was higher in those younger than age 65 than in those older than 65. Strikingly, persons less than 65 years old accounted for more than 99 percent of all excess influenza-related deaths in 1918–1919 ( Simonsen et al., 1998 ). In contrast, the less-than-65 age group accounted for only 36 percent of all excess influenza-related mortality in the 1957 H2N2 pandemic and 48 percent in the 1968 H3N2 pandemic. Overall, nearly half of the influenza-related deaths in the 1918 influenza pandemic were young adults aged 20 to 40 ( Simonsen et al., 1998 ) ( Figure 1-2 ). Why this particular age group suffered such extreme mortality is not fully understood (see below).

Influenza and pneumonia mortality by age, United States. Influenza and pneumonia specific mortality by age, including an average of the interpandemic years 1911–1915 (dashed line), and the pandemic year 1918 (solid line). Specific death rate is (more...)

The 1918 influenza had another unique feature: the simultaneous infection of both humans and swine. Interestingly, swine influenza was first recognized as a clinical entity in that species in the fall of 1918 ( Koen, 1919 ) concurrently with the spread of the second wave of the pandemic in humans ( Dorset et al., 1922–1923 ). Investigators were impressed by clinical and pathological similarities of human and swine influenza in 1918 ( Koen, 1919 ; Murray and Biester, 1930 ). An extensive review by the veterinarian W.W. Dimoch of the diseases of swine published in August 1918 makes no mention of any swine disease resembling influenza ( Dimoch, 1918–1919 ). Thus, contemporary investigators were convinced that influenza virus had not circulated as an epizootic disease in swine before 1918 and that the virus spread from humans to pigs because of the appearance of illness in pigs after the first wave of the 1918 influenza in humans ( Shope and Lewis, 1931 ).

Thereafter the disease became widespread among swine herds in the U.S. midwest. The epizootic of 1919–1920 was as extensive as in 1918–1919. The disease then appeared among swine in the midwest every year, leading to Shope's isolation of the first influenza virus in 1930, A/swine/ Iowa/30 ( Shope and Lewis, 1931 ), 3 years before the isolation of the first human influenza virus, A/WS/33 by Smith, Andrewes, and Laidlaw ( Smith et al., 1933 ). Classical swine viruses have continued to circulate not only in North American pigs, but also in swine populations in Europe and Asia ( Brown et al., 1995 ; Kupradinun et al., 1991 ; Nerome et al., 1982 ).

During the fall and winter of 1918–1919, severe influenza-like outbreaks were noted not only in swine in the United States, but also in Europe and China ( Beveridge, 1977 ; Chun, 1919 ; Koen, 1919 ). Since 1918 there have been many examples of both H1N1 and H3N2 human influenza A virus strains becoming established in swine ( Brown et al., 1998 ; Castrucci et al., 1993 ; Zhou et al., 2000 ), while swine influenza A virus strains have been isolated only sporadically from humans (Gaydos et al., 1977; Woods et al., 1981 ).

The unusual severity of the 1918 pandemic and the exceptionally high mortality it caused among young adults have stimulated great interest in the influenza virus strain responsible for the 1918 outbreak ( Crosby, 1989 ; Kolata, 1999 ; Monto et al., 1997 ). Because the first human and swine influenza A viruses were not isolated until the early 1930s ( Shope and Lewis, 1931 ; Smith et al., 1933 ), characterization of the 1918 virus strain previously has had to rely on indirect evidence ( Kanegae et al., 1994 ; Shope, 1958 ).

Serology and Epidemiology of the 1918 Influenza Virus

Analyses of antibody titers of 1918 influenza survivors from the late 1930s suggested correctly that the 1918 virus strain was an H1N1-subtype influenza A virus, closely related to what is now known as “classic swine” influenza virus ( Dowdle, 1999 ; Philip and Lackman, 1962 ; Shope, 1936 ). The relationship to swine influenza is also reflected in the simultaneous influenza outbreaks in humans and pigs around the world ( Beveridge, 1977 ; Chun, 1919 ; Koen, 1919 ). Although historical accounts described above suggest that the virus spread from humans to pigs in the fall of 1918, the relationship of these two species in the development of the 1918 influenza has not been resolved.

Which influenza A subtype(s) circulated before the 1918 pandemic is not known for certain. In a recent review of the existing archaeoserologic and epidemiologic data, Walter Dowdle concluded that an H3-subtype influenza A virus strain circulated from the 1889–1891 pandemic to 1918, when it was replaced by the novel H1N1 virus strain of the 1918 pandemic ( Dowdle, 1999 ).

It is reasonable to conclude that the 1918 virus strain must have contained a hemagglutinin gene encoding a novel subtype such that large portions of the population did not have protective immunity ( Kilbourne, 1977 ; Reid and Taubenberger, 1999 ). In fact, epidemiological data collected between 1900 and 1918 on influenza prevalence by age in the population provide good evidence for the emergence of an antigenically novel influenza virus in 1918 ( Jordan, 1927 ). Jordan showed that from 1900 to 1917, the 5 to 15 age group accounted for 11 percent of total influenza cases in this series while the >65 age group similarly accounted for 6 percent of influenza cases. In 1918 the 5- to 15-year-old group jumped to 25 percent of influenza cases, compatible with exposure to an antigenically novel virus strain. The >65 age group only accounted for 0.6 percent of the influenza cases in 1918. It is likely that this age group accounted for a significantly lower percentage of influenza cases because younger people were so susceptible to the novel virus strain (as seen in the 1957 pandemic [ Ministry of Health, 1960 ; Simonsen et al., 1998 ]), but it is also possible that this age group had pre-existing H1 antibodies. Further evidence for pre-existing H1 immunity can be derived from the age-adjusted mortality data in Figure 1-2 . Those individuals >75 years had a lower influenza and pneumonia case mortality rate in 1918 than they had for the prepandemic period of 1911–1917.

When 1918 influenza case rates by age ( Jordan, 1927 ) are superimposed on the familiar “W”-shaped mortality curve (seen in Figure 1-2 ), a different perspective emerges ( Figure 1-3 ). As shown, those <35 years of age in 1918 accounted for a disproportionately high influenza incidence by age. Interestingly, the 5 to 14 age group accounted for a large fraction of 1918 influenza cases, but had an extremely low case mortality rate compared to other age groups ( Figure 1-3 ). Why this age group had such a low case fatality rate cannot yet be fully explained. Conversely, why the 25 to 34 age group had such a high influenza and pneumonia mortality rate in 1918 remains enigmatic, but it is one of the truly unique features of the 1918 influenza pandemic.

Influenza and pneumonia mortality by age (solid line), with influenza morbidity by age (dashed line) superimposed. Influenza and pneumonia mortality by age as in Figure 1-2. Specific death rate per age group, left ordinal axis. Influenza morbidity presented (more...)

One theory that may explain these data concerns the possibility that the virus had an intrinsically high virulence that was only tempered in those patients who had been born before 1889. It can be speculated that the virus circulating prior to 1889 was an H1-like virus strain that provided partial protection against the 1918 virus strain ( Ministry of Health, 1960 ; Simonsen et al., 1998 ; Taubenberger et al., 2001 ). Short of this cross-protection in patients older than 29 years of age, the pandemic of 1918 might have been even more devastating ( Zamarin and Palese, 2004 ). A second possibility remains that the high mortality of young adults in the 20 to 40 age group may have been a consequence of immune enhancement in this age group. Currently, however, the absence of pre-1918 human influenza samples and the lack of pre-1918 sera samples for analysis makes it impossible to test this hypothesis.

Thus, it seems clear that the H1N1 virus of the 1918 pandemic contained an antigenically novel hemagglutinin to which most humans and swine were susceptible in 1918. Given the severity of the pandemic, it is also reasonable to suggest that the other dominant surface protein, NA, also would have been replaced by antigenic shift before the start of the pandemic ( Reid and Taubenberger, 1999 ; Taubenberger et al., 2000 ). In fact, sequence and phylogenetic analyses suggest that the genes encoding these two surface proteins were derived from an avian-like influenza virus shortly before the start of the 1918 pandemic and that the precursor virus did not circulate widely in either humans or swine before 1918 ( Fanning et al., 2002 ; Reid et al., 1999 , 2000 ) ( Figure 1-4 ). It is currently unclear what other influenza gene segments were novel in the 1918 pandemic virus in comparison to the previously circulating virus strain. It is possible that sequence and phylogenetic analyses of the gene segments of the 1918 virus may help elucidate this question.

Phylogenetic tree of the influenza virus hemagglutinin gene segment. Amino acid changes in three lineages of the influenza virus hemagglutinin protein segment, HA1. The tree shows the numbers of unambiguous changes between these sequences, with branch (more...)

Genetic Characterization of the 1918 Virus

Sequence and functional analysis of the hemagglutinin and neuraminidase gene segments.

