Download sabin vaccine report - Sabin Vaccine Institute

SABIN VACCINE REPORT
the newsletter of the Albert B. Sabin Vaccine Institute at Georgetown University
Volume II, Number 2, June 1999
Hepatitis B controversy
sparks concern
Sabin Vaccine Institute counters
anti-vaccine propaganda.
3, 6
Malaria Follow-up
Thailand program managers explore
future of a malaria vaccine.
3
SPECIAL REPORT: CANCER VACCINES
Immunologists develop vaccines
to treat cancer.
4, 5
Vaccines combat biological
warfare threat
Smallpox and Anthrax pose
formidable challenges as
bioterrorism weapons of choice.
7
Cancer vaccine meeting generates collaborations
BY
CHARLENE FLASH
Thirty-six of the world’s top cancer immunologists, microbiologists, and vaccinologists gathered at the first Walker’s Cay Colloquium on Cancer Vaccines and Immunotherapy to explore the
latest research in the molecular immunology of tumor vaccines
and to determine how this knowledge can be translated into effective cancer therapies.
The Albert B. Sabin Vaccine Institute organized the think
tank-style meeting in conjunction with the Lombardi Cancer Center at Georgetown University.
The colloquium gathered scientists in fields ranging from
statistics to microbiology who
specialize in cancer vaccine research and development.
The historic setting for
the meeting was Walker’s Cay,
a small island in the northern
Bahamas, where President
Nixon was a frequent guest.
It was while visiting Walker’s
Cay that Nixon decided to
make conquering cancer a national priority.
The
colloquium marked the 28th
anniversary of Nixon’s declaColloquium chairs, Drew Pardoll and
ration of “war” on Cancer.
remarks.
James P. Allison, Director of the Cancer Research Laboratory at the Howard Hughes
Medical Institute at the University of California Berkeley, and
Drew Pardoll of Johns Hopkins University co-chaired the meeting. They set the scientific agenda for the colloquium and oversaw
selection of the distinguished participants including John L. Gerin
of Georgetown University who proved that hepatitis B vaccine
also prevents hepatocellular carcinoma, which affects the liver and
is the most common type of cancer in the world.
According to Dr. Richard Bucala, head of the medical biochemistry laboratory at the Picower Institute for Medical Research
in New York, these research scientists “normally go to meetings
with people in their own disciplines, so they rarely get an opportunity to share their ideas and have them constructively challenged
by colleagues” who have a different perspective.
The unique format of the colloquium was no accident. “We
set out to create a meeting that would be very different, to encourage scientists to debate their theories…,” said H. R. Shepherd,
chairman of the Sabin Vaccine Institute. The congenial atmosphere and blend of participants served to stimulate a vigorous
exchange of ideas and create a sense of collegiality. Dr. Pardoll said
the colloquium “stimulated a lot of critical thinking and new ideas
about vaccines for cancer.”
A. Bennett Jenson, co-developer of a vaccine to prevent
human papillomavirus and cervical cancer and a member of the
Sabin Vaccine Institute Scientific Advisory Committee, agreed: “It
was one of the most intellectually exciting meetings I have ever
attended.” Several scientists echoed Dr. Hyam Levitsky of Johns
Hopkins University who said, “The intimate setting [promoted]
serious exchange of ideas and the establishment of new
collaborations.”
National Cancer Institute scientist Dr. Suzanne L.
Topalian said she left Walker’s
Cay with “several new ideas
to try in my laboratory.” According to Dr. Carl H. June,
Director of Translational Research Programs at the
University of Pennsylvania
Cancer Center, the Walker’s
Cay Colloquium was “one of
the best meetings… I have
attended in the past fifteen
years.”
The Sabin Vaccine
Institute’s colloquia foster
James Allison discuss plenary
partnerships
between
academia, industry and government to stimulate vaccine
research and development. Noting author Alexander Benis’ axiom,
“None of us is as smart as all of us,” Mr. Shepherd urged participants to consider joining a cancer vaccine consortium. The blueprint
for such a partnership is being prepared by Clark McFadden of
Dewey Ballantine, LLP, an attorney involved in creating the
SEMATECH consortium that revolutionized semiconductor
manufacturing in the U.S. A vaccine consortium would encourage ongoing research collaboration and attract more research
funding and faster commercialization of new technologies. [See –
Government-Industry Partnerships: The Wave of the Future – and the
Past, page 2]
The Walker’s Cay Colloquium “opened participants’ eyes to
the different challenges involved in developing cancer vaccines
and will enable them to contribute more to the quest” observed
Dr. Pardoll. The colloquium was supported by an unrestricted
grant from the Walker’s Cay Corporation. Other co-sponsors included the Richard Nixon Library & Birthplace Foundation and
the Sabin Vaccine Institute. v
photo by Carol Ruth Shepherd
IN THIS ISSUE
AIDS vaccine trials offer hope
Sabin Vaccine Report
Albert B. Sabin Vaccine Institute
58 Pine Street
New Canaan, CT 06840
BY
ELIZABETH DE LA PAZ
“If the 21st century is to be the century of biology, let us make
an AIDS vaccine its first great triumph,” President Clinton
declared in June 1997. He challenged the United States to
develop an AIDS vaccine by 2007. Now, two years later, the
question becomes: How close are we to achieving such a goal?
There’s no doubt that an HIV vaccine is greatly needed.
A study conducted by UNAIDS, the joint United Nations
Programme on HIV/AIDS, estimated that 8,500 people are
newly infected with HIV every day, and about 5.8
million people worldwide became infected in 1997 alone. At
the end of 1997, approximately 30.6 million people were living with the HIV virus. Although retroviral drugs have
improved the quality and length of life of HIV-infected people
in countries like the United States, no interventions have been
available to residents of developing countries, who account
for an astonishing 90 percent of new infections. Moreover, the
antiviral drugs and therapies cannot be relied on forever, due to
drug tolerance and emerging drug-resistant viral strains.
The toll that AIDS has taken on the world, through the
loss of millions of lives as well as through economic cost, makes
finding an HIV vaccine a worldwide public health priority. A
safe and effective vaccine would provide protection from HIV
infection and eventually end the worldwide epidemic. A vaccine
could induce immune responses that attack and destroy any
incoming virus and cells that have been infected. If HIV is
already well-established in the body, a vaccine might control
the replication of the virus and decrease the chance of
transmission and disease progression.
Various types of vaccines are being used in current HIV
vaccine trials. Most of them emphasize the use of the envelope
glycoprotein gp160 or gp120 which forms the outer spike
projection of the HIV virus. Experiments with live-attenuated
vaccines that consist of weakened HIV viruses are also being
performed, but not yet on humans for fear that the virus might
mutate and become virulent. An advantage to the development
of a live-attenuated vaccine is the need for only
one immunization, eliminating worries for follow-up for
booster shots.
Human clinical trials are now under way in the United
States and Thailand using recombinant subunit vaccines. This
type of vaccine uses pathogen protein derivatives that are
purified and combined with vaccine enhancers. Although these
vaccines have afforded some protection, the immune response is
not very strong. Additional human clinical trials in Uganda are
testing vector-type vaccines, using attenuated canarypox viruses
to induce HIV-specific immune responses in uninfected people.
Other scientists are investigating DNA-type vaccines, in which
DNA plasmids encoded with a viral antigen are injected into
the muscle of the patient, where they produce HIV proteins
that eventually elicit an immune response. The ultimate vaccine
Continued on page 6
2
SABIN VACCINE REPORT
June 1999
Government-Industry Partnerships:
The Wave of the Future - and the Past
by Charles Wessner, PhD
Charles W. Wessner is the Program Director for Technology and Competitiveness for the National Research Council
Board on Science, Technology and Economic Policy. Dr. Wessner directs a project on Government-Industry Partnerships
for the Development of New Technologies which directs both U. S. partnerships and international collaboration. Dr.
Wessner has served as adviser to the Secretary of Commerce and the Under Secretary of the Technology Administration.
SABIN VACCINE REPORT
58 Pine Street
New Canaan, CT 06840
phone: 203.972.7907
facsimile: 203.966.4763
email: [email protected]
The Albert B. Sabin Vaccine Institute is a non-profit
institute dedicated to continuing the work and achieving
the vision of Albert B. Sabin: to fully realize the potential
of vaccination to prevent disease.
Founded in 1994, the Institute strives to prevent
disease by promoting the
development of new vaccines and delivery systems.
Dedicated to Disease Prevention
www.sabin.georgetown.edu
CHAIRMAN
H.R. Shepherd
When Americans think of technological innovation, they often visualize a lone inventor. Examples such as Thomas
Edison’s light bulb and Alexander Graham Bell’s telephone dominate the view of late-19th-century advances. Today, the
garage in Silicon Valley and the university dorm room are the typical settings, and people such as Steve Jobs, Bill Gates, and
Michael Dell come to mind. Such images are powerful for a good reason; the relative ease with which an individual can turn
an idea into a high-growth company is a unique strength of the U.S. economic system.
Less prominent in the popular mind — but equally important to creating new technologies — is the role of government-industry partnerships in stimulating innovation. From the nation’s earliest days, the federal government has frequently
played a crucial role in supporting new inventions. For example, in 1842 Congress appropriated $30,000 for Samuel
Morse’s telegraph, launching the information economy. In the 1960s, the Department of Defense funded ARPANET, a
communications network that linked researchers in universities and government labs. ARPANET evolved into the Internet,
which today fuels the burgeoning electronic commerce industry. More recently, the fiercely independent companies of the
U.S. semiconductor industry came together to form SEMATECH. From 1988 to 1996, this consortium received half of its
$200 million annual budget from the government, and it helped restore U.S. competitiveness. Today, many biotechnology
firms and such large biotech companies as Amgen and Genentech can trace their origins to research initially funded by the
National Institutes of Health.
