Standardizing COVID-19 data analysis to aid international research efforts

March 27, 2020

Science Daily/Center for Genomic Regulation

Researchers from the Centre for Genomic Regulation (CRG) have launched a new database to advance the international research efforts studying COVID-19.

The publicly-available, free-to-use resource (https://covid.crg.eu) can be used by researchers from around the world to study how different variations of the virus grow, mutate and make proteins.

"Scientists are working round the clock to understand SARS-CoV-2, the virus causing COVID-19, so that we can find its weak spots and beat it. A huge amount of scientific data is being published around the world," says Eva Novoa, a researcher at the CRG in Barcelona.

"However, some of the technologies we use to study SARS-CoV-2, such as nanopore RNA sequencing, are so new that the results of one paper aren't comparable to another due to the patchwork of different standards and methodologies used. We are taking all this data and analyzing it so that it meets a more universally comparable standard. This will help researchers more quickly and accurately spot the strengths and weaknesses of the coronavirus."

To understand how the coronavirus grows, mutates and replicates, scientists have to sequence the RNA of COVID-19. The RNA sequence reveals crucial information about the proteins the virus makes to invade human cells and replicate, which in turn informs governments on the infectiousness and severity of the pandemic.

Traditional sequencing tools can take a long time to provide results. In recent years, sequencing data in real time has become a reality thanks to the use of nanopore sequencing technologies, revolutionizing genomics research and disease outbreak monitoring. Nanopore sequencing provides scientists and clinicians with immediate access to the DNA and RNA sequence information of any living cell in real-time, enabling a rapid response against the threat of a pandemic.

However, the raw data produced by nanopore sequencing is highly complex. Scientists and clinicians currently lack systematic guidelines for the reproducible analysis of the data, limiting the vast potential of the nascent technology.

To standardize the analysis of publicly available SARS-CoV-2 nanopore sequencing data, researchers at the Centre for Genomic Regulation (CRG) in Barcelona are using MasterOfPores, a computer program developed by the group of Eva Novoa and CRG Bioinformatics Unit. The software was first described last week in Frontiers in Genetics.

"The internet and an increasing culture of open science, data sharing and preprints have transformed the research landscape. Infrastructure that would take months to set up to research an emerging virus can now be done in just a few days owing to novel scientific computing approaches," says Julia Ponomarenko, Head of the Bioinformatics Unit at the CRG.

MasterOfPores can be executed on any Unix-compatible OS on a computer, cluster or cloud without the need of installing any additional software or dependencies, and is freely available in Github. The publicly-available, free-to-use resource has currently analysed 3TB of SARS-CoV-2 nanopore RNA sequencing data. The CRG researchers will continue to update the resource with new data as soon as it becomes available.

https://www.sciencedaily.com/releases/2020/03/200327122315.htm

COVID-19 coronavirus epidemic has a natural origin

 March 17, 2020

Science Daily/Scripps Research Institute

An 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.

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," Goulding 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.

https://www.sciencedaily.com/releases/2020/03/200317175442.htm

COVID-19 appears less severe in children

March 13, 2020

Science Daily/Wolters Kluwer Health

As outbreaks of COVID-19 disease caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continue worldwide, there's reassuring evidence that children have fewer symptoms and less severe disease. That's among the insights provided by an expert review in The Pediatric Infectious Disease Journal, the official journal of The European Society for Paediatric Infectious Diseases. The journal is published in the Lippincott portfolio by Wolters Kluwer.

Like previous epidemic coronaviruses, "SARS-CoV-2 [seems] to cause fewer symptoms and less severe disease in children compared with adults," according to the review by Petra Zimmerman, MD, PhD, of the University of Fribourg, Switzerland and Nigel Curtis, FRCPCH, PhD, of The University of Melbourne, Australia. They summarize available evidence on coronavirus infections in children, including COVID-19.

"There is some suggestion that children are just as likely as adults to become infected with the virus but are less likely to be unwell or develop severe symptoms," Drs. Zimmerman and Curtis write. "However, the importance of children in transmitting the virus remains uncertain."

The Evidence on SARS-CoV-2 -- Focusing on Risks to Children

Coronaviruses are a large family of viruses that can cause infection and disease in animals. "Coronaviruses are capable of rapid mutation and recombination, leading to novel coronaviruses that can spread from animals to humans," Drs. Zimmerman and Curtis write. There are four coronaviruses that circulate in humans, mostly causing respiratory and gastrointestinal symptoms -- ranging from the common cold to severe disease.

