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NIH Responds to SARS
NIAID Holds International SARS Workshop, Draws Large Crowd

By Rich McManus

Photos by Bill Branson

On the Front Page...

Key players in the global response to the outbreak of severe acute respiratory syndrome (SARS) jammed the Natcher auditorium May 30 as NIAID — NIH's lead component in addressing the emerging infectious disease — hosted an international research colloquium on "SARS: Developing a Research Response." Authorities from government, academia, public health and industry joined for a daylong workshop; the morning was devoted to plenary sessions defining the scope of the problem, while afternoon sessions addressed specific strategies in vaccine and antiviral development, as well as clinical research and epidemiology.

Continued...

HHS Secretary Tommy Thompson, appearing by live video, launched the meeting with praise for the scientific community's "rapid, skillful and amazingly successful start so far" in containing and characterizing SARS, and noted that the SARS challenge "is big enough to keep all of us busy for a very long time...The hopes and prayers of many people around the world are with you today."

NIAID director Dr. Anthony Fauci cautioned that the session "is certainly not the last meeting we'll have on this very important disease," then displayed a slide he has shown for years depicting emerging and reemerging diseases around the globe. "This slide requires almost continual updating," he said. "Some (of the diseases) are merely curiosities, others have great public health impact both in their reality and potential." As of May 28, he said, there had been 8,240 reported cases of SARS, with 745 deaths, most of them in the Far East. Addressing SARS "will require many partners...all of us working in synergy," Fauci said.

Dr. Klaus Stöhr of the WHO addresses meeting.

Describing SARS epidemiology was Dr. Klaus Stöhr, project leader of the World Health Organization's global influenza programme. In spite of signs that the SARS outbreak was declining at the end of May, Stöhr warned, "Complacency can lead to the reemergence of this disease."

He said the outbreak began in the last quarter of 2002. Health care workers were at greatest risk of contracting SARS in the early stages of the outbreak. The illness appears to have a 15 percent fatality rate, but he cautioned the sample size has been small. Almost three-quarters of SARS deaths occur in people over age 60. "Age is definitely a risk factor, as is comorbidity," he said. "Males are slightly more at risk than females, but again, the sample size is small."

His slides were fact-laden and his presentation rigorous: A person is most infectious in the first 7 days after acquiring the disease; it is not known if the route of infection (direct mucous membrane contact, fecal/oral contact) influences the incubation period; there is no evidence of SARS transmission before the onset of first symptoms; the people most ill are also the most infectious to others; there is no evidence of food- or water-borne SARS; there has been no transmission on an airliner since Mar. 23; seroconversion can occur in the absence of disease; children seem to have a built-in defense against the virus, getting only mildly ill in most cases.

A veterinarian by training, Stöhr is exploring whether masked palm civets, raccoon dogs and other animals found in Chinese food markets are reservoirs for SARS.

Dr. Malik Peiris
Explaining SARS etiology was Dr. Malik Peiris, professor in the department of microbiology at the University of Hong Kong, which helped identify a new coronavirus as the cause of SARS. He said that people in the United States who have not traveled to Asia recently "can't have a feel for how devastating in social and economic terms SARS is."

He recounted early reports last February of an outbreak of atypical pneumonia in Guangdong province in China, and said it was quickly appreciated that something other than influenza or other conventional respiratory virus was at work. Scientists soon learned that the SARS coronavirus was more stable in the environment than other respiratory viruses, and could survive for as long as a few days on dry surfaces at room temperature, Peiris reported.

"For the front-line health care workers, it was basically fighting a war," he said, to a spontaneous wave of applause.


Offering a view from the trenches was Dr. Allison McGeer, director of infection control at Mt. Sinai Hospital in Toronto, who expressed both her gratitude for a "phenomenal degree of collaboration and willingness to help" on the part of the international public health community, and her pleasure at finally being able to spend a day without wearing a mask.

Dr. Allison McGeer
"Hospitals are the epicenter of this outbreak," she reported; patients, visitors and health care workers are at highest risk of infection. The venues next most susceptible to SARS transmission are doctors' offices, households and family members of SARS patients. The virus rarely pops up in the community outside these sites, she said, and only one instance of workplace (other than hospital) transmission has been reported in Toronto.

She related a fearsome tale of a SARS patient who arrived at a Toronto hospital by ambulance with his wife, who did not yet realize she was infected. In mere hours in the ER and adjoining rooms, the pair infected almost everyone in the vicinity, even housekeepers, visitors and passersby. Commented Fauci, "It's astounding that we have only 8,000 cases, and not 80,000 or 800,000 cases, given this level of infectivity."


