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Coronavirus Biology and Pathogenesis
On the Front Lines
Approaches to Vaccines and Drug Development
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SARS in the Context of Emerging Infectious Threats SARS in the Context of Emerging Infectious Threats
Executive Summary

SARS: More Questions Than Answers

It seemed to appear out of nowhere: A virulent foe that bears a striking resemblance to other pathogens in its class and yet deals a quick and lethal blow to many it infects. Unbeknownst to the world, it had been spreading quietly in southern China since at least November 2002, but only in February did the world suddenly become aware of it. And within weeks, the mysterious new illness, called SARS (a pithy nickname for severe acute respiratory syndrome, a constellation of symptoms that cannot be attributed to any known infection), was linked to a coronavirus, which is the same family of viruses that causes the common cold. By May—a very short period of time by biomedical research standards—the scientific and medical community had identified the enemy, deciphered its genetic code, and made swift and effective strides in controlling its spread.

Yet for all this success, SARS still presents more questions than answers, as demonstrated by a series of presentations made at the New York Academy of Sciences on May 17 at a conference called SARS in the Context of Emerging Infectious Threats. As of that date, SARS—characterized by a high fever, dry cough, difficulty breathing, and sometimes diarrhea—had infected 7,761 people worldwide and claimed 623 of those lives.

Where did it come from? Did it start in an infected animal and mutate to infect humans? Why do some people succumb to its grip while others survive? Why does it seem to claim more victims in China than in other countries? What is the natural course of the disease? Are patients who recover still able to spread the infection to others? Can we create targeted therapies that throw a wrench in the viral replication process? Can we develop a vaccine to prevent SARS infection, and if so, what is the best approach? These and other questions were tackled by 18 scientists, physicians, public-health officers, and pharmaceutical representatives who made presentations at the Academy's SARS meeting, one of the first multidisciplinary assemblies early in the course of this medical story. The conference was assembled in just three weeks.

"Some of the best things the Academy has done is convene people across disciplines and barriers. Never in the history of the Academy have we convened a meeting as quickly as this one," said Ellis Rubinstein, CEO of the New York Academy of Sciences, as he welcomed the conference participants. "This meeting typifies what we'll see from the Academy in the coming months. This is our future."

The meeting was sponsored by the Academy in partnership with Columbia University's Mailman School of Public Health and the National Institute of Allergy and Infectious Diseases (NIAID). It was organized by Scott M. Hammer, M.D., chief of the Division of Infectious Diseases and the Harold C. Neu Professor of Medicine at Columbia Presbyterian Medical Center in New York; and W. Ian Lipkin, M.D., director of the Center for Immunopathogenesis and Infectious Disease, professor of Epidemiology and Neurology, and Special Advisor to China for Scientific Research and International Cooperation in the Fight Against SARS. Due to respiratory symptoms that began following a trip to Beijing, Dr. Lipkin participated by phone from his home where he is in quarantine through May 25. He is now asymptomatic and is not believed to have had SARS. Generous support for the meeting was provided by Pfizer Inc., Bristol-Myers Squibb Company, Merck Research Laboratories, and Novartis.


Where Did It Come From?
Session I: Coronavirus Biology and Pathogenesis

Coronaviruses owe their crown-like appearance to a multitude of spike (S) proteins studding their surfaces, explained Paul S. Masters, Ph.D., an investigator and professor of molecular genetics at the Wadsworth Center of the New York State Department of Health. These S proteins take on the task of fusing the virus to a victim's cells, enabling the pathogen to set up shop in the cell. The coronavirus' other three proteins—the membrane (M) protein, envelope (E) protein, and nucleocapsid (N) protein—then go to work, essentially turning the host cell into a factory that manufactures and exports newly formed coronaviruses which can attack other cells in the body.

Coronaviruses are highly species-specific, noted Kathryn V. Holmes, Ph.D., a molecular biologist at the University of Colorado Health Sciences Center in Denver. They cause a variety of respiratory, gastrointestinal, and neurologic infections in animals and humans. But because host cell receptors differ between species, a coronavirus that causes a respiratory infection in a pig, for example, has no effect on humans or chickens . . . unless the virus mutates. Such mutation might explain the origin of the SARS virus, which researchers speculate may have come from an animal in south China, where the first SARS cases materialized. "Many of these viruses have probably been with their hosts for a long time," Holmes said. "But how much change does there have to be for a virus to jump to a different host?"

Holmes studies the mouse hepatitis virus, a coronavirus that may shed light on the behavior of the SARS virus. She outlined several potential targets for treating the SARS coronavirus, including those that interfere with its replication machinery as well as vaccines. "If we can develop these therapies, they will be applicable not only to SARS, but also to a large number of diseases in animals," she concluded.

Two species that could be especially helped by such treatments are pigs and cows. Linda J. Saif, Ph.D., a professor and researcher with Ohio State University's Agricultural Research and Development Center, described coronaviruses that cause severe and often fatal respiratory and gastrointestinal infections in these animals, gleaning information about coronavirus infection progression and potential modes of treatment. Studies have shown that these infections may be exacerbated when the virus is administered via aerosol, at high doses, with immunosuppressive drugs, or in the presence of other viral or bacterial infections—data that may yield clues about who is most vulnerable to SARS infection.