Over the past two decades, there have been three major disease outbreaks due to novel coronaviruses: SARS-CoV in 2002, MERS-CoV in 2012, and now SARS-CoV-2 in 2019. Arising in the Chinese city of Wuhan, SARS-Cov-2 spread rapidly around the world and has been declared a pandemic by the World Health Organization. "The term COVID-19 is used for the clinical disease caused by SARS-CoV-2," according to the authors. Transmission of SARS-CoV-2 appears similar to that of the related SARS and MERS coronaviruses, but with a lower fatality rate. SARS-CoV-2 can still cause serious and life-threatening infections -- particularly in older people and those with pre-existing health conditions.

What are the risks for children from SARS-CoV-2? It's a pressing question for pediatric infectious disease specialists and concerned parents alike. Children appear to have milder clinical symptoms than adults and to be at substantially lower risk of severe disease -- which was also true in the SARS and MERS epidemics.

In Chinese data from February 2020, children and adolescents accounted for only two percent of SARS-CoV-2 hospitalizations, Drs. Zimmerman and Curtis write. However, as children are less frequently symptomatic and have less severe symptoms they are less often tested, which might lead to an underestimate of the true numbers infected. Also, children are less frequently exposed to the main sources of transmission.

Again based on Chinese data, "Most infected children recover one to two weeks after the onset of symptoms, and no deaths had been reported by February 2020," the researchers add. Most reported infections with SARS-CoV-2 have occurred in children with a documented household contact. Children with COVID-19 may be more likely to develop gastrointestinal symptoms.

The experts also review the diagnostic findings (laboratory tests and imaging studies) of children with COVID-19 laboratory and imaging findings in children. Whole genome sequencing approaches have enabled rapid development of molecular diagnostic tests for SARS-CoV-2. For now, treatment is supportive; no specific antiviral medications are available.

Several approaches are being considered for development of new drugs and vaccines -- some targeting a "spike glycoprotein" involved in interactions between coronaviruses and cells. Until such treatment and preventive measures are available, the researchers emphasize the importance of the full range of strategies for controlling SARS-CoV-2 -- as for the "highly effective global public health response" that led to containment of the SARS epidemic.

https://www.sciencedaily.com/releases/2020/03/200313112145.htm

New study on COVID-19 estimates 5.1 days for incubation period

Median time from exposure to symptoms affirms earlier estimates and supports CDC's current 14-day quarantine period

March 10, 2020

Science Daily/Johns Hopkins University Bloomberg School of Public Health

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 will be 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.

https://www.sciencedaily.com/releases/2020/03/200310164744.htm

Drug meant for Ebola may also work against coronaviruses

Drug meant for Ebola may also work against coronaviruses

Understanding how drugs work is an important step in developing new treatments for COVID-19

February 27, 2020

Science Daily/University of Alberta Faculty of Medicine & Dentistry

Researchers who have discovered why the drug remdesivir is effective in treating the coronaviruses that cause Middle East respiratory syndrome (MERS) and severe acute respiratory syndrome (SARS) expect it might also be effective for treating patients infected with the new COVID-19 strain.

A group of University of Alberta researchers who have discovered why the drug remdesivir is effective in treating the coronaviruses that cause Middle East respiratory syndrome (MERS) and severe acute respiratory syndrome (SARS) expect it might also be effective for treating patients infected with the new COVID-19 strain.

"Even if you know a drug works, it can be a red flag if you don't know how it works," said virologist Matthias Götte. "It is reassuring if you know exactly how it works against the target.

"We know the drug works against different coronaviruses, like MERS and SARS, and we know the novel coronavirus is very similar to SARS. So I would say I'm cautiously optimistic that the results our team found with remdesivir and MERS will be similar with COVID-19."

The study, published in the Journal of Biological Chemistry this week, is among the first in Canada to discuss the COVID-19 strain.

Until now, there has not been a published explanation of why remdesivir may work against coronaviruses, said Götte, who added his study is an important step in answering that question.

Developed by Gilead Sciences as a response to the 2014 West African Ebola virus epidemic, remdesivir was first used on a patient with the novel coronavirus earlier this year in the United States.

