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'Stealth Transmission' Fuels Fast Spread of Coronavirus Outbreak

New Study on COVID-19 Estimates 5.1 Days for Incubation Period

The COVID-19 coronavirus epidemic has a natural origin, scientists say

Coronavirus Spreads Quickly and Sometimes Before People Have Symptoms, Study Finds

'Stealth Transmission' Fuels Fast Spread of Coronavirus Outbreak

Undetected cases, many of which were likely not severely symptomatic, were largely responsible for the rapid spread of the COVID-19 outbreak in China, according to new research by scientists at Columbia University Mailman School of Public Health. The findings based on a computer model of the outbreak are published online in the journal Science.

The researchers report:

• 86 percent of all infections were undocumented prior to the January 23 Wuhan travel shutdown
• Per person, these undocumented infections were half (52 percent) as contagious as documented infections yet were the source of two-thirds of documented infections
• Government control efforts and population awareness have reduced the rate of spread of the virus in China; after travel restrictions and control measures were imposed, it spread less quickly

“The explosion of COVID-19 cases in China was largely driven by individuals with mild, limited, or no symptoms who went undetected,” says co-author Jeffrey Shaman, PhD, professor of environmental health sciences at Columbia University Mailman School. “Depending on their contagiousness and numbers, undetected cases can expose a far greater portion of the population to virus than would otherwise occur. We find for COVID-19 in China these undetected infected individuals are numerous and contagious. These stealth transmissions will continue to present a major challenge to the containment of this outbreak going forward.”

The researchers used a computer model that draws on observations of reported infection and spread within China in conjunction with mobility data from January 10-23 and January 24-February 8. They caution that major changes to care-seeking or patient documentation practices, as well as rapid developments with regard to travel restrictions and control measures, may make predictions difficult.

“Heightened awareness of the outbreak, increased use of personal protective measures, and travel restriction have helped reduce the overall force of infection; however, it is unclear whether this reduction will be sufficient to fully stem the virus spread,” says Shaman. “If the novel coronavirus follows the pattern of 2009 H1N1 pandemic influenza, it will also spread globally and become a fifth endemic coronavirus within the human population.”

Additional co-authors include first author Ruiyun Li, Imperial College London, London; Bin Chen, University of California, Davis; Yimeng Song, University of Hong Kong; Tao Zhang, Tsinghua University, Beijing; and Sen Pei and Wan Yang at the Columbia Mailman School.

A version of the article was posted in February in medRxiv, a preprint server for health sciences. 

This research was supported by U.S. National Institutes of Health grants (GM110748, AI145883). Shaman and Columbia University report partial ownership of SK Analytics, a provider of influenza forecasting and analytics services. Shaman also reports receiving consulting fees from Merck.

Source: Columbia University's Mailman School of Public Health.

New Study on COVID-19 Estimates 5.1 Days for Incubation Period

An analysis of publicly available data on infections from the new coronavirus, SARS-CoV-2, that causes the respiratory illness COVID-19 yielded an estimate of 5.1 days for the median disease incubation period, according to a new study led by researchers at Johns Hopkins Bloomberg School of Public Health. This median time from exposure to onset of symptoms suggests that the 14-day quarantine period used by the U.S. Centers for Disease Control and Prevention for individuals with likely exposure to the coronavirus is reasonable.

The analysis suggests that about 97.5 percent of people who develop symptoms of SARS-CoV-2 infection will do so within 11.5 days of exposure. The researchers estimated that for every 10,000 individuals quarantined for 14 days, only about 101 would develop symptoms after being released from quarantine.

The findings were published online March 9 in the journal Annals of Internal Medicine.

For the study, the researchers analyzed 181 cases from China and other countries that were detected prior to February 24, were reported in the media, and included likely dates of exposure and symptom onset. Most of the cases involved travel to or from Wuhan, China, the city at the center of the epidemic, or exposure to individuals who had been to Hubei, the province for which Wuhan is the capital.

