September 2021
Analyzing metabolic and immune changes in COVID-19 hyperinflammation
In new work published Sept. 6 in Nature Biotechnology, researchers from Fred Hutch and Seattle’s Institute for Systems Biology dove deep into the metabolic changes in patients suffering from COVID-19. The team combined metabolic measurements from blood samples with analysis of the genes and proteins being used by individual immune cells to define the metabolic changes and immune cell populations associated with COVID-19 hyperinflammation.
The team compared data from patients with COVID-19 who were not hospitalized to those who were hospitalized. They mapped out immune-cell metabolic signatures and found that certain immune cell populations increased in percentage and metabolic activity as disease severity intensified. The scientists also identified five blood metabolites that predicted poor outcomes in patients being hospitalized with COVID-19.
“We know that there are a range of immune responses to COVID-19, and the biological processes underlying those responses are not well understood,” said co-first author and Hutch M.D./Ph.D. student Jihoon Lee in a press release from the ISB. “The deeper understanding gained here may eventually lead to better therapies that can more precisely target the most problematic immune or metabolic changes.”
July 2021
Measuring COVID-19's impact on cancer clinical trials
A study published on July 29 in JAMA Network Open reports on enrollment during the COVID-19 pandemic to cancer clinical trials run by the SWOG Cancer Research Network, a cancer clinical trials group funded by the National Cancer Institute. Led by Dr. Joseph Unger, a SWOG health services researcher and biostatistician based at Fred Hutch, the researchers found that during the early weeks of the pandemic, from late February through mid-April 2020, registrations to cancer clinical trials dropped precipitously compared to previous years. This drop was followed by an initial recovery period lasting through the summer of 2020; in fact by the end of the summer, enrollment totals actually slightly exceeded what would have been expected without the pandemic. Enrollments again dropped during the wave of increasing COVID-19 virus infections in the winter of 2020/2021, but much more modestly compared to the initial wave of the pandemic.
"After the initial COVID-19 outbreak, we observed a dramatic drop-off in trial enrollments," Unger noted. "Now, a year later, we wanted to assess enrollment over an entire year of the pandemic, especially given the flexibilities that had been introduced into the system."
Read more in a press release from SWOG about the study.
Charting ACE2 binding in SARS-related coronaviruses
Researchers in the Bloom Lab published a preprint on July 20 tracing the evolutionary history of ACE2 binding by SARS-related coronaviruses (also known as sarbecoviruses).
“ACE2 binding is only seen sporadically among the broader lineage of sarbecoviruses that cirvulate in bats,” said lead investigator Dr. Tyler Starr in a Tweetorial on the work.
He found that ACE2 binding has a spotty history in these viruses: though the earliest sarbecoviruses could bind ACE2, this capability was lost along some branches of the sarbecovirus evolutionary tree. Of those that retained ACE2 binding, it may take only as little as one change in the amino acid sequence of their receptor-binding domains to enable binding to ACE2 in a new species.
But single changes can have very different effects in different SARS-related viruses, the team found. One amino acid change seen in several SARS-CoV-2 variants of concern gives the COVID-19 virus a binding boost, but dampens ACE2 binding by SARS-CoV-1.
Discovering antibodies that resist viral escape
In a study published in Nature on July 14, Dr. Tyler Starr of the Bloom Lab described the ability of 12 monoclonal antibodies to bind divergent receptor-binding domains, or RBDs, drawn from 45 divergent SARS-related coronaviruses, including some isolated from bats and pangolins. He and his colleagues in the lab of Hutch evolutionary biologist Dr. Jesse Bloom also mapped which mutations would allow the SARS-CoV-2 RBD to escape neutralization by the antibodies.
