The Coming Influenza Pandemic Part III

In Parts I and II I discussed the biology, morphology and genetics of influenza and how the virus makes people sick. In Part III I will talk about various influenza pandemics that have occurred over the past century and the development of Highly Pathogenic Avian Influenzas (HPAI).

Seasonal flu does not usually kill many healthy adults and morbidity declines with age. Adults have already been exposed to several strains in their lifetimes and have developed immunity to many of these. Further, as far as scientists are aware, highly pathogenic strains, such as the H5N1 avian flu, do not yet have the ability to easily infect humans. So, why should anyone worry about deadly flu pandemics?

From Wikipedia

It is true that H5N1 cannot yet pass easily from person to person. However, as a result of antigenic shift, it could acquire a hemagglutinin that allows easy transmission between people. Alternatively, a flu strain such as H1N1 that is already easily transmissible between humans, but that is currently not especially deadly, could acquire virulence from another strain through antigenic shift. If either of these scenarios were to occur, we could see a repeat of 1918, with a new strain that is highly transmissible, extremely lethal, and for which we lack immunity.^3(p16) It should be remembered that the 1918 pandemic began with relatively low virulence, and then returned in a much deadlier form.

On average, a significant antigenic shift has occurred each generation, producing a new pandemic strain.^3(p11) 

Even without high mortality, influenza can still be enormously costly to society. For example, over $10 billion has been spent and over 200 million birds have been slaughtered in efforts to contain H5N1, which at this point has killed very few people.¹⁰   With highly transmissible strains like the recent H1N1 swine flu, which was not particularly lethal, there can still be high numbers of infections that keep many people home from school and work. At the beginning of the swine flu pandemic of 2009-2010, President Obama’s Advisory Council on Science and Technology warned that up to 50% of the population could contract the disease.¹⁷ Had this happened, there could have been shortages of food, medicine and water due to high absenteeism and the impact on the economy could devastating.

The 1919 Spanish flu pandemic was the deadliest and most devastating pandemic ever. However, it primarily killed those under the age of 60. It is thought that those who were over the age of 60 at the time of this outbreak had developed partial immunity due to past exposures to related viruses. However, it is not currently known for certain what strain the Russian flu was or how it related to the 1919 strain. Jeffrey Taubenberger, of National Institute of Allergy and Infectious Diseases, says that every major human flu strain in the past 90 years has been a member of the 1918 family, each built on the same basic framework of the 1918 H1N1 strain.⁶ This may explain why there has not been a pandemic since then with comparable mortality and morbidity rates: constant re-exposure to its relatives has primed our immune systems.⁶

In 1947-1948 a mutated version of the 1919 Spanish flu reappeared and sickened hundreds of millions of people. Fortunately, it had lost much of it virulence and mortality rates were similar to seasonal flu.^3(p33)

In 1957-1958, there was another deadly pandemic. The strain was H2N2 strain with avian surface antigens, human internal proteins and a swine vector.^{3(p35),13(p583)} An estimated 1.5 to 2 million people died world-wide; 80,000 in U.S., alone.³⁽³⁶⁾ 

In 1968, there was another pandemic, this time an H3N2 strain originating in Guangdong or Hong Kong.^13(p583) This time, mortality rates were relatively low (e.g., 34,000 died in U.S., while approximately 1 million died worldwide. Most seasonal flus since 1968 have been variants of 1968 H3N2 strain.^13(p583) 

In 1976 there was a swine flu scare, based on the reappearance of H1N1.^13(583) The CDC warned that the 1918 strain had returned, creating panic by many governments. In reality, however, both mortality and morbidity were low. It has since been shown that the CDC’s warning was exaggerated and premature.⁶ As a precaution, the U.S. government launched a massive vaccination program. There was much criticism of the Ford administration for its “wasteful” and “unnecessary” vaccination program; however, many flu experts argue that it is better to have a vaccine without a pandemic, than a pandemic without a vaccine.^3(p43)

The recent pandemic of H1N1 turned out to have relatively low mortality, mostly among the young. One possible explanation is that exposure to post-1918 H1N1 strains, especially 1957-8, primed older peoples’ immune systems.⁶ A study by the CDC found that over 50% of people who received the 1976 swine flu vaccine had powerful immune responses to the 2009 H1N1 virus, while those who did not receive the 1976 vaccine had weak immune responses to the current vaccine. ⁶ Perhaps Ford’s swine flu vaccination program was more beneficial than we realized.

So far, we have been spared a repetition of the devastating 1918-1919 pandemic. However, this does not mean we should assume that 1918 was an historical aberration that will not occur again. An antigenic shift combining human and avian antigens could still result in a devastating modern pandemic.