Government-industry partnerships take many forms. In the Small Business Innovation Research (SBIR) program, a
$1.2 billion annual program, government agencies set aside 2.5 percent of their extramural research budgets for R&D grants
to small business. Not only do these grants help the government carry out research missions in areas such as public health and
defense, but they also accelerate commercialization of innovations from the small business sector. In the Advanced Technology Program (ATP), funded at $220 million per year, the government supplements private-sector funds for developing
technologies whose potential benefits broadly accrue to one or more industries. These technologies often cause private
investors to hesitate, both because of the technical risk and the diffused nature of the benefits. To advocates of partnerships,
these same widely diffused benefits in fact justify public funding because the country as a whole receives the benefits.
In an era characterized by rapid technological change, government-industry partnerships are becoming ever more
important. One reason is the growing cost and technological complexity of innovations. For instance, the number of circuits
on an electronic chip continues to double every 18 to 24 months. But maintaining that pace is expensive — a single
fabrication facility for semiconductor chips costs close to $2 billion and has to be retooled every few years. The conversion to
the next generation of semiconductor manufacturing (from 200 to 300 mm wafers) will cost the industry $10-20 billion,
but larger wafer sizes mean better manufacturing productivity, which is needed to pay for expensive fabrication facilities and
R&D. Government support for R&D, through partnerships like SEMATECH and tax policy, has traditionally been an
important component to the semiconductor industry’s productivity equation.
Similarly, the Human Genome Project (HGP) combines enormous expense — in excess of $2 billion — with
incredible complexity as it begins to make exciting medical breakthroughs through genome sequencing. The HGP requires
not only scientific breakthroughs but also advances in electronics technology. An important element of the HGP is DNA
array technology, in which “gene chips” can quickly gather and analyze DNA sequences, detecting a person’s susceptibility to
various diseases or potential reactions to medication. Genometrix, Inc., one company that has developed “gene chip” technology, recently completed a study for the Food and Drug Administration that involved screening the blood of 800 patients for
10,000 genotypes in one week’s time. Without the Genometrix chip, this task would have taken a year. Genometrix
developed its technology with the help of an ATP grant.
Another reason that partnerships will remain important is global competition. The German government is increasing
its support to its biotechnology industry. Japan, notwithstanding its current economic slump, continues to support largescale partnership programs in electronics and other technologies. More generally, the European Union and individual
European governments are using partnerships to improve the climate for entrepreneurship. Many markets for high-tech
goods tend toward “winner-take-all” outcomes. If other governments can effectively use public funds to support winning
partnership programs, they can capture many of the benefits of new, welfare-enhancing, wealth-generating technologies —
including jobs, know-how, and economic growth.
To succeed, U.S. partnership programs must be appropriate to the technology and the nation’s system. Usually this
means they must be industry-led. At the same time, government-supported technologies must be disseminated as widely as
possible to ensure the maximum public benefit to taxpayers. We are not certain what technological opportunities we will face
in the next century. What we can affirm is that the challenges of today — and tomorrow — will often best be met by industry
and government working together. v
The Sabin Vaccine Report is published by the
Albert B. Sabin Vaccine Institute
at Georgetown University.
Subscriptions are free.
Please direct inquiries to:
ALBERT B. SABIN VACCINE INSTITUTE
AT GEORGETOWN UNIVERSITY
EDITOR
Charlene A. Flash
WRITERS/STAFF
John M. Clymer
Elizabeth de la Paz
Jane Fox
Judith B. Hopkins
Gboku Lumbila
Robin Netherton
Jessica Quinn
Erica Seiguer
CONTRIBUTORS
Valaikanya Plasai, PhD
H.R. Shepherd
Krongthong Thimasarn, PhD
Charles W. Wessner, PhD
A scientist who is also a human being cannot rest
while knowledge which might be used to reduce
suffering sits on the shelf.
Albert B. Sabin
EXECUTIVE VICE PRESIDENT
Edward Neiss MD PhD
BOARD OF DIRECTORS
Jason S. Berman
Zev Braun
Kenneth L. Dretchen PhD
Robert E. Fuisz MD
E. Andrews Grinstead III
Jerome Jacobson
David J. Meiselman Esq
Lewis A. Miller
Louis Padovano SJ MD
Maj. Gen. Philip K. Russell MD
Heloisa Sabin
Carol Ruth Shepherd
H.R. Shepherd
BOARD OF TRUSTEES
Ruth Arnon PhD
Nancy Gardner Hargrave
Joseph L. Melnick PhD
Gustav J.V. Nossal MD PhD
George C. St. Laurent Jr
Andrea Scott
Kathryn G. Thompson
Donna Twist PhD
Stephen G. Valensi Esq
James D. Watson PhD
Barbara Wilson
INTERNATIONAL COUNCIL
OF SCIENTIFIC ADVISORS
Peter J. Hotez MD PhD Chair
Kenneth I. Berns MD PhD
Fred Brown PhD FRS
Robert M. Chanock MD
Stephen N. Chatfield PhD
Jonathon M. Fine MD
Warren Grundfest MD
Ian Furminger PhD
Neal A. Halsey MD
Maurice R. Hilleman PhD
Brian R. Murphy MD
Erling Norrby MD PhD MTC
Wade P. Parks MD PhD
Michael Sela PhD
James D. Watson PhD
SCIE
IN MEMORIAM
Mary Lou Clements-Mann MD MPH
SCIENTIFIC ADVISORY COMMITTEE
Herbert B. Herscowitz PhD Chair
Joseph A. Bellanti MD
John L. Gerin PhD
A. Bennett Jenson MD
C. Richard Schlegel MD PhD
Joseph G. Timpone Jr MD
BOARD OF ADVISORS
Mary Alderman
Francis E. Andre MD
John V. Bennett MD
Barry Bloom PhD
Betty F. Bumpers
Francis Cano PhD
Ciro A. de Quadros MD MPH
Phyllis Freeman Esq
Bruce G. Gellin MD MPH
Lance K. Gordon PhD
Scott B. Halstead MD
Samuel L. Katz MD
Stanley M. Lemon MD
Sister Collette Mahoney
Frederick C. Robbins MD
Harvery S. Sadow PhD
Ronald J. Saldarini PhD
Donald S. Shepard PhD
Arnold Stang
Patricia Thomas
SABIN VACCINE REPORT
June 1999
3
Thailand program managers describe challenges of malaria control
BY
KRONGTHONG T HIMASARN, MD, PHD AND VALAIKANYA PLASAI, DR. PH
Although the concept of global eradication of malaria achieved considerable success in reducing morbidity and mortality in certain geographical regions, the eradication campaign has
jeopardized the malaria control effort by expending cheap, reliable and relatively safe tools
such as DDT and chloroquine which unfortunately gave rise to the insurmountable problems of vector resistance to insecticide and drug resistant malaria parasites.
Today, some 50 years since the inception of the malaria eradication effort, malaria is
still as rampant as ever, if not worse among developing countries. In Africa alone, an incredible one million deaths per year are reportedly due to malaria. Most of the deaths occurred
among children under five: an estimate of one death every 30 seconds. Five decades and
millions of dollars after the launch of malaria eradication, the world is still suffering from
malaria.
Development of malaria control interventions has not
been able to keep up with emergence of malaria vector and
“Malaria... poses the
parasite resistance, and has been outsmarted by malaria paragreatest economic
sites and vectors. Advanced knowledge and new technology
burden of all tropical
available to date such as DNA vaccine technology, new adjudiseases.”
vants, and various vaccine delivery systems, have yet to render
a new vaccine.
Although there are several candidate vaccines based on various antigens at different
parasitological stages, none has ever reached an operational utilization level. The SPF66
vaccine, which lit up our hopes in the early 1990s, turned out to take much longer than
expected to develop to an operational stage.
Mefloquine, the then-promising new antimalarial drug registered for operational use
in Southeast Asia in 1985, took a few years to develop, but parasite resistance emerged
swiftly in 5-7 years, even before countries in other regions had heard of the drug. Many new
insecticides discovered in the last few decades are now facing that same widespread problem
of vector resistance. Effective interventions have always been out-paced by emergence of
resistance.
Those who have been involved in malaria control have learned to accept the fact that
controlling malaria is a complex problem. In Southeast Asia, South and Central America, the
Middle East and Eastern Europe where 20% of malaria cases occur, malaria epidemiology
varies greatly. Problems of insecticide-resistant vectors, drug-resistant parasites, epidemics
due to the unstable political situation and massive population movement are all interwoven. They hinder the already weakened efforts of malaria prevention and control.
Currently, the situation has become even worse due to the recent economic crisis in
Southeast Asia. It seems that there is no light at the end of the tunnel when it comes to
planning for malaria control in these areas. Among new tools being developed, a malaria
vaccine seems to be the intervention everyone awaits. While we are “waiting for the vaccine”, there are lessons we must learn from past experience. We would certainly hope not to
exploit and expend malaria vaccines, once we have them, the way we did other malaria
control tools. We must not be naïve and hope that the vaccine is a magic bullet that will
solve all problems. Once it becomes available, we must utilize the vaccine wisely, perhaps in
combination with other existing measures. Judicious and effective use of the vaccine will
ensure that we will be using it for a long time.
