vs. Protean Foe
NIAID Tackles Malaria in Vaccine Lab
Across great stretches of the globe, malaria is an inescapable fact
of life. In some places, everyone is infected by this energy-sapping
malady. Every 30 seconds, someone — usually an African child
under 5 — dies of malaria.
|Malaria researchers (from l) Co-chief Allan
Saul, Jin Wang and Co-chief Louis Miller at the MVDB’s
Unlike diseases such as measles, in which a single encounter
confers life-long immunity, malaria can strike again and again,
bringing its victims recurring bouts of racking chills, high fevers,
sweating and extreme fatigue. Along with AIDS and tuberculosis,
malaria forms a deadly troika that not only takes millions of lives
every year, but also casts a deep shadow on the world's poorest
countries. According to some estimates, malaria costs the continent
of Africa $2 billion in lost gross domestic product annually.
There is no vaccine to prevent malaria, a parasitic disease spread
by Anopheles mosquitoes. Indeed, no vaccine exists against
any human parasite. But in a state-of-the-art laboratory in Rockville,
a team of NIAID scientists is at work to change that. Dr. Louis
Miller and Dr. Allan Saul, co-chiefs of the Malaria Vaccine Development
Branch (MVDB), believe the lab's holistic approach to vaccine development
makes the idea of a malaria vaccine feasible.
Several dozen scientists with a wide range of expertise moved
into the 7,000 square-foot MVDB lab in early 2001. Their mission:
bridge the gap between basic research and commercial vaccine production.
The MVDB, explains Miller, focuses on product development — taking
a promising vaccine candidate from concept through scale-up and
the early phases of clinical testing — a bottleneck in malaria
vaccine research and development.
In its organization, the lab departs from tradition, where each
researcher or small group works more or less in isolation. Instead,
every aspect of the facility, from the physical layout to the range
of expertise of the workers, is designed on an industrial model,
enabling a smooth transition from one phase of vaccine research
to the next. Essentially, says Saul, the MVDB is a small biotech
company. Beyond the scientific challenges inherent in creating
any new vaccine, the researchers also have had the challenge of
adopting a more business-oriented mindset, he adds. This means
that the team objectively assesses various vaccine candidates,
abandoning those that are weak while pursuing more promising ones.
Miller's sketch of the lab's many projects looks like a woven
textile. Each horizontal thread represents a different vaccine
candidate. Every candidate is guided by a "task force" of researchers
through the vertical threads of vaccine development, which begin
with molecular analysis; journey through scale-up, purification
and quality control; continue through immunological studies in
cells and animals; and end in clinical trials.
The unusual approach is a response to the difficulties of designing
a vaccine against Plasmodium falciparum, the parasite that
causes the most lethal kind of malaria. As it passes back and forth
between its human and mosquito hosts, the parasite shifts between
sexual and asexual forms. This shape-shifting hinders the ability
of the hosts' immune systems to pin down and eliminate the invader.
The parasite's many forms also present a daunting challenge to vaccine
designers. Vaccines work by giving the immune system a "preview" of
a disease organism. So the more complex and changeable the microbe
is, the harder it is for scientists to identify what kind of preview
will best stimulate the protective might of the immune system.
|Following fermentation, recombinant
proteins are highly purified using this device. Saul and
David Narum, who heads process development, stand by the
An optimist could view the complexity of the malaria parasite's
lifecycle as a boon to vaccine designers. Theoretically, vaccines
could be aimed at any point in the cycle. At the MVDB, several
candidate vaccines target malaria parasites during their sexual
stage within mosquitoes, while others are aimed at the blood stages
in humans that cause disease. The violent chills, high fever and
drenching sweats of malaria come when large numbers of parasite-laden
red blood cells burst at once, releasing tens of thousands of Plasmodium in
a form called merozoites. Many of the released merozoites go on
to infect additional blood cells, thus prolonging the infection.
A vaccine that halts or inhibits the parasites at this stage would
also eliminate or reduce malarial disease and deaths.
But to craft such a vaccine, the researchers must first identify
which of the parasite's 5,300 antigens provoke a strong immune
response. At each stage of its lifecycle, the parasite has a different
set of antigens, further complicating vaccine design. Finding,
purifying and making the appropriate antigens in sufficiently large
quantifies are among the tasks awaiting the vaccine developers.