Many varieties of highly pathogenic avian influenza (HPAI) have arisen over the past twenty years. Some, like H5N1, have extremely high virulence when they infect humans.^3,7,10 For many of these strains, humans have no immunity. Therefore, if one of these HPAI strains were to acquire the ability the easily infect humans, we would likely see both high morbidity and mortality, like in 1918.

H5N1 has already acquired the ability to infect mammals (80 Bengal Tigers died in Bangkok zoo after eating raw chicken, and there have been some cases of house cats transmitting it to each other.^3(p122) So far, there have been 442 human fatalities from H5N1, including several cases in which person to person transmission is suspected. If H5N1 becomes easily transmissible and maintains its present mortality rate, some estimate that one billion people could die.^3(p125) 

An H7N7 outbreak in Holland, 2003, led to the slaughter of over 30 million birds (one-third of the entire Dutch poultry industry).^3(p85-87) H7N7 is particularly alarming because it not only infects birds, but a variety of mammals, including seals & horses.⁷  It also infected as many as several thousand poultry workers and their family members and neighbors, mostly in Holland. Fortunately, this strain seems to have a hemagglutinin that allows infection the human conjunctiva, but not the respiratory tract, and has thus far shown very low lethality in humans.⁷

There are currently HPAI strains of H5, H9 and H7 circulating in domesticated poultry, each of which is considered to have pandemic potential.^3,7 The U.S. department of agriculture monitors and responds to all domestic HPAI outbreaks, but not to Low Pathogenic Avian Influenza (LPAI) strains. LPAI is endemic in poultry, with low mortality, but can reassort through antigenic shift and become highly lethal.^3(p91) A Southern California outbreak of LPAI H6N2 in 2001 became highly pathogenic to poultry and led to a massive cull.^3(p92)  H7N2 is currently LPAI. However, a 2008 analysis of a 2003 human infection showed that this strain may be evolving antigenic properties similar to the pandemic strains of 1918 and 1957.⁷

Check back tomorrow for a discussion of how the social, economic and political conditions today increase the likelihood and the potential devastation of another deadly pandemic.

References

1. AVERT, 2009, AVERTing AIDS website, October 28, 2009: http://www.avert.org/worldstats.htm
2. Bartlett, Donald L.,  and James B. Steele, 2004, “The Health of Nations,” New York Times, Oct 24,
3. Davis, Mike, 2005, The Monster at Our Door, The New Press, New York
4. Enserink, Martin, 2004, Science, 306, Dec ember 17, 2004
5. Kash, John C., Tumpey, Terrence M., Proll, Sean C., Carter, Victoria, Perwitasari, Olivia, Thomas, Matthew J., Basler, Christopher F., Palese, Peter, Taubenberger, Jeffery K., García-Sastre, Adolfo, Swayne, David E., and Katze, Michael G., 2006, “Genomic analysis of increased host immune and cell death responses induced by 1918 influenza virus,” Nature. October 5; 2006, 443(7111): 578–581.
6. Soares, Christine, 2009, “Pandemic Payoff,” Scientific American, November, 2009, p19-20
7. Various Authors, 2009, “Influenza:,” from Wikipedia, accessed November 7, 2009, http://en.wikipedia.org/wiki/Influenza
8. Various Authors, 2009, “Cytokine Storm,” from Wikipedia, accessed November 7, 2009: http://en.wikipedia.org/wiki/Cytokine_storm
9. Various Authors, 2009, “Black Death,” from Wikipedia, accessed November 8, 2009: http://en.wikipedia.org/wiki/Black_Death
10. Various Authors, 2009, “1918 flu pandemic,” from Wikipedia, accessed November 8, 2009: http://en.wikipedia.org/wiki/1918_flu_pandemic
11. Various Authors, 2009, “Seasonal Influenza: the Disease,” Centers For Disease Control and Prevention website, accessed November 14, 2009: http://www.cdc.gov/flu/about/disease/
12. Wallace, Amy, 2009, “An Epidemic of Fear: How Panicked Parents Skipping Shots Endangers Us All,” Wired, October 19, 2009: http://www.wired.com/magazine/2009/10/ff_waronscience/
13. Willey, Joanne M., Sherwood, Linda M., and Woolverton, Christopher J.,  2009, Prescott’s Principles of Microbiology, New York, NY, McGraw Hill
14. Various Authors, 2009, “Pearl River Delta” from Wikipedia, accessed November 14, 2009: http://en.wikipedia.org/wiki/Pearl_River_Delta
15. Various Authors, 2009, “Cortisol,” from Wikipedia,  accessed November 16, 2009: http://en.wikipedia.org/wiki/Cortisol
16. California Newsreel, 2008, “Unnatural Causes,”  video.  Transcript accessed November 16, 2009: http://www.unnaturalcauses.org/assets/uploads/file/UC_Transcript_1.pdf
17. President’s Council of Advisors on Science and Technology, 2009, “Report to the President on U.S. Preparations for 2009-H1N1 Influenza,” August 7, 2009: http://www.whitehouse.gov/assets/documents/PCAST_H1N1_Report.pdf

The Coming Influenza Pandemic Part II

In Part I, I discussed the deadly flu pandemic of 1918-1919 and started to explain the biology and morphology of Influenza. In Part II, we will look more at the genetics and morphology of Influenza as well as its etiology (how the disease progresses in humans) and its ecology.

