Study links vaccine immune response to age

old people

Older people appear to have fewer antibodies against the novel coronavirus, a new laboratory study from Oregon Health & Science University suggests.

Antibodies are blood proteins that are made by the immune system to protect against infection. They are known to be key players in protection against SARS-CoV-2 infection.

The study published today in the Journal of the American Medical Association.

“Our older populations are potentially more susceptible to the variants even if they are vaccinated,” said senior author Fikadu Tafesse, Ph.D., assistant professor of molecular microbiology and immunology in the OHSU School of Medicine.

Tafesse and colleagues emphasized that even though they measured diminished antibody response in older people, the vaccine still appeared to be effective enough to prevent infection and severe illness in most people of all ages.

“The good news is that our vaccines are really strong,” Tafesse said.

However, with vaccine uptake slowing in Oregon and across United States, researchers say their findings underscore the importance of promoting vaccinations in local communities.

Vaccinations reduce the spread of the virus and new and potentially more transmissible variants, especially for older people who appear to be more susceptible to breakthrough infections.

“The more people get vaccinated, the less the virus circulates,” Tafesse said. “Older people aren’t entirely safe just because they’re vaccinated; the people around them really need to be vaccinated as well. At the end of the day, this study really means that everybody needs to be vaccinated to protect the community.”

Researchers measured the immune response in the blood of 50 people two weeks after their second dose of the Pfizer vaccine against COVID-19. They grouped participants into age groups and then exposed their blood serum in test tubes to the original “wild-type” SARS-CoV-2 virus and the P.1 variant (also known as gamma) that originated in Brazil.

The youngest group—all in their 20s—had a nearly seven-fold increase in antibody response compared with the oldest group of people between 70 and 82 years of age. In fact, the laboratory results reflected a clear linear progression from youngest to oldest: The younger a participant, the more robust the antibody response.

“Older people might be more susceptible to variants than younger individuals,” Tafesse said.

The findings highlight the importance of vaccinating older people as well as others who may be more vulnerable to COVID-19, said co-author Marcel Curlin, M.D., associate professor of medicine (infectious diseases) in the OHSU School of Medicine.

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Differing immune responses discovered in asymptomatic cases versus those with severe COVID-19


The largest study of its type in the UK has identified differences in the immune response to COVID-19 between people with no symptoms and those suffering a more serious reaction to the virus.

Researchers from the Wellcome Sanger Institute, Newcastle University, University College London, University of Cambridge, EMBL’s European Bioinformatics Institute (EMBL-EBI) and their collaborators within the Human Cell Atlas initiative, found raised levels of specific immune cells in asymptomatic people. They also showed people with more serious symptoms had lost these protective cell types, but gained inflammatory cells. These differences in the immune response could help explain serious lung inflammation and blood clotting symptoms, and could be used to identify potential targets for developing therapies.

The research, published today (20th April 2021) in Nature Medicine, is one of the only studies to include people who were asymptomatic. This large-scale collaborative study is part of the Human Cell Atlas initiative to map every cell type in the human body, to transform our understanding of health, infection and disease.

So far, the COVID-19 global pandemic has caused millions of deaths and many more infections worldwide. Symptoms vary widely in severity and can range from a mild cough to severe respiratory distress, blood clots and organ failure. Several previous studies have highlighted a complex immune response in the blood, but until now the full coordinated immune response and how this differs between symptomatic and asymptotic patients had not been investigated in detail.

In a new study to understand how different immune cells responded to the infection, a large team of researchers came together to analyze blood from 130 people with COVID-19. These patients came from three different UK centers (Newcastle, Cambridge and London) and ranged from asymptomatic to critically severe.

The team performed single-cell sequencing from ~800,000 individual immune cells, along with detailed analysis of cell surface proteins and antigen receptors found on immune cells in the blood. They revealed differences in multiple types of immune cells that are involved in the body’s response to COVID-19.

In those with no symptoms, the team found increased levels of B cells that produce antibodies that are found in mucus passages, such as the nose. These antibodies may be one of our first line of defense in COVID-19. However, these protective B cells were missing in people with serious symptoms, indicating the importance of an effective antibody-associated immune response at the nose and other mucus passages.

The team discovered that whereas patients with mild to moderate symptoms, had high levels of B cells and helper T-cells, which help fight infection, those with serious symptoms had lost many of these immune cells, suggesting that this part of the immune system had failed in people with severe disease.

In contrast, people with more serious symptoms leading to hospitalization had an uncontrolled increase in monocytes and killer T-cells, high levels of which can lead to lung inflammation. Those with severe disease also had raised levels of platelet-producing cells, which help blood to clot.