McGeer said that abnormal chest X-rays don't show up in SARS patients until around day 7 of illness. "This is a slowly progressive disease," she emphasized. Severity peaks at days 13-17, and in cases that proceed to mortality, the process lasts around 7 weeks, she said.

An impressive amount of scholarship already has been devoted to coronaviruses, as evidenced in talks given by Dr. Kathryn Holmes of the University of Colorado and Dr. Mark Denison of Vanderbilt University Medical Center, both long-time NIH grantees. "A very large international group has been studying coronaviruses in animals and man," Holmes said. The coronavirus group was first recognized, by electron microscopy, in the late 1960's, she said. The spikes that characterize the surface of the round viral particles are viral fusion proteins, and are specific to certain tissues, she added. "Fifteen to 30 percent of colds in people are due to one of the coronaviruses," she reported. The SARS-CoV has a 30,000-base RNA genome, which Denison dubbed "the genome from hell."

Dr. Yuming Shao comments from the audience.

Coronaviruses fall into three distinct genetic groups, Holmes said; the SARS-CoV may belong to a new, fourth group. It appears to favor the lower respiratory tract in humans, and almost never the upper, and Holmes believes it can be enteric as well, mimicking the dual respiratory-enteric sites of other coronavirus infection in animals. She is optimistic that the SARS virus offers "many potential targets for drugs, including blocking and inhibition of various receptor interactions."

The morning session concluded with a rousing endorsement of the NIH model of funding basic research on the faith that it will reap benefits downstream. Vanderbilt's Denison, who described himself comically as "just a little old country virologist from Tennessee," applauded the value of basic research, which prompted another ovation from the audience. "I've been funded for 18 years by NIH," he said, "and I can tell you that the NIH investment in coronavirus biology in the past 20 years is less than the daily cost of the SARS epidemic worldwide."

He said the SARS outbreak "scares me — it has incredible pandemic potential." He said the health care workers who have responded to the epidemic "are my heroes," and cautioned that the outbreak could have been much worse. Glad for the newfound attention to his field, Denison reported that "there have been more coronaviruses sequenced in the past month than in the past 25 years."

The afternoon of the colloquium was devoted to breakout sessions designed to give NIAID what Secretary Thompson hoped at the outset would be "an aggressive set of goals" for containing and managing this new disease.

For more information on NIH's SARS response, visit www.niaid.nih.gov. For the most recent information on the SARS situation, visit www.cdc.gov/ncidod/sars/ and www.who.int/csr/sars/en/index.html.

Fauci Outlines NIH Response to SARS

The day before his institute hosted a major international meeting on SARS, NIAID director Dr. Anthony Fauci answered some questions about NIH's response to severe acute respiratory syndrome, an emerging viral illness that in some respects mirrors the emergence of AIDS more than two decades ago.

When did you first become aware of the epidemic and what were the first steps?

It was right around the end of February, the beginning of March. We had heard of these cases in Hong Kong, and there was an interesting series of events that had occurred in late 2002, when we were hearing rumors that there was some atypical type of pneumonia in China. And we were not sure whether it was a repeat of the H5N1 flu that jumped species from birds to human. We were a little concerned because we were afraid that there might be an H3N2 flu circulating in China. When you have somebody coinfected with H5N1 and H3N2, then you could wind up having a situation where the bird flu can be easily transmitted from human to human. Because when the two combine, they could assume the capabilities of not only jumping from a fowl to a human, which is H5N1, but (also) the naturally human infection, H3N2, can be combined in the same person. So we were thinking that maybe something was going on in China that was very vague — the reports were not very robust — it was just 'Something funny is going on in China.'

At the end of February, beginning of March, when the cases of something that clearly was not flu were going on in Hong Kong — and the reason we know is that the people in Hong Kong know what they are doing; they are very sophisticated, they know how to diagnose flu — and they were saying, 'We're having a strange cluster of cases where we do not know what it is, but it seems to be spreading from person to person, we do not have an etiologic agent, it appears to be respiratory-borne, and it is very high-risk among health workers taking care of the patients.'

VRC director Dr. Gary Nabel (r) chats with attendee Dr. Bruce Gellin of the HHS National Vaccine Program Office.

We had in Geneva one of our own NIAID people — Lone Simonsen — gathering information. She was there for another reason, (but) we told her to stay there and see what she could find out, at the same time that the CDC was trying to make contacts in Hong Kong as well as in China, if possible. It was at that point when I spoke to her and others on the phone that this was a serious issue. So then we said, 'Wait a minute — this we have to take very seriously.' And then everything exploded [in the world media].

