A VACCINE PRIMER
What is a vaccine? How is one made?
Vaccines have been around for centuries. The earliest ones may have been made by the Chinese, nearly 1000 years ago. The idea was to infect someone with a small amount of a virus to allow the body to develop antibodies against a later infection. Granted, up until the 1930’s, nobody actually understood that a virus existed, but that didn’t stop scientists from finding a practical way to confer immunity.
The father of modern vaccines is Dr. Edward Jenner, a country doctor in Britain who noticed that milkmaids seemed immune to smallpox. He did note that they all seemed to contract a milder form called cowpox, which left small blisters on their hands. He decided to extract some of the pus from a cowpox-infected milkmaid and inject it into a young boy over several days, and then expose him to the deadly small pox. The boy grew sick, but recovered rapidly. Jenner deduced that somehow the cowpox pus conferred immunity to the boy.
While hardly ethical by today’s standards, this experiment by Jenner opened a whole new world of medicine, and helped eradicate the scourge of smallpox from society.
Today, we use slightly more modern techniques, as our understanding of the cause of disease has expanded. We take a virus and kill it, usually with formaldehyde, and inject that into a patient. This killed virus induces the body to produce antibodies against the disease.
Today, vaccines are grown in eggs. And the time to produce large quantities of vaccine is measured in months. There is research on creating vaccines using cellular reproduction, which would likely cut the manufacturing time, but the ability to do so in any quantity is several years away.
How do we know if a vaccine works?
As opposed to Dr. Jenner’s day, it would not be ethical to inoculate someone and then expose them to a virus to see if it worked. Today, we measure the level of serum antibodies in the bloodstream after an inoculation. We know, based on observation, what level of antibodies are required to confer immunity for most diseases.
When a new, novel virus arrives, we must assume that the antibody levels found to be effective on similar diseases will be effective. This could be a faulty assumption. We won’t know until a vaccine is deployed and the results can be tallied.
Can a Vaccine make me sick? Are they safe?
Early vaccines often used a live virus, and could, on occasion, make someone sick with the disease it was designed to prevent. Today, we use a killed virus, and as long as the vaccine was properly produced, it should be impossible to get the disease from the virus.
Some people do suffer from egg allergies, and may have reactions to the vaccine. And in 1976, several hundred people contracted a rare disease from the Swine Flu vaccine, called Guillain-Berre Syndrome (GBS). No link between vaccines and GBS has been found since 1976, and we still don’t know why that particular vaccine produced this side effect.
Vaccines also contain small amounts of Timerisol, or mercury, used as a preservative. There are many doctors who worry about the toxic effects of Timerisol, and they have pushed for the removal of this preservative from vaccines, particularly for children.
While there may be side effects, particularly from new experimental vaccines, the incidence of those are likely to be small when compared to the mortality rate of a novel viral outbreak.
How much vaccine can we produce?
Not enough. Worldwide, it is estimated that we have the ability to produce 300 to 400 million doses of influenza vaccine a year. And that assumes a standard 15ug dose (more on that later). Thirty years ago, the United States had more than 2-dozen vaccine manufacturers. Today, that number is in the single digits. Most vaccine manufacturing is now done offshore and America would have to compete in a global marketplace to buy their product.
The reason for the decline in vaccine manufacturing can be traced to several reasons. First, vaccines are a low profit item. Second, the liability involved, particularly after the problems with the Swine Flu vaccine in 1976, has scared many companies away. And third, the time involved in creating and growing a vaccine is substantial.
At best, we can produce enough vaccine for between 5% and 10% of the world in a year’s time. Hopefully, we will find ways to increase our ability to manufacture vaccines, and will move away from the egg-based growing technique. But this will take time. Probably years.
How effective are influenza vaccines?
Each year we have to guess which strain of influenza will appear in the population a year from now, and create a vaccine to match. Usually a vaccine is designed to protect against 3 strains of influenza. It is a guessing game, and some years we guess right, and some years we guess wrong.
Assuming we pick the right virus in advance, a vaccine usually provides a 70% to 90% rate of protection.
Do we have a Vaccine for Avian Flu?
We have an experimental vaccine for an older version of the virus. In 2005 the US government contracted to buy 162 million dollars worth of vaccine for the Vietnam strain of the virus. It was hoped it would confer some immunity, even if the virus mutated.
Early trials of this vaccine produced disappointing results.