Professor Muzlifah Haniffa, senior author from Newcastle University and Senior Clinical Fellow at the Wellcome Sanger Institute, said: “This is one of the only studies of its kind that looks at samples collected from asymptomatic people, which helps us start to understand why some people react differently to COVID-19 infection. It could also explain symptoms such as lung inflammation and blood clots. The immune system is made up of lots of different groups of cells, similar to the way an orchestra is made up of different groups of instruments, and in order to understand the coordinated immune response, you have to look at these immune cells together.”

While it is not yet understood how the infection stimulates these immune responses, the study gives a molecular explanation for how COVID-19 could cause an increased risk of blood clotting and inflammation in the lungs, which can lead to the patient needing a ventilator. This also uncovers potential new therapeutic targets to help protect patients against inflammation and severe disease. For example, it may be possible to develop treatments that decrease platelet production or reduce the number of killer T-cells produced, however more research is required.

Professor Menna Clatworthy, senior author and Professor of Translational Immunology at the University of Cambridge and Wellcome Sanger Institute Associate Faculty, said: “This is one of the most detailed studies of immune responses in COVID-19 to date, and begins to help us understand why some people get really sick while others fight off the virus without even knowing they have it. This new knowledge will help identify specific targets for therapy for patients that get sick with COVID-19.”

In the future, research may identify those who are more likely to experience moderate to severe disease by looking at levels of these immune cells in their blood.

This study used samples from three centers in the UK, and found that some antibody responses were similar in individuals in one geographic area compared with those at a different center, hinting that this part of the immune response may be tailored to different variants of the virus.

Dr. John Marioni, senior author and head of research at EMBL’s European Bioinformatics Institute (EMBL-EBI) and Senior Group Leader at the Cancer Research UK Cambridge Institute, said: “Using data from three different centers has allowed us to look at how people react to COVID-19 throughout the UK. The amount of data collected in this study has given us crucial insight into the immune reaction in various different severities of COVID-19 infection.”

Professor Berthold Göttgens, senior author and professor of molecular hematology at the University of Cambridge, said: “Along with the findings, the way this study was conducted is noteworthy, as it was a new way of doing biomedical science. By bringing different experts together, we were able to employ a divide and conquer approach, which allowed us to complete the work in extra quick time. This study required a large teamwork effort, in the middle of the pandemic when labs were being shut down. This was an incredibly rewarding study to work on, with everyone understanding the importance of the work and willing to go the extra mile.”

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Chemical found in 1,000 processed foods may harm the immune system

Two chemicals that are commonly found in processed foods may harm the immune system, according to a new study.

The chemicals are the preservative tert-butylhydroquinone (TBHQ), found in Kellogg’s Pop-Tarts, Cheez-Its and more than 1,000 other foods; and per- and polyfluoroalkyl substances (PFAS), a group of chemicals that can leach into food from packaging, according to the study authors, from the Environmental Working Group (EWG), a health-focused nonprofit. 

“The pandemic has focused public and scientific attention on environmental factors that can impact the immune system,” study author Olga Naidenko, EWG vice president for science investigations, said in a statement. “Before the pandemic, chemicals that may harm the immune system’s defense against infection or cancer did not receive sufficient attention from public health agencies. To protect public health, this must change.”

The study, published March 24 in the International Journal of Environmental Research and Public Health, found that these chemicals showed potentially harmful effects on the immune system in studies conducted in animals and in lab dishes. However, results from these types of studies don’t always translate to humans, so the new study cannot prove that these chemicals harm the immune system in people.

Nonetheless, the findings are enough to warrant concern, according to Dr. Kenneth Spaeth, a specialist in occupational and environmental medicine at Northwell Health in Great Neck, New York.

“The products that this particular study has looked at are obviously very popular, widely used food products,” Spaeth told Live Science. “That becomes a key element, because obviously when exposures happen, the broader the exposure, the greater the chance of harm to result.” 

Spaeth added that “there have been, historically, a number of health and safety issues that result from food contaminants [and] food additives.” Some of these chemicals are there “by design” because they are directly added to food. But others arise through the breakdown of other chemicals, and some, like PFAS, can enter food through packaging, he said. “It’s important for those reasons to ensure as best we can that the products we’re using and the food that we’re eating [are] assessed for any potential hazards. Studies like this one are a means of monitoring that,” Spaeth said. 