For the most part, Starr saw that antibodies traded potency for breadth: Those that neutralized SARS-CoV-2 RBD very effectively were less able to recognize RBD from more distantly related viruses. A few antibodies bucked this trend, including a standout dubbed S2H97 that binds a site deeply hidden within the closed RBD that only becomes accessible when it opens to contact ACE2. S2H97 bound RBDs separated by sometimes hundreds of years of evolution, including a divergent group of RBDs from bat coronavirus that have never spilled over into humans.
Though rarely recognized by our immune system, this epitope is incredibly similar across SARS-related coronaviruses, Starr said. If an antibody binds this site, it can block a wide range of those viruses.
Mapping antibody-escape mutations
Scientists in the Bloom Lab examined how mutations in the RBD may help SARS-CoV-2 escape antibodies that bind in different areas. Led by graduate student Allison Greaney, they examined binding by both monoclonal antibodies — single antibodies that bind just one place on the virus — and polyclonal convalescent plasma, containing whatever mixture of antibodies were produced by a person infected with SARS-CoV-2. They tested mutations that aren’t yet found in prominent viral lineages, but could theoretically arise as the virus continues evolving.
Greaney and her colleagues found that how much an RBD mutation affected antibody binding varied among patients. Even so, a few spots on the RBD grabbed most of the immune system’s attention — including a rapidly changing location called E484. This result was “a bit worrying,” Greaney said, because changes here were most likely to affect how well polyclonal plasma bound RBD — and it had already mutated in the novel coronavirus’ beta and gamma variants.
June 2021
Recovery of deleted deep sequencing data sheds more light on the early Wuhan SARS-CoV-2 epidemic
In a preprint published on bioRxiv, Fred Hutch's Dr. Jesse Bloom reported his discovery of SARS-CoV-2 sequences from early in the Wuhan outbreak that had been deleted from a National Institutes of Health database. In a complementary Twitter thread, he explained how he found and reconstructed 13 of these sequences and what he learned from his analysis of them.
He wrote that the sequences support other lines of evidence that SARS-CoV-2 was circulating in Wuhan before the December 2019 outbreak in a seafood market. They do not provide evidence either for or against either a natural animal origin for the virus or an accidental lab leak. More early sequences are probably out there, he wrote, and scientists should focus on identifying them and analyzing all available data to determine the origins of the pandemic.
Read more in Fred Hutch News: Deleted SARS-CoV-2 sequences from early in Wuhan outbreak offer clues
Comparing vaccine and natural immunity
In work published in Science Translational Medicine on June 30, investigators in the Bloom lab compared the binding patterns of antibodies generated by the Moderna vaccine to those elicited by natural SAR-CoV-2 infection. Looking at where antibodies bind on the receptor-binding domain of the novel coronavirus' spike protein, they found that that vaccination appears to promote antibodies with a broader binding pattern than those generated by infection.
Expanded study in young adults
The Prevent COVID U study launched in late March to evaluate SARS-CoV-2 infection and transmission among university students vaccinated with the Moderna COVID-19 vaccine. On June 22, the study team announced that it has expanded beyond the university setting to enroll young adults ages 18 through 29, and that it will now also include people in this age group who choose not to receive a vaccine.
The expanded trial continues to test if, and to what degree, the Moderna COVID-19 vaccine can prevent infection with SARS-CoV-2, limit the amount of virus in the nose, and reduce transmission of the virus from vaccinated persons to their close contacts. It is being conducted through the federally funded COVID-19 Prevention Network, whose operational headquarters is at Fred Hutch.
"If our study demonstrates that a COVID-19 vaccine works to prevent infection and transmission of the virus, many more people may decide to get vaccinated, which has huge public health implications," the Hutch’s Dr. Larry Corey, principal investigator of the network's operations, told Reuters.
Math model shows tradeoffs in one- vs. two-dose vaccines
In a paper published June 8 in Nature Communications, Dr. Laura Matrajt and colleagues used a mathematical model and optimization algorithms to determine the optimal use of COVID-19 vaccines when supply is limited. This work, which Matrajt started last September before COVID-19 vaccines were available, remains important as worldwide vaccination efforts continue.
