A8 August 2006

Before I ask you to believe anything I write, I should start with my credentials. At one time I was Chief, Laboratory of Virology & Rickettsiology, Division of Biologics Standards, National Institutes of Health (for more detail check my Curriculum Vitae on my web site: www.drtauraso.com ). The Division, which is now the Bureau of Biologics, FDA, was the regulatory agency concerned with, among other things, overseeing the manufacture, safety, potency, and efficacy of all biologic products, including vaccines. During the last few years of my tenure there, I was the principal officer in charge of ALL aspects of influenza vaccine control. It is important to note that, at the time, there were 6 United States influenza vaccine manufacturers (presently in 2006 there is only one!).

It was during the influenza epidemic known at the time as “The Hong Kong Flu” in 1967/68 that my laboratory was able to revamp and update the methods of determining influenza vaccine potency. Up until that time such tests were dreadfully inadequate.

It is my feeling today that epidemiologists -- scientists who study how epidemics develop and how to control them -- have either forgotten history or are asleep at the wheel.

When we examine how many contagious diseases were controlled (prevented or cured) in the past, it was good epidemiology which did it. Cholera and dysentery, once scourges in many countries, were eliminated when we cleaned up the water supply by separating sewage from clean water. In those countries where the water supply is not cleaned up by public health methods, these diseases still occur from time to time.

Yellow Fever which killed many people in this hemisphere, preventing the French from completing the Panama Canal , was virtually eliminated once Dr. Gorgas controlled the mosquitoes which carried the virus. Many do not know that the largest viral epidemic killing tens of thousand of people in Philadelphia in the mid 1850's was caused by Yellow Fever. Today this viral disease just does not occur here nor anywhere in the Western Hemisphere . Although there is now a Yellow Fever Vaccine, what eliminated the disease was a public health measure of getting rid of the mosquito vector.

Antibiotics, of course, was the great “wonder drug” in the 1940's which cured many bacterial diseases such as strep throat (and its related scarlet fever and complicating rheumatic fever), bacterial pneumoniae of various kinds, urinary tract infections, and many more too numerous to list here.

We should not belittle the contribution of vaccines which can be credited in virtually eliminating polio, measles, mumps, rubella, whooping cough, and tetanus, again to name a few.

The purpose of this article is to evaluate the use of influenza vaccine in preventing epidemics and to suggest a novel new approach to the prevention of the much dreaded “Bird Flu.”

At one time when I was the Influenza Vaccine Control Officer working at the Division of Biologics Standards, I was skeptical about the value of influenza vaccine in preventing influenza epidemics. The influenza virus is complex and the vaccine must be made correctly, it must contain adequate potency, and sufficient numbers of individuals must be immunized to achieve “herd immunity” or it will not work. Another problem is the fact that the virus mutates (changes) and a new vaccine must be made with each change which occurs quite frequently. Additionally, there might not be sufficient time to make enough vaccine in time to distribute among the population at risk before the epidemic hits.

Traditionally, and we do not really know why, a new strain emerges in the Far East . The subsequent epidemic migrates to the West. The degree and seriousness of the epidemic is usually related to how different the new strain is from the previous strain.

But the vaccine is the best and only thing we have at this time, and it behooves us to determine how we can make it work for us.

As mentioned earlier, the influenza virus is complex as viruses go. It contains two proteins which stimulate the body to make antibodies to them. The Hemagglutinin (shortened with the letter “H”) and the Neuraminidase enzyme protein (shortened with the letter “N”). So the virus is identified by these two proteins: H5N1 as in the case of the bird flu virus.

*Even though some strains had similar subtypes this did not prevent them from resulting in epidemics as in the case with the three H2N2 strains listed here. It would also appear that those viruses with N2 seem to cause more human pandemics of influenza than strains with other N subtypes. Although there was a great scare when swine flu hit in 1976, it really did not produce any significant epidemic among the population. What caused more problems was the high incidence of Guillian Barre syndrome – a paralytic disease -- resulting in individuals getting the “bad” vaccine.

** Some have believed the 1918 pandemic was cause by a bird-type influenza. Others believed it was caused by a swine strain. The fact is that at this time we really are not sure.

Influenza A, B and C viruses are known to cause disease in humans. Although influenza B and C viruses are strictly human pathogens, influenza A viruses are readily isolated from avian species, pigs and other animals. Influenza A viruses are divided into subtypes based on differences in their surface glycoprotein antigens, hemagglutinin (H) and the enzyme, neuraminidase (N). There are 14 recognized H subtypes and 9 recognized N subtypes. All of these subtypes have been isolated in birds but only 3 different H and two different N subtypes have been isolated in humans (See TABLE II)

TABLE II: Influenza Subtypes
Host	H Subtypes	N Subtypes
Humans	H1, H2, H3	N1, N2
Birds	H1 – H14	N1-N9