The study authors said further testing of these chemicals and their potentially toxic effects should be a priority for research, and they called on the U.S. Food and Drug Administration (FDA) to review the latest science on TBHQ and other food additives.

In a statement to Live Science, Kellogg spokesperson Kris Bahner said, “Providing safe, delicious, quality food for consumers is our top priority. TBHQ is a common antioxidant, approved for safe use by the FDA, that many companies use in numerous products to help protect food’s flavor and freshness.”

Harmful chemicals? 

The EWG researchers analyzed data from the Environmental Protection Agency’s Toxicity Forecaster (ToxCast) program, which uses automation to screen large numbers of chemicals for their effects on cells in lab dishes and on proteins in test tubes. They wanted to test how well the program could predict chemicals’ potential harm to the immune system. They analyzed the ToxCast data to determine how the chemicals that are most commonly added to — or end up in — food, such as TBHQ and PFAS, affect genes and proteins related to immune function. The researchers also reviewed the scientific literature to see whether studies had reported that a given chemical affected the immune system.

For TBHQ, the results of the ToxCast tests and the literature review both indicated that the chemical affects the immune system. The ToxCast tests indicated that TBHQ affects proteins, such as chemokines and cytokines, that coordinate the immune system’s response to pathogens, the study authors wrote. 

It’s hard to predict from ToxCast data alone whether those effects might be harmful to the immune system in animals or humans, study author and EWG toxicologist Alexis Temkin told Live Science. Yet according to the literature review, animal studies have found that TBHQ was associated with changes in immune function and immunomodulation, the tuning up or down of the immune response, the authors wrote in their paper. 

As for PFAS, both animal and epidemiological studies suggest that these chemicals can be toxic to the immune system, the authors wrote in their study. Higher PFAS levels in people have been associated with lower antibody production in response to vaccinations, the authors wrote in their study. For example, a 2013 study in the Journal of Immunotoxicology reported that children who were exposed to higher levels of PFAS chemicals in the womb had lower antibody production in response to childhood vaccinations. 

Yet the ToxCast data do not reveal the immune system effects of PFAS. For example, according to the ToxCast tests, PFOA —  a type of PFAS that epidemiological studies indicate may suppress the human immune system — weakly affected just one out of 19 immune system molecules tested.  

Based on the studies involving TBHQ, the researchers concluded that ToxCast can identify molecules that pose risks to the immune system. But ToxCast’s failure to flag PFAS chemicals as harmful to the immune system does not mean they are safe; rather, it points to limitations of the screening, the authors wrote. 

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The FDA approved TBHQ decades ago, the authors wrote. National and international agencies, such as the U.S. National Toxicology Program and the European Food Safety Authority, reviewed TBHQ for safety, yet the chemicals’ effects on the immune system went mostly under the radar. 

“Our research shows how important it is that the FDA take a second look at these ingredients and test all food chemicals for safety,” Scott Faber, senior vice president for government affairs at EWG, said in the statement.

The results of this study and others like it put consumers in a difficult position, as it can be virtually impossible to know whether certain chemicals are in food products, Spaeth said. Not all chemicals found in food are listed as ingredients, because some of the chemicals, like PFAS, are not direct additives. 

“As we learn more about contaminants, for those that are shown to be posing health risks, the consumer is left in a bind, because there may be knowledge of potential harm, but there’s not enough information for consumers to really make choices in real time [while] walking up and down the aisles,” he said.

Originally published on Live Science. 

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Immune response to insulin could identify, help treat those at risk for type 1 diabetes


Researchers from the Barbara Davis Center for Childhood Diabetes at the University of Colorado Anschutz Medical Campus have found that immune responses to insulin could help identify individuals most at risk for developing Type 1 diabetes.

The study, out recently in the Proceedings of the National Academy of Sciences, measured immune responses from individuals genetically predisposed to developing Type 1 diabetes (T1D) to naturally occurring insulin and hybrid insulin peptides. Since not all genetically predisposed individuals develop T1D, researchers sought to examine T-cell immune responses from the peripheral blood that could occur before the onset of clinical diabetes.

“We want to know why people develop T1D, and this research has helped provide a lot more information and data as to what it looks like when genetically at-risk individuals are headed towards clinical diagnosis,” says Aaron Michels, MD, the study’s lead researcher, Associate Professor of Medicine at CU Anschutz and researcher at the Barbara Davis Center. “Ideally, you want to treat a disease when it’s active, so this is a need in our field to understand when people have an immune response directed against insulin producing cells.”

