A recent genome-wide association (GWAS) study, published in the New England Journal of Medicine (NEJM), finds that gene variants in two regions of the human genome are associated with severe COVID-19 and correspondingly carry a greater risk of COVID-19-related death.
The two stretches of DNA implicated as harboring risks for severe COVID-19 are known to carry some intriguing genes, including one that determines blood type and others that play various roles in the immune system. In fact, the findings suggest that people with blood type A face a 50 percent greater risk of needing oxygen support or a ventilator should they become infected with the novel coronavirus. In contrast, people with blood type O appear to have about a 50 percent reduced risk of severe COVID-19.
These new findings – the first to identify statistically significant susceptibility genes for the severity of COVID-19 – come from a large research effort led by Andre Franke, a scientist at Christian-Albrecht-University, Kiel, Germany, along with Tom Karlsen, Oslo University Hospital Rikshospitalet, Norway. Their study included 1,980 people undergoing treatment for severe COVID-19 and respiratory failure at seven medical centers in Italy and Spain.
In search of gene variants that might play a role in the severe illness, the team analyzed patient genome data for more than 8.5 million so-called single-nucleotide polymorphisms, or SNPs. The vast majority of these single “letter” nucleotide substitutions found all across the genome are of no health significance, but they can help to pinpoint the locations of gene variants that turn up more often in association with particular traits or conditions – in this case, COVID-19-related respiratory failure. To find them, the researchers compared SNPs in people with severe COVID-19 to those in more than 1,200 healthy blood donors from the same population groups.
The analysis identified two places that turned up significantly more often in the individuals with severe COVID-19 than in the healthy people. One of them is found on chromosome 3 and covers a cluster of six genes with potentially relevant functions. For instance, this portion of the genome encodes a transporter protein known to interact with angiotensin converting enzyme 2 (ACE2), the surface receptor that allows SARS-CoV-2, to bind to and infect human cells. It also encodes a collection of chemokine receptors, which play a role in the immune response in the airways of our lungs.
The other association signal popped up on chromosome 9, right over the area of the genome that determines blood type. The researchers did find evidence suggesting a relationship between blood type and COVID-19 risk. They noted that this area also includes a genetic variant associated with increased levels of interleukin-6, which plays a role in inflammation and may have implications for COVID-19 as well.
NIH group weighs role of human challenge studies for SARS-CoV-2 vaccine development
Large, randomized, controlled trials are the fastest and most effective way to establish the safety and efficacy of SARS-CoV-2 vaccine candidates. However, parallel development of controlled human infection models (CHIMS) may provide complementary tools to address additional questions, such as the duration of immunity and correlates of protection, if such studies can be conducted ethically, concluded a working group of the National Institutes of Health (NIH).
In a perspective for the New England Journal of Medicine, members of the NIH’s Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV) Working Group assess practical considerations and prerequisites for using controlled human infection models (CHIMs), which can be used for human challenge studies, to support SARS-CoV-2 vaccine development.
In the article, the authors determine that it could take one or two years to develop robust CHIMs that meet the essential criteria for limiting risk for study volunteers.
In a CHIM study, participants are intentionally exposed to an infectious agent to help scientists understand the virus or test interventions to prevent or treat infection. CHIMs use well-characterized microorganisms that either do not cause serious disease, are easily treated, or both. In addition, CHIM studies must take place in laboratories with rigorous isolation to ensure that the infection does not spread into the community.
The authors note that ethical evaluation of the risk to participants and the potential value to society are essential to future considerations of whether to conduct CHIM studies for COVID-19; currently there is no highly efficacious treatment for moderate or severe illness.
The authors propose that development of a SARS-CoV-2 GMP stock, preferably with attenuating mutations, should proceed along with preparation of facilities and procedures and engagement of a broad set of stakeholders. Additionally, the researchers recommend developing CHIMs for seasonal coronaviruses, which cause about 30 percent of cases of the common cold and can provide insights into more deadly coronaviruses such as SARS-CoV, MERS-CoV, and SARS-CoV-2.
One mutation of SARS-CoV-2 dominates cases
In a new study, an international team of scientists show that the G614 variant of SARS-CoV-2 has come to dominate COVID-19 cases around the world. They report that this mutation does not make the virus more deadly, but it does help the virus copy itself, resulting in a higher viral load, or “titer,” in patients.
The new study, led by scientists at Duke University, Los Alamos National Laboratory and La Jolla Institute (LJI), was published July 2, 2020 in Cell.
Back in March, two variants of SARS-CoV-2 were circulating. In addition to the G614, the other variant was the D614. The variants had just a small difference in their “spike” protein – the viral machinery that coronaviruses use to enter host cells, explained La Jolla Institute Professor Erica Ollmann Saphire, PhD, who leads the Bill & Melinda Gates Foundation-supported CoVIC at the institute.