There are four issues to consider when designing an anti-malaria vaccine. First, the
attributes of a malaria vaccine must differ depending on malaria epidemiological features
of target regions. Blood-stage malaria vaccines would be ideal for reducing mortality
among children under five and pregnant women living in continuous and intense malaria
transmission areas such as tropical Africa. In these areas, pre-erythrocytic and transmission
blocking vaccines would not be appropriate. These two types of vaccine, on the other hand,
would be ideal for non-immune, or semi-immune individuals who remain in partially
inhibited malaria transmission areas for short period, if the length of protection is long
enough. For example, migrant workers and travelers from non-endemic areas working in,
or visiting, intense malaria transmission regions would benefit most from pre-erythrocytic
and transmission blocking vaccines. If such vaccines gave protection for a few months, we
could observe their impact on the disease incidence. Lastly, anti-TNF vaccines that will
prevent malaria disease are an exciting new hope, but we doubt the feasibility, hence their
use. We must not aim to produce a ”one-size-fits-all” vaccine for various types of malaria
epidemiological paradigms.
The next issue to consider when designing a vaccine is its cost: both the cost of the
vaccine itself and the cost of the vaccine delivery system. Malaria is a major infectious disease
and poses the greatest economic burden of all tropical diseases. Cost-effectiveness is vital
to success. A malaria vaccine, once available, needs a delivery system that is not only costeffective, but also inexpensive, simple and easy to maintain.
Malaria is endemic in remote areas characterized by lack of health and other facilities.
Even chloroquine, the most simple, efficacious, and inexpensive antimalarial drug, does
not have any impact on malaria morbidity and mortality in remote areas simply because it
cannot reach the target population. The most efficacious vaccine will not bring about
desired impact on a target population if it has a complicated and costly delivery system,
such as the cold-chain.
Thirdly, a malaria vaccine must not disturb, compete or interfere with existing public
health systems. The Expanded Programme on Immunization (EPI) program, for example, has established itself firmly in the community. It would be ideal if a malaria vaccine
could become part of the existing EPI system.
Lastly, a malaria vaccine must take into consideration the culture in which it will be
used. Desperate for relief, some people will take advantage of any available antimalarial
tools or technologies. A clear example: the use of antimalarial drugs among non-qualified
healers. Without understanding social, cultural, and economic forces underpinning malaria
transmission and the use of antimalarials by the community, any malaria vaccine could be
subject to misuse by the community. A thorough understanding of such factors is necessary
to ensure success implementing a malaria vaccine.
In 1992 the World Health Organization launched the Global Malaria Control Strategy,
a new effort to curb malaria. Abandoning the concept of malaria eradication altogether, the
Global Malaria Control Strategy focuses on malaria control, and it recognizes malaria ecology
and epidemiology as the foundation of planning for a malaria control effort. It calls for
collaborations among private and public health authorities and the affected communities.
Therefore, in order to be successful, the Global Malaria Control Strategy calls for strong
commitment, full support from all parties, and a greater coordinated effort from both technical
and managerial parties.
There will be a tendency to search for a “silver bullet” to do away with malaria. We
must resist that urge. We must embrace the lessons we have learned during the global
eradication campaign period and strive not to repeat mistakes. Today, malaria is in the
limelight again with the announcement of the Roll Back Malaria initiative by Dr. Gro
Harlem Brundtland, the newly installed Director General of the World Health Organization. The search for a malaria vaccine must not be the search for short cuts to save time and
effort in controlling malaria. The battle against malaria is a long process, in which small,
incremental but sustainable gains are desirable. Broad sweep and general interventions to
be used uniformly in all places must not be encouraged. “Tailor made” malaria control
interventions appropriate to each malaria paradigm, however, are the key to success for
sustainable malaria intervention. Desirable malaria vaccines used judiciously and appropriately must also follow this logic. v
Krongthong Thimasarn, MD, MPH is the director of the Malaria Control Programme
and Valaikanya Plasai, Dr. PH is the director of the Malaria Division of Thailand.
Editor’s Note: The views expressed are not necessarily those of the Sabin Vaccine Institute, but reflect
the opinions of the authors. [For more on malaria vaccines see Volume II, Number 1, March 1999.]
France’s medical meddling could cost millions their lives
BY
H.R. SHEPHERD
Some of the world’s top thinkers are debating what to do about smallpox, a disease that
ravaged humanity for at least 12,000 years. It struck the mighty and the powerless, from
Marcus Aurelius to Ali Maow Maalin, a cook in Somalia who in 1977 was the last person to
catch smallpox naturally.
The debate now is what to do with the remnants of the virus, whether to destroy them
or keep them in secure laboratories for further study. The breathtaking part is that we’re in a
position to be holding such a discussion.
Thanks to vaccines, smallpox is all but extinct. We’re lucky to have had a 200-year
head start on wiping out smallpox because today political road blocks would impede use
of the vaccine.
Take a look at the status of the vaccine for hepatitis B, one of the most prevalent and
deadly infectious diseases in the world. Over 300 million people are chronically infected
with hepatitis B, the leading cause of liver cancer. According to the World Health Organization (WHO), hepatitis B leads to more than 1 million deaths a year.
Last October, the French government suspended routine hepatitis B immunization of
school children because of anecdotal reports that the vaccine caused multiple sclerosis. The
French took action without any scientific evidence to back them up. Indeed, since this
vaccine became available in 1982, more than 1 billion doses have been administered worldwide.
It is 95 percent effective in preventing infection.
In countries where 8 percent to 15 percent of children were chronic carriers, vaccination
has cut the rate to less than 1 percent. The WHO calls hepatitis B vaccine “one of the safest”
vaccines available.
Never mind all that. The French government had something more pressing to
worry about: politics. Some activists intent on curtailing vaccinations latched onto a combustible accusation — the alleged hepatitis B vaccine- MS connection — and they demanded
action. The French government hastily bowed to their demands.
In contrast, the WHO turned to science. If the vaccine caused MS, somewhere in a
billion doses, something ought to turn up. But an exhaustive search came up empty. The
WHO reiterated the vaccine’s safety. This message was reinforced by the Multiple Sclerosis
Society of Canada, which cited “the lack of any scientific evidence” of a link between
hepatitis B vaccine an d MS.
Ironically, the French National Drug Surveillance Committee, a drug safety agency,
found lower frequency of neurological diseases, including MS, among those vaccinated
against hepatitis B than in the population at large.
The international health community is concerned about the French action because it
could erode confidence in vaccines. France’s announcement resulted in a 20 percent drop in
hepatitis B immunization rates.
Activists are trying to raise similar concerns in the United States. They have launched
Internet sites that attack universal vaccination, a principle widely advocated by public health
experts and medical practitioners. A recent television news magazine reported that since
1991, when the Centers for Disease Control and Prevention endorsed hepatitis B vaccination of infants, 274 deaths have been reported. For most, the cause of death was listed as
sudden infant death syndrome (SIDS). In contrast, 140,000 unvaccinated Americans become chronically infected with hepatitis B each year.
Does this mean some people might be considered expendable for the common good?
No, of course not. It means we cannot precisely forecast the future. We don’t know who is
going to catch a disease, or who may have a reaction to a vaccine, or who will get sick from
something completely unrelated right after getting vaccinated.
But we do know this: Vaccination prevents millions of deaths every year. Thanks to
vaccines, diseases that once struck fear in every town in every nation have been eradicated in
every corner of the world (smallpox) or nearly eradicated (polio).
Without universal vaccination, we would not be arguing over whether to preserve
the last remnants of the smallpox virus. Instead, in the case of smallpox, we’d be digging
graves — about 40 million of them in the last 20 years by the WHO’s reckoning. v
H. R. Shepherd is chairman of the Albert B. Sabin Vaccine Institute at Georgetown
University.
4
SABIN VACCINE REPORT
June 1999
Cancer Vaccines activate immune response
Vaccines are most often considered solely prophylactic, however, cancer vaccines may be
used to treat existing tumors as well.
An Historical Note…
William Coley, a surgeon in New York during the late 19th century, vaccinated patients
against bacterial infections using what have been coined as “Coley’s toxins.” Coley noticed
that immune response to certain bacterial infections seemed to create a general systemic
response that inhibits tumor development and sends cancers such as soft-tissue sarcoma
and lymphomas into remission. Decades later, scientists revisit these discoveries trying
to develop vaccines to activate the immune system and both prevent and treat cancer.
Photo by Carol Ruth Shepherd
Bacillus Calmette Guerin (BCG) and Corynebacterium
parvum are adjuvants, additives that enhance activity, that
may be added to antigen-based vaccines. Antigenics, L.L.C.
uses heat shock proteins (HSPs), the body’s natural adjuvants, to modulate the immune system to respond against
multiple antigens in a given cell in vaccine trials against renal
cell carcinoma, melanoma and gastric and colorectal cancer.
