FLICKR, NIAIDUnsure of its origin, mode of transmission, and the best course of treatment, clinicians have been working to quell Middle East respiratory syndrome (MERS) on a case-by-case basis since it emerged in Saudi Arabia last year. Writing in Nature Medicine today (September 8), a team led by investigators at the National Institute of Allergy and Infectious Diseases (NIAID) presents a therapeutic approach validated in nonhuman primates. Because the treatment was successful in vivo, the authors recommend it be used to treat human MERS patients. NIAID’s Darryl Falzarano and his colleagues showed in a rhesus macaque model of the disease that treatment with interferon-α2b and the nucleoside inhibitor ribavirin improved clinical outcome when administered eight hours post-infection.
“Our in vitro data suggested that we needed both together for it to work,” Falzarano told The Scientist. “We went with those two drugs because they’re available on the shelf, they’re approved for use in humans [and] easily accessible.”
“We started this combination therapy not because we think it is the greatest treatment strategy, but because it is something that can be applied quickly,” added study coauthor Heinz Feldmann, chief of NIAID’s Laboratory of Virology. “This is one option that now is out there.”
Although its first symptoms—fever, cough, and shortness of breath—are typical of most lower respiratory illnesses, MERS is an infectious disease unlike any seen in humans before. The coronavirus (CoV) that causes it appears similar to the infectious agent behind the 2002-2003 severe acute respiratory syndrome (SARS) outbreak that infected more than 8,000 people across the globe, killing 775. But MERS differs from SARS in several respects. For one, it is more deadly. Since September 2012, the World Health Organization (WHO) has recorded a total of 114 lab-confirmed cases of MERS-CoV infection worldwide, including 54 deaths—giving it a much higher fatality rate than SARS.
In the time since the first reported death last June, scientists have generated complete genome sequences for the novel CoV and resolved the crystal structure of its receptor-binding domain. Using advanced epidemiological and genomic surveillance techniques, they’ve even pinpointed a suspected source of the infectious agent—bats—and are gradually piecing together how it might be transmitted from the winged mammals to humans. Still, for all that’s now known about the MERS-CoV, there’s much more left to learn.
“People are dying in the Middle East,” Feldmann said. “SARS was a wake-up call. Is this going to be SARS, or is it going to be worse?”
Allison McGeer was among the researchers at the front lines of SARS when the outbreak reached Toronto 10 years ago. This May, she traveled to Al-Ahsa at the request of her colleague Ziad Memish, the assistant deputy minister of health for preventive medicine in Saudi Arabia. McGeer, Memish, and their colleagues published a paper describing a cluster of hospital-acquired MERS-CoV infections in the New England Journal of Medicine in August.
“The big difference at the moment between MERS and SARS is we don’t know what the exposure is . . . for MERS yet,” McGeer said. “The source of the exposure to humans before the outbreak was much more rapidly identified during SARS.”
Researchers who sequenced the MERS-CoV genome last year had an idea about its origins early on. Their initial phylogenetic analyses pointed them to bats. The researchers found that MERS-CoV was more similar to two viruses isolated from bats than to human SARS. And last month, scientists from Columbia University and the nonprofit EcoHealth Alliance, based in New York, reported in Emerging Infectious Diseases on their discovery of a stretch of viral RNA in a fecal sample from a single bat that matched similar sections of viral RNA found in humans infected with MERS-CoV. While the finding has yet to be validated, it marked the first tangible evidence of MERS’s animal origin.
“Although bats may ultimately turn out to be the origin of MERS, it is still a mystery as to exactly how the initial case patient became infected with MERS coronavirus,” said the University of California, San Francisco’s Charles Chiu, a clinical microbiologist specializing in viral diagnostics.
“To date, most patients with MERS have not reported any direct contact or exposures with bats, so there must be an intermediate source between bats and humans,” Alimuddin Zumla, a professor of infectious diseases and international health at University College London told The Scientist in an e-mail. “If we know that answer then we can interrupt that transmission and put control measures in place.”
Beyond identifying intermediate hosts, there are several other questions. In order to better detect and treat MERS, researchers must first fully resolve its epidemiology. “Are we looking at the tip of the iceberg with the 108 cases today?” NIAID’s Feldmann asked. “How many mild or asymptomatic cases do we have that could contribute big time to spread of the virus and transmission?”
The reproductive and mutation rates of the MERS-CoV also remain unclear, as do the functional consequences of its genomic characteristics. “We do not know the function of several MERS-CoV genes,” the Erasmus University Medical Center’s Ron Fouchier, who led one of the first teams to sequence the complete genome of the novel CoV, told The Scientist in an e-mail. “Understanding the function of the products encoded in the virus genome is crucial.”
Along those same lines, Chiu noted genomic surveillance is needed to help ascertain whether there are quasi-species of the MERS-CoV, and whether their existence might affect pathogenesis and/or host immune response.
While scientists continue to focus their efforts on understanding MERS in a field-specific manner, most agree that the most pressing need is to identify the origin of the CoV and how it spreads to humans. “If we know that, there’s a possibility we can stop it, like H7N9 and SARS—you close the animal markets, the risk goes away,” said McGeer. “If we knew what the risk was, then we might be able to stop it . . . and we wouldn’t have to worry about the virus evolving as it grows in humans, and we wouldn’t have to worry about ongoing hospital transmissions in the Arabian peninsula and henceforth, to other countries.”
A. Assiri et al., “Epidemiological, demographic, and clinical characteristics of 47 cases of Middle East respiratory syndrome coronavirus disease from Saudi Arabia: a descriptive study,” The Lancet, 13(9): 752-761, 2013.
A. Assiri et al., “Hospital outbreak of Middle East respiratory syndrome coronavirus,” New England Journal of Medicine, 369: 407-416, 2013.
Y. Chen et al., “Crystal structure of the receptor-binding domain from newly emerged Middle East respiratory syndrome coronavirus,” Journal of Virology, 87 (19): 10777-10783, 2013.
D. Falzarano et al., “Interferon-α2b and ribavirin treatment improves outcome in MERS-CoV-infected rhesus macaques,” Nature Medicine, doi: 10.1038/nm.3362, 2013.
Z. Memish et al., “Middle East respiratory syndrome coronavirus in bats, Saudi Arabia,” Emerging Infectious Diseases, doi: 10.3201/eid1911.131172, 2013.