Virus World

The global spread of SARS-CoV-2/COVID-19 is devastating health systems and economies worldwide. Recombinant or vaccine-induced neutralizing antibodies are used to combat the COVID-19 pandemic. However, recently emerged SARS-CoV-2 variants B.1.1.7 (UK), B.1.351 (South Africa) and B.1.1.248 (Brazil) harbor mutations in the viral spike (S) protein that may alter virus-host cell interactions and confer resistance to inhibitors and antibodies. Here, using pseudoparticles, we show that entry of UK, South Africa and Brazil variant into human cells is susceptible to blockade by entry inhibitors. In contrast, entry of the South Africa and Brazil variant was partially (Casirivimab) or fully (Bamlanivimab) resistant to antibodies used for COVID-19 treatment and was less efficiently inhibited by serum/plasma from convalescent or BNT162b2 vaccinated individuals. These results suggest that SARS-CoV-2 may escape antibody responses, which has important implications for efforts to contain the pandemic.

Preprint available (Feb. 11. 2021):

https://doi.org/10.1101/2021.02.11.430787 

Clinical setbacks reported this past week by Regeneron Pharmaceuticals and Eli Lilly have raised questions about the effectiveness of antibody therapies in patients with severe COVID-19 compared to patients with mild-to-moderate forms of the virus. Regeneron said Friday it agreed to hold off on further enrollment of patients requiring high-flow oxygen or mechanical ventilation in the Phase II/III portion (NCT04426695) of an adaptive Phase I/II/III trial assessing its two-antibody “cocktail” REGN-COV2 in hospitalized adult patients with COVID-19. In pausing enrollment of the sickest patients, Regeneron said it is following the recommendation of the trial’s independent data monitoring committee (IDMC) “based on a potential safety signal and an unfavorable risk/benefit profile at this time.” Regeneron did not disclose the potential safety signal that triggered the pause in patient enrollment—but did say it would inform the FDA of its findings, since the agency is evaluating the company’s request for an emergency use authorization (EUA) of REGN-COV2 for in mild-to-moderate outpatients at high risk for poor outcomes. Regeneron is the second developer of a leading antibody candidate against COVID-19 to suffer a clinical setback this past week. On October 26, the NIH’s National Institute of Allergy and Infectious Diseases (NIAID) halted the up-to-10,000 patient Phase III ACTIV-3 trial (NCT04501978) it was conducting to assess the safety and effectiveness of Lilly’s LY-CoV555, recently renamed bamlanivimab, compared with Gilead Sciences’ Veklury™ (remdesivir) and placebo in people who have been hospitalized with COVID-19.

“Disappointing replication”

“A disappointing replication: monoclonal antibodies to #SARSCoV2 don’t provide benefit to hospitalized patients w/ moderate-severe illness,” tweeted Eric Topol, MD, founder and director of the Scripps Translational Research Institute, on Friday.  Topol, who is also professor, molecular medicine and executive vice president of Scripps Research, added that the Regeneron and Lilly disappointments reflected “the need to treat #COVID19 early or preventatively.” Florian Krammer, PhD, professor at the department of microbiology, Icahn School of Medicine at Mount Sinai, also noted in a Twitter thread that early in COVID-19, monoclonal antibodies and other antivirals are likely to help infected patients.  “Late in infection, our own immune system does the damage, and immunomodulatory drugs likely help at this stage (like dexamethasone),” Krammer said. “Using mAbs late (like in the trials stopped by Eli Lilly and Regeneron) was unlikely to work. But using them early is very promising.” Reflecting that promise, the IDMC in Regeneron’s hospitalized patient trial of REGN-COV2 also recommended continuing enrollment of the less severely injured hospitalized patients—namely those requiring either no or low-flow oxygen, “as the risk/benefit remains acceptable in these cohorts.” The trial has an estimated enrollment of 2,970 participants....

An inhaled neutralizing antibody cleared the novel coronavirus from infected hamsters at a far lower dose compared with other experimental monoclonal antibodies. The drug is now being developed by Aridis Pharmaceuticals and could offer a self-administered option for COVID-19 if it succeeds in human testing. Monoclonal antibodies for COVID-19 recently took center stage as Regeneron’s experimental cocktail was used to treat President Donald Trump, who went on to rave about it. But that therapy, as is typical for antibody drugs, needs to be injected into the body. Aridis Pharmaceuticals is working on an inhaled neutralizing antibody for COVID-19 dubbed AR-711, which was discovered using samples from patients who had recovered from COVID-19. The drug successfully cleared signs of SARS-CoV-2 virus from infected hamsters at a far lower dose compared with other experimental monoclonal antibodies, according to results published on preprint site bioRxiv.

