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Vol. LVII, No. 9
May 6, 2005

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Hopeful Strategy vs. Protean Foe
NIAID Tackles Malaria in Vaccine Lab

Malaria researchers (from l) Co-chief Allan Saul, Jin Wang and Co-chief Louis Miller at the MVDB’s fermenter.  
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.

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.

Following fermentation, recombinant proteins are highly purified using this device. Saul and David Narum, who heads process development, stand by the machine.  
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.

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.

A technician operates a gleaming chrome fermenter where a soup of bacteria containing parasite DNA churns out quantities of parasite antigens.  
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.

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, he explains.

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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