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     Looking Back At Jenner, Vaccine Developers Prepare For 21st Century

Author: Kathryn S. Brown
Date: April 1, 1996

This year marks the 200th anniversary of the first vaccine, which was
developed against smallpox. As vaccine researchers launch a new century of
challenging disease science, they might find inspiration in the simple
beginnings of Edward Jenner's discovery.

According to lore, Jenner was a country doctor-albeit a well-educated
one-who heard a rumor that the cowpox virus could provide immunity to
smallpox. Investigating the theory, Jenner endured the disbelief of
colleagues-not to mention the stench of dairy farms-before proving his
point.

But prove it he did. In a now-famous 1796 experiment, Jenner scratched the
arm of eight-year-old James Phipps, infecting the boy with cowpox pus taken
from a milkmaid carrying the virus. Two months later, he scratched James
again, this time adding a touch of smallpox. The rest, as they say, is
history: James was fine. A smallpox vaccine-and the field of vaccinology-was
launched. Today, smallpox has been eradicated. In a similar vein, the
pioneering work of researchers like Albert Sabin and Jonas Salk roughly 150
years later led to vaccines against polio, now wiped from the Western
Hemisphere.

Since 1980, 14 new or improved vaccines have been released, including the
world's first genetically engineered varieties. Toting an arsenal of biotech
tools and painstakingly gathered information, today's vaccine seekers are
better equipped than Jenner. The pathogenicity of many microbes is
understood. Tissue-culture techniques provide a way to grow cells in the
lab. Recombinant DNA technology and monoclonal antibodies produce faster and
safer vaccines.

                     In fact, the very approach to vaccines has changed,
                     notes Donald Henderson, a professor of international
                     health and epidemiology at Johns Hopkins University.
                     "Not too long ago, we were doing things empirically,"
                     Henderson says. "With polio, measles, and rubella, we
                     would try [vaccines] out on people and see if the
                     reactions were reasonable. Now, we look at subunit
                     vaccines [containing only certain components of a
                     disease-causing organism] and we carefully test those
                     in the lab before doing any clinical trials. This is
where a basic understanding of elegant microbial genetics and the immune
system have made a major difference."

Still, Henderson is quick to point out a host of defiant diseases that
challenge 20th-century researchers: AIDS, malaria, influenza, and cancer,
among others. "We can engineer vaccines like never before," he comments,
"but there are still so many questions."

Henderson will explore those questions in his guest lecture, "The Miracle of
Vaccination," at a May symposium celebrating the bicentennial of Jenner's
smallpox vaccine. Jointly held at the Royal College of Physicians and the
Wellcome Institute for the History of Medicine in London, the conference is
titled "The Legacy of Jenner: Vaccination Past, Present, and Future."

Conference presenters will spotlight moments in vaccine history and share
information on new vaccines. By the end, Henderson says, he hopes
participants know where vaccines have been-and where they're going.

DNA Vaccines: A Fluke Emerges

When Margaret Liu, an immunologist at Merck Research Laboratories in West
Point, Pa., gives a presentation, she often includes a slide of Edward
Jenner's "little hut," where he first administered the smallpox vaccine.

"It's an important link to modern vaccines," says Liu, who will speak at the
London conference. "Jenner was administering a [cowpox] virus, with all its
DNA. The virus would replicate and provide proteins that triggered the
immune system."

Liu is developing a new twist on Jenner's technique: DNA vaccines. Rather
than injecting a whole or partial virus into patients, a DNA vaccine injects
mere snippets of key viral DNA. Taking up that DNA, a patient's cells should
make the encoded viral protein. Spotting the foreign protein, the patient's
class I major histocompatibility (MHC) proteins will alert killer T cells
and launch an immune attack. From that point on, the patient would be
immunized against the virus at hand.

Many vaccines begin as a fluke. For example, Louis Pasteur discovered the
notion of attenuated vaccines when old cholera cultures-forgotten on a lab
bench-lost their virulence. Inoculated with the aged cultures, chickens
unexpectedly developed immunity to a fowl form of cholera.

Similarly, DNA vaccines emerged as a surprise. In a 1990 experiment,
researchers at publicly owned Vical Inc., then a biotech startup in San
Diego, and the University of Wisconsin injected a control group of mice with
"naked" viral DNA. Unexpectedly, the control mice began churning out
significant amounts of viral proteins.