Vaccines may be composed of whole tumor cells that
Cancer defies medical sensibility as our own cells betray us, senting cells), or impede the generation of tolerance and block- have been irradiated so they can no longer reproduce or lygrowing uncontrollably and developing into tumors. ing inhibitory pathways such as the CTLA-4 pathway so an sates, i.e. particles remaining after a cell is destroyed. Tumor
Damaged genes within the human genome cause defects appropriate immune response can take place. An example of vaccines may also be composed of synthetic tumor antigens.
leading to tumor development. Tumors flourish when activating T-cells is seen in AVAX ovarian and malignant mela- Tumor cells may be genetically modified to emit proteins
growth-controlling genes such as oncogenes are activated noma cancer vaccine trials where a process known as that stimulate an immune response, or they may be adulterand tumor-suppressor genes
ated with a gene that will
are deactivated. Generally,
cause emission of a foreign
the human immune system
antigen which when exwould respond to antigen
pressed will elicit an immune
molecular markers on the
response. The ras oncogene
tumor surface by activating
is a potential tumor antigen
antibodies or immune cells
as is her-2/neu, another proagainst them, however, in the
tein that encourages tumor
case of cancer, tumor
growth.
antigens are tolerated by the
These techniques are
immune system. The
meant to yield a T-cell
immune system may tolerate
response that is antigenantigens rather than
specific.
combatting them if it is not
Peptides that mimic
activated properly by
the activity of certain antisurrounding circumstances (Top row)Andrews Grinstead, Stan Riddell, Suzanne Topalian, Nicholas Restifo, Jeffrey Schlom, Richard Bucala, Hyam Levitsky, Victor
gens may be synthesized. For
such as damage to Engelhard, Allesandro Sette, Linda Sherman, Sharon Hammer, John Clymer, (Middle row) Ronald Germain, Richard Simon, Eli Gilboa,
example, a person’s antigens
Edward Neiss, Charlene Flash, Philip Russell, A. Bennett Jenson, Carl June, John Gerin, and Ephriam Fuchs (Bottom row) H. R. Shepherd,
surrounding tissue or Steven Piantadosi, Lee Nadler, Philip Greenberg, Marc Lippman, James Allison, Drew Pardoll, Jay Berzofsky, Ralph Reisfeld, Larry Kwak,
may be cloned, manipulated
inflammation or if the Mitchell Cairo, David Liebowitz, Herbert Herscowitz, Kenneth Meehan, and Tom Gajewski gather outside conference room at Walker’s Cay
so that the immune system is
Cancer Vaccine and Immunotherapy Colloquium.
appropriate T-cell cobetter able to respond, or
stimullatory molecules, such
simply multiplied and then
as B7, are not present.
‘haptenization” is applied to an individual’s tumor cells; reintroduced to the patient. Compilations of multiple tuAccording to Dr. Drew Pardoll of Johns Hopkins Uni- haptenization enables the patient’s immune system to recog- mor antigens have been attempted as well to create a
versity, cancer inhibits a normal immune response because nize the cells as foreign entities and attack.
generalizable tumor antigen preparation.
tumors prevent appropriate antigen expression, generating
Although helping T-cells respond is arguably the
Robert Weinberg in his book, One Renegade Cell,
inhibitory molecules such as tumor necrosis factor B and fas most common tactic for tumor vaccine development, there predicts, “The big decreases in cancer deaths will … come
ligand, or impeding the cellular machinery that delivers for- are various other techniques. Some involve manipulation from preventing disease rather than discovering new
eign proteins to T-cells for action (the major histocompatibility of antigen presenting cells such as dendritic cells and cures.” (Weinberg, 153) Tumor vaccines will respond to
complex (MHC)) and processes antigens.
fibrocytes [See To Present or Not to Present, page 5], regulatory both needs by preventing as well as treating cancer.
The goal therefore is for tumor vaccines to stimulate agents of the immune system, or vectors that express mol- Although tumor vaccines may not replace current
the immune system to recognize tumor antigens. They ecules such as cytokines, growth factors, and tumor antigens. therapies, they have been and may more effectively be
must activate T-cells normally insensitive to tumor anti- Retroviral vectors may be used to insert cytokine genes into used in the future to encourage regression of existing
gens, stimulate or augment presentation of antigens by white blood cells from cancer patients to elicit immune re- tumors and to inhibit the appearance of future micromanipulation of the antigen itself (or of the antigen pre- sponse against tumor cells.
tumors. v
Gerin, Jenson and Schlegel prevent virus-based cancers
Photo by Carol Ruth Shepherd
Initially, tumor vaccines were only considered for strains of
cancer associated with viral infections. If a vaccine could eliminate the causal virus, scientists reasoned, then the cancer would
not take hold. Although not all cancers are associated with a
specific virus, the two most common cancers — hepatocellular carcinoma (liver cancer)
and cervical cancer — are.
Hepatoma is associated with
the hepatitis B virus (HBV),
and cervical cancer with the
human papillomavirus
(HPV). Other viruses associated
with
cancer
include Epstein-Barr virus
(EBV), which has been
linked to Burkitt’s lym- Hepatitis B and liver cancer
expert, John Gerin arrives at
phoma and nasopharyngeal
carcinoma, and certain
retroviruses — such as HTLV-1, which is associated with a
form of lymphoma.
Until the path by which cancer develops becomes clear,
a vaccine against the causative element is the best approach
for preventing virus-associated cancer; eliminating the harmful effects of the offending microorganism reduces the risk of
cancer. Unlike many other cancer vaccines, which strive to
provide therapies for cancer, vaccines for virus-associated cancers have been designed primarily to be preventive; they
prevent chronic infection with the virus, not the actual development of the tumor. However, current research is
exploring the therapeutic applications of this type of vaccine
for treatment of the viral infection itself.
Hepatitis B and liver cancer
In the 1970’s, John L. Gerin, now the director of the
Division of Molecular Virology in the Department of Microbiology and Immunology at Georgetown University and
a scientific advisor to the Sabin Vaccine Institute,
developed what is known as the “NIH Vaccine” against hepatitis B. At that time, infant trials in Beijing demonstrated
that the hepatitis B vaccine was very effective in preventing
HBV. Little did they know that it would soon be determined that hepatitis B caused liver cancer. Years later, Gerin’s
animal model work using the woodchuck and human studies in Taiwan would show a strong indication of the preventive
benefits of hepatitis B vaccine for liver cancer. Above and
beyond the 40 percent lifetime risk of liver cancer associated
with hepatitis B, HBV also causes chronic liver disease, a
progressive illness that becomes increasingly severe with time,
as well as cirrhosis of the liver.
Currently, the hepa- “... the hepatitis B
titis B vaccine is the only vaccine is the only
vaccine
that
has
vaccine that has
been definitively proven to
prevent cancer. Still, the in- been definitively
cubation
period proven to prevent
for development of HBV cancer.”
into chronic liver cancer can
be anywhere from 20 to
50 years, creating challenges for those who seek to do human
clinical trials.
Current research in Gerin’s lab involves a therapeutic
approach; antivirals suppress a host’s HBV viral load, and
subsequent vaccination triggers an immune response that
enables the host to eradicate the virus. Merck & Co., Inc.
and SmithKline Beecham markets hepatitis B vaccines; the
one Gerin’s lab is working on is more experimental in nature.
[See, Sabin counters vaccine campaign, page 8]
Humanpapillomavirus and cervical cancer
Cervical cancer attacks 500,000 people each year and
causes 300,000 deaths. Although Pap smear screening and
treatment make a big difference, the death toll is still staggering. Cervical cancer has been directly linked to the human
papillomavirus (HPV). This virus causes lesions in the cervix
that, over a period of up to 20 years, may develop into cancerous tumors. Aside from being directly associated with
cervical cancer, HPV may also play a causative role in cancers
of the vulva, vagina, penis, anus, head, and neck.
Alfred Bennett Jenson, a member of the Sabin Vaccine
Institute Advisory Committee and a professor at Georgetown
University, and Richard Schlegel of Georgetown University
have developed a vaccine against HPV and cervical cancer.
The vaccine is a genetically engineered virus-like particle based
on the major protein of the virus’s capsid coat. Because these
particles contain no DNA, they are not infectious and cannot cause cancer. The vaccine has been licensed to
MedImmune which is jointly developing it with Smith Kline
Beecham.
Currently the Sabin Vaccine Institute is funding research by the lab of Arthur Weissenger at North Carolina
State University to produce Jenson’s papillomavirus vaccine
in transgenic tobacco plants. This technology will enable inexpensive production of the vaccine in large quantities.
v
SABIN VACCINE REPORT
June 1999
5
To present or not to present
Fibrocytes and dendritic cells deliver antigen for immune attack
photo by Charlene Flash
Scientists have appreciated for many years that a patient’s proteins that stimulate the immune response into the tumor
immune system can be activated against a variety of differ- cells, or by-passing normal processing pathways by loading
ent tumors but that the immune response may not be suf- empty major histocompatibility complex (MHC) molecules
ficient to actually destroy the cancer. Recently, an on antigen-presenting cells.
Twenty-five years ago, Ralph Steinman and Zanvil
understanding as to why this might occur has spurred new
C o h e n
interest in the
reported that
development
dendritic cells
of an immucan act as
nological apantigenproach to the
presenting cells
treatment
that can initiate
and/or prei m m u n e
vention of
responses in
cancer. One
white blood
reason for the
cells, known as
lack of an eft-cells, that are
fective imresponsible for
m u n e
cell-mediated
response
cytotoxicity.
against a tu- Antigen presentation proponents, Herbert Herscowitz and Richard Bucala greet each other at
According to
mor is that Walker’s Cay as Institute chairman, H. R. Shepherd, and Bennett Jenson look on.
Francisco
tumors express self-antigens to which the patient is immunologically Bracho of the Lombardi Cancer Center at Georgetown
tolerant, that is, the patient does not respond to his or her University, dendritic cells “…capture antigen in the periphery,
own antigens. The question then becomes, how does one get migrate to the lymphoid areas, and present the antigen in the
around the problem of self-tolerance. One approach is to context of major histocompatibility complexes along with
increase the level of antigen presentation, the process that co-stimulatory molecules.”
