Just a few weeks ago, the world’s foremost experts on coronaviruses were putting the finishing touches on slides and posters, finalizing travel plans, and generally getting ready for the 15th International Nidovirus Symposium, planned for a small Dutch village on the North Sea coast.
Then the novel coronavirus SARS-CoV-2 turned academic research questions into matters of life and death.
But the answers remain elusive, and that fact might be the most important lesson of the current outbreak — because it’s not the first time this has happened.
In the Beginning
In 2002-2003, the first severe acute respiratory syndrome — caused by SARS-CoV — burst on the scene, sickening more than 8,000 people and killing 774 before disappearing. Naturally, there was intensive research on the virus, on possible therapeutics, on candidate vaccines.
“That all halted when the disease disappeared,” says Ravina Kullar, PharmD, a spokesman for the Infectious Disease Society of America and a consultant with Expert Stewardship, Inc., of Los Angeles.
The research stopped because other measures had succeeded, in what experts regarded afterward as a combination of good luck and good management. On the latter front, traditional public health tools — case-finding, case isolation and treatment, and contact tracing — worked well and allowed SARS to be contained and eventually extinguished, according to David Heymann, MD, and Guenael Rodier, MD, both then at the World Health Organization.
“Within four months after the first global alert about the new disease, all known chains of transmission had been interrupted in an outbreak that affected 27 countries on all continents,” they wrote in a 2004 analysis.
There was also some luck: the SARS virus caused sufficiently violent illness that most victims were in health care systems before they could spread the virus widely in the community. Indeed, much of the human-to-human transmission was nosocomial; in highly affected countries, health care workers accounted for between 37% and 63% of suspected SARS cases.
Moreover, it was fortunate that SARS in large part affected countries — mainly China and Canada — that had robust health care systems. “Had SARS established a foothold in countries where health systems are less well developed, cases might still be occurring, with global containment much more difficult, if not impossible,” Heymann and Rodier wrote.
A key lesson, they added, is that “inadequate surveillance and response capacity in a single country can endanger national populations and the public health security of the entire world.”
Then, in 2012, another coronavirus, the Middle East Respiratory Syndrome (MERS-CoV), emerged and is still not contained, with a total of 2,494 cases and 858 deaths as of last November. But while MERS is very nasty — that’s a case-fatality rate of about 35% — it’s highly localized in the Middle East and has never really made the world’s front pages.
That didn’t stop the coronavirus experts — they kept their eyes on the ball. But it’s perhaps a sign of how highly their research was valued that their regular symposia are held three years apart and attract so few researchers that they can all appear in a single group photo.
Maybe, Kullar mused, “we should have continued that research that was cancelled.” On the other hand, it is certainly true that the pace of research has accelerated dramatically in recent weeks.
It seems clear that the playing field for all three of the highly pathogenic coronaviruses was initially level — pretty much the entire human race has no natural immunity to any of the pathogens.
In the absence of good serological data, Kullar said, that’s probably a good bet. But then, why were SARS and MERS self-limiting, while SARS-CoV-2 seems to be essentially unbridled?
And Then the Other Shoe Dropped
The new kid on the block, SARS-CoV-2, is less lethal than either SARS or MERS and, because it usually causes milder disease than either SARS or MERS, it’s harder to detect and interrupt transmission chains.
Moreover, surveillance and response in several countries, such as Italy, Spain, and the U.S., seems to have been inadequate to stop outbreaks in their early stages, while other countries, such as Taiwan and South Korea, were more on the ball.
The coronaviruses are positive-sense single-stranded RNA viruses — their genetic material is mRNA that can be directly translated into proteins within the target cell — with a roughly 30-kilobase genome, which is large compared with other viral families.
Taxonomically, the coronaviruses fall into a sub-family of the order Nidovirales, dubbed Orthocronavirinae, which has four genera — the alpha-, beta-, delta-, and gamma-coronaviruses.
With the emergence of SARS-CoV-2, there are now seven coronaviruses that infect humans — two alphacoronaviruses (229E and NL63) and five betacoronaviruses (OC43, HKU1, SARS-CoV, MERS-CoV, and SARS-CoV-2.
The two alphacoronaviruses and the first two betacoronaviruses basically just cause colds, but the other three can cause substantial morbidity and mortality.
In shape, the coronaviruses look much like tiny horse chestnuts — small spheres with spikes sticking out. When the viral particles are imaged by an electron microscope, the two-D picture looks like a circle with a corona of smaller circles surrounding it — hence the name.
The original SARS-CoV and SARS-CoV-2 have very similar genomes — as you might guess from the names — with roughly an 80% similarity when you look nucleotide by nucleotide, according to Stuart Weston, PhD, and Matthew Frieman, PhD, both of the University of Maryland School of Medicine in Baltimore.
Writing in mSphere, a journal of the American Society for Microbiology, they noted that the closest known relative to SARS-CoV-2 is a bat virus, suggesting that — like the original SARS — the novel virus originated in bats and spilled over into humans via an intermediary (but thus far unknown) host.
An important similarity, several studies showed, is that both viruses use their spike proteins to attach to the angiotensin converting enzyme 2 (ACE2) molecule on the surface of ciliated endothelial cells and type II pneumocytes in the lung.