Researchers collected blood samples from genetically at-risk adolescents every 6 months for two years. Inflammatory T-cell responses to hybrid insulin peptides correlated with worsening blood glucose measurements and progression to T1D development. The results indicate an important advancement in identifying the risk of T1D early as well as the potential for intervention.

“There are now therapies used in research studies that have delayed the onset of clinical type 1 diabetes,” says Michels. “Patients with these specific immune responses, may benefit from immune intervention to delay T1D onset and possibly prevent it for years.”

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What are the Three Lines of Defense?

The human body has three primary lines of defense to fight against foreign invaders, including viruses, bacteria, and fungi. The immune system’s three lines of defense include physical and chemical barriers, non-specific innate responses, and specific adaptive responses.

Image Credit: Yurchanka Siarhei/

What is the immune system?

The immune system is a complex network of specific immune cells and proteins that work in synergy to protect the body against foreign invaders and harmful toxic materials coming from the environment.

Foreign substances that trigger an immune response are called antigens. However, under certain circumstances, such as in autoimmune diseases, the immune system can be activated by self-antigens, leading to the destruction of the body’s cellular components.

In general, the immune system can be activated to generate two types of immune responses: nonspecific response (innate immunity) and specific adaptive response (acquired immunity).

What are the three lines of defense of the immune system?

The immune system comprises three levels of defense mechanism that a pathogen needs to cross to develop infection inside the body.

Physical barrier

The innate immune system provides the first line of defense, which is divided broadly into two categories – physical/chemical barriers and nonspecific resistance.

Physical barriers, including the skin and mucosa of the digestive and respiratory tracts, help eliminate pathogens and prevent tissue and/or blood infections. Moreover, components that are secreted by the skin or mucosa, such as sweat, saliva, tears, mucous, help provide a basic barrier against invading pathogens.

The skin is the impermeable physical/mechanical barrier that protects many pathogens from entering the body. Similarly, mucosa or mucous membranes that line the immediate internal systems help trap pathogens by producing mucous. Hairs inside the nasal cavity as well as cerumen (earwax) also trap pathogens and environmental pollutants.

Some acidic fluids, such as gastric juice, urine, and vaginal secretions, destroy pathogens by creating low pH conditions. Also, lysozyme found in tears, sweat, and saliva acts as a vital antimicrobial agent to destroy pathogens.    

Image Credit: Kateryna Kon/

Nonspecific innate response

Pathogens that successfully cross the physical barriers are next encountered by the second line of defense. This innate immune response mostly involves immune cells and proteins to nonspecifically recognize and eliminate any pathogen that enters the body.

Phagocytosis is a crucial phenomenon of the innate immune system that utilizes a special type of immune cells called phagocytes. There are two types of phagocytes namely macrophages and neutrophils. These cells are found in the tissues and blood.

In the beginning, phagocytes recognize and bind pathogens and then use the plasma membrane to surround and engulf pathogens inside the cell. As a result, a separate internal compartment (phagosome) is generated, which subsequently fuses with another type of cellular compartment called the lysosome. The digestive enzymes present inside lysosomes finally destroy pathogens by breaking them into fragments.       

Digestion of pathogens inside a phagosome produces indigestible materials and antigenic fragments; of which, indigestible materials are removed by exocytosis. However, the antigenic fragments are displayed on the surface of phagocytes, which are subsequently recognized and destroyed by cytotoxic T cells.

In addition, complement proteins are activated, which in turn recruit more white blood cells (neutrophils, eosinophils, and basophils) at the site of infection, leading to an inflammatory response (swelling, redness, pain).

Specific adaptive response

The third line defense aims at eliminating specific pathogens that have been encountered by the immune system previously (adaptive or acquired immune response). Instead of being restricted to the site of infection, the adaptive immune response occurs throughout the body.

The adaptive immune system mainly involves two types of white blood cells (lymphocytes) – B lymphocytes (B cells) and T lymphocytes (T cells). B cells are involved in antibody-mediated immune responses (humoral immunity), whereas T cells are involved in cell-mediated immune responses.

In antibody-mediated immunity, B cells are activated when they encounter a ‘known’ antigen. Activated B cells then engulf and digest the antigen, which is followed by a representation of MHC (major histocompatibility complex)-bound antigenic fragments on the B cell surface.

The combination of antigen-MHC further activates helper T cells, which in turn secrete cytokines (interleukins) to trigger the growth and maturation of antigen-presenting B cells into antibody-producing B cells (plasma cells). At this point, some B cells are transformed into memory cells to keep the immune system ready for the next attack.