Vical presented its results to Merck, which decided to fund further DNA
vaccine research. In 1993, a collaborating Merck/ Vical team reported that a
DNA vaccine could indeed prevent influenza infection in mice (J.B. Ulmer et
al., Science, 259:1745-9, 1993).

Since then, Merck has acquired rights to Vical's work on DNA vaccines for
HIV, tuberculosis, hepatitis B and C, herpes, and human papilloma viruses.
With other collaborators, Vical is also developing DNA vaccines for malaria,
Lyme disease, cytomegalovirus, and other conditions.

In February, the Food and Drug Administration (FDA) granted approval to
begin the first DNA vaccine clinical trials on healthy volunteers. The Phase
I trials will test the safety of a potential AIDS vaccine carrying genes
that code for noninfectious HIV proteins. Investigators from the University
of Pennsylvania and the private biotech firm Apollon Inc. in Malvern, Pa.,
will conduct the trials.

Other researchers also are developing DNA vaccines. "So
far, this approach seems safe and effective," comments
Stephen Johnston, a professor of internal medicine and
biochemistry at the University of Texas Southwestern
Medical Center in Dallas. Johnston and colleagues
created a DNA-based vaccine against a lung pathogen
found in rodents (M.A. Barry et al., Nature, 377:632-5,
1995). "As our genome-sequencing technology improves,
we should be able to systematically sequence a
pathogen, break up the genome, and shoot in the
relevant DNA," Johnston says.

DNA vaccines may offer several advantages over other
vaccines (W.M. McDonnell, F.K. Askari, New England
Journal of Medicine, 334:42-5, 1996). One is
immunogenicity. Many vaccines consist of viral surface proteins that provoke
an antibody response. Such antibody-mediated immune responses can be weak.
By contrast, DNA vaccines work from the inside of cells, attracting MHC
proteins and a potentially stronger cell-mediated response.

DNA vaccines may also outsmart forever-mutating viruses like influenza A. By
changing its surface proteins, the influenza A virus foils immune system
memory, rendering the latest vaccine ineffective. However, the Merck/Vical
DNA vaccine relies on a core influenza A nucleoprotein that rarely changes.
The vaccine should survive influenza's surface mutations.

"The next key issue for the field is to demonstrate clinical utility," notes
Liu. If researchers can do that, she says, DNA vaccines are here to stay.

Cancer Vaccines: Cautious Optimism

While DNA vaccines for infectious disease have galloped into trials,
vaccines against cancer have crawled. Why? It's the nature of the beast,
according to Alan Houghton, head of the immunology program at Memorial
Sloan-Kettering Cancer Center in New York.

                  "The big distinction is that infectious agents are
                  foreign, so the immune system can usually see them that
                  way," Houghton explains. "But cancer grows from tissues in
                  the body, so a vaccine is essentially trying to trigger an
                  immune response against yourself. It is a much harder
                  problem."

                  After a decade of intense research, more than a dozen
                  cancer centers and nine biotechnology companies are
                  conducting various types of cancer vaccine clinical
                  trials, according to the National Cancer Institute (NCI).

                  Cancer vaccines aim to boost immune response to existing
                  tumors (R. Lewis, The Scientist, April 3, 1995, page 15).
                  One popular approach has been to isolate a tumor antigen
                  and fuse it to an adjuvant, a chemical agent that
                  kick-starts the immune system. Theoretically, this duo
                  should guide immune system molecules to tumor cells, which
will then be destroyed.

Sloan-Kettering scientists have administered a melanoma antigen/adjuvant
vaccine to patients in clinical trials. While initial results were
disappointing (P.O. Livingston, Journal of Clinical Oncology, 12:1036-44,
1994), Houghton says researchers have improved the vaccine and will test it
again in trials this spring.

Using another technique, researchers at Fordham University are exploring the
ability of common heat shock proteins (HSPs) to collect tumor antigen
fragments and display them to the immune system. In mice, doses of HSPs
generated an immune response (R. Suto, P.K. Srivastava, Science, 269:1585-8,
1995).

"It has been a long road with cancer vaccines," comments Olivera Finn,
director of the immunology program at the University of Pittsburgh's Cancer
Institute. "Our first break came when it was possible to grow human T cells
in culture. Then, we began learning about antigen presentation pathways. Now
the question is whether we can take tumor antigens and make them
immunogenic."