ACE2 is widely distributed in other tissues, according to a 2004 study in The Journal of Pathology, but some places — cells in the lungs and enterocytes of the small intestine — are “in contact with the external environment” and thus available as viral targets.
MERS, interestingly, infects unciliated bronchial epithelial cells and type II pneumocytes by using dipeptidyl peptidase 4, also known as CD26, as a receptor. And the NL63 virus, which usually only causes colds, uses the same ACE2 receptor as SARS and SARS-CoV-2.
The spikes consist of two parts — a binding subunit S1 and a fusion sub-unit S2; they only activate and allow the virus entry to the host cell when they are broken apart, in a process called proteolytic cleavage. A protease called furin, found on many human cells, can perform the cleavage, and crucially, there is a furin cleavage site on the SARS-CoV-2 spike protein that is not found on the original SARS spikes.
One study, in CELL, reported that the human serine protease TMPRSS2 appeared to prime the spike protein for entry to cells and that a commercially available TMPRSS2 inhibitor, camostat mesylate, helped to block that activity.
David Veesler, PhD, of the University of Washington, and colleagues, have speculated that widespread expression of furin-like proteases in human tissue could expand the cell and tissue targets of SARS-CoV-2, as well as “increasing its transmissibility and/or altering its pathogenicity,” compared with the original SARS.
Veesler and colleagues, as well as several other groups, have reported that the two viruses bind to ACE2 with a similar affinity, although one analysis, in Science from Jason McLellan, PhD, of the University of Texas at Austin, and colleagues, reported that SARS-CoV-2 had about 20-fold greater binding affinity than SARS-CoV.
Xinquan Wang, PhD, of Tsinghua University in Beijing, and colleagues suggested in Nature this week that the Science result is probably an outlier caused by different methods of analysis. In any case, they argue that “the binding affinity alone is unlikely to explain the unusual transmissibility of SARS-CoV-2.”
Other factors, such as the furin cleavage site on the SARS-CoV-2 spike, “may play more important roles in facilitating the rapid human-to-human transmission,” they argued.
Weston and Frieman noted that the role of the furin cleavage site is a bit of data that “will be important to determine.”
The bottom line, Kullar said, is that “we still don’t know why this virus is such a contagious pathogen.”
Numbers Do Matter
It will also be important to determine the true case count, Weston and Frieman noted, but that’s for the future — it will not help guide physicians, health authorities, and researchers to control the current outbreak. At the moment, it appears that about 80% of those infected by SARS-CoV-2 have mild upper respiratory symptoms, such as cough, fatigue, and fever.
But the rest have more serious disease in the lower respiratory tract, including pneumonia and acute respiratory distress syndrome (ARDS), and require hospital care, with a significant fraction needing intensive care, including intubation and ventilation or extracorporeal membrane oxygenation (ECMO).
On the other hand, it remains possible that some exposed people have no symptoms. A study of 72,314 case records in China showed that 1% were asymptomatic, even though they had tested positive for coronavirus nucleic acids.
But that rate is among people for whom there was thought to be a possibility of disease; how many asymptomatic carriers exist among untested people remains unknown.
There is solid evidence, however, that asymptomatic and presymptomatic people can transmit the virus.
Chinese researchers reported a case in late February in which a woman who never had symptoms but who was briefly positive for SAR-CoV-2 nucleic acids was apparently the vector for five other symptomatic infections.
And, a two-family cluster of seven patients in China was traced to a man who initially had no symptoms but became ill after several asymptomatic days, during which he transmitted the disease to relatives, who fell ill before he did.
As many as 25% of people infected with SARS-CoV-2 might not show Covid-19 symptoms, CDC director Robert Redfield, MD, said in an interview. “That’s important,” he told an Atlanta radio station, “because now you have individuals that may not have any symptoms that can contribute to transmission, and we have learned that in fact they do contribute to transmission.”
Redfield also noted that infected people appear to be shedding virus up to 48 hours before the onset of symptom.
“This helps explain how rapidly this virus continues to spread across the country, because we have asymptomatic transmitters and we have individuals who are transmitting 48 hours before they become symptomatic,” he said.
Sallie Glomb Reinmund, PhD, Sr. Scientific Content Director, @Point of Care, contributed insights and research during production of this series. This is the first in a special BreakingMED series examining the state of science in the Covid-19 pandemic.
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A look at the SARS family of illnesses — SARS-CoV-1, MERS-CoV, and SARS-CoV-2 — shows their similarity and the fact that there is no known human immunity to any of them.
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SARS-CoV-2 is so far the less lethal of the three, but where SARS-CoV-1 and MERS-CoV were self-limiting, SARS-CoV-2 presents as a mild illness and therefore spreads unbridled, given that it’s harder to detect and to interrupt its transmission chains.
Michael Smith, Contributing Writer, BreakingMED™
Kullar disclosed relevant relationships with Merck & Co.
The other researchers cited in this article disclosed no relevant relationships with industry.
Cat ID: 125
Topic ID: 79,125,730,933,125,190,520,926,192,927,151,928