Antibodies produced by the plasma cells are secreted into the bloodstream where they execute their functions in different ways. For example, by forming the antigen-antibody complex, antibodies can prevent antigens from binding host cells, leading to the prevention of infection. Antibodies also bind and mark pathogens for destruction through phagocytosis.

The antigen-antibody complex can initiate a series of signaling events to activate complement proteins, which in turn kills pathogens by rupturing their cell membrane. Complement proteins also trigger an inflammatory response, leading to the accumulation of white blood cells at the infection site.

In cell-mediated immunity, T cells are activated when they encounter antigen-presenting cells, such as B cells or dendritic cells. Activated T cells then secrete cytokines that further trigger the production and maturation of T cells.

T cells that mature into cytotoxic or killer T cells mainly destroy pathogen-infected cells, damaged cells, and cancer cells by rupturing the cell membrane. Whereas, T cells that mature into helper T cells facilitate B cells to execute antibody-mediated immune responses.   

Some T cells that mature into regulatory T cells help cease the immune response and maintain the immune system homeostasis when the threat is eliminated. Also, some T cells that mature into memory T cells remember the pathogen and initiate an immediate response when the body encounters the same pathogen for the second time.

Image Credit:


  • Science Olympiad. Immune System.…/2018_IMMUNE_SYSTEM_HANDOUT.pdf
  • Let’s talk science. 2019. The immune response.…/immune-response
  • Austin Community College. Immune System.
  • NCBI. 2020. How does the immune system work?

Further Reading

  • All Immune System Content
  • What is the difference Between a Phagocyte, Macrophage, Neutrophil and Eosinophil?
  • Does the Immune System Differ between Men and Women?
  • Effects of Tobacco on the Immune System

Last Updated: Jul 30, 2020

Written by

Dr. Sanchari Sinha Dutta

Dr. Sanchari Sinha Dutta is a science communicator who believes in spreading the power of science in every corner of the world. She has a Bachelor of Science (B.Sc.) degree and a Master's of Science (M.Sc.) in biology and human physiology. Following her Master's degree, Sanchari went on to study a Ph.D. in human physiology. She has authored more than 10 original research articles, all of which have been published in world renowned international journals.

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Will social distancing weaken my immune system?

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Will social distancing weaken my immune system?

In short, no.

Some worry a lack of contact with others will weaken their immune system by reducing its active contact with germs.

Some worry a lack of contact with others will weaken their immune system by reducing its active contact with germs.

But even when we're staying 6 feet from others or spending most of our time at home, our bodies are continuously responding to plenty of bacteria and other germs that inhabit indoor and outdoor environments.


“We’re constantly exposed to microbes,” said Akiko Iwasaki, an immune system researcher at Yale University. "Our immune system is always being triggered.”

The effects of childhood vaccines and other built-up immunity are also long-lasting, Iwasaki said, and won't disappear overnight because we're keeping our distance from others during the pandemic.


Experts say anyone looking to boost their immune health during the pandemic should practice habits such as stress management, healthy eating, regular exercise and getting enough sleep.


"These are the things that actually affect the immune system," Iwasaki said.

A seasonal flu shot will also help protect you from one more potential illness.

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Clinical trial finds inhaled immune response protein increases odds of recovery for hospitalised COVID-19 patients

Hospitalised COVID-19 patients in the UK who received an inhaled form of interferon beta-1a (SNG001) were more likely to recover and less likely to develop severe symptoms than patients who received a placebo, according to a new clinical trial published in The Lancet Respiratory Medicine journal. This is the first evidence published in a peer-reviewed medical journal that inhaled interferon beta-1a could lessen the clinical consequences of COVID-19 and serves as proof-of-concept that this treatment could help hospitalised patients recover, but further research is required.

As the number of COVID-19 infections continues to rise around the world, there is a pressing need to develop new treatments for the more severe and life-threatening symptoms such as pneumonia and respiratory failure.

Interferon beta is a naturally occurring protein that coordinates the body’s immune response to viral infections. Laboratory studies have found that the SARS CoV-2 virus directly suppresses the release of interferon beta, while clinical trials demonstrate decreased activity of this important protein in COVID-19 patients. The formulation of interferon beta used in this new study—SNG001—is directly delivered to the lungs via inhalation and has been trialled in the treatment of asthma and chronic obstructive pulmonary disease (COPD). This study aimed to evaluate the safety and efficacy of SNG001 to treat hospitalised COVID-19 patients.