In November of 1998, the Sabin Vaccine Institute
initiates an immune response.
Recently, some cancer vaccines have attempted to target and the Immunex Corporation hosted a mini-symposium at
antigens that can be recognized by the immune system to Georgetown University on the role of dendritic cells in
the appropriate antigen-presenting cells. This can be immunology. Michael Lotze of the University of Pittsburgh
accomplished in a number of ways including: adjusting the Comprehensive Cancer Center presented data demonstrating
adjuvant given together with the tumor antigen, transducing tumor regression in cancer patients treated with dendritic
or inserting specific genes such as GM-CSF that encode cells pulsed with a tumor-derived synthetic peptide. Patients
in his clinical trials were also less susceptible to future tumor
development.
Synthetic peptides, proteins, DNA, tumor lysates, or
apoptotic cells serve as a source of tumor antigen for dendritic cells. Alternatively dendritic cells can be introduced to
the intact tumor itself. Dendritic cells are found in all tissues
except the brain and can be cultured from a patient’s blood
and then “activated” by exposure to an offending protein.
When the “activated” dendritic cells are reintroduced into
the patient the immune system is better able to recognize the
offending antigen and attacks. Her-2/neu, which is expressed
on a number of human tumors including human breast cancer for example, is a tumor-associated antigen that is currently
being targeted for immunotherapy. Vaccines using dendritic
cells also show promise against prostate cancer, lymphoma
and malignant melanoma.
The new antigen-presenting cell
The fibrocyte is a recently-described type of circulating cell, a leukocyte, that was discovered only five years ago at
the Picower Institute for Medical Research in New York.
Like dendritic cells, fibrocytes can play an active role in antigen presentation. These potent antigen-presenting cells are
easy to isolate and to expand. Fibrocytes can be activated by
exposure to a particular patient’s cancer antigens by exposure to tumor tissue in the lab, fusion with tumor cells, or
via gene therapy.
Researchers at the Picower Institute have carried out
extensive research on fibrocytes. Currently Richard Bucala,
Director of the Medical Biochemistry Lab at the Picower
Institute, is collaborating with Cytokine Networks Inc. to
explore fibrocytes as a cancer therapy. According to Bucala,
antigen-presenting cells such as the fibrocyte “could yield
excellent results in the development of tumor vaccines.” v
Tissue-specific cancer vaccines offer hope
Restifo, Allison find pigment loss coincides with tumor regression
Cancer immunologists take advantage of the tenuous balance between cancer immunity and autoimmunity, attack of
one’s own cells by the immune system. Many cancers, such as
melanoma, prostate cancer, breast cancer and ovarian cancer
occur in tissues that if lost or removed would not compromise survival. Vaccine therapies that successfully attack a
patient’s tumors may also
attack the patient’s cells,
“...antigens found
causing disorders such as
on the surface of a
vitiligo. (An autoimmune
skin disorder in which
tumor may not be
patches of skin lose pigthe foreign body
ment.) Relevant tissuesome may
specific
antigens
envision...”
harvested from the “dispensable” tissues of the
skin, breast, ovaries, or penis may successfully act as tumorspecific antigens in tumor vaccines to elicit an immune response against tumors. [See Cancer vaccines activate immune
response, page 4]
Two examples of this technique were discussed during
the Walker’s Cay Colloquium on Cancer Vaccines and Cancer Immunotherapy. [See cover story, Colloquium generates
collaborations.] James Allison, director of the Cancer Research
Laboratory at the Howard Hughes Medical Institute at the
University of California Berkeley, found that our immune
system’s T-cells need a signal supplementary to the antigen
itself (co-stimulatory signal) in order to recognize and subsequently attack tumors. The CD28 co-stimulatory receptor
on the surface of T-cells needs stimulation by a substance
known as B7, the ligand that transmits signals to antigen
presenting cells. Because tumor antigens don’t of themselves
give an appropriate signal to the immune system, antigen
presentation gains importance. [See To present or not to present]
Vaccination techniques with antigens containing B7 could
be used to “jump start” the immune system.
Allison found that he could improve the immune
system’s response to antigens beyond causing an interaction
between CD28 and B7. Allison’s researchers found a substance homologue having a different function to CD28
called CTLA-4. CTLA-4 hinders the interaction between
B7 and CD28. If antibodies are used to block the activities
of CTLA-4, one can obtain much better results in the attack
of tumors by T-cells. In fact tumors treated with a “CTLA-4
blockade” and with vaccines expressing the B7 necessary to
bind the antigen presenting cell receptor CD28, regress.
Allison’s lab combines an irradiated cell vaccine with the
CTLA-4 blockade. (The blockade acts as an adjuvant for a
GM-CSF tumor cell vaccine.)
The trade-off is vitiligo. Vitiligo is an autoimmune
disorder in which T-cells kill normal melanin-producing cells
(melanocytes). This proves a theory held among immunologists that tumor antigens are more “self ” than “foreign.”
Researchers in Allison’s lab are now applying the CTLA-4
blockade and co-stimulation techniques to prostate cancer.
Nicholas Restifo, M.D., of the National Cancer Institute is also working with tissue-specific cancer vaccines. Restifo
treats humans with the growth factor interleukin-2 (IL-2) to
enhance the immune system’s response to cancer. He noticed that some of his patients, developing vitiligo, lost
pigment in patches of their skin. This occurred because the
cancer treatment induced an immune response against the
patient’s own cells.
Researchers in Restifo’s group created a panel of recombinant vaccinia viruses that encoded the mouse
homologues (versions) of human melanoma associated antigens. They found that vaccines containing tyrosinase related
protein-one (TRP-1) triggered the anti-tumor effects as well
as the vitiligo. TRP-1 is an enzyme that helps in the production of eumelanin. Eumelanin is responsible for giving the
skin, as well as malignant melanoma cells their dark color.
Currently Restifo, together with researchers at the NCI
surgery branch, collaborate with Therion Biologics Corporation of Cambridge, Massachusetts to test the hypothesis that
autoimmune disease is linked with tumor destruction in humans.
Tissue-specific vaccines concentrate on particular tissues for immune attack and as a result yield fewer negative
side effects. While other researchers seek out tumor-specific
antigens to be used in vaccines, researchers exploring tissuespecific vaccines find that the antigens found on the surface
of a tumor may not be the foreign body some may envision.
Radiation therapy and surgical procedures provide localized therapy for tumors. Tissue-specific vaccine therapy
yields an overall or systemic response, especially useful in that
cancerous tumors often form satellite microtumors known as
metastases that are not readily combated by localized treatment. v
This report on cancer vaccine research was written by Charlene
Flash, editor of the Sabin Vaccine Report and research fellow at the Sabin Vaccine Institute. Special thanks to
James Allison, Herbert Herscowitz, Nicholas Restifo,
Drew Pardoll, John Gerin, and A. Bennett Jenson for
their assistance with this feature.
Cancer vaccine research in phase-III trials
Brand/Code
Indication
Company
OncoVax-CL
M-Vax
GMK Vaccine
OVAREX
BEC2 Lung
Colorectal Cancer
Malignant Melanoma
Malignant Melanoma
Ovarian Cancer
Small cell lung cancer
Bionetics
BMS
Avax Technologies
Biomira
ImClone System
source: Datamonitor, 1998
6
SABIN VACCINE REPORT
June 1999
Conference shows hidden costs associated with needle and syringe
BY CHARLENE FLASH
According to John Lloyd of the World Health Organization (WHO), more than 12 billion skin injections are given
each year. Nearly all of these use needles and syringes. Although these injections often save lives or prevent disease,
the conventional needle-and-syringe method of delivery
poses substantial problems.
The strongest arguments for finding alternatives to
needle-and-syringe delivery
are the frequency of needle“Improper handling
stick accidents, which can
can
cause injections
transmit disease from pato carry unintended
tient to provider. Also, each
injection exposes the padisease.”
tient,
health
professionals, auxiliary staff,
and the community to sharps waste and contaminated
products. Improper handling can cause injections to carry
unintended disease: Offering a conservative estimate, Lloyd
says that 30 percent of all injections are not sterilely administered, and in 11 out of 14 developing nations, 50 percent
of injections pose the risk of transmitting hepatitis B and
C, HIV, ebola, or lassa virus.
These issues were among those raised at the Conference on Needle-free Injection Technology, held March 31
through April 1 in Bethesda, Md., on the heels of the National Foundation for Infectious Diseases Second
Annual Conference. Sponsors of the Needle-Free Conference were the Centers for Disease Control and Prevention
(CDC), the U.S. Agency for International Development
(USAID), the World Health Organization (WHO), the Program for Appropriate Technology in Health (PATH), and
the Association of Needle-free Injection Manufacturers
(ANFIM).
The conference enabled participants from both the
public and private sectors — including representatives of
public health agencies, nonprofit organizations, and manufacturers of needle-free injectors — to discuss the status
and future of needle-free injection technology. Speakers
presented cost-benefit analyses and examined the effectiveness of using needle-free injection to overcome the
Aids trials
Continued from page 1
would be one that would elicit simultaneous immune
responses by B lymphocytes (humoral immunity) and T
lymphocytes (cell-mediated immunity).