When it became clear that we were dealing with a new disease, the agent (of which) we did not know, we immediately gathered our forces at NIAID and said, 'This is another emerging disease, we've got to prepare for it, we've got to get our people ready to move as quickly as possible.' So as soon as the agent was identified as a coronavirus, then it became very clear that we had the opportunity to do drug screening and to grow the virus in culture. We started a vaccine endeavor with both intramural and extramural (scientists) and we began talking to industry about the possibility of getting drugs for them to put into our screening capability. We already have a contract that is a collaboration with CDC, USAMRIID (U.S. Army Medical Research Institute of Infectious Diseases), and NIAID — and it is a drug-screening contract, so we immediately plugged that in and started looking at the effect of certain already well-known antivirals, as well as some compounds that have not been fully developed. We started the screening process. Brian Murphy of our intramural Laboratory of Infectious Diseases got the virus from the CDC and began growing it in his lab for the purpose of developing a vaccine. Gary Nabel in NIAID's Vaccine Research Center got the sequences from the CDC, so began doing the molecular approach with his vector approach — he has been working with adenovirus vector with the company GenVec. He has been making an HIV vaccine using an adenovirus vector; he immediately adapted that to the SARS [virus] and is now working with that. Subsequently, we began sending out the word to our grantees, particularly those who have been funded on coronavirus over the years — not the SARS coronavirus, but coronavirus in general — getting them interested in using their expertise to start thinking and talking about the coronavirus that's causing SARS...We put together a first-stage research agenda involving basic research, pathogenesis, antiviral screening, targeted antiviral, vaccines, animal model development, and then a clinical component, and that was what you read about and heard about with the Clinical Center being involved. We felt we had the responsibility, if it came to that, to study SARS-infected people in the Clinical Center. As it turns out we don't have a lot of cases [in the U.S.], so the worry about that, which I think was understandable, [did not materialize]. We were very concerned about safety. So we are looking at not only studying acutely infected people — which there are not very many around in this country, in fact there are none right now — but also how long people shed virus. What about people in the convalescent stage? If we bring people in who have been infected, [we want to] look at their immunological response, to see if there is any residual evidence of virus. If they are asymptomatic, does the asymptomatic state coincide with a good immunological response? So there are a whole host of questions that are involved.

Is there still a possibility that the Clinical Center will admit SARS patients?

Yes. Oh, absolutely.

Are there such things as "superspreaders" in other infectious diseases or is this a novelty?

Superspreaders is somewhat of a misleading term. There is a biological variability; there are people who, for a variety of reasons, shed more virus, or shed virus when they are asymptomatic, which gives them a greater opportunity to come in contact with other people and spread it more readily versus a person who is very sick and would only have contact with close family members or hospital people. So the idea about a superspreader is not a new concept. There are people with HIV infection who are very efficient transmitters of HIV, for a number of reasons — they may have genital ulcers that allow the virus to be shed more readily in their genital tract, they may have a high titer of virus that easily spills over into seminal fluid or vaginal secretions — so the answer to your question is that it is not unheard of...The typical distribution curve of efficiency of transmission is very common in different diseases.

NIAID director Dr. Anthony Fauci visits with Dr. Kathryn Holmes, a virologist at the University of Colorado who has studied coronaviruses for many years.

How similar is the emergence of SARS to AIDS in your personal experience?

It's different because HIV/AIDS is a behaviorally spread disease. SARS is a respiratory disease and hence everyone could be at risk, so there is a big, big difference in how it is spread. The similarities are that A) It is a brand new disease, B) It is a newly recognized virus that belongs to a class of viruses that has been known. [AIDS] was a retrovirus; we knew about retroviruses but we did not know about AIDS. This is a coronavirus; we knew about coronaviruses, but we did not know about SARS. It is brand new, it causes a serious disease, it could be fatal, and it very likely jumped from an animal species to a human, so it is what we call a zoonotic infection. The primary animal reservoir(s) of SARS are currently unknown; with AIDS, the chimpanzee likely was the main source of HIV-1 and the monkey the main source of HIV-2.

Are other NIH institutes and centers involved in SARS research?

Right now, I do not know of any others that are involved...There may be...but there's no major involvement other than NIAID.

How likely is it that the current outbreak is a "herald wave" or harbinger of worse things to come next fall?

We don't know, and that's the big unknown, and that's the reason why we have to be very vigilant and take this extremely seriously, because we are still in the evolutionary stage of an epidemic. We do not know whether it is going to plateau a little bit, then take off again, or whether it is going to drop dramatically and then come back in a seasonal way. We just do not know.

Is it surprising to you that there has been a reemergence of SARS in Toronto (as of late May)?

Not at all. I've been saying that before congressional committees. It ain't over 'til it's over. You've really got to be careful; there could be undetected chains of transmission that might pop up again, and that's exactly what happened in Canada.


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