The trial was conducted at nine UK hospitals with patients who had a confirmed SARS-CoV-2 infection. It compared the effects of SNG001 and placebo given to patients once daily for up to 14 days, and followed up patients for a maximum of 28 days after starting the treatment. Patients were recruited from March 30 to May 30, 2020, and were randomly assigned to receive the treatment or a placebo. All members of the research team were blinded to which group the patients were allocated. During the study, changes in the clinical condition of patients were monitored.

Of the 101 patients enrolled in the study, 98 patients were given the treatment in the trial (three patients withdrew from the trial) – 48 received SNG001 and 50 received a placebo. At the outset of the trial 66 (67%) patients required oxygen supplementation at baseline (29 people in the placebo group and 37 in the SNG001 group). Patients who received SNG001 were twice as likely to show an improvement in their clinical condition at day 15 or 16, compared with the placebo group.

In the placebo group, 11 (22%) of 50 patients developed severe disease (defined in this study as requiring mechanical ventilation) or died between the first dose and day 15 or 16, compared with six (13%) of 48 patients who received SNG001 (this includes three deaths in the placebo groups and none in the treatment group).

Over the 14-day treatment period, patients who received SNG001 were more than twice as likely to recover, compared to those in the placebo group—with 21 (44%) patients in the SNG001 group recovering compared with 11 (22%) patients in the placebo group (patients were deemed to have recovered when they were no longer limited in their activity). In a secondary analysis, the authors found that at 28 days, SNG001 patients were over three times more likely to recover than patients receiving placebo.

Lead author, Professor Tom Wilkinson from the University of Southampton, UK, says: “The results confirm our belief that interferon beta, a widely known drug approved for use in its injectable form for other indications, may have the potential as an inhaled drug to restore the lung’s immune response and accelerate recovery from COVID-19. Inhaled interferon beta-1a provides high, local concentrations of the immune protein, which boosts lung defences rather than targeting specific viral mechanisms. This might carry additional advantages of treating COVID-19 infection when it occurs alongside infection by another respiratory virus, such as influenza or respiratory syncytial virus (RSV) that may well be encountered in the winter months.”

The safety of inhaled interferon beta-1a was assessed by monitoring adverse events over 28 days. 26 (54%) patients in the SNG001 group and 30 (60%) patients in the placebo group had adverse events during treatment, with the most frequently reported being headache. Fewer patients in the SNG001 group had serious adverse events, compared with the placebo group.

The authors note some limitations of their study. The sample size was small and, as such, findings cannot be generalised to wider populations and healthcare settings. There were differences between the two groups at recruitment: patients in the SNG001 group had more severe disease at baseline and more patients had hypertension, and in the placebo group more patients had diabetes and cardiovascular disease. However, these factors were considered in the statistical model used, and beneficial signals for therapy were enhanced when a priori adjustments were made. Larger trials should be able to address these limitations with randomisation of more varied groups, according to the researchers.

The same research group is also assessing the effectiveness of the treatment in pre-hospital cases of COVID-19. To assess the treatment for patients who are critically ill and requiring mechanical ventilation, an alternative delivery method than the current nebuliser is needed.

Writing in a linked Comment, lead author Nathan Peiffer-Smadja (who was not involved in the study), from Assistance Publique—Hôpitaux de Paris, France, pointed out that preliminary results from the SOLIDARITY/DisCoVeRy randomised clinical trial in COVID-19 patients (which includes 8% who were mechanically ventilated) has so far failed to show efficacy of subcutaneous injectable interferon beta-1a. One potential explanation is because this route of administration doesn’t provide the targeted delivery of the drug to the lungs, which occurs with inhaled delivery. The Comment also highlights concerns that in severe COVID-19 patients the use of the drug could increase the inflammatory response and be associated with safety issues.

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Biologist uses rabies-like virus to illuminate how SARS-CoV-2 blocks immune response

Vanderbilt University researcher Yi Ren is part of an international team that has confirmed the mechanism by which SARS-CoV-2, the scientific name for the strain of coronavirus causing COVID-19, targets and impacts its host factor protein. The article “SARS-CoV-2 Orf6 hijacks Nup98 to block STAT nuclear import and antagonize interferon signaling” was published in the journal Proceedings of the National Academy of Sciences on Oct. 23.

Ren, an assistant professor of biochemistry, studies the basic mechanism by which proteins are expressed within cells, and how different viruses target and hijack the function of critical immune factors within the cells’ machinery.

Her expertise is in influenza A—the only influenza virus known to cause global flu disease epidemics—and vesicular stomatitis virus. VSV is a rabies-like virus that predominantly infects cattle, horses and pigs. The virus is highly sensitive to interferons, the signaling proteins that are made by host cells when they sense a virus. The interferons’ purpose is to induce nearby cells to boost their anti-viral defenses.