Samples of frozen and fixed lung tissue from five second-wave influenza victims (dating from September 1918 to February 1919) have been used to examine directly the genetic structure of the 1918 influenza virus. Two of the cases analyzed were U.S. Army soldiers who died in September 1918, one in Camp Upton, New York, and the other in Fort Jackson, South Carolina. The available material consists of formalin-fixed, paraffin-embedded autopsy tissue, hematoxylin and eosin-stained microscopic sections, and the clinical histories of these patients. A third sample was obtained from an Alaskan Inuit woman who had been interred in permafrost in Brevig Mission, Alaska, since her death from influenza in November 1918. The influenza virus sequences derived from these three cases have been called A/ South Carolina/1/18 (H1N1), A/New York/1/18 (H1N1), and A/Brevig Mission/1/18 (H1N1), respectively. To date, five RNA segment sequences have been published ( Basler et al., 2001 ; Reid et al., 1999 , 2000 , 2002 , 2004 ). More recently, the HA sequences of two additional fixed autopsy cases of 1918 influenza victims from the Royal London Hospital were determined ( Reid et al., 2003 ). The HA sequences from these five cases show >99 percent sequence identity, but differ at amino acid residue 225 (see below).

The sequence of the 1918 HA is most closely related to that of the A/ swine/Iowa/30 virus. However, despite this similarity the sequence has many avian features. Of the 41 amino acids that have been shown to be targets of the immune system and subject to antigenic drift pressure in humans, 37 match the avian sequence consensus, suggesting there was little immunologic pressure on the HA protein before the fall of 1918 ( Reid et al., 1999 ). Another mechanism by which influenza viruses evade the human immune system is the acquisition of glycosylation sites to mask antigenic epitopes. The HAs from modern H1N1 viruses have up to five glycosylation sites in addition to the four found in all avian HAs. The HA of the 1918 virus has only the four conserved avian sites ( Reid et al., 1999 ).

Influenza virus infection requires binding of the HA protein to sialic acid receptors on the host cell surface. The HA receptor binding site consists of a subset of amino acids that are invariant in all avian HAs, but vary in mammalian-adapted HAs. Human-adapted influenza viruses preferentially bind sialic acid receptors with α(2-6) linkages. Those viral strains adapted to birds preferentially bind α(2-3) linked sugars ( Gambaryan et al., 1997 ; Matrosovich et al., 1997 ; Weis et al., 1988 ). To shift from the proposed avian-adapted receptor-binding site configuration (with a preference for α(2-3) sialic acids) to that of swine H1s (which can bind both α(2-3) and α(2-6)) requires only one amino acid change, E190D. The HA sequences of all five 1918 cases have the E190D change ( Reid et al., 2003 ). In fact, the critical amino acids in the receptor-binding site of two of the 1918 cases are identical to that of the A/swine/Iowa/30 HA. The other three 1918 cases have an additional change from the avian consensus, G225D. Because swine viruses with the same receptor site as A/swine/Iowa/30 bind both avian- and mammalian-type receptors ( Gambaryan et al., 1997 ), A/ New York/1/18 virus probably also had the capacity to bind both. The change at residue 190 may represent the minimal change necessary to allow an avian H1-subtype HA to bind mammalian-type receptors ( Reid et al., 1999 , 2003 ; Stevens et al., 2004 ; Gamblin et al., 2004 ; Glaser et al., 2004 ), a critical step in host adaptation.

The crystal structure analysis of the 1918 HA ( Stevens et al., 2004 ; Gamblin et al., 2004 ) suggests that the overall structure of the receptor binding site is akin to that of an avian H5 HA in terms of its having a narrower pocket than that identified for the human H3 HA ( Wilson et al., 1981 ). This provides an additional clue for the avian derivation of the 1918 HA. The four antigenic sites that have been identified for another H1 HA, the A/PR/8/34 virus HA ( Caton et al., 1982 ), also appear to be the major antigenic determinants on the 1918 HA. The X-ray analyses suggest that these sites are exposed on the 1918 HA and thus they could be readily recognized by the human immune system.

The principal biological role of NA is the cleavage of the terminal sialic acid residues that are receptors for the virus's HA protein ( Palese and Compans, 1976 ). The active site of the enzyme consists of 15 invariant amino acids that are conserved in the 1918 NA. The functional NA protein is configured as a homotetramer in which the active sites are found on a terminal knob carried on a thin stalk ( Colman et al., 1983 ). Some early human virus strains have short (11-16 amino acids) deletions in the stalk region, as do many virus strains isolated from chickens. The 1918 NA has a full-length stalk and has only the glycosylation sites shared by avian N1 virus strains ( Schulze, 1997 ). Although the antigenic sites on human-adapted N1 neuraminidases have not been definitively mapped, it is possible to align the N1 sequences with N2 subtype NAs and examine the N2 antigenic sites for evidence of drift in N1. There are 22 amino acids on the N2 protein that may function in antigenic epitopes ( Colman et al., 1983 ). The 1918 NA matches the avian consensus at 21 of these sites ( Reid et al., 2000 ). This finding suggests that the 1918 NA, like the 1918 HA, had not circulated long in humans before the pandemic and very possibly had an avian origin ( Reid and Taubenberger, 2003 ).

Neither the 1918 HA nor NA genes have obvious genetic features that can be related directly to virulence. Two known mutations that can dramatically affect the virulence of influenza virus strains have been described. For viral activation, HA must be cleaved into two pieces, HA1 and HA2, by a host protease ( Lazarowitz and Choppin, 1975 ; Rott et al., 1995 ). Some avian H5 and H7 subtype viruses acquire a mutation that involves the addition of one or more basic amino acids to the cleavage site, allowing HA activation by ubiquitous proteases ( Kawaoka and Webster, 1988 ; Webster and Rott, 1987 ). Infection with such a pantropic virus strain can cause systemic disease in birds with high mortality. This mutation was not observed in the 1918 virus ( Reid et al., 1999 ; Taubenberger et al., 1997 ).

The second mutation with a significant effect on virulence through pantropism has been identified in the NA gene of two mouse-adapted influenza virus strains, A/WSN/33 and A/NWS/33. Mutations at a single codon (N146R or N146Y, leading to the loss of a glycosylation site) appear, like the HA cleavage site mutation, to allow the virus to replicate in many tissues outside the respiratory tract ( Li et al., 1993 ). This mutation was also not observed in the NA of the 1918 virus ( Reid et al., 2000 ).

Therefore, neither surface protein-encoding gene has known mutations that would allow the 1918 virus to become pantropic. Because clinical and pathological findings in 1918 showed no evidence of replication outside the respiratory system ( Winternitz et al., 1920 ; Wolbach, 1919 ), mutations allowing the 1918 virus to replicate systemically would not have been expected. However, the relationship of other structural features of these proteins (aside from their presumed antigenic novelty) to virulence remains unknown. In their overall structural and functional characteristics, the 1918 HA and NA are avian-like, but they also have mammalian-adapted characteristics.

Interestingly, recombinant influenza viruses containing the 1918 HA and NA and up to three additional genes derived from the 1918 virus (the other genes being derived from the A/WSN/33 virus) were all highly virulent in mice ( Tumpey et al., 2004 ). Furthermore, expression microarray analysis performed on whole lung tissue of mice infected with the 1918 HA/ NA recombinant showed increased upregulation of genes involved in apoptosis, tissue injury, and oxidative damage ( Kash et al., 2004 ). These findings were unusual because the viruses with the 1918 genes had not been adapted to mice. The completion of the sequence of the entire genome of the 1918 virus and the reconstruction and characterization of viruses with 1918 genes under appropriate biosafety conditions will shed more light on these findings and should allow a definitive examination of this explanation.

Antigenic analysis of recombinant viruses possessing the 1918 HA and NA by hemagglutination inhibition tests using ferret and chicken antisera suggested a close relationship with the A/swine/Iowa/30 virus and H1N1 viruses isolated in the 1930s ( Tumpey et al., 2004 ), further supporting data of Shope from the 1930s ( Shope, 1936 ). Interestingly, when mice were immunized with different H1N1 virus strains, challenge studies using the 1918-like viruses revealed partial protection by this treatment, suggesting that current vaccination strategies are adequate against a 1918-like virus ( Tumpey et al., 2004 ). In fact, the data may even allow us to suggest that the human population, having experienced a long period of exposure to H1N1 viruses, may be partially protected against a 1918-like virus ( Tumpey et al., 2004 ).

Because virulence (in the immunologically naïve person) has not yet been mapped to particular sequence motifs of the 1918 HA and NA genes, what can gene sequencing tell us about the origin of the 1918 virus? The best approach to analyzing the relationships among influenza viruses is phylogenetics, whereby hypothetical family trees are constructed that take available sequence data and use them to make assumptions about the ancestral relationships between current and historical influenza virus strains ( Fitch et al., 1991 ; Gammelin et al., 1990 ; Scholtissek et al., 1993 ) ( Figure 1-5 ). Because influenza viruses possess eight discrete RNA segments that can move independently between virus strains by the process of reassortment, these evolutionary studies must be performed independently for each gene segment.

