The experimental drug TEMPOL may be a promising oral antiviral treatment for COVID-19, suggests a study of cell cultures by researchers at the National Institutes of Health.

TEMPOL can limit SARS-CoV-2 infection by impairing the activity of a viral enzyme called RNA replicase. The work was led by researchers at NIH’s Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD). The study appears in Science.

“We urgently need additional effective, accessible treatments for COVID-19,” said Diana W. Bianchi, M.D., NICHD Director. “An oral drug that prevents SARS-CoV-2 from replicating would be an important tool for reducing the severity of the disease.”

The study team was led by Tracey A. Rouault, M.D., head of the NICHD Section on Human Iron Metabolism. It discovered TEMPOL’s effectiveness by evaluating a more basic question on how the virus uses its RNA replicase, an enzyme that allows SARS-CoV-2 to replicate its genome and make copies of itself once inside a cell.

Researchers tested whether the RNA replicase (specifically the enzyme’s nsp12 subunit) requires iron-sulfur clusters for structural support. Their findings indicate that the SARS-CoV-2 RNA replicase requires two iron-sulfur clusters to function optimally. Earlier studies had mistakenly identified these iron-sulfur cluster binding sites for zinc-binding sites, likely because iron-sulfur clusters degrade easily under standard experimental conditions.

Identifying this characteristic of the RNA replicase also enables researchers to exploit a weakness in the virus. TEMPOL can degrade iron-sulfur clusters, and previous research from the Rouault Lab has shown the drug may be effective in other diseases that involve iron-sulfur clusters. In cell culture experiments with live SARS-CoV-2 virus, the study team found that the drug can inhibit viral replication.

Based on previous animal studies of TEMPOL in other diseases, the study authors noted that the TEMPOL doses used in their antiviral experiments could likely be achieved in tissues that are primary targets for the virus, such as the salivary glands and the lungs.

“Given TEMPOL’s safety profile and the dosage considered therapeutic in our study, we are hopeful,” said Dr. Rouault. “However, clinical studies are needed to determine if the drug is effective in patients, particularly early in the disease course when the virus begins to replicate.”

The study team plans on conducting additional animal studies and will seek opportunities to evaluate TEMPOL in a clinical study of COVID-19.

NIH authors on the study include researchers from the National Cancer Institute, the National Institute of Allergy and Infectious Diseases, and the National Institute of Neurological Disorders and Stroke. Authors from the Pennsylvania State University are funded by NIH’s National Institute of General Medical Sciences.

Original Source

A potential new vaccine developed by members of the Duke Human Vaccine Institute has proven effective in protecting monkeys and mice from a variety of coronavirus infections — including SARS-CoV-2 as well as the original SARS-CoV-1 and related bat coronaviruses that could potentially cause the next pandemic.

The new vaccine, called a pan-coronavirus vaccine, triggers neutralizing antibodies via a nanoparticle. The nanoparticle is composed of the coronavirus part that allows it to bind to the body’s cell receptors, and is formulated with a chemical booster called an adjuvant. Success in primates is highly relevant to humans.

The findings appear Monday, May 10 in the journal Nature.

“We began this work last spring with the understanding that, like all viruses, mutations would occur in the SARS-CoV-2 virus, which causes COVID-19,” said senior author Barton F. Haynes, M.D., director of the Duke Human Vaccine Institute (DHVI). “The mRNA vaccines were already under development, so we were looking for ways to sustain their efficacy once those variants appeared.

“This approach not only provided protection against SARS-CoV-2, but the antibodies induced by the vaccine also neutralized variants of concern that originated in the United Kingdom, South Africa and Brazil,” Haynes said. “And the induced antibodies reacted with quite a large panel of coronaviruses.”

Haynes and colleagues, including lead author Kevin Saunders, Ph.D., director of research at DHVI, built on earlier studies involving SARS, the respiratory illness caused by a coronavirus called SARS-CoV-1. They found a person who had been infected with SARS developed antibodies capable of neutralizing multiple coronaviruses, suggesting that a pan-coronavirus might be possible.

