Big challenges for SARS researchers

The World Health Organization (WHO) announced at a press conference July 5 that the last known case of human severe acute respiratory syndrome (SARS) was detected and isolated in Taiwan on June 15—more than two incubation periods ago.But even Director-General Gro Harlem Brundtland admitted that the disease may return and that a great deal of work is needed to understand it.The scale of the task is now becoming clear. Speaking to The Scientist from Beijing, Klaus Stöhr, who put together the WHO laboratory network that identified the SARS coronavirus, outlined WHO's public health research priorities before the winter flu season."First, we have to understand if there is a potent risk for the disease to reemerge from an animal reservoir," said Stöhr."Second, we have to invest every resource we have into the development of rapid diagnostic tests, to work in the hospital, and quickly distinguish between SARS and flu."Third, we need to understand the reasons for the success and effectiveness of the control measures here in China. A relatively small number of health care workers were affected here, with an apparently very low case fatality."Of course, work on drugs and vaccines should not be stopped, but this is long-term investment," Stöhr added.Stöhr's visit to Beijing is offering China "opportunities to strengthen international collaborations," he said. "We want to find areas where our Chinese colleagues wish to have more collaboration, or areas where they would move ahead slowly with collaboration, or would not start at all," said Stöhr.But there is a much wider agenda for research on SARS. Maria Zambon of the UK's Health Protection Agency, a member of WHO's original SARS research network, told The Scientist there are also fundamental questions concerning "comparative evolution, genomic structure and organization, coding strategies, and host-range tropism." She added.that short- to medium-term questions would include, "Is the virus evolving in the human population, what is the role of different population groups in transmission, and what is the best way of containing an outbreak?" Even determining the animal origin of SARS is by no means easy, however, and China may be letting down its guard too soon, according to Laurie Gleeson of the Australian Animal Health Laboratory. Gleeson works on animal diseases in Asia and will be going to China next week to report on its work on the animal origins of SARS for the UN Food and Agriculture Organization. Gleeson told The Scientist that he had heard the Chinese Ministry of Agriculture team studying the issue had been disbanded. "If it goes off the boil, the senior veterinary virology institutes [in China] will lose impetus."The key technical problem will be to find a single diagnostic test that will detect antibodies to the SARS virus in a wide range of wildlife. (The polymerase chain reaction is less useful than antibody tests, as the antibody can be expected to last much longer in the animals' bodies than the virus.)According to Gleeson, virus neutralization tests are available, but they need live viruses and therefore require high-level containment. "The best idea is to use an inactivated antigen," said Gleeson. But ELISA (enzyme-linked immunosorbent assay) tests would need anti-animal conjugates and would be impractical to make for hundreds of wild animals. Tests without conjugates would have to be developed, which would take time.Validation could take a further 6 months. "In a species that's never been put into a serological test before, how do you interpret the result? How much confidence can you have in that?" asked Gleeson.An antibody test would probably be used first to do a rapid survey of a population, but positive results would also have to be checked against virus neutralization tests. "It's not a trivial task, especially if you are going to really understand where this came from, where it sits in how many species, and how likely it is to cross the divide into humans."The Chinese will have to get to the point where they believe it is in their best interests to sort this out. If they don't come to that conclusion, it's very difficult to drive it with a big stick from outside," said Gleeson.Like Australia, Canada is a partner in WHO's SARS animal network. Hana Weingartl, research scientist in charge of the Winnipeg level-four containment laboratory for special pathogens in the National Centre for Foreign Animal Disease, told The Scientist that the network has decided initially "to support China, so they can do the surveillance first and, based on what they find, we would pick up the important points and confirm their findings."Weingartl's as yet unpublished inoculation and reisolation experiments in pigs and chickens, completed in May, had shown no transmission, she said. With regard to human diagnostics, Stöhr said, "We need better human tests to detect cases at 3 to 5 days after onset of clinical signs, so we can identify SARS cases when they come to the hospital."This means detecting the virus, but creating better tests is difficult because patients release so few virus particles. "SARS infection is deep down in the lungs and rather inaccessible," said Wolfgang Preiser of the Institute fur Medizinische Virologie, Johann Wolfgang Goethe-Universität, Frankfurt, who worked on the two German cases of SARS and who was part of WHO's first team to visit Guandong in South China to investigate the origin of the disease in that province. "Patients don't produce sputum because it's a nonproductive cough and, although you can get virus by doing a bronchioalveolar lavage, you'd be exposing yourself to high amounts of infectious agent. The upper respiratory tract specimens and swabs are unfortunately not very good, at least not in the early stages."Preiser also said that the epidemiological history is cloudy. "Although China had most cases, and they have a treasure trove [of patients' tissue samples] in their freezers, and we know they are working on that, there isn't the openness we would have hoped for.""One gets the impression that material is not to leave China, which is a problem. They are very capable of doing much of this work themselves but, if they do so, will it be published and open to discussion and scientific scrutiny?" Preiser asked.How is all this work to be funded? "The money is still a question mark," Andrea Ellis, WHO coordinator for the SARS animal network, told The Scientist. "WHO will not be funding research directly, but it is trying to get funds available through several donors for many different aspects of SARS. At present the plan is to survey the research needs, then determine how best to get the work done, what it will cost, and who can fund it."Last week, the European Commission came up with €9 million ($10 million) for SARS research. It requires applicants to have Asian partner institutions, but whether this will support research done primarily in China is unclear. This is the first significant EC funding specifically for SARS science, underlining complaints by the EC Communicable Disease Network Committee in April that "the Commission does not currently possess the appropriate mechanisms to provide rapid support" for disease emergencies.In the United States, the Centers for Disease Control (CDC) is "in transition" from the emergency state to thinking about preparedness for the return of the disease. This includes research on "early and reliable" diagnostics, the animal source, and many other matters, Rima Khabazz, associate director for Epidemiological Science at the National Center for Infectious Diseases, told The Scientist. Encouragingly, Khabazz felt China had "come around" and was "quite keen to address the issues." The CDC was equally keen to assist them, she said. "We are talking about surveillance and diagnostics and understanding the transmission and the source animals. All of that is on the table," she said. And though she could give no figures she believed that "resources are coming our way" from Congress to support the work.

Big challenges for SARS researchers

Current outbreak over but now animal research, diagnostics, interactions with China, and funding loom large

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