Change in hemagglutinin (HA) and neuraminidase (NA) proteins over time. The number of amino acid changes from a hypothetical ancestor was plotted versus the date of viral isolation for viruses isolated from 1930 to 1993. Open circles, human HA; closed (more...)

A comparison of the complete 1918 HA ( Figure 1-5 ) and NA genes with those of numerous human, swine, and avian sequences demonstrates the following: Phylogenetic analyses based on HA nucleotide changes (either total or synonymous) or HA amino acid changes always place the 1918 HA with the mammalian viruses, not with the avian viruses ( Reid et al., 1999 ). In fact, both synonymous and nonsynonymous changes place the 1918 HA in the human clade. Phylogenetic analyses of total or synonymous NA nucleotide changes also place the 1918 NA sequence with the mammalian viruses, but analysis of nonsynonymous changes or amino acid changes places the 1918 NA with the avian viruses ( Reid et al., 2000 ). Because the 1918 HA and NA have avian features and most analyses place HA and NA near the root of the mammalian clade (close to an ancestor of the avian genes), it is likely that both genes emerged from an avian-like influenza reservoir just prior to 1918 ( Reid et al., 1999 , 2000 , 2003 ; Fanning and Taubenberger, 1999 ; Fanning et al., 2000 ) ( Figure 1-4 ). Clearly, by 1918 the virus had acquired enough mammalian-adaptive changes to function as a human pandemic virus and to form a stable lineage in swine.

Sequence and Functional Analysis of the Non-Structural Gene Segment

The complete coding sequence of the 1918 non-structural (NS) segment was completed ( Basler et al., 2001 ). The functions of the two proteins, NS1 and NS2 (NEP), encoded by overlapping reading frames ( Lamb and Lai, 1980 ) of the NS segment, are still being elucidated ( O'Neill et al., 1998 ; Li et al., 1998 ; Garcia-Sastre et al., 1998 ; Garcia-Sastre, 2002 ; Krug et al., 2003 ). The NS1 protein has been shown to prevent type I interferon (IFN) production by preventing activation of the latent transcription factors IRF-3 ( Talon et al., 2000 ) and NF-κB ( Wang et al., 2000 ). One of the distinctive clinical characteristics of the 1918 influenza was its ability to produce rapid and extensive damage to both the upper and lower respiratory epithelium ( Winternitz et al., 1920 ). Such a clinical course suggests a virus that replicated to a high titer and spread quickly from cell to cell. Thus, an NS1 protein that was especially effective at blocking the type I IFN system might have contributed to the exceptional virulence of the 1918 virus strain ( Garcia-Sastre et al., 1998 ; Talon et al., 2000 ; Wang et al., 2000 ). To address this possibility, transfectant A/WSN/33 influenza viruses were constructed with the 1918 NS1 gene or with the entire 1918 NS segment (coding for both NS1 and NS2 [NEP] proteins) ( Basler et al., 2001 ). In both cases, viruses containing 1918 NS genes were attenuated in mice compared to wild-type A/WSN/33 controls. The attenuation demonstrates that NS1 is critical for the virulence of A/WSN/33 in mice. On the other hand, transcriptional profiling (microarray analysis) of infected human lung epithelial cells showed that a virus with the 1918 NS1 gene was more effective at blocking the expression of IFN-regulated genes than the isogenic parental mouse-adapted A/WSN/33 virus ( Geiss et al., 2002 ), suggesting that the 1918 NS1 contributes virulence characteristics in human cells, but not murine ones. The 1918 NS1 protein varies from that of the WSN virus at 10 amino acid positions. The amino acid differences between the 1918 and A/WSN/33 NS segments may be important in the adaptation of the latter virus strain to mice and likely account for the observed differences in virulence in these experiments. Recently, a single amino acid change (D92E) in the NS1 protein was associated with increased virulence of the 1997 Hong Kong H5N1 viruses in a swine model ( Seo et al., 2002 ). This amino acid change was not found in the 1918 NS1 protein.

Sequence and Functional Analysis of the Matrix Gene Segment

The coding region of influenza A RNA segment 7 from the 1918 pandemic virus, consisting of the open reading frames of the two matrix genes, M1 and M2, has been sequenced ( Reid et al., 2002 ). Although this segment is highly conserved among influenza virus strains, the 1918 sequence does not match any previously sequenced influenza virus strains. The 1918 sequence matches the consensus over the M1 RNA-binding domains and nuclear localization signal and the highly conserved transmembrane domain of M2. Amino acid changes that correlate with high yield and pathogenicity in animal models were not found in the 1918 virus strain.

Influenza A virus RNA segment 7 encodes two proteins, the matrix proteins M1 and M2. The M1 mRNA is colinear with the viral RNA, while the M2 mRNA is encoded by a spliced transcript ( Lamb and Krug, 2001 ). The proteins encoded by these mRNAs share their initial 9 amino acids and also have a stretch of 14 amino acids in overlapping reading frames. The M1 protein is a highly conserved 252-amino-acid protein. It is the most abundant protein in the viral particle, lining the inner layer of the viral membrane and contacting the ribonucleoprotein (RNP) core. M1 has been shown to have several functions ( Lamb and Krug, 2001 ), including regulation of nuclear export of vRNPs, both permitting the transport of vRNP particles into the nucleus upon infection and preventing newly exported vRNP particles from reentering the nucleus. The 97-amino-acid M2 protein is a homotetrameric integral membrane protein that exhibits ion-channel activity and is the target of the drug amantadine ( Hay et al., 1985 ). The ion-channel activity of M2 is important both during virion uncoating and during viral budding ( Lamb and Krug, 2001 ).

Five amino acid sites have been identified in the transmembrane region of the M2 protein that are involved in resistance to the antiviral drug amantadine: sites 26, 27, 30, 31, and 34 ( Holsinger et al., 1994 ). The 1918 influenza M2 sequence is identical at these positions to that of the amantadine-sensitive influenza virus strains. Thus, it was predicted that the M2 protein of the 1918 influenza virus would be sensitive to amantadine. This was recently demonstrated experimentally. A recombinant virus possessing the 1918 matrix segment was inhibited effectively both in tissue culture and in vivo by the M2 ion-channel inhibitors amantadine and rimantadine ( Tumpey et al., 2002 ).

The phylogenetic analyses suggest that the 1918 matrix genes, while more avian-like than those of other mammalian influenza viruses, were mammalian adapted ( Reid et al., 2002 ). For example, the extracellular domain of the M2 protein contains four amino acids that differ consistently between the avian and mammalian clades (M2 residues #14, 16, 18, and 20). The 1918 sequence matches the mammalian sequence at all four of these residues ( Reid et al., 2002 ), suggesting that the matrix segment may have been circulating in human virus strains for at least several years before 1918.

Sequence and Functional Analysis of the Nucleoprotein Gene Segment

The nucleoprotein gene (NP) of the 1918 pandemic influenza A virus has been amplified and sequenced from archival material ( Reid et al., 2004 ). The NP gene is known to be involved in many aspects of viral function and to interact with host proteins, thereby playing a role in host specificity ( Portela and Digard, 2002 ). NP is highly conserved, with a maximum amino acid difference of 11 percent among virus strains, probably because it must bind to multiple proteins, both viral and cellular. Numerous studies suggest that NP is a major determinant of host specificity ( Scholtissek et al., 1978a , 1985 ). The 1918 NP amino acid sequence differs at only six amino acids from avian consensus sequences, consistent with reassortment from an avian source shortly before 1918. However, the 1918 NP nucleotide sequence has more than 170 differences from avian consensus sequences, suggesting substantial evolutionary distance from known avian sequences. Both the 1918 NP gene and protein sequences fall within the mammalian clade upon phylogenetic analysis.

Phylogenetic analyses of NP sequences from many virus strains result in trees with two main branches, one consisting of mammalian-adapted virus strains and one of avian-adapted virus strains ( Gammelin et al., 1990 ; Gorman et al., 1991 ; Shu et al., 1993 ). The NP gene segment was not replaced in the pandemics of 1957 and 1968, so it is likely that the sequences in the mammalian clade are descended from the 1918 NP segment. The mammalian branches, unlike the avian branch, show a slow but steady accumulation of changes over time. Extrapolation of the rate of change along the human branch back to a putative common ancestor suggests that this NP entered the mammalian lineage sometime after 1900 ( Gammelin et al., 1990 ; Gorman et al., 1991 ; Shu et al., 1993 ). Separate analyses of synonymous and nonsynonymous substitutions also placed the 1918 virus NP gene in the mammalian clade ( Reid et al., 2004 ). When synonymous substitutions were analyzed, the 1918 virus gene was placed within and near the root of swine viruses. When nonsynonymous viruses were analyzed, the 1918 virus gene was placed within and near the root of the human viruses.