The CDC and many other public health authorities around the world have been using a 14-day quarantine or active-monitoring period for individuals who are known to be at high risk of infection due to contact with known cases or travel to a heavily affected area.

“Based on our analysis of publicly available data, the current recommendation of 14 days for active monitoring or quarantine is reasonable, although with that period some cases would be missed over the long-term,” says study senior author Justin Lessler, an associate professor in the Bloomberg School’s Department of Epidemiology.

The global outbreak of SARS-CoV-2 infection emerged in December 2019 in Wuhan, a city of 11 million in central China, and has resulted in 95,333 officially confirmed cases around the world and 3,282 deaths from pneumonia caused by the virus, according to the World Health Organization’s March 5 Situation Report. The majority of the cases are from Wuhan and the surrounding Hubei province, although dozens of other countries have been affected, including the U.S., but chiefly South Korea, Iran, and Italy.

An accurate estimate of the disease incubation period for a new virus makes it easier for epidemiologists to gauge the likely dynamics of the outbreak, and allows public health officials to design effective quarantine and other control measures. Quarantines typically slow and may ultimately stop the spread of infection, even if there are some outlier cases with incubation periods that exceed the quarantine period. 

Lessler notes that sequestering people in a way that prevents them from working has costs, both personal and societal, which is perhaps most obvious when health care workers and first responders like firefighters are quarantined.

The new estimate of 5.1 days for the median incubation period of SARS-CoV-2 is similar to estimates from the earliest studies of this new virus, which were based on fewer cases. This incubation period for SARS-CoV-2 is in the same range as SARS-CoV, a different human-infecting coronavirus that caused a major outbreak centered in southern China and Hong Kong from 2002–04. For MERS-CoV, a coronavirus that has caused hundreds of cases in the Middle East, with a relatively high fatality rate, the estimated mean incubation period is 5–7 days.

Human coronaviruses that cause common colds have mean illness-incubation periods of about three days.

Lessler and colleagues have published an online tool that allows public health officials and members of the public to estimate how many cases would be caught and missed under different quarantine periods.

“The incubation period of COVID-19 from publicly reported confirmed cases: estimation and application” was written by co-first authors Stephen Lauer and Kyra Grantz, and Qifang Bi, Forrest Jones, Qulu Zheng, Hannah Meredith, Andrew Azman, Nicholas Reich, and Justin Lessler.

Support for the research was provided by CDC (NU2GGH002000), the National Institute of Allergy and Infectious Diseases (R01 AI135115), the National Institute of General Medical Sciences (R35 GM119582), and the Alexander von Humboldt Foundation.

Source: Johns Hopkins University Bloomberg School of Public Health

The COVID-19 coronavirus epidemic has a natural origin, scientists say

The novel SARS-CoV-2 coronavirus that emerged in the city of Wuhan, China, last year and has since caused a large scale COVID-19 epidemic and spread to more than 70 other countries is the product of natural evolution, according to findings published today in the journal Nature Medicine.

The analysis of public genome sequence data from SARS-CoV-2 and related viruses found no evidence that the virus was made in a laboratory or otherwise engineered.

“By comparing the available genome sequence data for known coronavirus strains, we can firmly determine that SARS-CoV-2 originated through natural processes,” said Kristian Andersen, PhD, an associate professor of immunology and microbiology at Scripps Research and corresponding author on the paper.

In addition to Andersen, authors on the paper, "The proximal origin of SARS-CoV-2," include Robert F. Garry, of Tulane University; Edward Holmes, of the University of Sydney; Andrew Rambaut, of University of Edinburgh; W. Ian Lipkin, of Columbia University.

Coronaviruses are a large family of viruses that can cause illnesses ranging widely in severity. The first known severe illness caused by a coronavirus emerged with the 2003 Severe Acute Respiratory Syndrome (SARS) epidemic in China. A second outbreak of severe illness began in 2012 in Saudi Arabia with the Middle East Respiratory Syndrome (MERS).

