High stakes, fast track: Bio R&D at a full gallop

A race for new therapies, diagnostics, vaccines

An unprecedented federal investment in bioterrorism scientific research is leading to breakthroughs in vaccines, treatment, and diagnostics for a murder’s row of most-feared agents, one of the nation’s top bioterrorism researchers reported.

"One of the things that has been most gratifying is the extraordinary speed and competence with which our research community has responded to the call to work on and develop new therapies [and] diagnostics," said Anthony Fauci, MD, director of the National Institute of Allergy and Infectious Diseases (NIAID) at the National Institutes of Health in Bethesda, MD. Fauci gave a keynote address recently in San Diego at the Interscience Conference on Antimicrobial Agents and Chemotherapy.

The major investment in bioterrorism research also will provide substantial benefits in the long-underfunded battle against emerging and reemerging infections, he emphasized. "Although money that’s allocated for biodefense will be spent for biodefense, the fact is the people, the brain power, the expertise, the experience all is mergeable one into the other," he said. "What we are doing with biodefense really does take its place among our efforts of emerging and reemerging diseases."

With natural occurring disease no longer the prime focus, the infectious disease community has been drafted to become "biodefense civilian-scientists," said Fauci. Yet while biowarfare has long involved using infectious agents against soldiers in battle, biodefense scientists have the harder job of protecting a vulnerable civilian population. "The people [the military] have to protect, by definition, are a relatively homogeneous group of people who, by definition of being in the military, are young and healthy. In contrast, when one thinks in terms of biodefense against bioterrorism, we are looking at a population that makes our job infinitely more complex. We need to think, when we reflect on therapies and vaccines, of a range from infants to the elderly, pregnant women, [and] immunosuppressed individuals."

To accomplish the mission, the federal government is providing the National Institutes of Health (NIH) and other key agencies a level of funding that is unprecedented. "In 2000 and 2001, we had put in between $50 million and $75 million on biodefense preparedness," Fauci said. "[There was] a supplement of about $155 million dollars in 2002. [Then] a massive leap — the president’s budget for 2003 — bringing the total to $1.7 billion. [That is] the largest single increase [for] any discipline, disease, or institute in the history of the NIH. It is associated with, as you might imagine, an awesome responsibility to spend that money well."

Fauci made it clear that the money comes with a clear expectation from the White House of clinically relevant results — not research for its own sake. "The conversation, if I could distill it down, was that we’ll give you money, and you can do your basic research; but at the end of a few years, I don’t want you to come to me when I ask you what you’ve accomplished and say, We’ve learned a lot.’ That is not the right answer. The right answer is: We have vaccines; we have therapeutics; and we have diagnostics. That’s the mode we’re in."

Given the charge, the NIH and affiliated researchers are aggressively pursuing cutting-edge research , such as gene sequencing, with the major bioterrorism agents. In addition to NIAID, the research is being conducted by the Department of Defense and the Centers for Disease Control and Prevention. The genetic research has immediate implications for immunology and host response, Fauci said. "This could serve as an important shot in the arm to understanding host defense mechanisms against microbes in general; particularly, the important relationship between the innate and adaptive immunity, something that has captured the imagination of host-defense experts for some time," he said. "This is not going to be easy. The question arises: Can you nonspecifically boost the immune system?"

Fashioning an umbrella

If that could be done, researchers may be able to provide a broader spectrum of protection — an "umbrella" against several bioterrorism agents at once. The ongoing attempts have been met with skepticism by some, but Fauci said it might be possible. "There is some good precedent that you could do that," he told attendees. "A good example is the striking results that the Chronic Granulomatous Disease [CGD] Cooperative Group has had in treating individuals with CGD with interferon gamma and remarkably controlling their ability — enhancing their ability — to fight atypical and typical mycobacterial disease."

On other fronts, researchers now have identified and isolated all three of the toxins of anthrax: lethal toxic, edema factor, and recombinant protective antigen. "That immediately opens up a lot of doors for diagnostics, therapeutics, and vaccine," Fauci said. New vaccine development — as well as efforts to improve the current anthrax vaccine — also are under way. Researchers have made substantial progress with a vaccine for Ebola that is showing efficacy in animal trials. "Within the next six months, hopefully, they will go into Phase I trial with the ultimate goal of having a single vaccine that includes Ebola, Lhasa, and Marburg."

Another challenge is developing new therapeutics, an important weapon in the biodefense armamentarium. "A good example is the realization that sodolfavir, which was originally developed as an anti-cytomegalovirus antiviral in HIV-infected individuals, has potent activity against orthopox viruses, including variola major [smallpox]," he said. "It is a difficult-to-administer antimicrobial. It needs to be [given] intravenously and also has significant renal toxicity, but [we are] working now on formulations that can be orally administered and, hopefully, will be less toxic."

Bacterial phages — viruses that can specifically invade and kill bacteria — also are under laboratory scrutiny. For example, researchers have found a bacteria phage specific for anthrax that can be used for rapid diagnosis. The anthrax bacteria phage — called PLYG lysin — also can be used to rapidly kill anthrax. "When you dump this lysin into a culture of Bacillus anthracis, you start to see these bacillus’s essentially explode," he said.

In the area of diagnostics, researchers are using the latest techniques of microbial gene expression on "gene chips" that may have a signature pattern or a distinct host response. If that can be accomplished, questions such as, "Is this chicken pox or smallpox?" can be answered easily. The impressive research agenda may seem a little sci-fi to some; but Fauci is operating under a mandate to produce clinical relevancy. "These are very, very important directions of research," he said. "[It may] seem like Star Wars’ in some respect, but not so; because these are things that are imminently doable."