The AIDS vaccine candidate farthest along in clinical trials is VaxGen’s AIDSVAX, which uses recombinant
gp120 envelope antigens and an aluminum adjuvant that
enhances immune response. This vaccine has already
proven to stimulate an immune response and to be safe
for use in humans. Now it is in Phase III clinical trials to
test how well it fights off HIV infection, to determine
side effects, and to see if prior immunization decreases viral
progression in the blood and reduces viral load. AIDSVAX
is being tested in the United States and began trials in
Thailand in February against HIV strains found in Asia.
The Thailand trials mark the first time that an HIV vaccine is being tested for efficacy outside the United States.
Although many people are excited to see an HIVpreventive vaccine reach Phase III trials, many doubt that
AIDSVAX will be effective, since it is not made with a
live-attenuated virus. Such concern is only one of several
challenges that must be faced in the development of a
successful vaccine. Jeffrey P. Kahn, director of the Center
for Bioethics at the University of Minnesota, worries that
testing the vaccines in humans could lead study subjects
to engage in high-risk behavior in the belief they are safe
from contracting the HIV virus. Another concern, Kahn
notes, is that any true test of the efficacy of a vaccine must
involve exposing individuals to the virus. Other
recognized challenges in finding an effective vaccine
against HIV are the variations among strains of the virus
and the complexity of transmission of HIV.
Despite these challenges, hope remains for developing an HIV vaccine. Whether the vaccines currently
being tested will be the long-awaited answer to the AIDS
epidemic is still not known. But collaborative efforts of
both industrialized and developing countries will increase
the likelihood of finding a safe, efficient, and cost-effective measure to protect people around the world from the
HIV virus. v
Elizabeth de la Paz is a graduate student at
Georgetown’s School of Nursing.
drawbacks of needle-and-syringe administration. They also
addressed the use of needle-free injection as an alternative
delivery system for insulin and other medications as well as
vaccines.
Given the chance to communicate with representatives of the commercial sector, public health proponents
encouraged manufacturers to accelerate the development of
needle-free injection technology. Participants also
offered recommendations for improving delivery systems.
Steve Landry of USAID, stressed the importance
of “increased partnership between the public sector and commercial groups.”
Meanwhile, manufacturers must consider ergonomic
challenges, performance standards, and cost. The few million syringes purchased by WHO for emergency use do not
create enough economic incentive for manufacturers to invest
in developing needle-free technology. Organizations like
UNICEF have the purchasing power to create incentive, but
before they as a public
health organization can
“... public health
make a substantive commitproponents
ment, the private sector
needs to invest in getting the
encouraged
technology up to proper
manufacturers to
standards. Todd Calendar
accelerate
of Genesis Medical Techthe
development
of
nologies spoke up for
manufacturers, stating needle-free injection
that government support
technology.”
would create a profit motive
for the private sector
to consider a greater investment. According to Bruce
Weniger, PhD of CDC, the U.S. government spent $600
million in 1998 to buy CDC discount-price contracts from
the vaccine manufacturers for vaccines used in childhood
immunizations.
While needle-free technology poses far less of a contamination risk than conventional methods, it is not
completely risk-free. Experiments done by Ram Abuknesha
at Kings College in London showed that even if the nozzle
of a needle-free delivery device did not contact the skin, at
times there was still contamination evident. (Studies have
shown that possibly as little as 10 picoliters may transmit
hepatitis B.) In response to this challenge, compliancy measures were developed in which the head of the nozzle was
wiped off. Nevertheless, enforcing compliant usage is difficult.
Colonel Charles Hoke, Director of the Infectious Disease Division of the U.S. Army Medical Research and Material
Command, noted that there is definitely a need for a new
delivery device, but suggested that advances in needle-free
injection technology seem to have slowed in recent years.
Needle-free devices are being developed and or manufactured by American Jet Injector, Inc., Bioject, Inc., Equidyne
Systems, Inc., National Medical Products, Inc., and
PowderJect, Inc, among others. .
Various types of devices were presented, each posing
different advantages — and different concerns. A standardized design, according to Dr. Weniger, would create a larger
market that ought to benefit all companies; the manufacturer that initially chose to pursue standardization would
incur all the associated risk and cost, but would reap great
benefit. Another design possibility involves
simultaneous injections with multiple cartridges.
Needle-free injections would minimize occupational
risks, disease transmission, and reuse problems created by
improper use of syringes and needles. Donatus Enkwueme,
PhD Bruce Weniger, PhD and Robert Chen, PhDof the
National Immunization Program of the Centers for Disease
Control spearheaded a study of the hidden costs of needles
and syringes in Africa and concluded that needles and syringes “carry a much greater risk and cost burden than other
vaccine delivery technologies that may cost more to purchase
or to maintain.” When one considers the cost of treating someone who contracts hepatitis B from a needle-stick injury, the
benefits of developing needle-free methods of delivery become more appealing. The use and development of alternative
delivery systems will revolutionize administration techniques
for vaccines and other medicaments, according to Julia
Mendez, MD and Joseph Bellanti, MD of the Georgetown
Immunology Center. v
Special thanks to Bruce Weniger, PhD, Julia Mendez, MD,
and Joseph A. Bellanti, MD.
Sabin counters anti-vaccine campaign
B Y JOHN M. C LYMER
A concerted public relations campaign by anti-vaccine activists is gaining media coverage and spawning legislation that
would weaken immunization programs in several states.
The Sabin Vaccine Institute and several other groups and
agencies that protect public health are countering this campaign.
The campaign led by the National Vaccine Information Center is intended to undermine public confidence in
vaccines. Activists allege causal links between vaccines and
various diseases such as multiple sclerosis, diabetes and autism. ABC’s “20/20” and numerous newspapers have
reported the activists’ charge that hepatitis B vaccine may
sometimes cause multiple sclerosis. Despite overwhelming
evidence disproving the allegation, some media afford the
misinformation as much time or space as they give to public
health experts who refute it.
The World Health Organization, Centers for Disease
Control and the National Multiple Sclerosis Society have
studied the allegation and found no evidence to support it.
They have issued statements affirming the safety of hepatitis B vaccines and urging the public to take advantage of the
vaccines to gain protection against this highly infectious form
of liver disease.
But even as medical and public health experts have
disproved the alleged vaccine-MS link, NVIC and its allies
have politicians’ attention. In
Washington
last month a
“Hepatitis B is 100
House subcommittee held a
times more hearing on “Hepatitis B Vaccontagious than cine: Helping or Hurting
HIV.” Public Health.” Subcommittee Chairman John Mica
(R-Fla.) publicly acknowledged NVIC’s role in staging the hearing.
Several state legislatures considered bills during their
1999 sessions to suspend hepatitis B vaccination requirements and measures that would reduce immunization rates.
Illinois, Indiana, Louisiana and Ohio were among the states
where such proposals were debated.
The Sabin Vaccine Institute submitted testimony to
the congressional hearing and wrote state lawmakers to give
them the facts about the hepatitis B vaccine and the importance of mass immunization to public and individual health.
Newspapers published Institute Chairman H. R. Shepherd’s
op-ed article containing the same message. [See France’s medical meddling could cost millions their lives, page 3]
“Hepatitis B is 100
times more contagious than
“... hepatitis B HIV, the virus that causes
leads to more than AIDS,” Mr. Shepherd told
1 million deaths a legislators. “Many people
year.” chronically infected with
hepatitis B do not know they
have it, so they unknowingly
spread it to others.” The WHO reports that hepatitis B leads
to more than 1 million deaths a year. “Fortunately, the hepatitis B vaccine is 95% effective in preventing both the viral
infection and the liver disease and cancer to which the infection lead,” Mr. Shepherd wrote. [See Gerin, Jenson and Schlegel
prevent virus-based cancers, page 4] He cited a comprehensive
study by a French drug safety
monitoring agency, the Na“Fortunately, the
tional Drug Surveillance
hepatitis B vaccine
Committee, that found lower
is 95% effective in
incidence of MS symptoms
preventing both the
among people vaccinated
against hepatitis B than in the
viral infection and
population at-large.
the liver disease
The American Acadand cancer to which
emy of Pediatrics, Infectious
the infection lead.”
Disease Society of America
(IDSA), American Liver
Foundation, Hepatitis Foundation International (HFI), Immunization Action Coalition, Parents of Kids with Infectious
Diseases (P-KIDS) and other organizations also are engaged
in countering the anti-vaccine campaign. Representatives of
HFI, IDSA and P-KIDS testified at the congressional hearing, along with officials from the CDC and Food and Drug
Administration, that vaccination against hepatitis B is safe
and should continue to be required. v
John M. Clymer is director of external affairs for the
Sabin Vaccine Institute.
SABIN VACCINE REPORT
June 1999
Vaccines combat biological warfare threat
B Y ERICA SEIGUER
Recent revelations of the bioterrorist capabilities of nations
such as Iraq and Russia, as well as a 1995 gas attack in the
Tokyo subway that killed 12 people and injured 5,000, have
revealed the vulnerability of the United States to bioterrorist
attacks. A terrorist attack with a biological agent is fundamentally different from a chemical or explosive attack. And it
requires a completely different response — a response the
United States cannot yet provide.
And that worries D.A. Henderson, director of the
newly inaugurated Center for Civilian Biodefense Studies at
Johns Hopkins University in Baltimore. Henderson, a lifelong vaccine scientist, led the World Health Organization’s
global smallpox eradication campaign in the 1960s and
1970s and earned a 1994 Sabin Gold Medal Award. He
became involved in developing strategies to defend the
United States from the threat of bioterrorism as Associate
Director for Life Sciences at the White House Office of Science and Technology Policy. It was there that he became
aware that biological warfare, or “BW,” was more of a problem than previously anticipated — yet scientists and
policy-makers were concerned primarily with chemical and
nuclear attack.