Saphire said that viruses regularly acquire mutations to help them “escape” antibodies made by the human immune system. When a virus acquires many of these individual changes, it “drifts” away from the original virus. Researchers call this phenomenon “antigenic drift.”
In the new study, researchers’ tracking showed that while the G and D viruses both spread widely around the world, the G virus was “fixed” as the dominant variant by mid-March. They also determined that viruses carrying spike with the G mutation grew two to three times more efficiently, leading to a higher titer.
Saphire and her colleagues then used samples from six San Diego residents to test how human antibodies neutralized the D and G viruses. Would the fast-growing G virus be harder to fight?
Their experiments showed that the human immune response could neutralize the new G virus as well or better than the original D virus. This meant the immune system did not need to produce more antibodies or better antibodies against the G virus, even though this variant was more successful at spreading. This finding was in line with what doctors saw in COVID-19 patients.
High cortisol levels associated with greater risk of death from COVID-19
COVID-19 patients with very high levels of the stress hormone cortisol in their blood are more likely to deteriorate quickly and die, say researchers.
The study, led by NIHR Research Professor Waljit Dhillo from Imperial College London and Consultant Endocrinologist at Imperial College Healthcare NHS Trust, provides the first data to show that cortisol levels are a marker of the severity of the illness. The researchers suggest they can be used to identify those patients who are more likely to need intensive care.
Cortisol is produced by the body in response to stress such as illness, triggering changes in metabolism, heart function and the immune system to help our bodies cope. Our cortisol levels when healthy and resting are 100-200 nm/L and nearly zero when we sleep.
When ill patients have low levels of cortisol, it can be life threatening. Excessive levels of cortisol during illness can be equally dangerous, leading to increased risk of infection and poor outcomes. In the new observational study of 535 patients, of whom 403 were confirmed to have COVID-19, cortisol levels in patients with COVID-19 were significantly higher than in those without. The levels in the COVID-19 group ranged as high as 3241 – considerably higher even than after major surgery, when levels can top 1000.
Amongst the COVID-19 patients, those with a baseline cortisol level of 744 or less survived on average for 36 days. Patients with levels over 744 had an average survival of just 15 days.
Initial COVID-19 infection rate may be 80 times greater than originally reported
Many epidemiologists believe that the initial COVID-19 infection rate was undercounted due to testing issues, asymptomatic and alternatively symptomatic individuals, and a failure to identify early cases. A study from Penn State estimates that the number of early COVID-19 cases in the U.S. may have been more than 80 times greater and doubled nearly twice as fast as originally believed.
In a paper published in Science Translational Medicine, researchers estimated the detection rate of symptomatic COVID-19 cases using the Centers for Disease Control and Prevention’s (CDC) influenza-like illnesses (ILI) surveillance data over a three-week period in March 2020.
“We analyzed each state’s ILI cases to estimate the number that could not be attributed to influenza and were in excess of seasonal baseline levels,” said Justin Silverman, Assistant Professor in Penn State’s College of Information Sciences and Technology and Department of Medicine. “When you subtract these out, you’re left with what we’re calling excess ILI – cases that can’t be explained by either influenza or the typical seasonal variation of respiratory pathogens.”
The researchers found that the excess ILI showed a nearly perfect correlation with the spread of COVID-19 around the country. Said Silverman, “This suggests that ILI data is capturing COVID cases, and there appears to be a much greater undiagnosed population than originally thought.”
Remarkably, the size of the observed surge of excess ILI corresponds to more than 8.7 million new cases during the last three weeks of March, compared to the roughly 100,000 cases that were officially reported during the same time period.
New All of Us Research Program launches COVID-19 initiatives
The All of Us Research Program, part of the National Institutes of Health (NIH), announced plans to conduct research on COVID-19, according to a press release. The program will gather data through three activities:
• Serology testing to detect the presence of IgG antibodies in participants to help assess rates of infections across regions and communities.
• An online survey, which will ask questions about how participants are coping with the pandemic. The 20- to 30-minute survey is designed both for participants who have been ill with COVID-19 and those who have not, and includes questions on COVID-19 symptoms, stress, social distancing and economic impacts.
• Standardization of information in participants’ electronic health records related to COVID-19. The goal is to provide a resource to help researchers learn more about COVID-19 symptoms, associated health problems, and the effects of different medicines and treatments.
The NIH said the All of Us Research Program will make data gathered through these activities broadly accessible to approved researchers over time through future releases of its data platform, which is currently in beta testing.
The All of Us Research Program, which launched national enrollment in 2018, is building a research resource with data and biological samples shared by nearly 350,000 participants for use in thousands of studies, spanning many different aspects of health and disease