The Achilles heel for the coronaviruses is their receptor-binding domain, located on the spike that links the viruses to receptors in human cells. While this binding site enables it to enter the body and cause infection, it can also be targeted by antibodies.

The research team identified one particular receptor-binding domain site that is present on SARS-CoV-2, its circulating variants and SARS-related bat viruses that makes them highly vulnerable to cross-neutralizing antibodies.

The team then designed a nanoparticle displaying this vulnerable spot. The nanoparticle is combined with a small molecule adjuvant — specifically, the toll-like receptor 7 and 8 agonist called 3M-052, formulated with Alum, which was developed by 3M and the Infectious Disease Research Institute. The adjuvant boosts the body’s immune response. 

In tests of its effect on monkeys, the nanoparticle vaccine blocked COVID-19 infection by 100%. The new vaccine also elicited significantly higher neutralizing levels in the animals than current vaccine platforms or natural infection in humans. 

Original Source

A Spanish study on mixing COVID-19 vaccines has found that giving a dose of Pfizer’s (PFE.N) drug to people who already received a first shot of AstraZeneca (AZN.L) vaccine is highly safe and effective, preliminary results showed on Tuesday.

The Combivacs study, run by Spain’s state-backed Carlos III Health Institute, found the presence of IgG antibodies in the bloodstream was between 30 and 40 times higher in people who got the follow-up Pfizer shot than in a control group who only received one AstraZeneca dose.

Meanwhile, the presence of neutralising antibodies rose sevenfold after a Pfizer dose, significantly more than the doubling effect observed after a second AstraZeneca shot.

Around 670 volunteers between the ages of 18-59 who had already received a first dose of AstraZeneca’s vaccine participated in the study, with some 450 given a Pfizer dose.

Just 1.7% of the participants reported severe side effects, which were limited to headaches, muscle pain and general malaise, said Dr Magdalena Campins, one of the study’s leaders.

“These are not symptoms that can be considered serious,” she said.

In a U.K. “mix-and-match” study, first findings recently showed that people vaccinated with a shot of Pfizer’s vaccine followed by a dose of AstraZeneca’s, or vice versa, were more likely to report mild or moderate symptoms such as headaches or chills than if they received two of the same type. Data on immune responses are expected in the coming months.

Spain embarked on the study to determine how best to proceed after limiting AstraZeneca’s shot to people aged over 60 due to concerns about blood clotting in younger people.

That restriction caused widespread uncertainty and meant some younger people who had already received a first dose have been excluded from getting a second. 

“Today’s results support the possibility of vaccinating patients who have received the first dose from AstraZeneca, but the decision is not up to the investigators of this study,” said Jesus Antonio Frias, clinical director at Carlos III.

Original Source

It took many months and tens of thousands of volunteers to gather the data showing that the current crop of COVID-19 vaccines are safe and effective.

But what if new vaccines are needed to deal with dangerous variants of the coronavirus? Waiting months is not an attractive option.

So researchers are trying to come up with tests that can be performed using a blood sample that will determine not only whether a vaccine will work but also for how long.

One approach for determining these so-called correlates of protection is underway at the University of Oxford. Researchers there are deliberately exposing volunteers to the coronavirus. The volunteers are all healthy young adults who have previously gotten sick with COVID-19.

“The reason we’re doing the study is that we expect to see some level of protection against reinfection,” says Helen McShane, professor of vaccinology and chief investigator for the project. “The key question is, how much? And what kind of immune response correlates with that protection.”

Here’s how McShane and her colleagues are hoping to answer that question.

When you get infected with a virus, your immune system produces antibodies that target the virus and fight it off.

If you recover from the viral infection, then the antibodies did their job.

What the Oxford researchers want to learn is what level of antibodies is enough to provide protection against future infection.

“It may be not possible to reinfect with an antibody level above a certain amount,” McShane says.

Measuring antibody levels is done with a blood test, and answering that question should be a significant help in coping with the COVID-19 pandemic.