Cancer vaccine researchers are cautiously optimistic, Finn states. "We've
learned that just because we can do it in the lab doesn't mean we can do it
in a person. It is difficult that we still see our patients die of cancer."

HIV: Outwitting The Host

If one disorder has come to dominate news at the end of the 20th century, it
is AIDS. According to the National Institute of Allergy and Infectious
Diseases (NIAID), more than 400,000 people in the United States have
developed AIDS-defining diseases. Up to 1 million Americans are believed to
be infected with HIV (NIAID, Annual Report: Accelerated Development of
Vaccines, 1995).

Since 1987, NIAID has supported clinical trials of more than 25 experimental
HIV vaccines across the world. At least 24 companies are developing an HIV
vaccine. The vaccine candidates range from conventional whole-inactivated
viruses to genetically engineered subunit vaccines, which administer a
noninfective yet immunogenic portion of the virus.

Some HIV vaccines consist of recombinant versions of glycoprotein gp120, an
HIV surface protein (E. Race et al., Vaccine, 13[1]:54-60, 1995). While some
of these vaccines showed early promise in lab assays, they failed to
stimulate neutralizing antibodies to actual HIV taken from infected
individuals, NIAID reports. The search for an effective AIDS vaccine
continues.

HIV has completely beguiled researchers, observes Arthur Silverstein, a
professor, emeritus, of immunology at Johns Hopkins and now at the
university's Institute of the History of Medicine.

"[HIV] is
amazing, the
way it changes
itself
continually,"
Silverstein
remarks. "It
boils down to
the same thing
Jenner,
Pasteur, and
others
struggled with:
the battle
between the
organism and
the host. It's
a constant
struggle
between
pathogenicity
and immunity."

Liu agrees:
"Everyone is
very impressed
with how the
[HIV] virus has
managed to
outwit many of
the host's
defenses," she
says. The
virus, she
predicts, will
remain one of
the great
challenges
facing
vaccinologists.

A 21st-Century
Approach

No matter what
the disease,
genetic
engineering,
gene discovery,
and other
technological
feats should
speed vaccine
development,
researchers
believe.
"Today, we
apply genetic
engineering to
produce
vaccines that
weren't even
conceivable
just a few
years ago,"
says James Kaper, an immunologist at the University of Maryland in
Baltimore.

For example, Kaper and colleagues crafted the first genetically engineered
cholera vaccine, now licensed in Switzerland and soon to be submitted to FDA
for United States distribution. The vaccine is a recombinant version of an
attenuated Vibrio cholerae pathogen engineered to omit its toxic subunit
(M.M. Levine et al., Lancet, 2[8609]:467-70, 1988).

Kaper predicts the future will bring better live-vector vaccines: for
example, an attenuated salmonella pathogen engineered to carry antigens
protecting against malaria.

                   Still, equaling the success of smallpox eradication will
                   require more than scientific prowess, notes Philip
                   Russell, a professor of international health at Johns
                   Hopkins and president of the Albert B. Sabin Vaccine
                   Foundation, a New Canaan, Conn.-based nonprofit
                   organization that promotes vaccine research and policy.
                   The development of a successful new vaccine relies on
                   social and economic networks to distribute it.

                   "One problem in the vaccine field is a huge disconnect
                   between industrial vaccine developers, research
                   scientists, government, and vaccines' end users, like
                   pediatricians," Russell says. "These people don't talk to
                   each other well. In some instances, they don't talk to
each other at all."

The Sabin Foundation brought these sectors together to discuss vaccine
policy in two forums held at Cold Spring Harbor; one in December 1994 and
the other in November 1995. A third forum is being planned. The ultimate
goal, Russell says, is to develop an improved international vaccine
development and distribution system.

Meanwhile, scientists plug away at the vaccine research bench. Drawing on
history, they search for the next discovery. Liu likes to note that Jenner
himself built from the Chinese, who initiated primitive inoculations with
aging smallpox scabs. "In a sense," she says, "we are all standing on each
other's shoulders."

Kathryn S. Brown is a freelance science writer based in Columbia, Mo.


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     (The Scientist, Vol:10, #7, p. 14, 17 , April 1, 1996)
     (Copyright  The Scientist, Inc.)

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