Moreover, cows that co-mingle with other cattle from different farms and/or have experienced stress during shipping (causing "shipping fever") are more susceptible to coronaviral infections. "We see something similar to this in SARS patients who recently experienced the stress of travel," noted Saif. She described various vaccines that have been developed for these infections in animals, some of which are effective but most of which offer limited protection.

Thanks to a mix of classic and modern techniques, scientists are refining the way the SARS virus is being detected, explained Thomas G. Ksiazek, D.V.M., Ph.D., acting chief of the Special Pathogens Branch in the Division of Viral and Rickettsial Diseases at the Centers for Disease Control and Prevention (CDC). He chronicled the efforts of medical detectives to isolate and characterize the virus—initially using immunohistochemical staining, and later confirming its identity and genome with RT-PCR sequencing and array technology. Indirect fluorescent antibody testing and ELISA have been employed to garner more information. "The sequencing of the virus' genome so rapidly is a good use of modern technology, and will make diagnosis of the infection and therapy with vaccines possible in the future," concluded Ksiazek.


A Disease of Tribes
Session II: On the Front Lines

The first appearance of SARS in people began last fall, when sporadic cases began to emerge in the southern Chinese province of Guangdong. But the seminal event triggering the current epidemic took place on February 21, when a doctor from Guangdong stayed on the ninth floor of Hong Kong's Metropole Hotel. Ten other people contracted his infection, taking it with them as they continued to travel. Within weeks, the illness popped up in other nations, including Vietnam, where it took the lives of healthcare workers such as Carlo Urbani, the World Health Organization doctor who first identified the outbreak.

The virus most frequently has been spread in hospital settings, indicating that community transmission is less likely, said Larry Anderson, M.D., chief of the CDC's Respiratory and Enteric Viruses Branch. "There is a likelihood that with good infection control practices, we can control the spread of SARS," he contended. Indeed, the infection has already been controlled in Canada, Singapore, Thailand, Vietnam, and the United States. "The good news is that the SARS outbreak has been controlled in some settings, but not in others. We still have a great deal to learn," he added.

For example, who is most likely to develop severe, if not fatal, SARS? Evidence to date indicates that elderly patients and those with diabetes or certain other co-existing chronic medical conditions are more likely to succumb to the illness, but more data is needed to confirm and explain these associations. Investigators also want to know more about the optimal time during the illness to collect specimens such as urine, respiratory secretions, and stool samples so they can correlate their findings with disease progression.

In Toronto, investigators are analyzing the blood of 100 healthcare workers who were exposed to SARS and 100 others who were not, to see if they can pinpoint any indicators of early SARS infection. Donald E. Low, M.D., chief microbiologist at Toronto's Mount Sinai Hospital, explained the SARS outbreak that, as of the date of the conference, had taken 23 lives and caused economic hardship for the city. Their saga began when a woman returned to Toronto after visiting Hong Kong. She developed SARS symptoms and died on March 5, but not before infecting her husband and her son. Her son in turn infected two other men in nearby hospital beds, who set off a chain of infection that included relatives, members of a church group that had been visiting the hospital emergency room, and patients at other hospitals in Toronto before all was said and done. The infection is now under control there.

"The outbreak is over. It is safe to come to Toronto," Low asserted, noting the valuable lessons learned from Toronto's SARS experience. One is that strict infection control is a must. Second, the disease is more often spread in hospitals—via droplets and contact—than via casual contact in the community. And finally, Low called SARS "a disease of tribes," whether those tribes include family members, hospital workers, or close communities such as religious groups.

Recent reports from China indicate that the outbreak there may be abating as well. Scott Hammer delivered a presentation prepared by Chen Zhu, Sc.D., vice president of the Chinese Academy of Sciences, who could not be at the meeting. According to his presentation, China has established a central command and ten task forces and is also evaluating potential treatments (including the serum of convalescent patients), building international collaborations, and establishing research centers to study the virus.

"The situation in China illustrates the awakening and the multidimensional approach that China is taking to control SARS," said Hammer. "It's not just a public health event, but a major political and economic event for China."

Turning Challenge Into Opportunity
Session III: Approaches to Vaccines and Drug Development

Despite more than two decades of research, the clever HIV pathogen has continued to elude us. But some new good may come out of all those years of study: The coronavirus that causes SARS appears to fuse to host cells in much the same way as HIV. Harnessing this knowledge, David Ho, M.D., scientific director of the Aaron Diamond AIDS Research Center at The Rockefeller University—who has scrutinized HIV for 22 years—and his team have designed a peptide that may inhibit this fusion. Preliminary studies in Hong Kong are producing promising results in tissue culture. Ho speculates that this peptide would have little toxicity in clinical applications. "There are still many obstacles in the way, but this is an example of what one can do in a very short time," he concluded.