“Because we can use that level, or that cutoff if you like, to say, ‘OK, anyone who has that level of antibodies, either induced by natural infection or by vaccination, is protected,’ ” says Chris Houchens, division director for chemical, biological, radiological and nuclear countermeasures at the U.S. government’s Biomedical Advanced Research and Development Authority.

Knowing that cutoff level, also called the cutoff titer, should be particularly useful for figuring out how long the protection afforded by a vaccine will last. If, for example, you have antibody titers above that threshold 18 months after being vaccinated, then you can expect the vaccine will still be working.

Houchens says the antibody cutoff becomes what’s called a correlate of protection, that is the levels of antibodies in the blood that will indicate whether a new vaccine would protect someone without having to test it in tens of thousands of volunteers.

“We’re going to want to be able to use the correlates of protection to conduct smaller studies that are going to involve the enrollment of patients rather than tens of thousands of patients,” he says.

Houchens is involved in another effort to get at the antibody levels needed to achieve protection. Researchers are comparing antibody levels in people who received the Moderna vaccine but still got COVID-19 with levels in people who received the vaccine but didn’t get sick.

Biostatistician Peter Gilbert from the Fred Hutchinson Cancer Research Center is leading the data analysis team for that effort.

Original Source

Almost 60% of frontline health and social care workers (HSCWs) experienced a mental health disorder during the first COVID-19 lockdown, with many suffering “very high rates of distress”, suggests a new study led by researchers at UCL and the University of Haifa, Israel.

Given the significantly high levels of mental health disorders across all HSCWs, the researchers (part of the UCL-led COVID Trauma Response Working Group*), are now calling for long-term planning to meet the needs of staff from across health and social care, including specialist trauma services to be set up for healthcare workers, similar to the specialist commissioned NHS psychological trauma services for military veterans.

The ‘Frontline-COVID study’, published in the European Journal of Psychotraumatology, surveyed 1,194 HSCWs, who worked in UK hospitals, nursing or care homes and other community settings, to identify and compare the rates of mental health disorder across different job roles and places of work.

The study, carried out just after the first wave of COVID in the UK between 27 May and 23 July, 2020, found that 58% of HSCWs met the threshold for any mental health disorder; 22% met criteria for post-traumatic stress disorder (PTSD); 47% had clinically significant anxiety and 47% had depression. Symptom levels were high across all job roles and settings.

Importantly, the study found that it was not just doctors and nurses who were experiencing clinically significant distress, but all staff from across health and care.

Furthermore, the research also identified some specific mental health risk factors, principally: concern about infecting others with COVID; being unable to talk with their managers about how they were coping; feeling stigmatised (about their role); and not having had reliable access to personal protective equipment (PPE). Key predictors for PTSD included staff being redeployed to other teams and having had COVID themselves.

The research was conducted by the COVID Trauma Response Working Group, formed by UCL psychiatrists and psychologists, who are calling for immediate additional mental health support for HSCWs. This is the first UK study to assess mental health disorders across all health and social care settings during COVID-19.

Lead author, Dr Talya Greene (UCL Psychiatry and University of Haifa), said: “Our study shows that more than half of health and social care staff surveyed met criteria for a mental disorder following the first wave of COVID-19 in the UK. Importantly, we found that rates of distress were high, not only among doctors and nurses, but across a wide range of health and social care roles, such as allied health professionals, ambulance workers, hospital porters, pharmacists, and care home staff.

“Let’s be clear: we may be on the verge of a mental health crisis across the health and social care sector. So we need to make sure that specialist help is offered and accessible across all the different roles and settings.

“It is important that this support (for those that need it) is planned for the long-term. Our findings highlight the urgency for immediate long-term funding for specialist mental health services for health and social care workers.”

Co-author, Dr Jo Billings (UCL Psychiatry), said: “A really important finding from our study is that it showed that, in addition to doctors and nurses, all staff across the health and social care sector need to be offered help. This study also highlights the need for reliable access to PPE for all staff working in health and social care roles, and further investigation of barriers to communication between managers and staff. Our findings also highlight that staff redeployed into new frontline roles are at particular risk of being traumatised and are likely to require additional support during redeployment.”

