The Great Influenza: The Epic Story of the Deadliest Plague in History - John M. Barry (2004)
Part II. THE SWARM
AN INFECTION is an act of violence; it is an invasion, a rape, and the body reacts violently. John Hunter, the great physiologist of the eighteenth century, defined life as the ability to resist putrefaction, resist infection. Even if one disagrees with that definition, resisting putrefaction certainly does define the ability to live.
The body’s defender is its immune system, an extraordinarily complex, intricate, and interwoven combination of various kinds of white blood cells, antibodies, enzymes, toxins, and other proteins. The key to the immune system is its ability to distinguish what belongs in the body, “self,” from what does not belong, “nonself.” This ability depends, again, upon reading the language of shape and form.
The components of the immune system—white blood cells, enzymes, antibodies, and other elements—circulate throughout the body, penetrating everywhere. When they collide with other cells or proteins or organisms, they interact with and read physical markings and structures just as the influenza virus does when it searches for, finds, and latches on to a cell.
Anything carrying a “self” marking, the immune system leaves alone. (It does, that is, when the system works properly. “Autoimmune diseases” such as lupus or multiple sclerosis develop when the immune system attacks its own body.) But if the immune system feels a “nonself” marking—either foreign invaders or the body’s own cells that have become diseased—it responds. In fact, it attacks.
The physical markings that the immune system feels and reads and then binds to are called “antigens.” The word refers to, very simply, anything that stimulates the immune system to respond.
Some elements of the immune system, such as so-called natural killer cells, will attack anything that bears any nonself-marking, any foreign antigen. This is referred to as “innate” or “nonspecific” immunity, and it serves as a first line of defense that counterattacks within hours of infection.
But the bulk of the immune system is far more targeted, far more focused, far more specific. Antibodies, for example, carry thousands of receptors on their surface to recognize and bind to a target antigen. Each one of those thousands of receptors is identical. So antibodies bearing these receptors will recognize and bind only to, for example, a virus bearing that antigen. They will not bind to any other invading organism.
One link between the nonspecific and specific immune response is a particular and rare kind of white blood cell called a dendritic cell. Dendritic cells attack bacteria and viruses indiscriminately, engulf them, then “process” their antigens and “present” those antigens—in effect they chop up an invading microorganism into pieces and display the antigens like a trophy flag.
The dendritic cells then travel to the spleen or the lymph nodes, where large numbers of other white blood cells concentrate. There these other white blood cells learn to recognize the antigen as a foreign invader and begin the process of producing huge numbers of antibodies and killer white cells that will attack the target antigen and anything attached to the antigen.
The recognition of a foreign antigen also sets off a parallel chain of events as the body releases enzymes. Some of these affect the entire body, for example, raising its temperature and causing fever. Others directly attack and kill the target. Still others serve as chemical messengers, summoning white blood cells to areas of invasion or dilating capillaries so killer cells can exit the bloodstream at the point of attack. Swelling, redness, and fever are all side effects of the release of these chemicals.
All this together is called the “immune response,” and once the immune system is mobilized it is formidable indeed. But all this takes time. The delay can allow infections to gain a foothold in the body, even to advance in raging cadres that can kill.
In the days before antibiotics, an infection launched a race to the death between the pathogen and the immune system. Sometimes a victim would become desperately ill; then, suddenly and almost miraculously, the fever would break and the victim would recover. This “resolution by crisis” occurred when the immune system barely won the race, when it counterattacked massively and successfully.
But once the body survives an infection, it gains an advantage. For the immune system epitomizes the saying that that which does not kill you makes you stronger.
After it defeats an infection, specialized white cells (called “memory T cells”) and antibodies that bind to the antigen remain in the body. If any invader carrying the same antigen attacks again, the immune system responds far more quickly than the first time. When the immune system can respond so quickly that a new infection will not even cause symptoms, people become immune to the disease.
Vaccinations expose people to an antigen and mobilize the immune system to respond to that disease. In modern medicine some vaccines contain only the antigen, some contain whole killed pathogens, and some contain living but weakened ones. They all alert the immune system and allow the body to mount an immediate response if anything bearing that antigen invades the body.
The same process occurs in the body naturally with the influenza virus. After people recover from the disease, their immune systems will very quickly target the antigens on the virus that infected them.
But influenza has a way to evade the immune system.
The chief antigens of the influenza virus are the hemagglutinin and neuraminidase protruding from its surface. But of all the parts of the influenza virus that mutate, the hemagglutinin and neuraminidase mutate the fastest. This makes it impossible for the immune system to keep pace.
By no means do the antigens of all viruses, even all RNA viruses, mutate rapidly. Measles is an RNA virus and mutates at roughly the same rate as influenza. Yet measles antigens do not change. Other parts of the virus do, but the antigens remain constant. (The most likely reason is that the part of the measles virus that the immune system recognizes as an antigen plays an integral role in the function of the virus itself. If it changes shape, the virus cannot survive.) So a single exposure to measles usually gives lifetime immunity.