Reviewing coronavirus-related research early in 2020, Ren came upon an article that suggested the SARS-CoV-2 protein had similar characteristics to VSV, in that it acts to tamp down the interferons that would otherwise kick off an immune response in the host. “From the literature review, I understood that I had the requisite specialist knowledge of how protein expression is blocked in VSV to meaningfully contribute to COVID-related research,” Ren said.

Together with longtime collaborators at the University of Texas Southwestern Medical Center and the Icahn School of Medicine at Mount Sinai, “We were able to test the direct interaction between the host factor that I work with and the SARS-CoV-2 protein. We found that, indeed, they interact,” Ren said.

The findings show that SARS-CoV-2 uses a similar strategy as VSV to target the same susceptible protein known as a host factor. The difference is that SARS-CoV-2 has a mechanism that stops proteins from sharing genetic information with the host cell nucleus. This blocking behavior enables suppression of the immune system. This mechanistic finding was a huge surprise for Ren, who has spent so much time in the lab with VSV.

“Even though SARS-CoV-2 is an entirely new virus that the world is grappling with, it deploys a similar strategy to target the same host factor as VSV, making me feel somewhat familiar with the virus. After so many years of studying influenza A and VSV, to see such a small difference on a cellular level resulting in what we’ve seen during this pandemic puts these ‘small’ differences into perspective,” said Ren.

The lab continues to work on the structural characterization of the virus-host interaction so researchers can explore it further. Ren’s team soon will be able to show how the virus protein targets the host machinery and its consequences on the atomic level, an essential step in designing therapeutics to enable an appropriate host immune response.

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‘Multi-omics’ adds new cell to immune family tree

WEHI researchers have used powerful ‘single cell multi-omics’ technologies to discover a previously unknown ancestor of T and B lymphocytes, which are critical components of our immune system.

Using an approach akin to breaking a sports team’s performance down to the individual player statistics, the researchers looked at multiple aspects of single developing immune cells to define which cells would only give rise to T and B lymphocytes. This revealed a new stage in lymphocyte development, information which could enrich future studies of the immune system. The discovery has also led to new research opportunities, with WEHI establishing of one of Australia’s first dedicated and integrated single cell research platforms in 2018, which is now being used to solve other research questions.

The research, which was published in Nature Immunology today, was led by Dr. Shalin Naik, Dr. Daniela Zalcenstein, Mr Luyi Tian, Mr Jaring Schreuder and Ms Sara Tomei.

Focussing on single cells

Our immune system comprises many different types of cells with different functions, but all immune cells are derived from a single type of cell, a blood stem cell. The development of different immune cell types occurs through a branching ‘family tree’ of immature cells. At earlier stages of immune cell development, individual cells can give rise to several different types of mature cell, but as development progresses, cells become more limited in which final mature cells they can produce.

T and B lymphocytes—which are critical for targeted, specific immune responses—are closely related immune cells, meaning they share many common steps in their development, said Dr. Naik. “Decades of research have defined how T and B lymphocytes develop, and the ‘branch points’ in their family tree when the developing cells lose the capacity to develop into other immune cell types,” he said.

Dr. Zalcenstein said that to gain new insights into questions such as how immune cells develop, the team established Australia’s first ‘single cell multi-omics’ platform, which is now available to all researchers within the Single Cell Open Research Endeavour (SCORE) established by Dr. Naik and Dr. Zalcenstein in collaboration with Dr. Stephen Wilcox of WEHI’s Genomics Hub and Associate Professor Matthew Ritchie.

“Multi-omics technologies combine different biological data sets—such as genomics, transcriptomics and proteomics—to compare different samples in more detail than is possible by looking at one data set. We have applied this approach to study individual cells, in this case developing immune cells, to understand in more detail which cells can give rise to lymphocytes. This approach is called single cell multi-omics,” she said.

“Rather than looking at data combined from many cells in a sample, we focus in on individual cells to understand the differences that exist within a larger population. It’s like looking at a football team—you can average out the number of goals, tackles and kicks per player in a game, but if you look at individual player statistics, you may discover that one player scored lots of goals, while another player was responsible for most of the tackles,” she said.

A new lymphocyte progenitor

SCORE’s study of immune cell precursors revealed a previously unrecognised cell type that could give rise to T and B lymphocytes, but not other immune cells.