Original Source

Scientists say they still have more to learn about the symptoms of Covid-19 infections, long Covid, and the new variants.

It’s been more than a year since Covid-19 landed in the United States. And the once-perplexing array of symptoms like coughing, fever, shortness of breath, and loss of taste and smell are now very familiar to doctors around the country.

The range of possibilities when someone shows up to a doctor’s office with new respiratory symptoms “is very, very narrow these days,” said Anish Mehta, medical director for clinical quality and virtual health at Eden Health, and an assistant clinical professor of medicine at the Icahn School of Medicine at Mount Sinai. “It’s probably Covid if you have fever and you’re coughing, or if you have a fever and feel muscles aches.”

Medical researchers have also learned more about how a Covid-19 infection can ripple through the circulatory, nervous, and immune systems with symptoms like rashes, blood clots, strokes, and even foot lesions dubbed “Covid toes.” They’re also more familiar with the more than 10 percent of Covid-19 survivors who are reporting long-term symptoms, including difficulty thinking and focusing, heart palpitations, hair loss, and mood swings.

Yet even now researchers are finding new symptoms. Tim Spector, a professor of molecular epidemiology at King’s College London, has been studying Covid-19 throughout the pandemic through a Covid-19 Symptom Study smartphone app. He recently started receiving reports of mouth ulcers and something he calls Covid tongue — a fuzzy yellow-white coating on the tongue.

“It came about because people sent me images of their tongue,” said Spector. “I posted them and then people started … realizing that’s what they had originally when they had Covid. It’s a strange phenomenon that no doctor thought was related.”

Though cases and hospitalizations are falling, and multiple Covid-19 vaccines are rolling out, the SARS-CoV-2 virus that causes Covid-19 is still spreading, and new variants are threatening to undo some of the progress made during the pandemic. The more the virus spreads, the more likely it is to acquire new mutations. Changes in symptoms could be a warning sign of these changes to the virus. So doctors have to remain on their toes.

“I think the lesson is unusual symptoms can come out of the blue with no clear explanation,” said Andrew Chan, a professor of immunology and infectious disease at the Harvard T.H. Chan School of Public Health, who collaborated with Spector on the symptom study app. “It has to be on every health care provider’s mind.”

The list of Covid-19 symptoms is still getting longer

The fact that Covid-19 has spread so widely, with 115 million cases worldwide to date, means the disease has had opportunities to affect people under a variety of circumstances including preexisiting health conditions, age, nutrition, living standards, and access to health care. How Covid-19 interacts with these variables is part of why there are so many different symptoms.

Original Source

As the fight against COVID-19 continues, scientists have turned to an unlikely source for a potentially effective treatment: tiny antibodies naturally generated by llamas.

While the world has welcomed the news of multiple vaccines against COVID-19, the search for effective treatments for those who contract the virus is ongoing. Now scientists are looking to what might seem to be an unlikely source: the South American llama.

Researchers are using the ultrabright X-rays of the Advanced Photon Source (APS), a U.S. Department of Energy (DOE) Office of Science User Facility at DOE’s Argonne National Laboratory, to help turn naturally generated llama antibodies into potentially effective therapies against SARS-CoV-2, the virus that causes COVID-19. Antibodies are the immune system’s natural defense against infection, and when extracted from blood, they can be used to design treatments and vaccines.

“Llamas generate these nanobodies naturally in high yields, and they fit into the pockets on the surface of proteins that larger-size antibodies can’t access.” — Jason McLellan, The University of Texas at Austin.

“We have received more than 50 llama antibodies with several proteins of SARS-CoV-2,” said Andrzej Joachimiak, director of the Structural Biology Center (SBC) at the APS and co-director of the Center for Structural Genomics of Infectious Diseases. (Researchers at the APS do not work with the live virus, but with crystals grown from simulated proteins.) These antibodies are part of ongoing collaborations with several partners, including researchers at the National Institutes of Health (NIH) and the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), Joachimiak said, and will be analyzed using the APS to see if they combat the virus’s infectivity.