Encouraged by the preclinical results, Aridis plans to start testing AR-711 in non-hospitalized mild-to-moderate COVID-19 patients in the first half of next year. If the drug eventually succeeds in human trials, the company could offer a self-administered option for COVID-19, saving patients the need to travel to healthcare facilities for infusions that could take hours to complete. Encouraged by the preclinical results, Aridis plans to start testing AR-711 in non-hospitalized mild-to-moderate COVID-19 patients in the first half of next year. If the drug eventually succeeds in human trials, the company could offer a self-administered option for COVID-19, saving patients the need to travel to healthcare facilities for infusions that could take hours to complete. Most antibodies and vaccines that are being developed by drug companies target the receptor-binding domain (RBD) of the novel coronavirus’s spike protein. This small part plays an important role in viral infection, as it docks to the ACE2 receptors on human cells to gain entry.

A team of scientists from the University of Alabama at Birmingham and the Texas Biomedical Research Institute isolated RBD-specific B cells from recovered patients to produce monoclonal antibodies that can neutralize SARS-CoV-2, the virus that causes COVID-19. One candidate, 1212C2, emerged with potent inhibition of RBD binding to ACE2.  Recent research has shown hamsters to be a good model for COVID-19-related research. So the researchers injected the antibody into hamsters’ abdomens before challenging the animals with SARS-CoV-2. While control hamsters developed live virus in their nasal cavities and lungs, animals that got 1212C2 before the challenge showed a meaningful viral load reduction after two days, and three of four animals eradicated the virus after four days. The treated hamsters also experienced significantly less lung disease compared with control rodents. The scientists further modified 1212C2 to increase its half-life and used a proprietary technology to stabilize it to allow for delivery with a nebulizer. In hamsters, the inhaled version cleared COVID-19 in the lungs of all animals after four days, while all control hamsters had detectable virus in their lungs at that time point. Lung lesions were also significantly decreased in 1212C2-treated hamsters compared with those in the control group...

Preprint available in bioRxiv (Oct. 14, 2020):

https://doi.org/10.1101/2020.10.14.339150

The drugmaker’s experimental antibody treatment is similar to the one President Trump received from Regeneron. A government-sponsored clinical trial that is testing an antibody treatment for Covid-19 developed by the drugmaker Eli Lilly has been paused because of a “potential safety concern,” according to emails that government officials sent on Tuesday to researchers at testing sites. The company confirmed the pause. The news comes just a day after Johnson & Johnson announced the pause of its coronavirus vaccine trial because of a sick volunteer, and a month after AstraZeneca’s vaccine trial was halted over concerns about two participants who had fallen ill after getting the company’s vaccine. The Eli Lilly trial was designed to test the benefits of the antibody therapy on hundreds of people hospitalized with Covid-19, compared with a placebo. All of the study participants also received another experimental drug, remdesivir, which has become commonly used to treat coronavirus patients. It is unclear exactly what safety issues prompted the pause. In large clinical trials, pauses are not unusual, and declines in health in volunteers are not necessarily the result of the experimental drug or vaccine. Such halts are meant to allow an independent board of scientific experts to review the data and determine whether the event may have been related to the treatment or occurred by chance.

Enrollment for the Eli Lilly trial, which was sponsored by several branches of the National Institutes of Health and the Department of Veterans Affairs, among other organizations, had been continuing. But on Tuesday, multiple officials sent emails to researchers telling them to stop adding volunteers to the study out of an “abundance of caution.” In a statement, an N.I.H. spokeswoman said the trial, which had enrolled 326 Covid-19 patients, was paused when the independent safety board found that after five days of treatment, the group of patients who had received the antibodies showed a different “clinical status” than the group who had received a saline placebo — a difference that crossed a predetermined threshold for safety. The N.I.H. statement did not specify the nature of the participants’ conditions. But the so-called stopping rules for the trial lay out the conditions for “futility” — the idea that a treatment has a very low chance of working, based on the data so far. A trial could also be halted if there is evidence that patients in one group are faring much worse than those in the other. Given the ambiguity in the statements released on Tuesday, all scenarios remain possible, said Dr. Eric Topol, a clinical trials expert at the Scripps Research Institute. “It’s so amorphous,” Dr. Topol said...

Scientific American is the essential guide to the most awe-inspiring advances in science and technology, explaining how they change our understanding of the world and shape our lives. While the world waits for a COVID-19 vaccine, many researchers are focused on developing effective therapeutics that can be rolled out quickly and cheaply. Monoclonal antibodies—a potentially promising laboratory-manufactured therapy modeled on antibodies extracted from the blood of recovering patients—made headlines recently when President Trump received a not-yet-approved antibody cocktail made by the company Regeneron. And pharmaceutical giant Eli Lilly recently announced that its monoclonal antibody reduced the risk of hospitalization in 300 people who had mild or moderate symptoms of COVID-19, in a small clinical trial. But David Baker, a biochemist at the University of Washington’s Institute for Protein Design, and his colleagues think they can produce an even better therapy. They have designed a synthetic peptide—a short string of amino acids, the building blocks of proteins—20 times smaller than a monoclonal antibody that is designed to bind to the infamous “spike” protein on the surface of the SARS-CoV-2 virus particle. Doing so would directly block the virus from binding to the ACE-2 receptors on human cells, functioning much like an antibody produced by an infected person’s immune system. Baker and his colleagues described these “miniprotein inhibitors” in September in Science. Although the study only tested these synthetic proteins in the lab, mixing viral particles with monkey cells in vitro, he says that unpublished data show they can protect mice and hamsters from SARS-CoV-2 infection. 