Hemagglutinin and neuraminidase, however, can shift into different forms and still function. The result: their mutations allow them to evade the immune system but do not destroy the virus. In fact, they mutate so rapidly that even during a single epidemic both the hemagglutinin and neuraminidase often change.
Sometimes the mutations cause changes so minor that the immune system can still recognize them, bind to them, and easily overcome a second infection from the same virus.
But sometimes mutations change the shape of the hemagglutinin or neuraminidase enough that the immune system can’t read them. The antibodies that bound perfectly to the old shapes do not fit well to the new one.
This phenomenon happens so often it has a name: “antigen drift.”
When antigen drift occurs, the virus can gain a foothold even in people whose immune system has loaded itself with antibodies that bind to the older shapes. Obviously, the greater the change, the less efficiently the immune system can respond.
One way to conceptualize antigen drift is to think of a football player wearing a uniform with white pants, a green shirt, and a white helmet with a green V emblazoned on it. The immune system can recognize this uniform instantly and attack it. If the uniform changes slightly—if, for example, a green stripe is added to the white pants while everything else remains the same—the immune system will continue to recognize the virus with little difficulty. But if the uniform goes from green shirt and white pants to white shirt with green pants, the immune system may not recognize the virus so easily.
Antigen drift can create epidemics. One study found nineteen discrete, identifiable epidemics in the United States in a thirty-three-year period—more than one every other year. Each one caused between ten thousand and forty thousand “excess deaths” in the United States alone—an excess over and above the death toll usually caused by the disease. As a result influenza kills more people in the United States than any other infectious disease, including AIDS.
Public health experts monitor this drift and each year adjust the flu vaccine to try to keep pace. But they will never be able to match up perfectly, because even if they predict the direction of mutation, the fact that influenza viruses exist as mutating swarms means some will always be different enough to evade both the vaccine and the immune system.
But as serious as antigen drift can be, as lethal an influenza as that phenomenon can create, it does not cause great pandemics. It does not create firestorms of influenza that spread worldwide such as those in 1889–90, in 1918–19, in 1957, and in 1968.
Pandemics generally develop only when a radical change in the hemagglutinin, or the neuraminidase, or both, occurs. When an entirely new gene coding for one or both replaces the old one, the shape of the new antigen bears little resemblance to the old one.
This is called “antigen shift.”
To use the football-uniform analogy again, antigen shift is the equivalent of the virus changing from a green shirt and white pants to an orange shirt and black pants.
When antigen shift occurs, the immune system cannot recognize the antigen at all. Few people in the world will have antibodies that can protect them against this new virus, so the virus can spread through a population at an explosive rate.
Hemagglutinin occurs in fifteen known basic shapes, neuraminidase in nine, and they occur in different combinations with subtypes. Virologists use these antigens to identify what particular virus they are discussing or investigating. “H1N1,” for example, is the name given the 1918 virus, currently found in swine. An “H3N2” virus is circulating among people today.
Antigen shift occurs when a virus that normally infects birds attacks humans directly or indirectly. In Hong Kong in 1997 an influenza virus identified as “H5N1” spread directly from chickens to people, infecting eighteen and killing six.
Birds and humans have different sialic-acid receptors, so a virus that binds to a bird’s sialic-acid receptor will not normally bind to—and thus infect—a human cell. In Hong Kong what most likely happened was that the eighteen people who got sick were subjected to massive exposure to the virus. The swarm of these viruses, the quasi species, likely contained a mutation that could bind to human receptors, and the massive exposure allowed that mutation to gain a foothold in the victims. Yet the virus did not adapt itself to humans; all those who got sick were infected directly from chickens.
But the virus can adapt to man. It can do so directly, with an entire animal virus jumping to humans and adapting with a simple mutation. It can also happen indirectly. For one final and unusual attribute of the influenza virus makes it particularly adept at moving from species to species.
The influenza virus not only mutates rapidly, but it also has a “segmented” genome. This means that its genes do not lie along a continuous strand of its nucleic acid, as do genes in most organisms, including most other viruses. Instead, influenza genes are carried in unconnected strands of RNA. Therefore, if two different influenza viruses infect the same cell, “reassortment” of their genes becomes very possible.
Reassortment mixes some of the segments of the genes of one virus with some from the other. It is like shuffling two different decks of cards together, then making up a new deck with cards from each one. This creates an entirely new hybrid virus, which increases the chances of a virus jumping from one species to another.
If the Hong Kong chicken influenza had infected someone who was simultaneously infected with a human influenza virus, the two viruses might easily have reassorted their genes. They might have formed a new virus that could pass easily from person to person. And the lethal virus might have adapted to humans.