The evolutionary distance of the 1918 NP from avian and mammalian sequences was examined using several different parameters. There are at least three possibilities for the origin of the 1918 NP gene segment ( Reid et al., 2004 ). First, it could have been retained from the previously circulating human virus, as was the case with the 1957 and 1968 pandemic virus strains, whose NP segments are descendants of the 1918 NP. The large number of nucleotide changes from the avian consensus and the placement of the 1918 sequence in the mammalian clade are consistent with this hypothesis. Neighbor-joining analyses of nonsynonymous nucleotide sequences or of amino acid sequences place the 1918 sequence within and near the root of the human clade. The 1918 NP has only a few amino acid differences from most bird virus strains, but this consistent group of amino acid changes is shared by the 1918 NP and its subsequent mammalian descendants and is not found in any birds, resulting in the 1918 sequence being placed outside the avian clade ( Reid et al., 2004 ). One or more of these amino acid substitutions may be important for adaptation of the protein to humans. However, the very small number of amino acid differences from the avian consensus argues for recent introduction from birds—80 years after 1918, the NP genes of human influenza virus strains have accumulated more than 30 additional amino acid differences from the avian consensus (a rate of 2.3 amino acid changes per year). Thus it seems unlikely that the 1918 NP, with only six amino acid differences from the avian consensus, could have been in humans for many years before 1918. This conclusion is supported by the regression analysis that suggests that the progenitor of the 1918 virus probably entered the human population around 1915 ( Reid et al., 2004 ).

A second possible origin for the 1918 NP segment is direct reassortment from an avian virus. The small number of amino acid differences between 1918 and the avian consensus supports this hypothesis. While 1918 varies at many nucleotides from the nearest avian virus strain, avian virus strains are quite diverse at the nucleotide level. Synonymous/nonsynonymous ratios between 1918 and avian virus strains are similar to the ratios between avian virus strains, opening the possibility that avian virus strains may exist that are more closely related to 1918. The great evolutionary distance between the 1918 sequence and the avian consensus suggests that no avian virus strain similar to those in the currently identified clades could have provided the 1918 virus strain with its NP segment.

A final possibility is that the 1918 gene segment was acquired shortly before 1918 from a source not currently represented in the database of influenza sequences. There may be a currently unknown influenza host that, while similar to currently characterized avian virus strains at the amino acid level, is quite different at the nucleotide level. It is possible that such a host was the source of the 1918 NP segment ( Reid et al., 2004 ).

Future Work

Five of the eight RNA segments of the 1918 influenza virus have been sequenced and analyzed. Their characterization has shed light on the origin of the virus and strongly supports the hypothesis that the 1918 virus was the common ancestor of both subsequent human and swine H1N1 lineages. Sequence analysis of the genes to date offers no definitive clue as to the exceptional virulence of the 1918 virus strain. Thus, experiments testing models of virulence using reverse genetics approaches with 1918 influenza genes have begun.

In future work it is hoped that the 1918 pandemic virus strain can be placed in the context of influenza virus strains that preceded it and followed it. The direct precursor of the pandemic virus, the first or “spring” wave virus strain, lacked the exceptional virulence of the fall wave virus strain. Identification of an influenza RNA-positive case from the first wave would have tremendous value in deciphering the genetic basis for virulence by allowing differences in the sequences to be highlighted. Identification of pre-1918 human influenza RNA samples would clarify which gene segments were novel in the 1918 virus.

In many respects, the 1918 influenza pandemic was similar to other influenza pandemics. In its epidemiology, disease course, and pathology, the pandemic generally was different in degree but not in kind from previous and subsequent pandemics. Furthermore, laboratory experiments using recombinant influenza viruses containing genes from the 1918 virus suggest that the 1918 and 1918-like viruses would be as sensitive to the Food and Drug Administration-approved anti-influenza drugs rimantadine and oseltamivir as other virus strains ( Tumpey et al., 2002 ). However, there are some characteristics of the pandemic that appear to be unique: Mortality was exceptionally high, ranging from 5 to 20 times higher than normal. Clinically and pathologically, the high mortality appears to be the result of a higher proportion of severe and complicated infections of the respiratory tract, not with systemic infection or involvement of organ systems outside the influenza virus's normal targets. The mortality was concentrated in an unusually young age group. Finally, the waves of influenza activity followed each other unusually rapidly, resulting in three major outbreaks within a year's time. Each of these unique characteristics may find their explanation in genetic features of the 1918 virus. The challenge will be in determining the links between the biological capabilities of the virus and the known history of the pandemic.

Research Agenda for the Future

The work on the 1918 influenza virus, especially its origin, has led to the support of more comprehensive influenza virus surveillance and genomics initiatives for both human and animal influenza A viruses. We believe significant advancement in the understanding of influenza biology and ecology can be made by the generation of full genomic sequences of a large number of influenza viruses from different hosts. In conclusion, some of the questions that need to be addressed in pandemic influenza include the following:

• Can an entire avian influenza virus adapt directly in a human, or is reassortment necessary to generate a pandemic strain?
• Does adaptation of an avian influenza virus to humans require an intermediate host?
• Can all possible subtypes of avian influenza virus reassort to form functional human pandemic strains, or are there biological limitations to particular HA and NA subtypes?
• A novel HA seems to be required for a pandemic strain; what about the other gene segments?
• Can genetic changes be mapped to “virulence”?
• Can features of virulence be separated from the host in question? Can the viral genetic component of human virulence be modeled in experimental animal or in vitro systems?
• What molecular changes are necessary for avian strains to adapt to mammals, and to humans in particular?
• Can host-adaptive changes (genetic fingerprints) be used to trace the evolution of a pandemic strain through intermediate hosts?

Unless we make progress in understanding these and other issues involving the complex ecology and biology of influenza viruses, we will face the risk of revisiting the past in our future.

PANDEMIC INFLUENZA AND MORTALITY: PAST EVIDENCE AND PROJECTIONS FOR THE FUTURE 5

L. Simonsen, 6 D.R. Olson, 7 C. Viboud, 8 E. Heiman, 6 R.J. Taylor, 9 M.A. Miller, 8 and T.A. Reichert 10

Pandemic influenza is often thought of as a tornado—a sudden disaster that arrives with little warning and does its worst in a relatively short time. Only three of these calamities occurred in the twentieth century. Their mortality impact ranged from devastating (the 1918 “Spanish” A(H1N1) influenza) to moderate (the 1957 Asian A(H2N2) pandemic) to mild (the 1968 “Hong Kong” A(H3N2) virus). In this paper we review the “pandemic age shift,” a signature change of mortality impact from the elderly to younger age groups that has occurred during each of these pandemics. We also suggest that the “tornado” paradigm may not be completely apt, in that past pandemics have given epidemiologic warning signs of their arrival, and generally play out over several years.

For the 1918 Spanish influenza pandemic, a new study by Olson et al. documents substantial mortality impact during a pandemic “herald wave” in early spring of 1918 in New York City, and a general lack of increased pandemic mortality in those over 45 years of age. For the 1957 pandemic, a classic study documented that the emerging H2N2 influenza virus caused substantial excess mortality during the first three seasons it was in circulation. The 1968 pandemic mortality impact was only “smoldering” in Europe during the first season and did not break into open flame until the next season, during which the majority of mortality impact occurred. Although mortality caused by the 1968 pandemic virus was unimpressive relative to surrounding severe epidemics, the age shift signature sets it apart. Furthermore, antibodies to H3-like antigens—the result of exposure to these antigens in childhood prior to 1892—relatively protected people aged 77 years and older.

Because our experience with pandemic influenza is so limited, it is difficult to predict the mortality impact of future pandemics except to say that the likely range is wide (from ~20 to ~500 deaths per 100,000 population) and that those under 65 years of age will account for a high proportion of the deaths. It may be helpful to think of pandemic mortality impact as the sum of influenza-related deaths that occur over several seasons dominated by the emerging virus until the pandemic age shift pattern gives way to “business as usual,” which typically occurs after a decade or less.

The good news from epidemiological studies for pandemic preparedness planning is that past pandemics gave significant warning signs of their arrival. In 1918, a pandemic herald wave occurred 6 months or more before the majority of mortality impact the following fall. The Asian H2N2 influenza virus was characterized by early summer, 1957, but significant mortality in the United States did not occur until October. In 1968, the pandemic wave of mortality in Europe crested a full year after the pandemic strain first arrived. Furthermore, in both the 1957 and 1968 pandemics, much of the total impact occurred as a series of smaller “twisters” in the first several seasons after its emergence, before the total population had been affected. These facts suggest that there may well be sufficient time for production and distribution of vaccine and antiviral drugs to prevent much of the mortality impact of the next pandemic, and that these medical interventions will continue to play an important role in limiting “pandemic” mortality for years after the pandemic season. Finally, the pandemic age shift documented for all pandemics studied begs the crucial question of who should be given first priority for vaccine and antivirals, should these be in short supply in the early phase of a pandemic.

