The Historical Medical Library of The College of Physicians of Philadelphia
Patient with Spanish influenza
Influenza is an infectious disease commonly characterized by fever, muscles aches, sore throat, headache, and fatigue. It is generally caused by one of two types of influenza virus: influenza A or influenza B. (Influenza C causes upper respiratory tract infections in young people but is not as common as the other two types.) Most people infected with influenza feel ill for several days and then recover. In some instances, though influenza can lead to pneumonia, other complications, and even death.
People’s protection from viruses depends on having their having been exposed to the virus before, through infection or from a vaccine for that virus. In either case, the immune system “remembers” the virus and creates virus-specific antibodies that will neutralize the virus when it next enters the body. But influenza viruses can mutate, or change, rapidly. Every few years, influenza viruses mutate enough to result in a new strain. This process is known as antigenic drift. People who have been exposed to a related strain of that virus will likely have some pre-existing immunity to it in the form of antibodies, and the illness that results may be mild. Occasionally, a major change in a virus produces a strain so different from the others before it that humans have little or no preexisting immunity. This process is known as antigenic shift, and it can result in widespread, serious illness.
An influenza pandemic occurs when a new subtype or strain of influenza virus develops from antigenic shift and spreads globally. Three pandemics occurred in the 20th century, all of them caused by antigenic shift in influenza A strains. A pandemic in 2009, less deadly than the 20th-century outbreaks, was the result of a unique combination of genetic changes. The 1918-19 pandemic is the event against which all other pandemics are compared because of its unprecedented death toll.
Spanish Influenza, 1918-19
No other epidemic has claimed as many lives as the Spanish Influenza epidemic in 1918-1919. Worldwide, as many as 40 million people died as this virulent illness swept through city after city (some estimates put total deaths closer to 70 million). Stories abounded of people dying within hours of first feeling ill. The mortality rate was highest among adults under age 50, who were, for unknown reasons, particularly vulnerable to serious disease resulting from this strain of influenza.
The first cases of influenza appeared in Kansas in early spring 1918. Later that spring, officials reported large numbers of cases from Europe, though this flu seemed no more dangerous than the usual variety. However, in late summer, the virus became more deadly. Soon, waves of infection moved through towns, nations, and continents, overwhelming hospitals and medical personnel. The name Spanish Influenza came from the devastating effects of the flu in Spain in autumn 1918.
In 1918 influenza had neither treatment nor an effective vaccine. Indeed, most experts at the time thought that a bacterium caused influenza, rather than a virus. And though vaccines existed for several other diseases, and a few useless and possibly harmful anti-flu vaccines were concocted, an effective influenza vaccine was decades away. Nor were there antibiotics to treat the virulent bacterial infections that sprang up in influenza’s wake.
Late spring of 1919 saw the last of the Spanish Influenza. The virus drifted into relative harmlessness through the 1920s and continued to circulate for several decades. Scientists have since been able to classify the virus responsible for the 1918-19 pandemic as an H1N1 influenza.
Asian Influenza, 1957-58
Influenza remained a yearly occurrence after the 1918 pandemic, but no new, virulent influenza type emerged until early 1957. In February of that year, evidence began to surface about a serious wave of flu cutting a path through China.
Maurice Hilleman, a microbiologist at Walter Reed Army Medical Center, noticed news reports about influenza in Asia. The number of cases led him to think that a new type of influenza was emerging and that a pandemic threatened.
Hilleman and his team obtained a sample of the virus from a U.S. serviceman. They soon determined that most people lacked antibody protection from the new influenza virus, which was an H2N2 type. Only certain older people who had survived an influenza pandemic of 1889-1890 showed antibody response to the new virus.
Hilleman jump-started vaccine production by sending virus samples to manufacturers and urging them to develop a vaccine in four months.
The U.S. epidemic reached its worst in October 1957, when about 7 million people had received the vaccine. Worldwide, from 1957-1958, about 2 million people died from Asian flu, with about 70,000 deaths in the United States.
Hong Kong Flu, 1968-69
As in the pandemic just ten years earlier, the first signs of a new influenza A strain emerged in Asia. The virus (H3N2) reached the United States in September 1968 and peaked in the winter months. A vaccine became available but was not produced early enough to provide significant protection. About 34,000 people died in the United States during this pandemic. Some scientists think that a similarity with the 1957-58 Asian flu may have helped protect people from more serious disease. (Like the Asian flu, the Hong Kong flu had an N2 component.)
Avian Flu Threat, 1997-Present
The next significant threat to emerge in influenza came again from Asia, where an avian influenza (H5N1) infected birds and then spread to humans. A number of humans became ill and died from the virus.
The outbreaks were particularly severe in 2003-2004, when tens of millions of poultry and waterfowl died from the flu. The virus, however, did not spread from person to person, but only among birds and then to humans. The lack of human-to-human spread limited disease incidence. After widespread destruction of poultry flocks, the threat diminished. The threat of bird flu remains, however, in that another deadly strain could arise that would be capable of spreading from human to human and causing a pandemic.