The United States has been complacent in the face of
an increasing possibility of attack with agents such as smallpox, anthrax, or plague, Henderson says. With no immediate,
visible threat, however, the urgency needed to mobilize the
resources and political will to mount an adequate biodefense
plan has not materialized. Until now.
U.S. pledges millions for defense
Through the Department of Health and Human Services
(HHS), the U.S. government has pledged $158 million for
FY1999 to develop a bioterrorism defense. The funds will be
allocated to improving surveillance, preparing
emergency response teams, and stockpiling vaccines and antibiotics. These are currently in such short supply that experts agree an attack tomorrow would find almost any city,
state, or locality completely overwhelmed — once physicians
and public health officials figure out what happened.
The budget President Clinton proposed in January
1999 included about $2.8 billion to be divided among developing defense strategies against biological, chemical, and
computer terrorism. Clinton commented that scientific
research leading to the development of vaccines to protect
citizens would be one of our best defenses.
At the February 1999 national symposium on “Medical and Public Health Response to Biological Terrorism,” HHS
Secretary Donna Shalala stressed the importance of creating a
sense of urgency and opening the national dialogue on the
topic. The symposium, the first nonmilitary public meeting
on the subject, was organized by the new Center for Civilian
Biodefense Studies and cosponsored by 13 other agencies
and organizations.
Clearly, the level of coordination necessary to address
the issue of BW is a significant hurdle. According to
Rockefeller University’s Joshua Lederberg, preparing for BW
and mounting an appropriate response requires
collaboration between very different sectors of society. As he
writes in Biological Weapons: Limiting the Threat (MIT Press,
1999), “The transcendence of BW over medicine and public health, private criminal acts, terrorism, interstate warfare,
and international law directed at the elimination of BW, makes
this one of the most intricate topics of discourse, poses very
difficult security problems, and opens some novel challenges
in the ethical domain.”
Lederberg continues, “[H]ealth authorities will need
to negotiate with the military, with law enforcement, with
environmental managers. And all will have to cope with how
to enhance security without imposing intolerable stresses
on personal liberties and on freedom of travel and of commerce.”
Challenges of war
Two aspects of BW are particularly disturbing. One is the
delay that may occur before health officials realize that an act
of terrorism has been perpetrated. In contrast to explosive or
chemical attacks, a biological attack such as a minuscule amount
of anthrax dumped from a plane might take days to
be recognized for what it is. Most physicians have never seen,
much less diagnosed, a case of smallpox, anthrax, or plague,
and so early intervention would be unlikely.
Second, even if we were able to figure out early on
what had happened, an appropriate response would be difficult. The supply of vaccines and biologicals needed to
contain an epidemic is insufficient. Also, hospitals are not set
up to deal with large numbers of affected individuals, and
facilities for quarantine and isolation are inadequate.
Vaccines and other antibiologicals
needed
Henderson cites smallpox, anthrax, and plague as the top
three BW threats today. Given that we already have a smallpox vaccine, why is smallpox considered a threat? There are
several reasons. Since the United States stopped vaccinating
against smallpox, the amount of vaccine we stockpile
would never meet the needs of citizens during a bioterrorist
attack. A second-generation smallpox vaccine is in the works,
says Henderson, but it is not available yet; nor is it clear that
mass vaccination of Americans would be feasible. “In general,” he says, “preventive measures are adopted with
great difficulty.”
Lacking the urgency that normally comes with a crisis
such as an epidemic, vaccination rates are less than desirable.
Waiting until a catastrophe occurs, however, will most definitely mean more death and disease. Research
and development of vaccines and therapeutics has been conContinued on page 8
Smallpox: Gone for Good?Others, however, see preservation of the smallpox
BY JESSICA
QUINN
As recently as 1967, the smallpox virus ravaged the
earth, with 10-15 million cases leading to close to 2
million deaths. In an effort to control this disease, the
World Health Organization (WHO) launched a worldwide vaccination campaign against smallpox. Within
13 years, the smallpox virus was declared eradicated,
with the only remaining samples stored in research laboratories.
In 1981 the WHO recommended that all remaining stocks of the virus be destroyed, except for
those held at the Centers for Disease Control (CDC)
in Atlanta and at the Institute for Viral Preparations in
Moscow. The proposed target date to destroy the last
official stocks was June 30, 1999. This proposal brought
much debate over the values of these stores and the
consequences of destroying them. As a result of the
uncertainty, a WHO panel met in Geneva on May 21,
1999 and agreed to postpone the destruction of the
virus until at least 2002.
Those wishing to eliminate the virus altogether
contend that maintaining it has dangerous potential,
as it could be used in biological warfare or terrorism
and unleashed, could cause another epidemic and result in many lost lives, since — as a result of its
eradication — most people are no longer
vaccinated against smallpox.
virus as important in the advancement of science. As the
only virus of its kind unique to humans, smallpox may
provide insights into biomedicine that cannot be obtained
elsewhere. The DNA sequence of the smallpox virus codes
for a unique sequence of proteins that neutralizes human
antiviral defense mechanisms. Studying how smallpox
accomplishes this may help scientists understand and control HIV, ebola, or other viral illnesses.
Preservationists argue that the stores should be maintained for development of a treatment in case of a future
smallpox outbreak. They raise several scenarios in which
the virus might reemerge — for example, from stocks that
are unknowingly stored in non-WHO laboratories, from
virus that is somehow preserved in buried smallpox victims, or by resurfacing through a monkeypox variant.
Proponents of destruction claim that those situations
are highly unlikely and that studies can be done without
the live virus. These scientists claimthat genetic sequences
mapped from viral plasmids can provide any information
that might be needed in the future. However, others argue
that the complete virus is necessary, not just plasmid clones,
for the greatest understanding of smallpox pathogenesis.
The two sides do agree on one thing. If the last
stocks are destroyed, smallpox would become the first species deliberately eliminated by man. The bioethics of such
an event opens up an entirely new forum for question and
debate. v
7
Anthrax threat
causes fear
BY JESSICA
QUINN
Anthrax combines many of the properties most feared in
disease. It is highly lethal, killing 99 percent of its victims.
It can be carried invisibly in the air. And it lies dormant
for years before emerging to do its damage. Little wonder,
then, that analysts worry that this potent toxin may be
used for biological warfare.
Anthrax bacteria can survive for many years in the
form of spores, thanks to a strong protective coat. Infection occurs when the spores enter a person’s lungs. They
move to the lymph nodes, where they reproduce and produce anthrax toxins.
Antibiotics may suppress the infection if used before
the person develops symptoms. This poses difficulties as
there is usually no indication a person has been exposed.
The spores do not form a visible cloud, and they have no
smell or taste. Twenty-four to 48 hours after exposure,
victims suffer from flu-like aches and pains, tightness in the
stomach, severe skin infections, fever, fatigue, and
difficulty breathing. Shock and death usually occur within
24-36 hours of the onset of these symptoms.
Anthrax is seen as a viable biological warfare threat.
In the 1980s, U.N. inspectors discovered that Iraq produced 8,000 liters of anthrax spores — an amount that
could annihilate the entire human population. Authorities at the Pentagon believe that almost a dozen countries
are developing biological weapons, with anthrax a
chief candidate. The potential of anthrax as a weapon is
compounded by the ability of anthrax spores to remain
toxic in water or soil for many years. The Pentagon worries
about the possibility of anthrax being made into a dry
powder and then stored for later use in war.
Fortunately, a vaccine against anthrax is available
for people at risk of exposure. The vaccine, developed in
the 1950s and 60s and finally approved by the FDA in
1970, is produced by Bioport Corporation of Lansing,
Michigan. The vaccine is a cell-free filtrate, meaning it
uses dead bacteria rather than live, and the bacteria used
are a strain that does not cause disease. It is used primarily
by the military.
In May 1998, U.S. Secretary of Defense William
Cohen approved a plan to vaccinate the entire armed
forces. By 2003, nearly 2.4 million men and women will
have started the six-shot series of the anthrax vaccine,
with those going to Southwest Asia and Korea given top
priority. The shots are given over a period of 18 months,
with an annual booster shot. The estimated cost of purchase and administration of the anthrax vaccine is $130
million.
Despite the Pentagon’s staunch support of the anthrax vaccine, the vaccination program has raised
controversy. Some members of the military have refused
to be inoculated and face dismissal as a result; they argue
that it has not proved effective in humans against airborne anthrax spores and that it may cause side effects.
Authorities contend that the vaccine, in use since 1970, has
no record of serious side effects, and that although its
effectiveness has not been tested in humans, it has proved
effective in animal tests, protecting 95 percent of exposed
Rhesus monkeys from contracting the disease. Even proponents of vaccine use, however, are concerned about the
efficacy of the vaccine against strains of anthrax created
specifically to defy the vaccine’s effectiveness.
Other objections involve the vaccine’s former manufacturer Michigan Biological Products Institute. FDA
reports in February of 1998 cited sloppiness in recordkeeping and testing procedures at the manufacturing plant,
raising questions about the sterility of the vaccine. Such
reports reached the Internet, causing concern among
people required to receive the vaccine. The manufacturer
was sold in September 1998, and the FDA and Pentagon
state that the current manufacturer, Bioport Corporation,
and vaccine are safe.