In a study of over 400 volunteers who received varying doses of the vaccine, only those who received the highest dose achieve a better than 50% immune response. If it turns out that this higher dose will be needed, the sixty million doses of vaccine we have stockpiled will only inoculate 4 million people.
The only reasonably effective dose in this study was two shots of 90ug each, or a total of 180ug of antigen (the active ingredient in a vaccine). That is 12 x’s the normal dose. And that only produced an antibody level deemed sufficient to provide immunity in 54% of the recipients.
This two shot regimen would also increase the time before immunity is acquired. Normally, an inoculation takes around 2 weeks before the body builds up enough antibodies to acquire resistance. If two shots are required, and they are given 1 month apart, the recipient may have to wait 5 or 6 weeks before they are protected.
To make matters worse, we don’t know right now how effective a vaccine against the Vietnam strain will be against a mutated virus.
So the answer is, Today, we have enough vaccine to inoculate around 4 million people, and only half of them would likely develop immunity.
Can we do anything about increasing the effectiveness?
There are additives, called adjuvants, that are being tested that will hopefully allow us to stretch our vaccine supply. Alum and MF59 are adjuvants that NIAID plans to evaluate in an H5N1 vaccine in future clinical trials.
In addition, there is research ongoing on the delivery of the vaccine. There is some thought that an intradermal injection, rather than an intramuscular injection, might allow for a smaller dose of the vaccine.
What is a serum? Can we make one for H5N1?
Harvesting serum antibodies from someone who has been vaccinated, or who has contracted a disease and recovered, is not a new idea. Recently Chinese scientists have suggested infecting horses with an attenuated (weakened) H5N1 and producing a serum.
The process is relatively simple. Once someone (or an animal) is able to produce antibodies, a quantity of blood can be removed and through a process called plasmapheresis, the blood cells are removed from the blood plasma. This is done by passing the blood through a special filter, or by using a centrifuge. The blood plasma will contain antibodies that could then be injected into people.
There are problems involved, however. It takes a large amount of blood product to produce a small amount of serum. Human donors would have to be screened for AIDS and Hepatitis, among other blood borne diseases. Horse serum is still used today, although sparingly, because of `serum sickness’, a reaction to the serum that can be fatal.
And lastly, a serum is not a vaccine. It confers a temporary immunity, not a permanent one. The effects of a serum would last a few weeks, and then another injection would be needed. With each new injection, the likelihood of a bad reaction increases.
While a serum might be produced and even used, it is unlikely to be available in any quantity, and it will have a greater potential for side effects.
How soon could we expect an effective vaccine?
The `official’ answer seems to be at least six months after a pandemic starts.
And while it is likely that some vaccine will be available after six months, few scientists believe it will be available in the quantity that would be needed to inoculate more than a small portion of the population. Dr. Michael Osterholm (CIDRAP) predicts 3 to 5 years, and he is not alone in this assessment.
The problems are two fold. First production capacity is limited. And secondly, the H5N1 virus is a moving target. It will continue to mutate once it becomes a pandemic and the vaccine manufacturers will always be six months or more behind the curve.
If we had a vaccine, could we deliver it?
In 1976 we managed to vaccinate 40 million Americans in 8 weeks time. This was considered a national priority, and was done prophylactically, before a pandemic started. During the first few days of the program, too many people showed up for their shots, and many were turned away.
The logistics of delivering a vaccine, and distributing it to 300 million Americans, even under ideal conditions would be enormous. No one knows how difficult it would be during a pandemic situation. If two shots, a month apart are required, then this will double the effort required.
If a vaccine could be delivered it would be easier to inoculate the country before a pandemic broke out, but after the problems in 1976 there is little appetite for injecting the populace with an experimental vaccine for a disease that might not become a pandemic.
This seems to be a bit of a catch-22. If we wait for an outbreak, then people would have to stand in line, perhaps for hours, to receive an inoculation that wouldn’t protect them for several weeks.
Organizing a national immunization campaign, either before, or during a pandemic, would be an enormous task.
What’s the bottom line?
For now, there is no effective vaccine for H5N1. Our stockpile of vaccine may confer limited immunity to those who can receive it. If adjuvant testing proves that an additive can extend the supply of vaccine, we have enough to inoculate about 20% of the population of the United States. If the higher dose is required, we have enough to inoculate less than 2%.
Research is ongoing, and there are a variety of vaccines being tested. Hopefully a breakthrough will be made in time. Until then, the prospects of a vaccine being made available to the general public are small.
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