From Wikipedia

 The first step to any viral infection involves adherence to the host cell. Influenza does this by using its hemagglutinin to bind to sialic acid sugars on surface of epithelial cells in the nose, throat and lungs of mammals or intestine of birds.⁷ Host proteases (enzymes that break down protein) cleave the hemagglutinins, leading to endocytosis (engulfment) into the host cell.⁷ The low pH of the endosome (a vesicle made of host membrane surrounding the virus) causes the viral core to dissemble, releasing its RNA. Viral core proteins enter the host nucleus, forcing host cells to make positive-sense viral RNA (vRNA).⁷ The host then translates the viral genes and assembles new influenza virions, which escape the host cell with the aid of neuraminidase.

From Wikipedia

 Virulent strains have hemagglutinins that can be cleaved by proteases found throughout the body, especially deep in the lungs, where an infection has much more serious consequences than infections higher up in the respiratory tract.⁷ Mild strains have hemagglutinins that can only be cleaved by proteases found in the trachea, producing less severe symptoms.⁷ Strains such as H5N1, which have the ability to infect numerous different species, have hemagglutinins that can be cleaved by proteases from a variety of hosts (e.g., duck, chicken, pig, human). While avian hemagglutinins typically can only be cleaved by proteases found in the avian gut, H5N1 has the ability to infect the avian gut, as well as the mammalian respiratory tract, allowing it to infect a variety of avian and mammalian species.⁷

Influenza is usually acquired by inhalation or ingestion, but can also be transmitted through the eyes.^13(p582) Influenza is stable on surfaces and can be picked up from tables, doorknobs, shared food and utensils. It has an incubation period of 1-2 days and is highly infectious even before symptoms appear. Influenza destroys the ciliated cells of the respiratory tract which are important for sweeping away dust and germs.⁷ Damage to these cells increases susceptibility to secondary infections by bacteria that cause pneumonia (e.g., Haemophilus influenza, Staphylococcus aureus and Streptococcus pneumonia).^3(p22)

Acute strains also may kill directly through pulmonary edema, hemorrhage, rapid destruction of the respiratory epithelium⁵ or through a cytokine storm (a potentially lethal immune response that involves the sudden release of over one hundred inflammatory regulators).⁸ Both the 1918 pandemic H1N1 strain, and the current, highly pathogenic avian strain, H5N1, are thought to be able to kill through a cytokine storm.⁸

 

The influenza genome contains 7-8 segments of single-stranded, negative sense RNA, for a total of approximately 10,000 nucleotide bases.^7,13 The high error rate of RNA Polymerase (1 error every 10,000 nucleotides) leads to an average of one mutation each time the genome is replicated.⁷ In other words, every time a host cell lyses and releases new virions, the new virions have a slightly different genotype than their parents. This mutation rate, while fast compared to DNA-based genomes, is still slow enough that people may retain some immunity over the course of two or three flu seasons because the newer strains often retain some of the surface antigens of their parents.^7,13(p583) This gradual evolution of the virus is known as antigenic drift.^7,13

Antigenic shift is a much more sudden and dramatic change in the surface antigens that results from genetic reassortment between different strains. Such gene swapping can occur when a host is coinfected with two or more different subtypes of influenza.^3(p16)

From Wikipedia

 The human immune system produces white blood cells called B lymphocytes.^13(p700-3) One type of B lymphocyte is the plasma cell, which produces proteins on its surface called antibodies. B plasma cells, like influenza, mutate very rapidly, resulting in thousands of different varieties, each with different antibodies. An antibody with a complementary shape to an antigen can bind to it, setting off a cascade of immune responses that help to destroy the pathogen carrying that antigen. This is called a primary response and occurs whenever we are exposed to a new germ to which we lack immunity. Another type of immune cell is also produced, called memory B cells, whose function is to retain the DNA for a particular antibody. If we are later re-infected with the same germ, the memory cells rapidly kick into action to destroy the pathogen before it makes us sick. This is called a secondary response. Vaccines function by training our immune systems to make B cells for a particular illness so that we have a secondary response and avoid illness if we are ever exposed to that disease. Vaccines by-pass the initial phase of immune response where you first get sick by using killed or attenuated germs or antigens that do not cause disease, but still stimulate an immune response.