The virus may also adapt indirectly, through an intermediary. Some virologists theorize that pigs provide a perfect “mixing bowl,” because the sialic-acid receptors on their cells can bind to both bird and human viruses. Whenever an avian virus infects swine at the same time that a human virus does, reassortment of the two viruses can occur. And an entirely new virus can emerge that can infect man. In 1918 veterinarians noted outbreaks of influenza in pigs and other mammals, and pigs today still get influenza from a direct descendant of the 1918 virus. But it is not clear whether pigs caught the disease from man or man caught it from pigs.
And Dr. Peter Palese at Mount Sinai Medical Center in New York, one of the world’s leading experts on influenza viruses, considers the mixing-bowl theory unnecessary to explain antigen shift: “It’s equally likely that co-infection of avian and human virus in a human in one cell in the lung [gives] rise to the virus…. There’s no reason why mixing couldn’t occur in the lung, whether in pig or man. It’s not absolute that there are no sialic acid receptors of those types in other species. It’s not absolute that the avian receptor is really that different from the human, and, with one single amino acid change, the virus can go much better in another host.”*
Antigen shift, this radical departure from existing antigens, led to major pandemics long before modern transportation allowed rapid movement of people. There is mixed opinion as to whether several pandemics in the fifteenth and sixteenth centuries were influenza although most medical historians believe that they were, largely because of the speed of their movement and the number of people who fell ill. In 1510 a pandemic of pulmonary disease came from Africa and “attacked at once and raged all over Europe not missing a family and scarce a person.” In 1580 another pandemic started in Asia, then spread to Africa, Europe, and America. 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.”
There is no dispute, though, that other pandemics in the past were influenza. In 1688, the year of the Glorious Revolution, influenza struck England, Ireland, and Virginia. In these places “the people dyed…as in a plague.” Five years later, influenza spread again across Europe: “all conditions of persons were attacked…. [T]hose who were very strong and hardy were taken in the same manner as the weak and spoiled,…the youngest as well as the oldest.” In January 1699 in Massachusetts, Cotton Mather wrote, “The sickness extended to allmost 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 weer sick together, in some towns allmost all weer sick so that it was a time of disease.”
At least three and possibly six pandemics struck Europe in the eighteenth century, and at least four struck in the nineteenth century. In 1847 and 1848 in London, more people died from influenza than died of cholera during the great cholera epidemic of 1832. And in 1889 and 1890, a great and violent worldwide pandemic—although nothing that even approached 1918 in violence—struck again. In the twentieth century, three pandemics struck. Each was caused by an antigen shift, by radical changes in either the hemagglutinin or the neuraminidase antigens, or both, or by changes in some other gene or genes.
Influenza pandemics generally infect from 15 to 40 percent of a population; any influenza virus infecting that many people and killing a significant percentage would be beyond a nightmare. In recent years public health authorities have at least twice identified a new virus infecting humans but successfully prevented it from adapting to man. To prevent the 1997 Hong Kong virus, which killed six of eighteen people infected, from adapting to people, public health authorities had every single chicken then in Hong Kong, 1.2 million of them, slaughtered. (The action did not wipe out this H5N1 virus. It survives in chickens and in 2003 it infected two more people, killing one. A vaccine for this particular virus has been developed, although it has not been stockpiled.)
An even greater slaughter of animals occurred in the spring of 2003 when a new H7N7 virus appeared in poultry farms in the Netherlands, Belgium, and Germany. This virus infected eighty-three people and killed one, and it also infected pigs. So public health authorities killed nearly thirty million poultry and some swine.
This costly and dreadful slaughter was done to prevent what happened in 1918. It was done to stop either of these influenza viruses from adapting to, and killing, man.
One more thing makes influenza unusual. When a new influenza virus emerges, it is highly competitive, even cannibalistic. It usually drives older types into extinction. This happens because infection stimulates the body’s immune system to generate all its defenses against all influenza viruses to which the body has ever been exposed. When older viruses attempt to infect someone, they cannot gain a foothold. They cease replicating. They die out. So, unlike practically every other known virus, only one type—one swarm or quasi species—of influenza virus dominates at any given time. This itself helps prepare the way for a new pandemic, since the more time passes the fewer people’s immune systems will recognize other antigens.
Not all pandemics are lethal. Antigen shift guarantees that the new virus will infect huge numbers of people, but it does not guarantee that it will kill large numbers. The twentieth century saw three pandemics.
The most recent new virus attacked in 1968, when the H3N2 “Hong Kong flu” spread worldwide with high morbidity but very low mortality—that is, it made many sick, but killed few. The “Asian flu,” an H2N2 virus, came in 1957; while nothing like 1918, this was still a violent pandemic. Then of course there was the H1N1 virus of 1918, the virus that created its own killing fields.