On December 31 of last year, Chinese authorities alerted the World Health Organization of an outbreak of a novel strain of coronavirus causing severe illness, which was subsequently named SARS-CoV-2. As of February 20, 2020, nearly 167,500 COVID-19 cases have been documented, although many more mild cases have likely gone undiagnosed. The virus has killed over 6,600 people.

Shortly after the epidemic began, Chinese scientists sequenced the genome of SARS-CoV-2 and made the data available to researchers worldwide. The resulting genomic sequence data has shown that Chinese authorities rapidly detected the epidemic and that the number of COVID-19 cases have been increasing because of human to human transmission after a single introduction into the human population. Andersen and collaborators at several other research institutions used this sequencing data to explore the origins and evolution of SARS-CoV-2 by focusing in on several tell-tale features of the virus.

The scientists analyzed the genetic template for spike proteins, armatures on the outside of the virus that it uses to grab and penetrate the outer walls of human and animal cells. More specifically, they focused on two important features of the spike protein: the receptor-binding domain (RBD), a kind of grappling hook that grips onto host cells, and the cleavage site, a molecular can opener that allows the virus to crack open and enter host cells.

Evidence for natural evolution

The scientists found that the RBD portion of the SARS-CoV-2 spike proteins had evolved to effectively target a molecular feature on the outside of human cells called ACE2, a receptor involved in regulating blood pressure. The SARS-CoV-2 spike protein was so effective at binding the human cells, in fact, that the scientists concluded it was the result of natural selection and not the product of genetic engineering.

This evidence for natural evolution was supported by data on SARS-CoV-2’s backbone – its overall molecular structure. If someone were seeking to engineer a new coronavirus as a pathogen, they would have constructed it from the backbone of a virus known to cause illness. But the scientists found that the SARS-CoV-2 backbone differed substantially from those of already known coronaviruses and mostly resembled related viruses found in bats and pangolins.

“These two features of the virus, the mutations in the RBD portion of the spike protein and its distinct backbone, rules out laboratory manipulation as a potential origin for SARS-CoV-2” said Andersen.

Josie Golding, PhD, epidemics lead at UK-based Wellcome Trust, said the findings by Andersen and his colleagues are “crucially important to bring an evidence-based view to the rumors that have been circulating about the origins of the virus (SARS-CoV-2) causing COVID-19.”

“They conclude that the virus is the product of natural evolution,” Golding adds, “ending any speculation about deliberate genetic engineering.”

Possible origins of the virus

Based on their genomic sequencing analysis, Andersen and his collaborators concluded that the most likely origins for SARS-CoV-2 followed one of two possible scenarios.

In one scenario, the virus evolved to its current pathogenic state through natural selection in a non-human host and then jumped to humans. This is how previous coronavirus outbreaks have emerged, with humans contracting the virus after direct exposure to civets (SARS) and camels (MERS). The researchers proposed bats as the most likely reservoir for SARS-CoV-2 as it is very similar to a bat coronavirus. There are no documented cases of direct bat-human transmission, however, suggesting that an intermediate host was likely involved between bats and humans.

In this scenario, both of the distinctive features of SARS-CoV-2’s spike protein—the RBD portion that binds to cells and the cleavage site that opens the virus up—would have evolved to their current state prior to entering humans. In this case, the current epidemic would probably have emerged rapidly as soon as humans were infected, as the virus would have already evolved the features that make it pathogenic and able to spread between people.

In the other proposed scenario, a non-pathogenic version of the virus jumped from an animal host into humans and then evolved to its current pathogenic state within the human population. For instance, some coronaviruses from pangolins, armadillo-like mammals found in Asia and Africa, have an RBD structure very similar to that of SARS-CoV-2. A coronavirus from a pangolin could possibly have been transmitted to a human, either directly or through an intermediary host such as civets or ferrets.