Since so little is known about the virus' behavior, some doctors have been treating SARS patients with ribavirin and steroids such as dexamethasone, a treatment approach that has not been effective. In fact, corticosteroids may actually delay viral clearance in patients with viral respiratory infections, explained Frederick G. Hayden, M.D., professor of internal medicine and pathology at the University of Virginia School of Medicine. "One has to be very cautious about the effects of corticosteroids on viral replication, particularly in the absence of antiviral drugs," he asserted. Antiviral agents that appear intriguing for use in SARS patients include oseltamivir, zanamivir, and interferon. "We need a better understanding of the natural history of the infection, including mechanisms of injury and host immunopathologic responses," he added. "Controlled clinical trials are going to be essential to understand what really works in this illness."

Drugs with the potential for treating SARS will go through an intensive screening process jointly coordinated by the CDC, the U.S. Army Medical Research Institute of Infectious Diseases, and the NIAID. "There are many steps in the viral life cycle where fusion inhibitors might play a role," said Catherine Laughlin, Ph.D., chief of the Virology Branch of the Division of Microbiology and Infectious Diseases at the NIAID. Other potential drug targets include cysteine protease, RNA-dependent RNA polymerase, helicase, genome replication and transcription, and the N protein. Laughlin hypothesized that the most effective treatment will probably be a combination of an antiviral agent and another drug that interferes with the viral replication process.

The race is on between pharmaceutical companies setting out to make a name for themselves in the SARS arena. GenVec, Inc., a Maryland-based biopharmaceutical company, is developing a vaccine against SARS using its adenovector technology, in collaboration with the Vaccine Research Center of the NIAID and the U.S. Navy Medical Research Center. C. Richter King, Ph.D., vice president of research at GenVec, explained that the "AdVaccine" is based on an adenovirus that is modified to contain a therapeutic protein. The resulting adenovector bears a therapeutic gene capable of triggering an immune response. Moreover, King noted that the highly targeted vaccine is safe and well tolerated, and easily manufactured.

Acambis, a pharmaceutical company specializing in vaccine development, has begun its own investigations into a vaccine for SARS, hoping to build on the success it has had creating vaccines against smallpox and travel-related diseases. Thomas Monath, M.D., chief scientific officer at Acambis, noted the scarcity of effective vaccines to treat coronavirus infections in animals, and highlighted the need for a suitable animal model of SARS. (So far, macaque monkeys have been the only animals offering promise in this regard.) He cautioned that it could take at least five to six years to develop an effective vaccine, at a cost of some $60-100 million and requiring the collaboration of academic and industrial scientists. "We need to understand the natural history of this disease and develop appropriate animal models, and that will allow us to develop rational approaches," he advised.

The session concluded with a panel discussion that also included representatives from Bristol-Myers Squibb Company, Pfizer Inc, and Merck Research Laboratories.

An Emerging Threat
Session IV: Future Perspectives on Emerging Infections

Ebola. West Nile. And now SARS. "Every year or two we see a new virus, an old virus that wasn't supposed to be here, or an old virus doing something new," noted C.J. Peters, M.D., professor of microbiology, immunology, and pathology at the University of Texas Medical Branch in Galveston. He described how viruses travel with their hosts, bringing them to areas they may not have been able to get to on their own. "Viruses can't just pick up and go—they are ecologically constrained. The age of exploration started mixing viruses. But today we don't have to wait for Columbus—there's the airplane."

Peters explained how the genetic variability of viruses, multiple ecologic niches, urbanization, and global travel have combined to create evolutionary opportunities for viruses. But we have to learn to understand social, cultural, and economic differences among populations in order to control viruses effectively. "We have to find a way to get ahead of this. If SARS gets into certain areas of the world, we will not eradicate it," he contended.

When SARS does strike, especially in a major urban area, an effective public health response is critical for controlling its spread, said Marcelle Layton, M.D., assistant commissioner for communicable diseases for the New York City Department of Health. Such a response includes prompt detection of the outbreak, notification of key partners (including the medical community and law enforcement agencies), epidemiologic surveillance, medical and public health interventions (such as mass treatment or mass prophylaxis), and—most importantly—accurate and ongoing public communication. "Effective communication underlies every aspect of a successful response," emphasized Layton. "If you don't communicate well, and if you lose trust with misinformation, it's extremely hard to regain."

"We really are facing an important problem," added John La Montagne, Ph.D., Deputy Director of the NIAID. "SARS is an unpredictable and serious disease with dramatic impacts. It could have happened here (in this country)—we're very lucky." La Montagne supported continued collaboration both nationally and internationally, and credited the toils of SARS investigators. "It is an unbelievable testimony to the effectiveness of our public health institutions—not just nationally, but globally—that so much work and so much progress have been achieved in such a short period of time."

Note: Dr. Malik Peiris, the virologist from the University of Hong Kong that was credited with identifying the unique coronavirus as the cause of SARS, was unable to attend the conference. However, he spoke on May 31, 2003, at New York's Aaron Diamond AIDS Research Center and a report on his talk, including slides, was prepared for this Web site.

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