“This cell occurred much earlier in lymphocyte development than we had suspected,” Dr. Naik said. “Previous techniques had grouped different immune progenitors together, but by studying individual cells we were able to identify one cell type that was committed to developing into T and B lymphocytes.”

The discovery adds a new layer to the family tree of T and B lymphocytes and could provide a boost to other areas of research.

“Understanding in more detail how T and B lymphocytes develop could lead to better approaches to regenerate these cells as a treatment for certain diseases,” Dr. Naik said. “We also know that many types of leukaemia arise from defects in early stages of immune cell development, so we are curious to know whether this progenitor cell has links to any forms of leukaemia.”

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Immune cell activation in severe COVID-19 resembles lupus

In severe cases of COVID-19, Emory researchers have been observing an exuberant activation of immune cells, resembling acute flares of systemic lupus erythematosus (SLE), an autoimmune disease.

Their findings point towards tests that could separate some COVID-19 patients who need immune-calming therapies from others who may not. They also may begin to explain why some people infected with SARS-CoV-2 produce abundant antibodies against the virus, yet experience poor outcomes.

The results were published online on Oct. 7 in Nature Immunology.

The Emory team’s results converge with recent findings by other investigators, who found that high inflammation in COVID-19 may disrupt the formation of germinal centers, structures in lymph nodes where antibody-producing cells are trained. The Emory group observed that B cell activation is moving ahead along an “extrafollicular” pathway outside germinal centers—looking similar to they had observed in SLE.

B cells represent a library of blueprints for antibodies, which the immune system can tap to fight infection. In severe COVID-19, the immune system is, in effect, pulling library books off the shelves and throwing them into a disorganized heap.

Before the COVID-19 pandemic, co-senior author Ignacio (Iñaki) Sanz, MD and his lab were focused on studying SLE and how the disease perturbs the development of B cells.

Sanz is head of the division of rheumatology in the Department of Medicine, director of the Lowance Center for Human Immunology, and a Georgia Research Alliance Eminent Scholar. Co-senior author Frances Eun-Hyung Lee, MD is associate professor of medicine and director of Emory’s Asthma/Allergy Immunology program.

“We came in pretty unbiased,” Sanz says. “It wasn’t until the third or fourth ICU patient whose cells we analyzed, that we realized that we were seeing patterns highly reminiscent of acute flares in SLE.”

In people with SLE, B cells are abnormally activated and avoid the checks and balances that usually constrain them. That often leads to production of “autoantibodies” that react against cells in the body, causing symptoms such as fatigue, joint pain, skin rashes and kidney problems. Flares are times when the symptoms are worse.

Whether severe COVID-19 leads to autoantibody production with clinical consequences is currently under investigation by the Emory team. Sanz notes that other investigators have observed autoantibodies in the acute phase of the disease, and it will be important to understand whether long-term autoimmune responses may be related to the fatigue, joint pain and other symptoms experienced by some survivors.

“It’s an important question that we need to address through careful long-term follow-up,” he says. “Not all severe infections do this. Sepsis doesn’t look like this.”

In lupus, extrafollicular B cell responses are characteristic of African-American patients with severe disease, he adds. In the new study, the majority of patients with severe infection were African-American. It will be important to understand how underlying conditions and health-related disparities drive the intensity and quality of B cell responses in both autoimmune diseases and COVID-19, Sanz says.

The study compared 10 critically ill COVID-19 patients (4 of whom died) admitted to intensive care units at Emory hospitals to 7 people with COVID-19 who were treated as outpatients and 37 healthy controls.

People in the critically ill group tended to have higher levels of antibody-secreting cells early on their infection. In addition, the B cells and the antibodies they made displayed characteristics suggesting that the cells were being activated in an extrafollicular pathway. In particular, the cells underwent fewer mutations in their antibody genes than seen in a focused immune response, which is typically honed within germinal centers.

The Nature Immunology paper was the result of a collaboration across Emory. The co-first authors are Matthew Woodruff, Ph.D., an instructor in Sanz’s lab, and Richard Ramonell, MD, a fellow in pulmonary and critical care medicine at Emory University Hospital.

Ramonell notes that the patients studied were treated early during the COVID-19 pandemic. It was before the widespread introduction of the anti-inflammatory corticosteroid dexamethasone, which has been shown to reduce mortality.

The team’s findings could inform the debate about which COVID-19 patients should be given immunomodulatory treatments, such as dexamethasone or anti-IL-6 drugs. Patients with a greater expansion of B cells undergoing extrafollicular activation also had higher levels of inflammatory cytokines, such as IL-6.

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