Matrajt and coauthors found that there is not a “one size fits all” for the best use of vaccine. The optimal vaccine allocation depends on how much transmission is occurring, vaccine supply, and the efficacy after one and two doses of vaccine. For instance, in the U.S. in February 2021 when transmission was high and vaccine supply was not yet high, it made the most sense to prioritize people who are at higher risk of dying of COVID-19. And, since there wasn't enough evidence about the efficacy and durability of a single dose, Matrajt said that the “less risky” approach was to give two doses to people at high risk.
Matrajt hopes that more data will become available on how well a single dose works: If a single-dose is proven to be durable and effective, one-dose vaccination strategies could be crucial to stretch supply and speed up worldwide vaccinations. In contrast, if a single-dose vaccine has low vaccine efficacy, one-dose strategies could result in a huge waste of precious resources.
May 2021
Charting viral escape routes from immunity
Investigators in Dr. Julie Overbaugh’s group examined the interaction between antibody binding and viral mutations in regions along the stem of the SARS-CoV-2 spike protein. In work published in Cell on May 27, Meghan Garrett, a graduate student in Overbaugh's lab, looked at the complex mixtures of antibodies produced in people naturall infected with the novel coronavirus. She found that most antibodiesmixtures homed in on just a couple of sites along the spike's stem, but individual immune responses still varied.
“Most people had responses to one site or the other, some had responses to both — but overall, the response was not uniform,” Overbaugh said.
Most people in Garrett’s study also had antibody targets sites that were unique to them as individuals, and not seen in other patients.
Garrett found less consistency among mutations that conferred antibody escape in this region of the spike. These areas are less changeable among viral variants, which means they may be attractive additions to future vaccines designed to provide people with broader protection against many different variants, Overbaugh said.
Call to investigate SARS-CoV-2 origins
In a letter published on May 13 in the journal Science, Dr. Jesse Bloom and colleagues argued that "greater clarity about the origins of this pandemic is necessary and feasible to achieve. We must take hypotheses about both natural and laboratory spillovers seriously until we have sufficient data." They wrote that such an investigation must be well managed to minimize the impacts of conflicts of interest, and be transparent, objective, data-driven, inclusive of broad expertise and have independent oversight.
“Most of the discussion you hear about SARS-CoV-2 origins at this point is coming from, I think, the relatively small number of people who feel very certain about their views,” Bloom told the New York Times, adding: “Anybody who’s making statements with a high level of certainty about this is just outstripping what’s possible to do with the available evidence.”
Detailed structure of a pan-coronavirus antibody
Whether they cause COVID-19, SARS or MERS — a camel disease that also can infect humans — all coronaviruses have a spike protein that acts like a lockpick to let the virus into our cells. As described in a paper published May 12 in Nature Structural & Molecular Biology, researchers at Fred Hutch and the University of Washington have identified a commonality could lead to the design of a future universal coronavirus vaccine. After immunizing mice against the spike protein of multiple coronaviruses, a team led by Dr. Andrew McGuire of Fred Hutch and Dr. David Veesler of UW identified and characterized one antibody that binds to a particular part of multiple coronavirus spikes that has been relatively unchanged over evolutionary history. This particular antibody can also block the spikes' lockpick action. The researchers hope that the detailed information they gained about this powerful antibody’s structure and function will help to inform the design of future vaccines that protect people against all types of coronaviruses, including those yet to jump to humans.
April 2021
Comparing immunity to SARS-CoV-2 generated by vaccination and infection
Though the novel coronavirus has taken a grim toll around the globe, worldwide vaccine efforts mean that eventually, most people will gain immunity against SARS-CoV-2 through vaccination. But the rise of viral variants has also raised the question of how much protection we'll retain as SARS-CoV-2 continues to evolve in ways that could help it escape the protective responses we’ve already mounted. Much of the immune protection in naturally infected or vaccinated people comes from specialized immune proteins called antibodies. By binding to proteins on the outside of viruses, neutralizing antibodies can block viruses from infecting their target cells.