The Charge: Using Lessons from Past Pandemics to Help Project the Impact of Future Pandemics

In the case of pandemics, we are planning for the equivalent of a tornado … rare and completely unpredictable until the last minute, when a “weather watch” (e.g., pandemic alert) appears on the TV screen ( Kilbourne, 1997 ).

The lesson of the history of pandemics appears to be that at least the initial attack may sometimes occur with gentleness and thus may afford a substantial breathing space for the preparation and use of specific vaccine ( Stuart-Harris, 1970 ).

Why worry about pandemics of the past? Three influenza pandemics occurred in the twentieth century, and the patterns and magnitude of pandemic mortality are the only impact data available for all three of these events ( Table 1-1 ). We believe, therefore, that continued epidemiological analyses of historic mortality data and sero-archaeology—the study of stored serum samples to uncover when specific influenza antigens were circulating—can expand our understanding of pandemic mortality patterns and severity, and that such studies will greatly aid public health planning for pandemic influenza.

Mortality Impact in the Three Pandemics of the Twentieth Century in the United States .

In this review, we present the story of pandemic influenza as seen through the lens of epidemiology. For the 1968 pandemic we present data comparing the mortality impact internationally—and highlight the still unexplained finding of “smoldering” pandemic activity in Europe. We review more recent efforts to characterize the signature “age shift” of pandemic influenza and highlight the value of sero-archaeology as a tool to understand what we call “the virtues of antigenic sin”—protection derived from exposure in childhood to influenza H-antigens that are recycled in later pandemic viruses. We revisit a classic study of the 1957 pandemic that analyzes age-specific mortality data from the United States, which shows that most of the mortality was spread over three seasons; we also compare the age-specific mortality impact in the United States to that in Japan. For the 1918 pandemic, we present a study of newly uncovered mortality data from New York City that tells a fetching story about a herald wave and the sparing of the elderly ( Olson et al., 2004 ).

These efforts to study the epidemiology of past pandemic impact on mortality are akin to the efforts by virologists who, in the interest of predicting the future, are hard at work identifying and studying preserved human and animal virus specimens from the 1918 Spanish flu pandemic ( Reid and Taubenberger, 2003 ). But instead of molecular clues to viral pathogenicity and recombination, mortality data provides some important insights into how the pandemic evolves over time, and which age groups are at highest risk for severe outcomes. First, a future pandemic may not appear as a completely unpredictable “tornado” that hits hard the first season and leaves little time for production and distribution of vaccines and antivirals. It is certainly true that, like a tornado, no one can predict precisely when a new pandemic strain might emerge. However, studies of past pandemics show that the next pandemic may well not do its worst in the first season. Instead, historical evidence shows that there can be herald waves or smoldering activity during the first season in which the pandemic influenza virus emerges, suggesting that the preparation time for pandemic vaccines and antivirals might be longer than a few months. Second, pandemic impact cannot be discussed without speaking of age. During a pandemic, the younger population is at substantially increased risk relative to non-pandemic influenza seasons; in some pandemics, this sparing of the elderly may occur as a consequence of antigen recycling. The pandemic age shift has important consequences for thinking about how best to protect the population and minimize years of life lost to future pandemic influenza.

The Pandemic Age Shift: A Signature of Pandemic Mortality Impact

It has previously been demonstrated that all three pandemics of this century were characterized by a shift in the age distribution of deaths ( Simonsen et al., 1998 ). The younger population (in that study, persons under 65 years of age) experienced a sharply elevated mortality risk and accounted for a markedly increased fraction of all influenza-related deaths. As we will discuss below, the 1968 pandemic age shift pattern was exacerbated by the protection of the very elderly by virtue of their experience with H3 antigens as children ( Simonsen et al., 2003 ). For the 1968 pandemic, then, the observed age shift was due to a combination of increased risk among the young and decreased risk among the elderly ( Simonsen et al., 2003 ).

During the 1957 A(H2N2) Asian pandemic in the United States, nearly 40 percent of all influenza-related deaths occurred in the younger population under 65 years of age. The proportion of deaths among people under age 65 that occurred during A(H2N2) epidemics dropped to 5 percent by 1968, when circulation of this virus ceased. In the 1968 A(H3N2) pandemic, this proportion was approximately 50 percent, but declined to less than 10 percent over the next decade ( Figure 1-6 ) ( Simonsen et al., 2003 ). The age shift in mortality was even more pronounced in the 1918 A(H1N1) Spanish influenza pandemic ( Collins, 1931 ; Simonsen, 1998 ; Olson et al., 2004 ).

A pandemic “decade”: Seasonal excess pneumonia and influenza (P&I) mortality rates for A(H3N2)-dominated seasons remained elevated for a decade after 1968 in persons aged 45–64 years, United States, 1968–1999. (more...)

The 1968 Hong Kong Pandemic: Some New Observations

The unimpressive impact of the 1968 pandemic on mortality in the united states.

The 1968 pandemic is the only one known in which a shift in the hemagglutinin antigen was not accompanied by a shift in the neuraminidase antigen. Perhaps for that reason, the 1968 pandemic mortality impact was not particularly severe compared to the severe epidemic in 1967–1968 (the last A(H2N2) epidemic), as well as two severe H3N2 epidemics in 1975–1976 and 1980–1981 ( Table 1-2 ). People aged 75 years and older were far less likely to die of influenza during the pandemic than during these three surrounding epidemics, whereas people aged 45–64 years were at nearly three-fold elevated risk. Despite the differences in relative risk among age groups in different years, the absolute risk of dying of influenza during the pandemic was about 3 times higher for the elderly than for the younger age group ( Table 1-2 ).

The Age-Specific Impact of the 1968 Pandemic in the United States: Comparison to Surrounding Severe Epidemics .

Virtues of Antigenic Sin: The Sparing of the Elderly

Sero-archaeological studies have demonstrated that the majority of the very elderly had H3 antibodies before they were exposed to the 1968 A(H3N2) pandemic virus ( Dowdle, 1999 ; Marine and Workman, 1969 ). These antibodies were remnants of the immune response to exposure to H3N? viruses that circulated before 1891 ( Marine and Workman, 1969 ); thus, the 1968 pandemic virus apparently contained an H3 antigen “recycled” after 77 years of absence. Marine and Workman hypothesized that the pre-existing anti-H3 antibodies were the result of “original antigenic sin” ( Davenport et al., 1953 )—childhood exposure to H3 antigens—and that these antibodies might have protected the elderly during the 1968 A(H3N2) pandemic ( Marine and Workman, 1969 ). We recently confirmed this hypothesis when we used U.S. national mortality data to demonstrate that people over the age of 77 were, in fact, protected from influenza-related mortality during the 1968 pandemic, compared to surrounding severe non-pandemic seasons ( Simonsen et al., 2003 ). Even so, the absolute risk of dying from 1968 pandemic influenza was always highest among the very elderly, although this risk was likely significantly lower than it would have been without the protection provided by the anti-H3 antibodies still present in this age group. Figure 1-7 shows the several-fold increase in pneumonia and influenza (P&I) mortality rates during the 1968 pandemic among younger age groups in the United States compared to the 1980–1981 season, and the absence of any such increase among the very elderly.

Evidence of protection of the very elderly by “virtues of antigenic sin”: Age-specific excess P&I mortality rates for the 1968 pandemic compared to the 1980–1981 season.

These findings have significant implications for both pandemic planning and the prioritization of high-risk groups for vaccination in the scenario of vaccine shortage. Indeed, if one wishes to minimize the number of years-of-life-lost should vaccine be in short supply, then it would be more effective to immunize the middle aged and younger elderly than the very elderly.

The European 1968 Experience: A “Smoldering” Pattern

The 1968 pandemic experience in Europe was different from that of the United States. It began with the rapid spread of a new virus, which reached Europe about 2 months after its emergence in Hong Kong ( Cockburn et al., 1969 ). But influenza activity remained curiously weak in the wave that occurred during the 1968–1969 winter in Europe ( Assaad et al., 1973 ; Stuart-Harris, 1970 ). At the same time, influenza-related mortality and morbidity increased substantially in the United States, especially among the young ( Housworth and Spoon, 1971 ). More surprising, a much more severe wave occurred in the United Kingdom during the winter of 1969–1970, although no change in the circulating strain had been identified ( Miller et al., 1971 ). We revisited the pandemic experience in the United States and the United Kingdom by extending the analysis of mortality data from both countries ( Figure 1-8 ) to better describe and possibly explain the geographical differences.