Then the other distinct spike protein characteristic of SARS-CoV-2, the cleavage site, could have evolved within a human host, possibly via limited undetected circulation in the human population prior to the beginning of the epidemic. The researchers found that the SARS-CoV-2 cleavage site, appears similar to the cleavage sites of strains of bird flu that has been shown to transmit easily between people. SARS-CoV-2 could have evolved such a virulent cleavage site in human cells and soon kicked off the current epidemic, as the coronavirus would possibly have become far more capable of spreading between people.

Study co-author Andrew Rambaut cautioned that it is difficult if not impossible to know at this point which of the scenarios is most likely. If the SARS-CoV-2 entered humans in its current pathogenic form from an animal source, it raises the probability of future outbreaks, as the illness-causing strain of the virus could still be circulating in the animal population and might once again jump into humans. The chances are lower of a non-pathogenic coronavirus entering the human population and then evolving properties similar to SARS-CoV-2.

Funding for the research was provided by the US National Institutes of Health, the Pew Charitable Trusts, the Wellcome Trust, the European Research Council, and an ARC Australian Laureate Fellowship.

Source: Scripps Research Institute.

Coronavirus Spreads Quickly and Sometimes Before People Have Symptoms, Study Finds

Infectious disease researchers at The University of Texas at Austin studying the novel coronavirus were able to identify how quickly the virus can spread, a factor that may help public health officials in their efforts at containment. They found that time between cases in a chain of transmission is less than a week and that more than 10% of patients are infected by somebody who has the virus but does not yet have symptoms.

In the paper in press with the journal Emerging Infectious Diseases, a team of scientists from the United States, France, China and Hong Kong were able to calculate what’s called the serial interval of the virus. To measure serial interval, scientists look at the time it takes for symptoms to appear in two people with the virus: the person who infects another, and the infected second person.

Researchers found that the average serial interval for the novel coronavirus in China was approximately four days. This also is among the first studies to estimate the rate of asymptomatic transmission.

The speed of an epidemic depends on two things — how many people each case infects and how long it takes for infection between people to spread. The first quantity is called the reproduction number; the second is the serial interval. The short serial interval of COVID-19 means emerging outbreaks will grow quickly and could be difficult to stop, the researchers said.

“Ebola, with a serial interval of several weeks, is much easier to contain than influenza, with a serial interval of only a few days. Public health responders to Ebola outbreaks have much more time to identify and isolate cases before they infect others,” said Lauren Ancel Meyers, a professor of integrative biology at UT Austin. “The data suggest that this coronavirus may spread like the flu. That means we need to move quickly and aggressively to curb the emerging threat.”

Meyers and her team examined more than 450 infection case reports from 93 cities in China and found the strongest evidence yet that people without symptoms must be transmitting the virus, known as pre-symptomatic transmission. According to the paper, more than 1 in 10 infections were from people who had the virus but did not yet feel sick.

Previously, researchers had some uncertainty about asymptomatic transmission with the coronavirus. This new evidence could provide guidance to public health officials on how to contain the spread of the disease.

“This provides evidence that extensive control measures including isolation, quarantine, school closures, travel restrictions and cancellation of mass gatherings may be warranted,” Meyers said. “Asymptomatic transmission definitely makes containment more difficult.”

Meyers pointed out that with hundreds of new cases emerging around the world every day, the data may offer a different picture over time. Infection case reports are based on people’s memories of where they went and whom they had contact with. If health officials move quickly to isolate patients, that may also skew the data.

“Our findings are corroborated by instances of silent transmission and rising case counts in hundreds of cities worldwide,” Meyers said. “This tells us that COVID-19 outbreaks can be elusive and require extreme measures.”

Zhanwei Du of The University of Texas at Austin, Lin Wang of the Institut Pasteur in Paris, Xiaoke Xu of Dalian Minzu University, Ye Wu of Beijing Normal University and Benjamin J. Cowling of Hong Kong University also contributed to the research. Lauren Ancel Meyers holds the Denton A. Cooley Centennial Professorship in Zoology at The University of Texas at Austin.

The research was funded by the U.S. National Institutes of Health and the National Natural Science Foundation of China.

Source: The University of Texas at Austin