DOTS alone not enough, report says; need for new vaccine called urgent
DOTS alone not enough, report says; need for new vaccine called urgent
ACET offers sobering reassessment of DOTS strategy
The Advisory Committee for the Elimination of Tuberculosis (ACET) has issued a strongly worded report urgently calling for the development of a new vaccine, signaling a marked shift in emphasis in the current philosophy of TB control.
The ACET report pointedly emphasizes the limits of directly observed therapy (DOT) and its global counterpart, directly observed therapy, short-course (DOTS), long the two cornerstones for TB control in this country and abroad. Though still the best tools available, DOT and DOTS alone can no longer be considered weapons powerful enough either to eliminate TB in the United States or to curtail its spread globally, the report says.
American TB experts interviewed say they fully agree with the report and its recommendations, which appeared in the Aug. 21 edition of the Morbidity and Mortality Weekly Report (MMWR).1 But some officials at the World Health Organization (WHO), though they agree about the need for a new vaccine, say they worry that the ACET report may dampen hard-fought efforts to convince decision makers and funding sources that DOTS is still the best strategy currently available. Some at WHO, which has mounted a massive campaign in recent years to convince high-incidence countries to buy into DOTS, also say they are a bit skeptical about the current enthusiasm for basic research.
DOTS alone "clearly cannot solve the problem," says Arata Kochi, MD, director of WHO's Global TB Program. "But the question is, when will this new vaccine become available?" Estimates for the time it will take to develop a TB vaccine that is more effective than Bacille Calmette-Guerin (BCG), and then to complete the lengthy trials that will be required, range anywhere from 10 to 40 years.
TB experts at WHO also cite concerns over whether the ACET report could detract from the DOTS campaign. "No one disputes the need for a new vaccine," says Mark Perkins, MD, medical research officer in the Global Tuberculosis Program of the World Health Organization, and a member of Immunology of Mycobacterial Diseases (IMMYC), a steering committee at WHO which advocates vaccine development for leprosy and TB. "But for now, we still have to keep fighting TB on the ground. We certainly don't want to give the message to decision makers in areas of endemic disease that they can ignore the problem, and simply wait for a vaccine to come along."
TB experts in the United States stress that's not their intent. "DOTS is a strategy we fully support," says Rick O'Brien, MD, chief of the research and evaluation branch at the Division of Tuberculosis Elimination at the Centers for Disease Control and Prevention (CDC). "In fact, we've tried to make the U.S. a DOTS program, and for all purposes have succeeded. We're simply saying that DOTS alone is not going to be enough."
Others agree. "DOTS and a new vaccine are not at all contradictory strategies - they're multiplicative; they're synergistic," says Ann Ginsberg, MD, PhD, head of the Respiratory Diseases Branch of the Division of Microbiology and Infectious Diseases at the National Institute of Allergy and Infectious Disease at the National Institutes of Health in Bethesda, MD.
Still, as the ACET report states, it's no longer possible to consider DOTS alone an adequate tool to fight TB. In the United States, levels of TB are 75 times higher than the goal of one case per million set forth in the 1989 strategic plan for elimination formulated by the CDC.
On the global scale, DOTS isn't doing as well as proponents had projected, either. In 1997, WHO estimated that DOTS could cut the global TB burden in half within the next 10 years. This year, with only 12% of the world's TB cases enrolled in the DOTS program, WHO announced it wouldn't meet its goals for the year 2000, and hopes began to dim that WHO would meet its 10-year goal.
The amount required to develop the new vaccine is $40 million a year for the next 20 years, or $800 million in all, according to a draft "blueprint" for vaccine development. That may sound like a lot, but it is estimated that the United States actually spends $700 million every year on TB control and treatment, O'Brien adds. (The blueprint was developed as the result of a process that began at a vaccine workshop held last March in Rockville, MD, to address the need for new TB control tools, Ginsberg says.)
DOTS isn't the first strategy to be misjudged as a panacea for TB, the blueprint notes. At first, experts also hailed the discovery of BCG and streptomycin as solutions that would once and for all put a swift end to TB.
Economic, social factors are key
Some of the trouble with DOTS-based strategies lie not in flaws inherent in the tool itself, but with political upheaval in the world today, experts say. "All you have to do is read the newspaper to see that social fabric and political structure in many parts of the world are deteriorating," says Charles Nolan, MD, TB controller for King County, WA, and ACET's acting chairman. "DOTS is a concept that depends on a stable government, an emerging wealth in a society, and a commitment to turn people's attentions to TB," he adds. Unlike directly observed therapy, the concept of DOTS incorporates specific elements of public-health infrastructure many resource-poor countries lack, including a consistent supply of medicines and systems of reporting and surveillance.