Monthly pneumonia and influenza (P&I) mortality rate during the first two waves of the 1968 pandemic (A/H3N2) in the United Kingdom. Epidemic threshold determined by a spline-Serfling regression model.

In both countries, we studied the age distribution of mortality rates associated with the first and second pandemic waves of A/H3N2, which occurred during the winters of 1968–1969 and 1969–1970 ( Table 1-3 ). Consistent with the epidemiologic signature of a pandemic ( Simonsen et al., 1998 ), a mortality shift towards younger age groups was observed simultaneously in both the United States and United Kingdom. The shift in the first pandemic wave (1968/1969) in the United Kingdom was not quite as definitive, but was nonetheless above the background of preceding epidemic seasons. In both countries, the proportion of deaths in younger age groups was highly elevated in the second wave. This age shift is consistent with the fact that virus surveillance systems reported widespread circulation of A(H3N2) in both countries during both seasons ( Miller et al., 1971 ; Housworth and Spoon, 1971 ).

Comparison of the Relative Impact of the First Two Waves of A/H3N2 Viruses and the Age Distribution of Influenza Deaths in the United States and United Kingdom, 1968–1970 .

Because pneumonia mortality rates throughout the year were more than two-fold higher in the United Kingdom than in the United States during the 1950s and 1960s ( Langmuir and Housworth, 1969 ; WHO, 1971 ), direct comparison of the absolute excess P&I mortality impact of the two pandemic waves is less revealing than their relative impact. In the United States, the first wave (1968–1969) accounted for 70 percent of the pandemic deaths, and the second season accounted for the remaining 30 percent. In the United Kingdom, however, the proportions were reversed: the first wave accounted for only 22 percent of UK pandemic deaths, whereas the remaining 78 percent occurred in the second ( Table 1-3 ). Given that circulation of the pandemic virus is well-documented, we use the term “smoldering pandemic” to characterize the first wave in the United Kingdom—the pandemic started slowly, but built to a more destructive conflagration in the second season. We are currently studying other countries, and it thus far appears that the UK pattern describes the typical “European” 1968 pandemic experience ( Stuart-Harris, 1970 ), while the U.S. pattern appears to represent the North American experience ( Viboud et al., 2004 ).

The impact of a novel influenza virus is thought to decrease over time as immunity increases in the population ( Cox and Subbarao, 2000 ; Miller et al., 1971 ). The European 1968 pandemic pattern, with its smoldering delay, did not fit this pattern, however. More than 30 years later, the reasons for the “smoldering waves” and the differences between North America and Europe are not clear ( Nguyen-Van-Tam and Hampson, 2003 ). It is possible that in Europe only, a high level of immunity to neuraminidase N2 protected the population during the first A/H3N2 wave ( Stuart-Harris, 1970 ). Such immunity would have been acquired through past exposure to A/H2N2 viruses. The “immunity” hypothesis is supported by a high rate of asymptomatic illnesses reported during the first pandemic wave in Europe ( Miller et al., 1971 ; Sohier and Henry, 1969 ). Alternatively, the different patterns may be due to minor genetic differences in the A/H3N2 viruses that circulated on the two continents. This hypothesis is difficult to address because only a very limited number of influenza A(H3N2) genetic sequences from the 1968–1970 period are available in the public domain. A new influenza genomics initiative recently funded by the National Institute of Allergy and Infectious Diseases (NIAID) should help change this situation, however. Under this program the Institute for Genomic Research (TIGR) will sequence qualified and properly prepared influenza virus samples for investigators ( http://www.niaid.nih.gov/dmid/genomes/mscs/projects.htm ). This initiative should encourage scientists everywhere to dig out old isolates sitting quietly in laboratory freezers, so that their complete sequences can be placed in GenBank for all to use.

From the perspective of pandemic planning, the smoldering European 1968 pandemic experience is encouraging, in that a repeat of this pattern in a future pandemic might allow the production and distribution of pandemic vaccines to occur in time to prevent a great many deaths. Indeed, had an effective pandemic vaccine become available in Europe even a full year after the emergence of A(H3N2) viruses in 1968, the majority of deaths associated with this pandemic might have been prevented. Whether smoldering patterns will occur in future pandemics is, of course, not known.

The 1957 Asian Pandemic: Impact Over Several Seasons

The 1957 influenza pandemic, which claimed the lives of more than one million people worldwide, has long been an unofficial model scenario for a future pandemic in the United States. In order to increase the utility of this model for pandemic planners, we have recently begun to compare the well-characterized mortality patterns observed in the United States during the pandemic ( Serfling et al., 1967 ) with those of other countries.

The U.S. Experience: Three Waves Between 1957 and 1963

The Asian H2N2 influenza virus is thought to have first emerged in China in February or March 1957. It reached the United States in early summer, at which time it caused sporadic outbreaks ( Jordan, 1958a ; Dunn, 1958 ). However, a measurable impact on U.S. mortality did not occur until October ( Serfling et al., 1967 ). Moreover, each of the first three seasons dominated by the emerging A(H2N2) virus—1957–1958, 1959–1960 and 1962–1963—resulted in roughly equivalent spikes in excess P&I mortality rates in the U.S. population ( Serfling et al., 1967 ) ( Table 1-4 ). These observations suggest that the second twentieth century pandemic did not strike in a sudden, overwhelming onslaught. Instead, measurable mortality impact occurred 4 to 6 months after the virus had begun to circulate and was isolated.

Relative Impact of First Three “Waves” of A(H2N2) Influenza in the United States, 1957–1963 (modified from data in Serfling et al., 1967) .

Serfling's analyses of the U.S. data also revealed that of all the deaths that occurred among age groups 45 years or younger during the first three serious H2N2 seasons, the majority occurred in the pandemic season of 1957–1958. Conversely, those 45 years and older felt the majority of the mortality impact in the next two A(H2N2)-dominated seasons, 1959–1960 and 1962–1963. For example, 71 percent of the excess deaths among 15–19 year olds in all three seasons occurred during the pandemic 1957–1958 season, while for people aged 75 and older only 33 percent of excess deaths occurred in the pandemic season ( Table 1-4 ). These differences in age-related mortality patterns closely reflected differences in age-specific attack rates of the influenza virus, which were available from the Cleveland Family Study ( Jordan et al., 1958a ) and Tecumseh, Michigan ( Hennessy et al., 1964 ). Indeed, the attack rate among school children was very high (72.9 percent) in 1957–1958 ( Jordan et al., 1958b ), but far lower in 1959–1960 and 1962–1963 ( Hennessy et al., 1964 ). It was considered possible that the lower 1957–1958 attack rates left a larger proportion of susceptible people among older cohorts during the subsequent seasons ( Hennessy et al., 1964 ). In summary, the bulk of A(H2N2) infection and mortality among younger age groups occurred in 1957/1958; much less occurred in the subsequent seasons, during which these younger age groups were probably protected by immunity gained through their first encounter with A(H2N2) viruses. However, for the middle aged and elderly, the “pandemic” impact was almost evenly divided between the first three seasons dominated by A(H2N2) viruses ( Serfling et al., 1967 ).

To investigate whether this age-specific mortality pattern also describes the international experience, we set out to develop a methodology for measuring pandemic mortality burden based on annual mortality data (Heiman et al., unpublished). Annual age-specific P&I mortality data were provided by WHO for the United States and Japan. We estimated the pandemic excess mortality in 1957 and 1958 by subtracting as background the number of deaths in surrounding years when there was little or no influenza A activity. We validated this approach by comparing these U.S. age-specific excess mortality estimates with those generated using actual seasonal data ( Serfling et al., 1967 ). We found that for Japan, the age pattern of relative impact over the first seasons was very similar to that observed in the United States ( Table 1-5 ). Also, in contrast to the United States where there was no measurable increase in influenza-related mortality until October, P&I mortality in Japan was elevated in the early summer of 1957 ( Reichert et al., 2001 ).

Relative impact of first 3 “waves” of A(H2N2) influenza in JAPAN, 1957–1963 (data from Heiman et al., unpublished) .

The 1918 Spanish Influenza Pandemic Revisited: Evidence for a Severe Herald Wave and Protection of the Elderly in New York City

The exact time and place that the 1918 pandemic virus originated has never been conclusively determined. Public health investigators recognized almost immediately that the so-called Spanish influenza, which spread across Europe in the late spring and summer of 1918 and exploded globally in the autumn and winter of 1918/1919, probably did not originate in Spain ( Low, 1920 ). Reports of influenza epidemics in U.S. military training camps in spring 1918, however, led some to identify the central United States as the “presumptive primary focus” of the pandemic ( Vaughn, 1921 ). Although this hypothesis has been cited many times over the years, it has never been subject to rigorous reexamination. Moreover, an old analysis of regional urban U.S. mortality statistics showed that excess mortality increased in several Atlantic seaboard cities in the spring of 1918, especially in New York City, suggesting that perhaps the pandemic strain might already have been spreading in this region ( Frost, 1919 ).