The influenza viruses are unique amongst the respiratory viruses in that they undergo significant antigenic variation. Antigenic drift involves minor antigen changes from one season to the next and may result in epidemic spread of the new strain. Antigenic shift involves major antigenic changes of the H and N molecules and occurs only with Influenza A viruses. These changes can result in the appearance of pandemic viruses. (a pandemic is an epidemic which is widespread throughout the world)

Some authorities believe individuals who survived the 1918 flu pandemic have antibodies to H1, others suggest it was H5, and so it is assumed that they were infected with a virus of similar protein composition. Was the virus which caused the 1918 pandemic of bird origin? Who really knows? We have named the present flu strain H5. Could the H5 then have been of swine origin or some other animal? This is unimportant to our present discussion. What ever the origin might have been the pandemic resulted in very many deaths world wide. So we must take this very seriously.

Current evidence suggests that the vaccine must induce the production of antibodies to both the H an N proteins to be efficacious. In the case of the swine influenza vaccine over 20 years ago, something happened to destroy the N protein during the inactivation process with formalin (formaldehyde). But, this not well known fact was withheld from the public. Public health officials were in a bind. President Gerald Ford publicly stated that we had to immunize the entire population. And so we embarked on this great program to immunize the public with a worthless vaccine. I was in private practice as a Pediatrician at the time and I refused to give it my patients, many of whom later thought I was a genius for this vaccine resulted in a very high incidence of the ascending paralysis known as Guillian Barre Syndrome. I, of course, took the credit but no one, including me, knew this complication was to occur. All I knew was the vaccine was no good, so why take the risk?

When one observes how chickens are penned up like sardines in the production houses in Asia and South East Asia – and in the United States --, it is little wonder that this virus originated there. I have seen pictures of these birds so crowded they are unable to move in any direction. These are both chicken and virus production houses .

Bird flu is a disease of birds and under normal situations infects mostly birds and spreads easily from bird to bird and does not seem to care what species of bird it infects, for it has been found in chickens, ducks, geese, swans, etc. The fact that it infects migratory birds is particularly important because migratory birds have been one of the principal means of spread from country to country. Although bird flu can spread from bird to humans, since humans are not the natural host, the infection usually does not spread from human to human. It has recently been shown that the bird flu has a particularly difficult time penetrating the respiratory mucosal cells of humans. And I believe there is a reason for this.

But let us not forget that the flu virus may mutate very easily to a strain somewhat related to but different from the originating strain. The new mutated strain is usually sufficiently different to make it contagious to the general public. This very important fact that flu virus can mutate makes it most formidable and is the reason why influenza epidemics occur every year or so. I am concerned if and when the Bird Flu virus ever mutates into H5N2. What we do not know is whether an H5N2 strain will be as serious a pathogen to humans as H5N1 is to birds. It could be that the N5N2 strain might not be contagious as we anticipate.

Observing the strains listed in the TABLES, it would appear that humans seem to be susceptible only to H2-containing strains. Remember what was stated above that the bird flu has a difficult time penetrating the respiratory mucosal cells in the human. It has been believed that the neuraminidase enzyme is responsible for how the influenza virus initially penetrates the cell and perhaps why the Swine flu vaccine was not effective because it lacked the capacity to elicit neuraminidase antibodies. Additionally the Swine flu never progressed into a full blown epidemic, probably because it contained N1 and not N2.

Anticipating a potential mutation of H5N1 to N5N2, a vaccine containing both antigens would be what is needed to prevent this potential disease.

Instead of waiting until the Bird Flu virus mutates to become a full fledged human pathogen able to transmit from human to human, why not anticipate this event. Prepare a vaccine containing the H5H1 antigens and begin a prospective vaccination program in humans. Since this would be prospective, we would have sufficient time to make this happen during a 1 - 1 ½ year time period.

This bold approach would be worth it considering the potential of Bird Flu causing such a serious pandemic. In initial smaller immunization programs of giving the H5N1 vaccine to individuals in Asia at risk of getting the virus directly from birds. But, I urge not to delay the larger program of immunizing individuals world wide.

A better approach would be to prepare a vaccine containing the following bivalent influenza strains: Bird Flu (H5H1), 500 CCA Units; the current A strain of H3N2, 500 Units; and not include any B influenza strain. High risk individuals in South East Asia should receive a similar vaccine. This is a most unique approach, for we usually do not prepare and administer a vaccine for a strain of virus which does not yet exist. But considering the potential harm we are anticipating if and when the Bird Flu is able to spread from human to human.

These vaccines can be administered either one cc subcutaneously or 0.1 cc intradermally, which we have been shown to be as effective in eliciting antibodies.

We still have adequate time to accomplish this. Unfortunately, as things usually move in government, committees are slow in making and executing decisions. I urge that in this case decisions are made quickly to prevent the spread of what might be a devastating disease -- “Human/Bird Flu.”

Formally Chief, Laboratory of Virology and Rickettsiology, Division of Biologics Standards, National Institutes of Health