In a recent preprint published on bioRxiv, researchers in Dr. Jesse Bloom’s lab at Fred Hutch compared neutralizing antibody responses from people who were infected with SARS-CoV-2 to the responses from people who received the Moderna RNA vaccine but were not exposed to the virus. RNA vaccines prompt vaccinated people’s cells to produce the spike protein that helps the novel coronavirus connect with its gateway to target cells, ACE2. Allison Greaney, a grad student in Bloom’s lab, found that over 90% of the neutralizing activity of antibodies produced after vaccination was focused on a specific region of the spike protein, called the receptor binding domain, or RBD. Immune responses to natural infection were more likely to include neutralizing antibodies that bound other regions of the spike protein, in addition to the RBD.
However, Greaney also found that vaccination generates antibodies that bind to more regions within the RBD than natural infection tends to. She found that this changed how easily single mutations in the RBD affected antibody neutralization (a lab-based proxy for measuring how a mutation may help the virus evade a protective immune response). Mutations in the RBD affected neutralization by vaccine-elicited antibodies less than neutralization by antibodies produced in response to natural infection. Her findings suggest that natural and vaccine-generated immunity to SARS-CoV-2 may respond differently to different viral variants.
Using machine learning to dampen the COVID-19 cytokine storm
An overactive immune response, or cytokine storm, is thought to underlie many of COVID-19’s worrying complications. In a preprint published on bioRxiv, Dr. Taran Gujral, with Drs. Julie McElrath and Eric Holland, used machine learning to identify key molecules that trigger this response when cells are exposed to a region of the novel coronavirus’ spike protein. This strategy also enabled the team to identify a drug that may hold potential to reduce immune overactivation to SARS-CoV2. They found several FDA-approved drugs, including one called ponatinib (trade name Iclusig), which block the activity of several molecules involved in the immune response to the virus. Treatment with these drugs inhibited the cytokine storm response when the researchers exposed cells in lab dishes to the spike protein from the novel coronavirus and its emerging variants.
Coronavirus evolution and immune escape
The team of Dr. Jesse Bloom and their colleagues sought to better understand SARS-CoV-2 by investigating the common-cold coronavirus 229E. A person who is infected with 229E develops an immune response against the signature coronavirus spike protein that protects them from reinfection with this virus, but only for a few years. Does reinfection then occur because the immune response wears off, or because 229E evolves to escape it? Their findings, published on April 8 in PLOS Pathogens, suggest the latter. Thus, it is possible that SARS-CoV-2 could undergo similar evolution, and that COVID-19 vaccines may require periodic updates to remain effective.
“It’s pretty clear that human coronaviruses undergo substantial antigenic evolution,” Bloom said about this study’s findings in a Bloomberg story about coronavirus evolution and COVID-19 vaccines.
Read the Bloom Lab’s Twitter thread on this research and a press release from PLOS Pathogens about the paper.
March 2021
Addressing vaccine hesitancy in BIPOC communities
In a perspective published on March 31 in the New England Journal of Medicine, Dr. Michele Andrasik and colleagues discuss how to build trust, partnership and reciprocity between vaccine researchers and Black, Indigenous and people of color (or BIPOC) communities, with a special focus on the work of the COVID-19 Prevention Network.
Can coronavirus vaccines block asymptomatic transmission?
The new Prevent COVID U study, designed and managed by researchers at the Hutch-based COVID-19 Prevention Network, will enroll thousands of college students to answer one of the world’s most pressing questions about COVID-19 vaccines: Can these shots, which protect against serious symptoms, also prevent those who might still get infected from silently spreading the disease to others?
“What we would like to see is that the vaccine recipients who become infected have lower levels of virus in the nose or a shorter duration of infection than participants who became infected and are not vaccinated,” Dr. Holly Janes told Fred Hutch News Service.