Dr. Carole A. Long, who heads the lab's immunology team, says
the MVDB offers "soup to nuts" in the vaccine process. The first
course is made inside a gleaming chrome fermenter where a soup
of bacteria containing parasite DNA churns out quantities of parasite
antigens that the scientists believe may have what it takes to
become a vaccine. The mailbox-sized fixture cost $100,000 and is
built to good manufacturing practice standards, which means candidate
vaccines are prepared to sufficient standards of purity to meet
Food and Drug Administration requirements for eventual human use.
Once produced in quantity, the antigens must be tested for their
ability to arouse the desired immune responses. The tests, or assays,
are indirect indicators of the candidate's protective value. Lab
measurements — the amount of antibody produced in an animal
following inoculation with a test vaccine, for example — may
or may not correlate to protection from infection or disease in
humans. Devising assays to detect meaningful correlates of protection
is one of the hardest tasks for immunologists, notes Long.
Still another hurdle for the MVDB researchers is the quest for a
suitable adjuvant to include in the vaccine's formulation; an adjuvant
is a substance that improves the immune system's response to an antigen.
Currently, only one kind of adjuvant — made from aluminum salts — is
widely used in human vaccines. The pharmaceutical industry does not
have much incentive to pursue new adjuvants, says Saul, because the
existing one is satisfactory. Exotic adjuvants are essentially a
niche business, pursued by smaller biotech companies. The MVDB is
partnering with these smaller companies to devise adjuvants specifically
designed to work well in malaria vaccine formulations, Saul adds.
|A technician operates a gleaming chrome
fermenter where a soup of bacteria containing parasite DNA
churns out quantities of parasite antigens.
Miller emphasizes the important collaborations between MVDB researchers
and scientists both inside and beyond NIH. Lab personnel work closely
with scientists in NIAID's Division of Intramural Research and
the extramural Division of Microbiology and Infectious Diseases,
for example. Partnerships also exist with other U.S. agencies,
nonprofit organizations and biotech companies, all of which bolster
efficient production of viable vaccine candidates.
Of course, all the technical success in the world means nothing
unless the vaccines can be tested and shown to work in malaria-endemic
settings. Ensuring that African scientists and clinicians have
the training and infrastructure support to conduct successful vaccine
trials in their own countries is a critical piece of the malaria
puzzle, says Miller. NIAID has a decade-old relationship with the
National School of Medicine of Mali and has worked with scientists
there to create the Malaria Research and Training Center in Bamako.
The MRTC addresses all aspects of the malaria problem, ranging
from strategies for distributing insecticide-impregnated bed nets
to formulating a national malaria drug use policy.
One of the MRTC's most important tasks in the future will be testing
and evaluating vaccine candidates as they emerge from the MVDB
and elsewhere. The MVDB has had substantial success in making clinical-grade
antigens, says Miller, which makes increasing the capacity for
phase I and II trials a top priority. The necessary technology
and trained personnel are being put in place in Mali to make clinical
trials there safe and scientifically productive. The first trials
of malaria vaccines were conducted by the MRTC last year. One vaccine,
called FMP-1, was developed by the Walter Reed Army Institute for
Research and GlaxoSmithKline Biologicals and the second was produced
at the MVDB called AMA1.
Ironically, notes Saul, malaria's ubiquity works to the advantage
of vaccine researchers when candidates move from the lab into clinical
testing. Because infection rates are so high — in some places
reaching 100 percent — any reduction in parasite burden shows
up readily in the vaccinated person's blood, and researchers can
rapidly learn whether a particular vaccine approach is working,
Considering the mountain of difficulties to be overcome on the
way to a successful malaria vaccine, victory might seem elusive.
Saul, though, is cautiously optimistic. A quarter-century ago,
when he first entered the field, Saul admits to being a bit starry-eyed
about vanquishing malaria. Now his optimism is tempered by what
he calls healthy skepticism. Nevertheless, he says the last 5 years
have been ones of steady progress. Both he and Miller emphasize
that the road to an even partially successful malaria vaccine will
be long, but they are both equally convinced that preventing malaria
through vaccination is not a vain hope. The MVDB has already played
an important role in advancing malaria vaccine science, they say.
With the commitment and expertise of its personnel clearly evident,
there's every reason to believe the branch will be instrumental
in lifting the burden of malaria from countless millions.
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