Antigenic drift is a gradual change in the surface antigens of influenza, specifically hemagglutinin and neuraminidase. Antigenic drift causes seasonal influenza to change slightly each year. This is why a single flu vaccine does not protect us for life, unlike many other vaccines (e.g., smallpox, chickenpox, and measles). New flu vaccines must be reformulated each year by carefully monitoring the various recent and novel strains that scientists have observed. Because antigenic drift is relatively slow and leads to only modest changes in the topography of the influenza virus, making effective seasonal flu vaccine is fairly easy and usually pretty successful.⁷

Antigenic shift, in contrast, because it involves gene swapping between different strains, can lead to sudden and dramatic changes in the surface topography of the virus. It can also lead to significant changes to the internal proteins, some of which influence virulence. Because it can occur suddenly, antigenic shift can make it difficult to produce an effective vaccine quickly enough to protect the public.^3,7,13

Many people routinely forego the flu vaccine because they do not see the point. Seasonal flu does not usually kill many healthy adults and morbidity declines with age. Adults have already been exposed to several strains in their lifetimes and have developed immunity to many of these. Further, as far as scientists are aware, highly pathogenic strains, such as the H5N1 avian flu, do not yet have the ability to easily infect humans. So, why should anyone worry about deadly flu pandemics?

Check tomorrow for Part III, where I will discuss the other deadly pandemics of the past century and the development of novel Highly Pathogenic Avian Influenzas (HPAI) that could evolve into the next deadly pandemic.

References

1. AVERT, 2009, AVERTing AIDS website, October 28, 2009: http://www.avert.org/worldstats.htm
2. Bartlett, Donald L.,  and James B. Steele, 2004, “The Health of Nations,” New York Times, Oct 24,
3. Davis, Mike, 2005, The Monster at Our Door, The New Press, New York
4. Enserink, Martin, 2004, Science, 306, Dec ember 17, 2004
5. Kash, John C., Tumpey, Terrence M., Proll, Sean C., Carter, Victoria, Perwitasari, Olivia, Thomas, Matthew J., Basler, Christopher F., Palese, Peter, Taubenberger, Jeffery K., García-Sastre, Adolfo, Swayne, David E., and Katze, Michael G., 2006, “Genomic analysis of increased host immune and cell death responses induced by 1918 influenza virus,” Nature. October 5; 2006, 443(7111): 578–581.
6. Soares, Christine, 2009, “Pandemic Payoff,” Scientific American, November, 2009, p19-20
7. Various Authors, 2009, “Influenza:,” from Wikipedia, accessed November 7, 2009, http://en.wikipedia.org/wiki/Influenza
8. Various Authors, 2009, “Cytokine Storm,” from Wikipedia, accessed November 7, 2009: http://en.wikipedia.org/wiki/Cytokine_storm
9. Various Authors, 2009, “Black Death,” from Wikipedia, accessed November 8, 2009: http://en.wikipedia.org/wiki/Black_Death
10. Various Authors, 2009, “1918 flu pandemic,” from Wikipedia, accessed November 8, 2009: http://en.wikipedia.org/wiki/1918_flu_pandemic
11. Various Authors, 2009, “Seasonal Influenza: the Disease,” Centers For Disease Control and Prevention website, accessed November 14, 2009: http://www.cdc.gov/flu/about/disease/
12. Wallace, Amy, 2009, “An Epidemic of Fear: How Panicked Parents Skipping Shots Endangers Us All,” Wired, October 19, 2009: http://www.wired.com/magazine/2009/10/ff_waronscience/
13. Willey, Joanne M., Sherwood, Linda M., and Woolverton, Christopher J.,  2009, Prescott’s Principles of Microbiology, New York, NY, McGraw Hill
14. Various Authors, 2009, “Pearl River Delta” from Wikipedia, accessed November 14, 2009: http://en.wikipedia.org/wiki/Pearl_River_Delta
15. Various Authors, 2009, “Cortisol,” from Wikipedia,  accessed November 16, 2009: http://en.wikipedia.org/wiki/Cortisol
16. California Newsreel, 2008, “Unnatural Causes,”  video.  Transcript accessed November 16, 2009: http://www.unnaturalcauses.org/assets/uploads/file/UC_Transcript_1.pdf
17. President’s Council of Advisors on Science and Technology, 2009, “Report to the President on U.S. Preparations for 2009-H1N1 Influenza,” August 7, 2009: http://www.whitehouse.gov/assets/documents/PCAST_H1N1_Report.pdf
18.