While it may seem surprising that scientists are turning to llamas, there’s a very good reason for it.

Llamas belong to a group of mammals called camelids, a group that also includes camels and alpacas. Thanks to a quirk of nature, camelids produce a unique type of antibody against disease. These antibodies, often referred to as nanobodies, are about half the size of the antibodies produced by humans. They’re also remarkably stable and easy for scientists to manipulate.

This genetic quirk, which causes camelids such as llamas to produce these smaller antibodies with single protein chains, was discovered by accident in the late 1980s by scientists in Belgium. Since then, scientists have worked with camelid nanobodies to create treatments against several diseases with great success. Their small size allows them to bind to areas of viral proteins that larger antibodies cannot fit into, blocking those proteins from connecting with cells.

“Llamas generate these nanobodies naturally in high yields, and they fit into the pockets on the surface of proteins that larger-size antibodies can’t access,” said Jason McLellan, an associate professor at The University of Texas at Austin.

McLellan has years of experience working with camelid nanobodies. He and his graduate student Daniel Wrapp, along with Xavier Saelens’ group in Belgium, have isolated nanobodies that have proven effective against respiratory syncytial virus (RSV) and two coronaviruses: severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS).

When the genetic sequence of SARS-CoV-2 was released in January of 2020, McLellan, Wrapp and Saelens worked quickly to test whether any of the antibodies that they had previously isolated against the original SARS-CoV (taken from a Belgian llama named Winter) could also bind and neutralize SARS-CoV-2.  They discovered that one of these nanobodies, which they had characterized using the SBC beamlines at the APS, might be effective against SARS-CoV-2. McLellan said this nanobody — called VHH72 — is now under development as a treatment for COVID-19. He and Wrapp received a 2020 Golden Goose Award for this research.

Original Source

Drug makers are increasingly turning to monoclonal antibodies to protect the millions of people who might not be able to use vaccines. But questions swirl about their cost and long-term viability.

AS THE COVID-19 vaccine rollout gathers pace, a population is at risk of being left behind: the millions of people around the globe who lack fully functional immune systems.

While the exact number of the immunocompromised worldwide is unknown, estimates suggest that about 10 million live in the U.S. alone, or around 3 percent of the national population. The number encompasses a diverse range of vulnerabilities, including rare genetic immune deficiencies, chronic illnesses that impair the immune system such as rheumatoid arthritis, and cancer and organ-transplant patients who must take immune-suppressing medications.

For them, vaccines might not be as effective, because they are less capable of making their own antibodies to neutralize the SARS-CoV-2 virus. Instead, pharmaceutical companies around the world are racing to develop alternative treatments that bypass the immune system altogether.

The most common option is called monoclonal antibody treatments. These artificially generated antibodies mimic the body’s natural immune response by binding to key sites on the virus’ spike protein, preventing it from entering cells and reproducing. Companies including AstraZeneca, Regeneron, and Eli Lilly are currently testing whether monoclonal antibodies can protect immunocompromised people from SARS-CoV-2.

“You often find that patients who have had bone marrow transplants end up getting terrible flu and other infections, which they can’t clear without additional help,” says Nicky Longley, an infectious diseases consultant at University College London Hospitals. “It was these heavily immune-suppressed populations who did very badly during the first wave of COVID-19.”

In addition, preventing immunocompromised people from getting infected will be a key part of keeping the disease in check in the long run, says Andrew Ustianowski, an infectious disease specialist at the U.K.’s National Institute for Health Research.

“If we want to control this virus and get back into normal life, then being able to protect everybody, so we don’t have ongoing transmission in subgroups of the population, is important,” he says.

But while many scientists are excited about the potential of monoclonal antibodies to address gaps in the world’s vaccination programs, questions remain. The coming months will tell us whether these treatments are sufficiently cost-effective to be used on a large scale, if they can really provide adequate protection for months at a time, and whether using monoclonal antibodies may inadvertently do more harm than good.

