13 Dec 2002
Source: Los Angeles Times,
October 29, 2001.
BY THOMAS H. MAUGH II
As anthrax exposures continue and the
specter of smallpox has loomed on the horizon, many officials have begun
discussing widespread vaccination against the two diseases in an effort to
reduce public concern about terrorist threats.
But the vaccines now in use present a number of problems --ranging from lack of
manufacturing capacity to side effects -- that render large-scale vaccination
Medical researchers have been working on efforts to produce safer vaccines. But
until now, drug companies have put relatively little money into what has been
considered a low-margin, low-priority part of the business. For both anthrax and
smallpox, the side effects of the vaccines are serious enough that widespread
vaccination could cause more damage than the diseases themselves unless the
vaccines are used only after a major outbreak has begun.
Anthrax vaccination of soldiers has
produced reports of severe side effects, such as bleeding and thyroid
malfunction, and has been linked to six deaths.
Just what degree of risk there is from the vaccine, however, is unclear. Many
medical authorities say it is safe, but some doctors have suggested it could be
one of the causes of the mysterious Gulf War syndrome, which some troops sent to
the Persian Gulf in the early 1990s have said they suffer from.
Fear of the vaccine is perhaps greater than fear of anthrax. As many as 400
members of the U.S. military have been court-martialed or have resigned rather
than submit to the vaccination because of the perceived risks. Some physicians
share their misgivings.
"You won't see me getting in line for the vaccine," says Dr. Meryl Nass, a
The vaccine is produced by only one manufacturer, BioPort Corp. of Lansing,
Mich., and the technology is nearly 40 years old. Although the company is
currently producing the vaccine, the Food and Drug Administration will not allow
it to be shipped because of various deficiencies in quality control and
manufacturing at the plant.
The vaccine is unusual in
that it is not targeted at the bacterium itself, as are most vaccines, but at
the toxin produced by the bacteria as they grow. That toxin produces the
cellular damage that can lead to death from an anthrax infection.
The toxin has three major components: protective antigen, lethal factor and
edema factor. When the toxin is released in the body, individual molecules of
the protective antigen clump together on the surface of target cells to form a
doughnut-shaped pore. This pore is then used by the other two components to
enter the cell, where they are lethal.
The vaccine is designed to stimulate antibodies to the protective antigen,
preventing it from attaching to cells. In theory, if the action of the toxin is
blocked, then the immune system can eradicate the bacteria or they can be killed
"We buy the individual some time to fight off the infection," said
microbiologist Darrell Galloway of Ohio State University.
BioPort grows a strain of Bacillus anthracis that secretes only
protective antigen. The bacterial culture is filtered -- in a process much like
making coffee in a filter pot -- to collect the antigen along with any other
materials that are secreted by the bacterium. The material that drips through
the filter becomes the vaccine. It contains no bacteria, either dead or alive.
But the antigen does not stimulate a strong immune response. To get good
immunity, six doses of the vaccine must be given at two-week intervals.
Critics fear that the other bacterial components collected along with the
antigen may cause side effects, so research has focused on eliminating them.
"The interest is in more highly defined vaccines so one knows precisely what one
is being immunized with," Galloway said.
The Army has been working with the National Institutes of Health to use genetic
engineering techniques to produce a pure antigen. Although both the military and
the NIH have consistently refused to talk about their work, other experts say
that human tests will begin early next year. That vaccine will also require
In his research, Galloway also is targeting the toxin. But instead of using the
antigen protein itself, he is injecting mice with the gene that causes the body
to produce the protein. Researchers have been producing such DNA vaccines
against a variety of diseases, and they are generally thought to produce a more
powerful immune response and fewer side effects than standard protein vaccines.
He also uses the gene for the lethal factor in his vaccine. "We get a greater
response with both than with one alone," he said. Preliminary results in mice
reported earlier this year indicate that the DNA vaccine can blunt anthrax
infections, but Galloway must conduct many more tests, including vaccination of
primates, before use of the vaccine in humans can be considered.
The most optimistic estimate would be 18 to 24 months before clinical trials
could begin, he said.
The smallpox vaccine
produces a different set of problems. Like the anthrax vaccine, it employs old
technology -- dating back to experiments by Edward Jenner, the pioneer of
vaccines, in 1796.
Smallpox is produced by a virus called variola, but researchers do not
use it to produce the vaccine. Instead, they use a related virus called
vaccinia, which produces a disease called cowpox.
The normally mild infection produced in humans by the live vaccinia
provides very good protection against smallpox -- so good that the disease has
been eradicated from nature. Today, variola is known to exist only in one
laboratory each in the United States and Russia, although U.S. officials suspect
that Iraq and perhaps other nations may also possess some virus stocks.
"The risk of its being used as a weapon is not very high, but it's there," said
Dr. Donald A. Henderson of Johns Hopkins University, who ran the global smallpox
eradication campaign. "And if you got an outbreak, it would be a terrible global
Existing stocks of the smallpox vaccine were grown in calf cells, collected and
freeze-dried more than 30 years ago.
The vaccines are believed to still be effective, but they are contaminated with
proteins and other materials from the cow cells that may produce adverse
reactions in some individuals.
New Rules From the
FDA no longer allows vaccines to
be grown in animal cells. The new contracts for vaccine production recently
signed with several companies require that vaccinia be grown in human
cells. That process is straightforward and should not introduce difficulties,
and manufacturers assume that the new vaccine will be as effective as the old
"There are no technical hurdles here," said Lance Gordon, chief executive of
vaccine manufacturer VaxGen Inc. "Everything that has to be done to make a
state-of-the-art smallpox vaccine is technology already in use."
But critics caution that a smallpox vaccine grown in human cells has never been
tested and that assumptions don't always hold up.
Vaccinia, moreover, can itself produce problems ranging from open sores
all over the body to death.
The death rate is estimated to be as high as 2 in a million cases, meaning that
if the entire U.S. population were vaccinated, about 600 people would die of the
Inadvertent contamination of the eye -- caused perhaps by touching the
vaccination site and then the eye -- can produce severe problems, including
Vaccinia itself is infectious. That's a valuable trait in a vaccination
program because it provides protection to people who weren't directly
But in a modern society with large numbers of people whose immune systems have
been damaged, by HIV infections or as a result of drugs taken for organ
transplants, that contagion could be a major problem that likely would lead to
All told, vaccinating all Americans against smallpox could cause 3,000 severe
adverse reactions and a much larger number of lesser problems, according to
Thomas Monath, an executive at British vaccine manufacturer Acambis.
If a terrorist group actually launched a smallpox attack, however, "we don't
have any choice as a society" other than to use the vaccinia vaccine, said
The U.S. population now is almost entirely unvaccinated -- the effect of the
vaccine largely wears off after about 20 years, so most people who received the
vaccine as children are no longer immune. An unprotected outbreak of smallpox
potentially could kill millions of people, experts say.
A small number of researchers have been exploring the possibility of using a
different type of vaccine, a killed-virus vaccine, which would eliminate the
danger to immunosuppressed individuals.
But development of such a vaccine, like that for anthrax, has been hindered by
lack of a market, and any product is still at least a couple of years from human
For that reason, officials have pushed for a major expansion of the current
smallpox vaccine supply. Right now, the country has about 15 million doses, not
nearly enough to contain a major outbreak.
The World Health
Organization once had 200 million doses in storage in Switzerland, but the
international body ran out of money to keep them, and they were destroyed after
President Reagan reduced U.S. payments to the United Nations. '