Apocalypse now
Roi Tzur and Dr. Zvi Ben-Yishai, virologist
Deputy Director (Emeritus) of the Hospital, and
responsible for patients’ relations in the Rambam Health Care Campus Administration

The scenario is already written and well known. One day, in one of the 15 laboratories of the World Health Organization dispersed all over the world, a new virus will be identified by the scanning mechanism. Its appearance and structure are still unknown, but upon its appearance, it will be identified immediately, and there will be no doubt that this is a new viral strain, more aggressive than any virus known to us until today. The world will be standing on the verge of a new worldwide epidemic.

In a short period of time, measured in hours, laboratories all over the world will start working on a vaccine against the new virus. However, the virus will spread very rapidly, much more rapidly than any rate of infection known to us until today. We already know that we won't have sufficient quantities of the new vaccine to stop the epidemic from spreading. Some of the patients will be kept in isolation; those belonging to high-risk groups will receive antibiotics in order to prevent the secondary infections and complications of the new epidemic. However, despite worldwide action and despite everything that is already known about the virus, the cost will still be high. According to the estimates, about 100 thousand people will die in the US alone, and the cost of stopping the epidemic will come to about 150 billion dollars. "We have no doubt whatsoever that the epidemic will indeed arrive," states Dr. Zvi Ben-Ishai, virologist and Deputy Director (Emeritus) of the Hospital. "It is only a matter of time. The only unknown variable is when exactly it will occur, and it is possible that we are already standing on the verge of a new epidemic."

This is not a new type of epidemic or a new disease unknown to us. This is not an epidemic of the plague or smallpox. This is influenza. Yes, a disease called "the flu," which affects almost every one of us at least once a year. How exactly will this happen and how will a disease, which is apparently transient and so easy to treat, turn into a worldwide epidemic that will cost millions of lives worldwide?

In order to understand the amazing biological story of influenza, we have to go back in time to 1918, the last days of World War I, when an epidemic of influenza broke out in Europe and North America, and rapidly spread around the world. This was the most fatal influenza epidemic in modern history. It affected a third of the population worldwide, and 50 million people lost their lives. "Not many people know that this disease actually put an end to World War I", says Dr. Ben-Yishai. "Antibiotics were not available then, and death was probably not caused by the virus directly, but rather by secondary infections that invaded the respiratory system, causing pneumonia, which was associated with most of the fatal cases."

Between "epidemic" and "pandemic"
"Influenza causes two types of disease incidence: there is a seasonal influenza epidemic that attacks us every year or once every two years. This is an "epidemic," caused by a viral attack in certain regions of the world, leading to a sharp increase in the number of missed work and school days due to the disease. "There is also a worldwide influenza epidemic, such as the one that broke out in 1918, called a "pandemic." A pandemic occurs once in 10 years or more. The difference between the two stems from structural variations in the virus, or more specifically, in its external envelope.

"A person infected with a virus becomes immune against it by developing antibodies against the virus," explains Dr. Ben-Ishai. "The antibodies remain in our bodies for the rest of our lives, and a person who has had the disease will never have it again, if an epidemic involving the same virus recurs. However, if the virus changes its structure and its viral envelope is altered to some extent, our antibodies can no longer protect us against it, because their structure enables recognition of the viral envelope of the virus against which they were originally formed."

The envelope of the influenza virus contains two "antigens" (molecules stimulating the immune system to produce antibodies), which are bound by the antibodies formed in our bodies. The antibodies neutralize the antigens, thus protecting us from viral infection and development of the disease.

In order to explain this, let’s look in more detail at the binding of antibodies to one of these antigens: this antigen (called hemagglutinin) has a structure containing five binding sites for the antibody. It builds its template exactly according to the different shapes of the binding sites, binds to them and blocks them. We can imagine this as a children’s game with various shapes (a square, a triangle, a star, etc.), which have to be inserted accurately into the corresponding templates (the square into the square template, the triangle into the triangular template, etc.). This is the way in which the antibody builds a template that binds to the binding sites and neutralizes them.

In an epidemic that occurs once a year or once every two years, the changes (mutations) occurring in the structure of the viral envelope antigens are slight (called a "drift"). Sticking to the example of the children’s game, the slight structural change in the viral envelope may resemble a star that has lost one of its points. In this case, the change in the virus and the nature of the disease will be minimal, and the antibody will still be able to include most of the various binding site shapes in its template. It takes time (a year or two) until there are sufficient people who lack antibodies capable of coping with the virus; they pass the virus on, thus causing a local/regional epidemic of the "drift" type.