If the ACET recommendation seems surprisingly strong, that's because it's an advocacy piece designed to accomplish a goal, adds O'Brien. "One tends to simplify things for decision makers," he says. "The message here is that DOTS isn't enough, and that we need a new tool - specifically, a vaccine."
Framing the issue as if there are only two possibilities - DOTS and a new vaccine - runs the risk of overlooking other worthwhile strategies, says Perkins. Some short-term strategies, such as improving current diagnostics, and finding medicines that are more convenient and more effective, could become available much sooner than a vaccine, yet could substantially bolster the effectiveness of DOTS, he says.
The same goes for what might be called "mid-range" strategies aimed at finding betters ways to use the healthcare system. Examples include identifying groups of patients who aren't getting their medicines, working on gender issues, and implementing other system-based reforms, Perkins says.
Others at WHO echo such concern. "If we continue to do business as usual, and wait 10, 20, even 40 years for a vaccine, what will happen is that in the meantime, between 30 to 100 million people will die," says a WHO expert who asked not to be identified. "We could avert that if we paid more attention to doing well what we already know how to do."
Such concerns mirror tensions that already exist at WHO between those pushing for more DOTS, and those who advocate more basic research. "There are those here who think it's pretty esoteric to be setting aside $20 million to look at genomes, on the grounds that someday it might lead to a TB vaccine," the expert says.
An influential model from Harvard
Several members of ACET say that part of what spurred them to issue the MMWR report was a model projecting TB cases for the next 30 years, given the use of various strategies, including vaccines. The model, developed by Chris Murray, MD, PhD, associate professor of International Health Economics at the Harvard University School of Public Health, projected various scenarios that involved using DOTS only, and with varying degrees of success, by manipulating two variables: how many cases were detected and how effective the treatment programs were.
When Murray and co-workers modeled the impact of adding vaccines to a DOTS strategy, they considered two kinds of vaccines: a conventional pre-infection one and a post-infection vaccine designed to prevent those already infected from developing active disease. Because the modelers assumed that a using a conventional vaccine would require the skin testing of subjects (to prevent those who were immunocompromised from suffering adverse effects), it was estimated that about a third of those skin tested would fail to come back for their readings.
That assumption made the post-infection, or "breakdown," vaccine appear substantially more effective than the conventional, pre-infection vaccine, notes Joshua Salomon, a research associate with the Murray project. Otherwise, the two kinds of vaccines came out looking about equally effective, he says.
At about the same time Murray and his colleagues were working on the Harvard model, WHO researchers were developing their own model to project the effects of implementing DOTS worldwide. Problems with the WHO model are said to be twofold: first, it estimated the rate of breakdown at about 30%, whereas most experts place it between 5% and 15%. Second, it calculated the risk of infection as a function only of time; Murray and co-workers also considered the infectiousness of the source.
Someday, half of all TB cases will be in U.S.
There were other reasons besides the Murray model for deciding to call for development of a post-infection vaccine, ACET members say. One, says O'Brien, is that a post-infection vaccine would work especially well in the United States, where soon, as many as half of all TB cases are expected to come from foreign-born people who arrived here already infected.
A second reason for supporting post-infections vaccines is that they lend themselves to less time-consuming trials, Ginsberg says. "If you give a vaccine only to neonates, and look 30 years later to see who got TB, then you'll know if that vaccine works in a pre-infection mode," she says. "If you give a candidate to young adults who've been exposed and who may or may not have been infected, then wait 10 to 15 years to see if they get TB, you're looking at a post-infection mode of efficacy."
Urging researchers to come up with a post-infection vaccine, as opposed to a pre-infection vaccine, doesn't necessarily mean that's what they'll be able to deliver, Ginsberg adds. "At this point, vaccine development isn't an engineering problem," she says. "It's still a problem of basic research. A lot of the answers we get will depend on what questions we ask - in other words, what kind of trials we design."
Reference
1. Centers for Disease Control and Prevention. Development of new vaccines for tuberculosis: Recommendations of the Advisory Council for the Elimination of Tuberculosis. MMWR 1998; 47:1-6.
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