Novel H1N1, 2009
The latest pandemic influenza appeared in Mexico in mid-March 2009. This flu appeared particularly troubling at first, because death rates in Mexico seemed unusually high. Soon cases appeared in California and Texas, and the disease continued to spread. Scientists identified the virus as influenza A H1N1, with its origin likely in pigs.
The World Health Organization provided global guidance on the emerging threat, and national, state, and local governments began implementing pandemic influenza plans. Though the disease spread rapidly, with an initial peak in the United States of early May, the resulting illness did not turn out to be as severe as the early Mexican reports indicated it might be. Still, the disease took a heavier toll on children and young adults than seasonal flu typically does. Usually, 90% of seasonal flu-related deaths occur in people over age 65, whereas 87% of deaths from H1N1-related illness occurred in people under age 65. One possible explanation for this is that many people born before 1950 seemed to have some pre-existing immunity to the virus, possibly because virus types related to the 1918 H1N1 flu pandemic were still circulating earlier in the 20th century.
A massive effort to produce vaccine for the new H1N1 strain began shortly after scientists identified the virus. The virus proved to grow slowly during the manufacturing process, which relies on cultivation of the virus in chicken eggs. In the United States, most vaccine arrived after the second peak of influenza cases in late October. In fact, experts had predicted that 160 million doses of the vaccine would be available by mid-October. But by that time, only 30 million doses had been delivered.
CDC estimates that between 42 million and 86 million cases of 2009 H1N1 occurred in the United States between April 2009 and February 13, 2010. Between 188,000 and 389,000 H1N1-related hospitalizations occurred during this period, as did 8,520-17,620 deaths.
Was 2009 H1N1 the result of antigenic shift or antigenic drift? No new H- or N-subtype entered the human population, which would indicate antigenic shift. But neither does the virus obviously fit with the definition of antigenic drift. As one report says,
“The emergence of the 2009 H1N1 virus is an unprecedented event in modern virology. The 2009 H1N1 virus does not fit the classic definition of a new subtype for which most of the population has no previous infection experience. Since 1977, H1N1 viruses have been in continuous circulation, and most persons born before 1956 have previous infection experience with H1N1 strains in the pre-H2N2 era. The 2009 H1N1 virus also does not fit the classic definition of drift because it has no direct evolutionary relationship with recently circulating H1N1 viruses of human origin” (Sullivan SJ, Jacobson RM, Dowdle WR, Poland GA. 2009 H1N1 Influenza).
The Future of Pandemic Influenza
The World Health Organization developed new pandemic guidelines in 2005 that prompted national and local authorities to revisit and upgrade their pandemic preparedness plans. The plans had been developed after the bird flu outbreaks of late 1990s. The 2009 H1N1 pandemic provided public health authorities a chance to implement new plans designed to respond to pandemic illness.
As groups study the 2009 pandemic response, many point to the need for quicker development and distribution of influenza vaccine. Industry and public health officials are examining new technologies and methods to increase vaccine availability. For instance, U.S. companies might begin to use adjuvant in influenza vaccine, as is done in the European Union and Canada, which would allow them to use smaller amounts of antigen in each dose. Additionally, they might begin to use new antigen cultivation technologies to avoid the slow process of vaccine production in eggs.
The need for continued attention to pandemic influenza plans is apparent. As a U.S. Department of Health and Human Services report states, “If a pandemic influenza virus with similar virulence to the 1918 strain emerged today, in the absence of intervention, it is estimated that 1.9 million Americans could die and almost 10 million could be hospitalized….” (Pandemic Influenza Plan, U.S. Department of Health and Human Services).
CDC. Avian Influenza, Current Situation. Accessed 03/15/2017.
CDC. Avian Influenza A Virus Infections in Humans. Accessed 03/15/2017.
Influenza A/Mexico/2009 (H1N1) - Questions & Answers. Virology Blog. Accessed 03/15/2017.
CDC. HHS Pandemic Influenza Plan. U.S. Department of Health and Human Services. Accessed 03/15/2017.
Reid, A.H., et al. 1918 influenza pandemic caused by highly conserved viruses with two receptor-binding variants. Emerging Infectious Diseases. Vol. 9, No. 10, October 2003. Accessed 03/15/2017.
Sullivan, S.J., Jacobson, R.M., Dowdle, W.R., Poland, G.A. 2009 H1N1 influenza. Mayo Clin Proc. 2010 January; 85(1): 64-76.
Timeline of Human Flu Pandemics. National Institute of Allergy and Infectious Diseases. Accessed 03/15/2017.
Trust for America’s Health. Pandemic Flu Preparedness: Lessons from the Front Lines. June 2009. Accessed 03/15/2017.
Xing, Z., Cardona, C.J. Preexisting immunity to pandemic (H1N1) 2009 [letter]. Emerging Infectious Diseases. November 2009. Accessed 03/15/2017.
Last update 15 March 2017
A pandemic occurs when a disease spreads __________.
- from animals to people
There have been no influenza pandemics in the 21st century (the 2000s).
Which influenza pandemic below killed the most people?
- The Spanish Influenza pandemic of 1918-19
- The Asian Influenza pandemic of 1957-58
- The Hong Kong Flu pandemic of 1968-69
- The 2009 H1N1 pandemic