To investigate whether and when the characteristic age shift occurred in influenza seasons preceding the 1918–1919 pandemic season in the United States, age-stratified excess deaths in New York City were analyzed ( Olson et al., 2004 ). Comparison of all-cause mortality data for people over and under age 45 indicated that a shift in age-specific excess mortality happened very early in 1918, in the midst of an ongoing influenza season. This pattern is consistent with the arrival of the pandemic virus in New York City at about this time, and the subsequent occurrence of a pandemic herald wave from February to April 1918 ( Figure 1-9 , Table 1-6 ).

Monthly all-cause deaths in New York City by age. Classic Serfling model estimates of baseline mortality and 95 percent confidence limits were calculated for under-45 [B] and 45-and-over [A] all-cause deaths. The seasonal pattern indicates that the 1917–1918 (more...)

Age-Specific Mortality Impact of the 1918–1919 A(H1N1) Pandemic in New York City (Population: 5 million) and During the “Herald Wave” in Early 1918 (modified from Olson et al., 2004) .

The New York City data also demonstrate that mortality among people aged 45 and older during the 1918–1919 pandemic influenza season was no worse than in surrounding years. For people under age 45, however, the 1918–1919 influenza season was very bad—people in this age group were far more likely to die of influenza than in previous years. Indeed, the age groups at highest absolute risk of dying during the 1918–1919 A(H1N1) pandemic were young children and young and middle-aged adults ( Table 1-6 ).

These findings suggest that the early 1918 pandemic herald wave was spreading as early as February 1918, 6–7 months before the beginning of the explosive 1918–1919 pandemic. Relative to preceding influenza epidemic seasons, both the herald and pandemic waves caused proportionally more mortality in younger age groups but less mortality among those over 45 years of age, possibly as the result of recycling of an H1-like antigen from half a century earlier ( Olson et al., 2004 ).

Conclusion: Lessons from Pandemics Past for Pandemics Still to Come

Epidemiologic studies of past pandemics offer at least three important insights into what we can expect when the next influenza pandemic occurs. We believe these observations can help to guide pandemic detection and preparedness planning.

1. Mortality impact is difficult to predict, but a shift to younger ages is highly likely. Because our experience with pandemic influenza is so limited (N = 3), it is difficult to predict the mortality impact of a future pandemic. One can say, however, that the likely range is wide (from ~20 to ~500 deaths per 100,000 people) and that people under 65 years of age will account for a high proportion of these death.

2. Pandemic mortality impact is not always “tornado-like.” Pandemic influenza is not always like a sudden storm, followed by a return to clear skies. Instead, mortality rates can remain elevated for several years—during which time an effective vaccine would be in high demand. For example, in the 1957 pandemic worldwide, and in the 1968 pandemic in North America, much of the pandemic mortality impact occurred in a series of smaller but still severe twisters in subsequent years. This seems well explained by attack rates: The pattern of cumulative age-specific mortality impact during the first waves mirrored the age-specific attack rates, at least for the 1957 pandemic ( Serfling et al., 1967 ). Thus, the majority of middle-aged and elderly people—age groups that account for most of the cumulative pandemic mortality—were only affected by the emerging strain during the second or third season after its emergence.

3. Often there is a warning . For the 1918 pandemic, a herald wave that caused substantial mortality occurred at least 6 months before the major force of the pandemic hit in September. The 1957 pandemic virus had been characterized in Asia by the spring and was known to be circulating in the United States as early as June—months before the pandemic mortality impact began. For the 1968 pandemic, the majority of European deaths occurred after a 1-year delay. Thus, in all three pandemics, some form of warning was available.

Although mortality data are useful to characterize the patterns and impact of past pandemics, in most countries such data would not be available to allow timely detection of mortality age shifts to reveal pandemic activity. Instead, influenza virus surveillance efforts are most likely to provide the first warning of a future pandemic. And because younger people are disproportionately infected by pandemic strains when these first emerge, focusing pandemic virus surveillance efforts on isolates from children and young adults with severe outcomes of upper respiratory diseases would help to ensure that pandemic activity is detected as quickly as possible.

The idea that the next pandemic may not do all or even most of its damage in the first season is certainly good news for preparedness planning. In all three pandemics in the twentieth century, the majority of associated deaths occurred 6 months to a year after the pandemic virus first emerged. This suggests that intense and timely surveillance of both age-specific mortality and new influenza viruses could provide sufficient time for production and distribution of vaccines and antivirals to prevent much, if not most, of the mortality impact. Moreover, these medical interventions are likely to continue to play an important role for many years after the pandemic season. One should also note that the 1957 and 1968 pandemics tended to respect normal seasonality patterns, giving one hemisphere of the world an extra 6 months to prepare.

Finally, the existence of the pandemic age shift documented for all pandemics studied raises a crucial question: Who should get vaccines and antivirals first if these are in short supply, younger people or the elderly? If a future pandemic were to be like the severe 1918/1919 pandemic, in which young and middle-aged adults were the age groups at highest absolute risk of dying, then younger people should clearly get priority. But if a future pandemic were like the 1957 or the 1968 pandemics, the answer would not be so obvious. In those years, young and middle-aged adults were facing the most dramatic risk increase relative to non-pandemic influenza, yet they remained at a lower absolute risk than the elderly. The situation would be made more complex if the pandemic virus were to contain a recycled influenza antigen. In this instance, elderly age groups with prior exposure to similar antigens might be at less risk than in preceding non-pandemic seasons.

Of course, with or without recycling, a pattern like those seen in 1957 or 1968 would result in the elderly having a higher absolute risk of death. If the metric used to measure effectiveness of vaccination were “numbers of deaths prevented,” then perhaps the elderly should be given priority—assuming they can produce an adequate antibody response to the pandemic vaccine. But if the concern is to minimize the years-of-life-lost, then the vaccine may be better used in young and middle-aged adults. This point was illustrated in a paper that sought to determine vaccination priorities by age and risk status; when basing priority on “returns due to vaccination,” an endpoint that is heavily influenced by years of life lost, the young and middle aged rose to the top of the priority list ( Meltzer et al., 1999 ). Other authors have proposed that children be given priority to receive pandemic vaccine ( Stuart-Harris, 1970 ; Longini et al., 1978 ; Reichert et al., 2001 ) and antivirals ( Longini et al., 2004 ) in order to reduce transmission in the community and thereby indirectly reduce influenza impact among the elderly. The 2004 U.S. Pandemic Influenza Preparedness and Response Plan developed by the National Vaccine Program Office has not yet defined such priority groups ( DHHS, 2004 :24).

Given the very different proposals for how to best employ pandemic vaccines and antivirals should a shortage occur, we urge that a framework for determining priority groups be developed immediately. Such a scheme should be agreed on beforehand and be flexible enough to adapt to the likely level of disaster at hand. Any such an assessment would depend on rapid interpretation of early data on transmissibility and case fatality in the pandemic epicenter.

Will the next pandemic be 1918-like or 1957/1968-like? That is the question.

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Correspondenz-Blatt fur Schweizer Aerzte, Basel, 11/5/18. 48, #40, “influenza epidemic,” E. bircher, p. 1338, quoted in JAMA 71(23):1946.

JAMA 71(16):1317 current comment, Vaccines in influenza.

October 16, 1918, minutes of Philadelphia General Hospital Woman's Advisory Council.

This work has been partially supported by National Institutes of Health grants, and previously by grants from the Veterans Administration and the American Registry of Pathology, and by the Armed Forces Institute of Pathology.

This work was partially supported by a research grant from the National Vaccine Program Office, Unmet Needs. We thank Steven S. Morse and David S. Fedson for their support of this research activity, and our many international colleagues who supplied mortality data for the Multinational Influenza Seasonal Mortality Study (MISMS) network.

National Institute of Allergy and Infectious Diseases, National Institutes of Health (NIH), Bethesda, MD.

Columbia University, New York, NY.

Fogarty International Center (FIC), NIH, Bethesda, MD.

Under contract to National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD.

Entropy Research Institute, NJ, under contract to FIC, NIH, Bethesda, MD.

• Cite this Page Institute of Medicine (US) Forum on Microbial Threats; Knobler SL, Mack A, Mahmoud A, et al., editors. The Threat of Pandemic Influenza: Are We Ready? Workshop Summary. Washington (DC): National Academies Press (US); 2005. 1, The Story of Influenza.
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The Haiti That Still Dreams

By Edwidge Danticat

I often receive condolence-type calls, e-mails, and texts about Haiti. Many of these messages are in response to the increasingly dire news in the press, some of which echoes what many of us in the global Haitian diaspora hear from our family and friends. More than fifteen hundred Haitians were killed during the first three months of this year, according to a recent United Nations High Commissioner for Human Rights report, which described the country’s situation as “ cataclysmic .” Women and girls are routinely subjected to sexual violence. Access to food, water, education, and health care is becoming more limited, with more than four million Haitians, around a third of the population, living with food insecurity, and 1.4 million near starvation. Armed criminal groups have taken over entire neighborhoods in Port-au-Prince and the surrounding areas, carrying out mass prison breaks and attacks on the city’s airport, seaport, government buildings, police stations, schools, churches, hospitals, pharmacies, and banks, turning the capital into an “ open air prison .”