As reported in the New England Journal of Medicine, the patient was given the drug on the seventh day of illness, and showed marked improvement the following day, with symptoms eventually disappearing altogether. And at a recent press conference in Beijing, the assistant director-general of the World Health Organization, Bruce Alyward, said remdesivir is the only drug available that may have real efficacy against COVID-19.

"What our study showed was that remdesivir essentially mimics one of the natural building blocks for RNA synthesis necessary for genome replication of the virus. Enzymes within the virus are synthesizing the viral RNA genome with these building blocks, but they mix up the bits they need with the drug. Once the drug is incorporated into the growing RNA chain, the virus can no longer replicate,"explained Götte.

He said the next step is to wait for results from ongoing clinical trials with remdesivir, which are expected by the end of April. Even then, that won't be the end of the story, he cautioned.

"It's likely we'll need more than one drug to properly fight emerging diseases like COVID-19, as we have with HIV and hepatitis C virus infections," Götte said.

"Ideally, we will have a couple of drugs because certain strains could be resistant to certain treatments."

Götte's study was supported by grants from the Canadian Institutes of Health Research and the Alberta Ministry of Economic Development, Trade and Tourism through the Major Innovation Fund Program and Antimicrobial Resistance -- One Health Consortium.

https://www.sciencedaily.com/releases/2020/02/200227122123.htm

COVID-19 vaccine development

February 26, 2020

Science Daily/Hong Kong University of Science and Technology

Scientists have recently identified a set of potential vaccine targets for SARS-CoV-2 coronavirus, to guide experimental efforts towards vaccine development against novel pneumonia (COVID-19).

A team of scientists at the Hong Kong University of Science and Technology (HKUST) has recently made an important discovery in identifying a set of potential vaccine targets for the SARS-CoV-2 coronavirus, providing crucial leads for guiding experimental efforts towards the vaccine development against the novel pneumonia (COVID-19) caused by the virus.

Like SARS-CoV, which caused the SARS (Severe Acute Respiratory Syndrome) outbreak in 2003, SARS-CoV-2 belongs to the same Betacoronavirus genus. By considering the genetic similarity between SARS-CoV-2 and SARS-CoV, the team leveraged experimentally-determined immunological data to identify a set of SARS-CoV- derived B cell and T cell epitopes that exactly match to SARS-CoV-2. Epitopes are biomarkers recognized by the immune system to trigger actions against the virus. As no mutation has been observed in the identified epitopes among the available SARS-CoV-2 genetic sequences, immune targeting of these epitopes may potentially offer protection against the novel pneumonia COVID-19.

The team, led by data scientists Prof. Matthew McKay and Dr. Ahmed Abdul Quadeer, expected that their work can assist in guiding experimental research towards the development of effective vaccines against SARS- CoV-2.

Prof. McKay highlighted that "Despite similarities between SARS-CoV and SARS-CoV-2, there is genetic variation between the two, and it is not obvious if epitopes that elicit an immune response against SARS-CoV will likely be effective against SARS-CoV-2. We found that only roughly 20% of the SARS-CoV epitopes map identically to SARS-CoV-2, and believe these are promising candidates."

"For the identified T cell epitopes, we also performed a population coverage analysis and determined a set of epitopes that is estimated to provide broad coverage globally as well as in China" said Dr. Quadeer. The estimated population coverage represents the percentage of individuals within the selected population that are likely to elicit an immune response to at least one epitope from the identified set.

Prof. McKay is a Professor in the Departments of Electronic & Computer Engineering and Chemical & Biological Engineering; Dr. Quadeer is a post-doctoral fellow in the Department of Electronic & Computer Engineering. Their findings were recently published in the scientific journal Viruses this month.

"Our objective was to try to assist with the initial phase of vaccine development, by providing recommendations of specific epitopes that may potentially be considered for incorporation in vaccine designs" Prof. McKay added. "More generally, our work is part of a global effort seeking to capitalize on data for COVID-19, made available and rapidly shared by the scientific community, to understand this new virus and come up with effective interventions."

The beginning of 2020 has seen the emergence of SARS-CoV-2 outbreak in mainland China, which has quickly spread to over 30 countries around the world, infecting over 80,000 people and causing over 2,600 deaths as of late February 2020.

https://www.sciencedaily.com/releases/2020/02/200226091227.htm