Zvi Ben-Ishai: "The chance of such a mutation being created, only in one binding site, in one viral particle, is one in a million (1/106). The chance of two mutations being created (in two antigen binding sites) in the same viral particle is
10–12 (1/1012), and so on. Therefore, the chance that mutations will appear in all five binding sites of the same particle is 1/1030, that is, in 1 out of 1030 viral particles. Fortunately, there are no 1030 strains of influenza virus. Thus, a new viral strain with changes in all the five binding sites cannot be generated by mutations.
However, in a pandemic that occurs once in 10 years, all the five binding sites of the virus are changed. How does this happen? It is not induced by mutations, but by another mechanism, which creates changes in all the five binding sites. This mechanism is called a "shift," and this is the change of which we are so afraid.

It turns out that the influenza virus infects not only humans, but also an enormous number of animals, such as birds, especially water birds, seals, pigs, horses and others. It is known that a certain virus only attacks a certain species, that is, human influenza virus only attacks humans, avian influenza virus only attacks birds, etc. However, from time to time, a viral particle specific to a certain species succeeds in infecting another species. 

Zvi Ben-Ishai: "Occurrence of a change of the "shift" type requires a situation in which an avian influenza virus and a human influenza virus penetrate into the same cell in the avian respiratory system. This usually occurs in regions where people and animals live close together, such as China and other countries in the Far East. In a cell infected with two viruses of different origins, the genetic material of the human influenza virus may mix with the genetic material of the avian influenza virus. Such mixing may result in the formation of an entirely new strain of influenza virus, having a viral envelope containing an avian antigen, with five binding sites not recognized by the various antibodies circulating in the human blood. Nevertheless, the new virus will contain genes enabling infection of humans and will be spread to the human population.
"Thus, the new virus is capable of infecting humans, but its envelope (five binding sites of the antigens) is entirely new, and none of the people in the world have antibodies against this virus."
Occurrence of such a change in nature, enabling a certain virus to pass from one species to another, results in the generation of a more aggressive and usually fatal virus. This is how the AIDS virus succeeded in passing from apes to humans, and to become more aggressive during this passage, although by a different mechanism.

Do people live with sheep?
The new aggressive viruses, those formed by a "shift," and causing worldwide epidemics (pandemics), come from the Far East. This was the case with the influenza pandemic that broke out in 1957, called the "Asian flu," as well as the case of "Hong Kong flu" that broke out in 1968.
Dr. Ben-Yishai: "As mentioned above, the underlying reason is the lifestyle of the residents of the Far Eastern rural regions, who live close to, even under the same roof as the animals they are raising, mainly chickens and pigs. Since the influenza virus is transferred mainly by sneezing (but also by handshaking), ideal conditions were formed for the transfer of human influenza virus into the lungs of one of the animals (a chicken, in the case of avian virus). Simultaneous infection of this chicken with avian influenza virus enabled mixing of the genetic material of the human virus with that of the avian virus in the same cell, thus creating the new dangerous strain, which no one in the world is able to fight, due to lack of suitable antibodies."
In the contemporary world, if one villager in the Far East who is infected with this flu strain infects his neighbor, the virus can spread all over the world within two weeks, via airplanes, ships and motor vehicles, and lead to the start of a new pandemic.

Dr. Ben-Ishai: "In contrast to the epidemics of 1918, 1957 or 1968, the world is now ready to cope with such an outbreak. The World Health Organization operates about 15 laboratories all over the world, in which viruses are isolated every year at the beginning of the influenza season. These laboratories examine and identify the precise structure of the viral envelope of the isolated viruses. The avian influenza virus can also be identified, so we understand that the day will come when the shift-virus will reach humans.

"Although the scanning mechanism of the World Health Organization will immediately identify the new strain and start preparing a vaccine against it, the virus may spread before sufficient vaccine can be prepared.
Identification of the influenza strain of the current year is completed in February, and the corresponding vaccine is ready by the following October. This vaccine includes antibodies against the newest strain that was identified in February. The whole world receives the same vaccine. Unfortunately, however, it is not prepared against the shift-virus, but only against the drift-virus.

So, what can be done?
Dr. Ben-Ishai: "Increased mortality among the elderly and people with chronic illnesses is observed during the flu season every year. Therefore, the influenza vaccine must be administered every year, and the disease must be handled seriously. Since the vaccine that we received last year does not cover the drift of the current year, only the new vaccine will prevent infection with the new viral strain, which will be widespread during this year's outbreak."
"The vaccine is recommended for all people over the age of 50, as well as for sick people (as specified in the vaccine prescription), and babies up to the age of 2 years. (Some experts say that children up to 5 years should be vaccinated.). The vaccine is contraindicated for people who are allergic to eggs, because the vaccine is prepared by injecting the virus into fertilized eggs."