Even those who know the country’s long and complex history will ask, “Why can’t Haiti catch a break?” We then revisit some abridged version of that history. In 1804, after a twelve-year revolution against French colonial rule, Haiti won its independence, which the United States and several European powers failed to recognize for decades. The world’s first Black republic was then forced to spend sixty years paying a hundred-and-fifty-million francs (now worth close to thirty billion dollars) indemnity to France . Americans invaded and then occupied Haiti for nineteen years at the beginning of the twentieth century. The country endured twenty-nine years of murderous dictatorship under François Duvalier and his son, Jean-Claude, until 1986. In 1991, a few months after Haiti’s first democratically elected President, Jean-Bertrand Aristide, took office, he was overthrown in a coup staged by a military whose members had been trained in the U.S. Aristide was elected again, then overthrown again, in 2004, in part owing to an armed rebellion led by Guy Philippe, who was later arrested by the U.S. government for money laundering related to drug trafficking. Last November, six years into his nine-year prison sentence, Philippe was deported by the U.S. to Haiti. He immediately aligned himself with armed groups and has now put himself forward as a Presidential candidate.

In 2010, the country was devastated by a 7.0-magnitude earthquake, which killed more than two hundred thousand people. Soon after, United Nations “peacekeepers” dumped feces in Haiti’s longest river, causing a cholera epidemic that killed more than ten thousand people and infected close to a million. For the past thirteen years, Haiti has been decimated by its ruling party, Parti Haïtien Tèt Kale (P.H.T.K.), which rose to power after a highly contested election in 2011. In that election, the U.S.—then represented by Secretary of State Hillary Clinton—and the Organization of American States helped the candidate who finished in third place, Michel Martelly, claim the top spot. Bankrolled by kidnapping, drug trafficking, business élites, and politicians, armed groups have multiplied under P.H.T.K, committing massacres that have been labelled crimes against humanity. In 2021, a marginally elected President, Jovenel Moïse, was assassinated in his bedroom , a crime for which many of those closest to him, including his wife, have been named as either accomplices or suspects.

The unasked question remains, as W. E. B. Du Bois wrote in “ The Souls of Black Folk ,” “How does it feel to be a problem?”

I deeply honor Haiti’s spirit of resistance and long history of struggle, but I must admit that sometimes the answer to that question is that it hurts. Sometimes it hurts a lot, even when one is aware of the causes, including the fact that the weapons that have allowed gangs to take over the capital continue to flow freely from Miami and the Dominican Republic, despite a U.N. embargo. Internally, the poorest Haitians have been constantly thwarted by an unequal and stratified society, which labels rural people moun andeyò (outside people), and which is suffused with greedy and corrupt politicians and oligarchs who scorn the masses from whose tribulations they extract their wealth.

Recently, at a loved one’s funeral, in Michigan, the spectre of other Haitian deaths was once again on the minds of my extended family members. Everywhere we gather, Haiti is with us, as WhatsApp messages continuously stream in from those who chose to stay in Haiti and can’t leave because the main airport is closed, and others who have no other home. In Michigan, during chats between wake, funeral, and repast, elders brought up those who can’t get basic health care, much less a proper burial or any of the rituals that are among our most sacred obligations. “Not even a white sheet over those bodies on the street,” my mother-in-law, who is eighty-nine, said, after receiving yet another image of incinerated corpses in Port-au-Prince. At least after the 2010 earthquake, sheets were respectfully placed on the bodies pulled from the rubble. Back then, she said, the armed young men seemed to have some reverence for life and some fear of death.

Lately, some of our family gatherings are incantations of grief. But they can also turn into storytelling sessions of a different kind. They are opportunities for our elders to share something about Haiti beyond what our young ones, like everyone else, see on the news. The headlines bleed into their lives, too, as do the recycled tropes that paint us as ungovernable, failures, thugs, and even cannibals. As with the prayers that we recite over the dead, words still have power, the elders whisper. We must not keep repeating the worst, they say, and in their voices I hear an extra layer of distress. They fear that they may never see Haiti again. They fear that those in the next generation, some of whom have never been to Haiti, will let Haiti slip away, as though the country they see in the media—the trash-strewn streets and the barricades made from the shells of burnt cars, the young men brandishing weapons of war and the regular citizens using machetes to defend themselves—were part of some horror film that they can easily turn off. The elders remind us that we have been removed, at least physically, from all of this by only a single generation, if not less.

We are still human beings, the elders insist—“ Se moun nou ye .” We are still wozo , like that irrepressible reed that grows all over Haiti. For a brief moment, I think someone might break into the Haitian national anthem or sing a few bars of the folk song “ Ayiti Cheri .” (“Beloved Haiti, I had to leave you to understand.”) Instead, they hum the music that the wozo has inspired : “ Nou se wozo / Menm si nou pliye, nou pap kase. ” Even if we bend, we will not break.

Except we are breaking. “It pains me to see people living in constant fear,” the Port-au-Prince-based novelist and poet Évelyne Trouillot recently wrote to me in an e-mail. “I dream of a country where children are not afraid to dream.” Internationally, U.S. deportations continue , Navy ships are ready to be deployed to intercept migrant boats, and Haitian asylum seekers could once again end up imprisoned on Guantánamo, as they did in the early nineteen-nineties. In conversations, whether with strangers or with younger family members, someone inevitably asks, “Is there any hope?”

I have hope, I say, because I grew up with elders, both in Haiti and here in the U.S., who often told us, “ Depi gen souf gen espwa ”—as long as there’s breath, there’s hope. I have hope, too, because the majority of Haitians are under twenty-five years old, as are many members of our family. Besides, how can we give in to despair with eleven million people’s lives in the balance? Better yet, how can we reignite that communal grit and resolve that inspired us to defeat the world’s greatest armies and then pin to our flag the motto “ L’union fait la force ”? Unity is strength.

The elders also remind us that Haiti is not just Port-au-Prince. As more and more of the capital’s residents are forced to return to homesteads and ancestral villages, the moun andeyò have much to teach other Haitians. “Historically, the moun andeyò have always been the preserver of Haiti’s cultural and traditional ethos,” Vivaldi Jean-Marie, a professor of African American and African-diaspora studies at Columbia University, told me. Rural Haitians, who have lived for generations without the support of the state, have had no choice but to rely on one another in close and extended family structures called lakou . “This shared awareness—I am because we are—will prevail beyond this difficult chapter in Haitian history,” Jean-Marie said.

Finally, I have hope because in Haiti, as the American writer and art collector Selden Rodman has written, “ art is joy .” This remains true even as some of the country’s most treasured cultural institutions, including the National School of the Arts and the National Library, have been ransacked. In the summer of 2023, Carrefour Feuilles, a district in Port-au-Prince that many writers, visual artists, and musicians call home, was attacked by armed criminal groups. The onslaught led to a petition that collected close to five thousand signatures. It read in part, “How many more hundreds of our women and children must be raped, executed, burned before the public authorities do everything possible to put an end to the plague of gangs and their sponsors?”

A few days later, the homes of two of the signatories, the multimedia artist Lionel St. Eloi and the writer Gary Victor, were taken over by a gang. The last time I saw St. Eloi was in 2019, in the courtyard of Port-au-Prince’s Centre d’Art, where he had a series of metal birds on display, their bejewelled bodies and beaks pointing toward the sky. Allenby Augustin, the Centre d’Art’s executive director, recently described how some artists, afraid of having to suddenly flee their homes and leave their work behind, bring their pieces to the center or keep them in friends’ homes in different parts of the city. Others add the stray bullets that land inside their studios— bal pèdi or bal mawon —to their canvasses.

St. Eloi, the patriarch of a family of artists, had lived in Carrefour Feuilles since the seventies, working with young people there. “The youth who were neglected or who could not afford to go to school were taken in by our family,” one of St. Eloi’s sons, the musician Duckyns (Zikiki) St. Eloi, told me. “We taught them to paint, to play guitar, and to play the drums. Now they are hired to run errands for gangsters who put guns in their hands.” In spite of what has happened, he still believes that art can turn some things around. He recently sent me a picture of a work by his younger brother Anthony—an image depicting gang members wearing brightly colored balaclavas and holding pencils, a book, a paint palette, a camera, and a musical instrument. “If there are gangs, we’d be better off with art gangs,” Zikiki said. “Gangs that paint, make music, recite poetry. Art is how we bring our best face to the world. Art is how we dream.” ♦

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