Some military personnel have also raised the issue
of the mystery surrounding Gulf War Syndrome. Although no symptomatic link has been established between
that illness and the anthrax vaccine administered to over
150,000 of the 500,000 people who served in the Persian Gulf War, some people have suggested that the
symptoms of Gulf War Syndrome are side effects from
exposure to the vaccine. Authorities and scientists
maintain that the current vaccine is both safe and effective. It is seen as a key factor in protecting the world from
biological warfare. v
SABIN VACCINE REPORT
June 1999
8
Sabin encourages next generation of leaders in vaccinology
BY JANE FOX Named as 1999 Sabin Hilleman Student Award winners at Intel ISEF were:
·
Bryan M. Roberts of Pennsylvania for his project examining p53 gene therapy in the human leukemia cell line
THP-1. The goal of gene therapy is to replace defective,
disease-causing genes with normal genes. His work supported the idea that p53 gene therapy might be effective in
treating human leukemia;
·
Jeet Minocha of California for work to develop a
potential live attenuated dysentery vaccine strain against a
photo by FocusOne
variety, may contain one or more substances capable of inhibiting the growth of human tumor cells.
Under the auspices of its Sabin-Hilleman Fellows Program,
The students’ research was completed in a variety of
the Albert B. Sabin Vaccine Institute honored six students
settings and under differing circumstances. For example,
for the scientific merit of the projects they presented at the
Joseph Markson’s work was undertaken as part of a schoolannual Intel-sponsored International Science and Engineersponsored internship at the University of Maryland Medical
ing Fair (ISEF).
School while Bryan Roberts’ work was an independent project
The Intel ISEF, held in Philadelphia in May, is now in
using the laboratories at Dickinson College. Coincidentally,
its 50th year and participation is widely recognized as the
both these students are also high school baseball players.
highest achievement in high school science competitions.
The judges were impressed by the students’ work.
The ISEF, the only international science project competiRouzer noted that the Sabintion for 9th through 12th
Hilleman Award recipients
graders, had over 1100 pardid most if not all of this
ticipants from more than 30
“very sophisticated” work incountries competing for over
dependently. One student
$2 million in scholarships and
worked with her high school
awards. Students attending
teacher, without the advanwere top winners from one of
tage of guidance from a
500 science fair competitions
lab-based scientist that most
held world-wide. With about
other participants had. Achalf of the participating stucording to Carol Rouzer,
dents female and 95% of
“The truly outstanding
finalists from the public
projects were those in which
schools, Intel ISEF has been
the students themselves took
successful at encouraging
the initiative.” Laura Kragie
participation by traditionally H.R. Shepherd, chairman of the Sabin Vaccine Institute presents awards to Kapualokelanipomaika’i K. Medeiros, Bryan M. Roberts,
concurred, noting that stuMaria Carolina Pavan, Carolina Glavao, Joseph S. Markson, and Jeet Minocha at the Intel International Science and Engineering Fair.
under-represented groups.
dents’ “independence” and
Judges are drawn from
“self-motivation” were among
science, engineering and industry and include Nobel Laure- form of shigella, Shigella flexneri virG SC602, which causes the key factors considered in making the awards decisions.
ates and Intel fellows. Judges must have the equivalent of a mild diarrhea in humans;
Kragie noted that all the awardees wanted to pursue
Ph.D.or M.D. and have eight years of related professional ·
Joseph S. Markson of Maryland, whose project inves- medicine or graduate study in the biomedical sciences. Stuexperience as the projects are often at the graduate level or tigated potential design improvements in, and the biology dents like these will lead the next generation in the field of
higher.
of, the genetically deactivated pertussis toxin used as a vector vaccinology. According to H.R. Shepherd, Chairman of the
Recognizing the need to help today’s young people for the delivery of HIV antigen peptides (epitopes) into a Institute, “The Albert B. Sabin Vaccine Institute is proud to
become tomorrow’s science professionals, the Albert B. Sabin cell in a developmental HIV vaccine; ·
honor these students, and we look forward to their future
Vaccine Institute has become a Special Awards Organiza- ·
Maria Carolina Pavan and Carolina Glavao of Sao scientific achievement. It is hoped that each of them will
tion for the Intel ISEF. Sabin Institute judges included Paulo, Brazil whose project developed a basis for a bovine continue with advanced scientific studies in the area of disHerbert Herscowitz, PhD of Georgetown University —a hybrid vaccine against Escherichia coli and Salmonella ease prevention, and will be as successful in their chosen
member of the Institute’s Scientific Advisory Committee, typhimurium to prevent infection in cattle, thereby indirectly career as they have been at the Intel Science Fair.”
v
Laura Kragie, PhD, President of Biomedworks, and Carol reducing human infection; and ·
Rouzer, MD, PhD a professor at Western Maryland College. ·
Kapualokelanipomaika’i K. Medeiros of Hawaii for Jane Fox is a Senior Marketing Consultant for Lubin Lawrence,
The six student winners received a classical library of books work examining the effectiveness of papaya seeds, a tradi- Inc. of New York.
that include classic treatises as well as modern texts to inspire tional Hawaiian medicine used to treat early stage cancer.
the recipients in their scientific endeavors.
The seeds of the papaya, especially those of the “Sunrise”
Biodefense
News from the Institute
Continued from page 7
Changing of the Guard
Erica Seiguer, editor of the last three issues of the Sabin Vaccine Report, concluded her one-year fellowship with the Sabin
Vaccine Institute. She is now doing research in the Washington, DC office of PATH, the Program for Appropriate Technology in Health. She will begin a M.D./Ph.D. program at
Harvard University this fall.
The Sabin Vaccine Institute is grateful to Erica for
greatly improving the quality of the Sabin Vaccine Report.
She set it on a new course to provide fresh information and
perspective, and news summaries targeted to a broad audience, including laypersons, vaccinologists, public health
officials, journalists, policy makers and industry leaders. The
new editor is Charlene Flash who, in addition to her publishing responsibilities, is a research fellow at Sabin. As this
issue illustrates, Charlene is up to the challenge of continuing
the forward momentum.
Wearing her research fellow hat, Charlene gave the
final presentation at the Sabin Vaccine Institute’s Colloquium
on Cancer Vaccines and Immunotherapy at Walker’s Cay in
March. She outlined how a consortium involving academia,
industry and government could accelerate development of
vaccines to treat and prevent cancer. Her discourse drew
effusive praise from the prominent scientists, CEOs and
others present.
Sabin wishes Erica Seiguer well in her promising future and is fortunate to have Charlene Flash contributing
talent, energy, and fresh ideas to its programs. v
Proposed law spurs vaccine development
B Y JOHN CLYMER
New federal legislation could create incentives for private
sector research and development on vaccines for diseases that
kill over 7 million people a year. Rep. Nancy Pelosi (D-CA)
introduced the Lifesaving Vaccine Technology Act in Congress this spring. It would establish a tax credit for pharmaceutical and biotechnology companies that do research and
development on vaccines to prevent malaria, tuberculosis and
HIV/AIDS.
The diseases cited by Rep. Pelosi disproportionately
affect developing countries that have limited funds for health
care. Vaccine research companies face the prospect of investing tens or hundreds of millions of dollars to develop vaccines
whose primary markets cannot afford them. The bill provides the special incentives needed to encourage firms to risk
capital on research and development of vaccines for these
diseases.
“Vaccines are our best hope to control the epidemics of
TB, malaria and HIV/AIDS, yet there are significant disincentives for investing in private sector research and
development of vaccines for these infectious diseases,” said
Pelosi. “[My bill] will leverage private sector resources, and
encourage the market to work more effectively to address the
biggest public health opportunities.”
Pelosi’s staff consulted Sabin Vaccine Institute founding president Philip K. Russell, M.D. while drafting the
legislation. A white paper issued by her office on the need for
vaccines against the most deadly diseases in the world quotes
Russell: “Unless there is vigorous investment from the private sector, vaccines won’t get through the [research and
development] pipeline.”
The Lifesaving Vaccine Technology Act (H. R. 1274)
has 18 co-sponsors in the House of Representatives. Gaining
Senate sponsors and additional House co-sponsors will increase its chances of passage. Copies of the bill (H. R. 1274)
and background information are available from the Sabin
Vaccine Institute.
Copies of the bill and additional information about
developing vaccines to prevent deadly diseases are also available directly from Pelosi’s office (202-225-4965). v
ducted mostly in the public sector, through the National
Institutes of Health and the U.S. Department of Defense.
The pharmaceutical industry has shied away from
such research programs.
Better late than never
Despite the relative state of unpreparedness, public health
officials are pleased at interest demonstrated by physicians,
nurses, emergency management professionals, and others
whose cooperation and insights are crucial for any successful
defense. Despite only two months’ advance notice for the
February conference at which Shalala spoke, registration surpassed 900 people from 46 states and 10 foreign countries,
says Henderson. A great deal of research, strategizing, and
implementation is needed to increase BW preparedness, and
it is clear that the issue has found an attentive audience. v
sabin calendar
The Institute is not responsible for
non-Institute events listed below.
December 2-5, 1999
Cold Spring Harbor, NY
MOLECULAR APPROACHES TO VACCINE
DESIGN
Sessions will include HIV/SIV, Mechanisms of
Protective Immunity, Mucosal versus Systemic
Immunity, Mechanisms of Immune Memory,
Co-stimulation and Dendritic Cells and Delivery
Systems.
December 5-7, 1999
Cold Spring Harbor, NY
FINANCING THE NEXT GENERATION OF
VACCINES
Sponsored by the Sabin Vaccine Institute and
organized by Jeffrey Sachs, M.D. Ph.D. and
Peter Hotez, M.D. Ph.D.