Original Source

What is the latest in COVID-19 vaccine advances?

8 COVID-19 vaccines gained authorization

Experts have explained time and again that in order to contain SARS-CoV-2 and prevent more coronavirus outbreaks in the future, vaccines are of utmost importance.

At the moment, there are eight COVID-19 vaccines with authorization in countries around the world.

So far, the Pfizer-BioNTech vaccine, which is an mRNA vaccine, has gained authorization for use in 50 countries. These include the United States, the United Kingdom, and the 27 countries that make up the European Union.

The vaccine developed by Moderna and the National Institute of Allergy and Infectious Diseases (NIAID), which is also an mRNA vaccine, is currently authorized in 36 countries. These include the U.S., the U.K., and E.U. countries.

Sputnik V, which is a viral vector vaccine developed by the Russian research institute Gamaleya, is authorized in eight countries: Algeria, Argentina, Belarus, Bolivia, Guinea, Russia, Serbia, and West Bank.

Close on its heels is the Oxford-AstraZeneca viral vector vaccine, which has gained use authorization in seven countries. These are Argentina, the Dominican Republic, El Salvador, India, Mexico, Morocco, and the U.K.

Other vaccines that have gained authorization in certain countries are:

• Covishield, a viral vector vaccine authorized in India
• Covaxin, an inactivated vaccine authorized in India
• The Sinopharm vaccine, also inactivated, which is authorized in six countries, including China, Egypt, and the United Arab Emirates
• The Sinovac vaccine, also inactivated, which is authorized in China, Indonesia, and Turkey

Original Source

Researchers are calling for clinical studies on vitamin B6, so we turned to the health experts.

By this point, several published research papers and clinical trials have shown that vitamins D and C, as well as minerals such as zinc and magnesium, may reduce the severity of symptoms in COVID-19 patients. Now, one researcher is calling on scientists to explore another helpful vitamin that may have been overlooked.

In an opinion article published in the journal Frontiers in Nutrition, Thanutchaporn Kumrungsee, an assistant professor at Hiroshima University in Japan, proposed that vitamin B6 could play a pivotal role in fighting the novel coronavirus. 

“There is growing evidence that vitamin B6 exerts a protective effect against chronic diseases such as cardiovascular diseases (CVD) and diabetes by suppressing inflammation, inflammasomes, oxidative stress, and carbonyl stress,” the article reads. “Additionally, vitamin B6 deficiency is associated with lower immune function and higher susceptibility to viral infection.”

However, some health experts remain suspicious—and for good reason. Ali Webster, PhD, RD, and director of research and nutrition communications at the International Food Information Council, says it’s still too soon to determine whether or not the vitamin could help lower your risk of experiencing adverse COVID-19 symptoms.

“There are plausible biological mechanisms for it doing so, and low levels of B6 in the body are associated with a weakened immune system,” she says. “But often, the promise of a positive impact is there but the outcome of well-designed studies is disappointing.”

Webster explains that the research on taking vitamin B6 in supplement form to reduce the risk for heart disease, stroke, certain types of cancer, and even cognitive decline is a bit inconclusive, as well.

“More research is needed in each of these areas in addition to the work to determine its effect on COVID-19 severity,” she adds.

Brittany Busse, MD, associate medical director at WorkCare, agrees that more research is needed. However, Busse notes that vitamin B6 is known to have an anti-inflammatory effect on the body, which could help you in both preventing and combating adverse COVID-19 symptoms.

“There are a lot of vitamins that can help decrease inflammation, potentially,” she says. “And B6 is one of them.”

Busse also adds that the severity of COVID-19 is based largely on how much inflammation your body creates in response to the virus. Thus, it’s key to keep inflammation levels low by eating a diet that’s rich in fruits, vegetables, and legumes; engaging in regular, moderate exercise; getting plenty of sleep; and managing stress.

Original Source