“We built these [tiny proteins] from scratch based on ‘first principles,’ using computers to model all the biochemical details of a theoretical protein that could stick to the virus,” explains Baker, who was awarded a $3 million Breakthrough Prize earlier in September for his decades of work pioneering the field of synthetic protein design. His team used computers to digitally design more than two million candidate “miniproteins,” crunched the data using algorithms, sifted out 118,000 candidate genes that encode these proteins, manufactured the proteins from scratch, and tested them directly against the virus in the lab—finding that seven designs could effectively bind to and thus disable the virus. Over the course of 3.5 billion years evolution has produced an incredible array of proteins and peptides. In recent years biochemists have tracked down and used some of these to create new drugs, such as Eptifibatide, an antiplatelet drug administered to prevent heart attacks whose active ingredient is extracted from the venom of the southern pygmy rattlesnake. The Protein Data Bank, an online repository of protein sequences and educational tools, contains the amino acid sequences and full 3-D structures for more than 160,000 peptides and proteins—but the natural world contains hundreds of millions of proteins. 

“It’s very challenging to discover in nature a peptide that does exactly what you want it to do,” explains Gaurav Bhardwaj, also a biochemist at the Institute for Protein Design, but who was not involved in the Science study. He is trying to design a bespoke peptide that would prevent SARS-CoV-2 from replicating within human cells. “Now we can computationally explore the possible design configurations for a peptide in order to perform the exact functions that we want.” Every protein’s function depends on its structure. Interactions between the atoms of the protein’s amino acids cause these chains to self-assemble in less than a second into a complex array of spirals and pleats. As the chain of amino acids grows, these helices and rippled sheets stack on top of and around one another into a dizzyingly complex series of folds, and it is these folds that give proteins their shape and function. Yet figuring out how one amino acid sequence turns into a specific fold has been a torturously difficult task, and it was only in the 1990s—with ever expanding databases of protein information—that scientists could begin to link sequence to form. “We can make up completely new proteins that have never been seen in nature because we now understand the nature of protein folding,” Baker says. “Our ability to use computers to design ‘de novo’ proteins has really only come into its own in the last few years–we might not have been able to apply ourselves to COVID-19 if the pandemic had happened five years ago....

The company said that doses of the unproven treatment would be available for 50,000 patients. It’s impossible to know whether it helped the president. The drugmaker Regeneron said on Wednesday that it had submitted an application to the Food and Drug Administration for emergency approval of the experimental antibody cocktail that President Trump had praised just hours earlier without evidence as a “cure” for the coronavirus. The company said access to the treatment would be extremely limited at first, with only enough doses for 50,000 patients, a far cry from the “hundreds of thousands” of doses that Mr. Trump, in a video released on Wednesday, said he would soon be making available to Americans free of charge. In the five-minute video, Mr. Trump said that it was a “blessing from God” that he had been infected with the coronavirus and that the Regeneron cocktail had suddenly made him feel better. “I felt unbelievable,” he said. “I felt good immediately.”  There is no evidence that the treatment is the reason he was feeling better, and his doctors have said he has taken other drugs as well. 

Mr. Trump gave the impression that he would push the F.D.A. to approve Regeneron’s treatment, even though the agency’s scientists are supposed to make independent decisions about approvals. “I have emergency-use authorization all set, and we’ve got to get it signed now,” Mr. Trump said. A spokeswoman for the F.D.A. declined to comment on Wednesday, saying the agency does not confirm or deny product applications. The news of Regeneron’s application on the same day that Mr. Trump effusively praised the unproven drug is likely to intensify fears that the president is pressuring federal health agencies to make decisions aimed at benefiting him politically. In the video, Mr. Trump repeated his desire to get a vaccine approved before the election on Nov. 3, even though the vaccine makers themselves have said that is highly unlikely...

Experts caution more data from larger trials will be needed to know how potentially beneficial monoclonal antibodies are. New data from the biotechnology firm Regeneron seem likely to add to the excitement about drugs called monoclonal antibodies as treatments for Covid-19, but experts caution more data will be needed to know how potentially beneficial the medicines are.  A high dose of the company’s antibody cocktail, REGN-COV2, led levels of the virus to decrease more quickly in infected, non-hospitalized patients, potentially indicating the treatment may help them get better, Regeneron reported Tuesday via press release. Full results will be published at a later date.  “There’s nothing bad about these results, you just can’t say much about how transformative this is going to be,” said Eric Topol, director of the Scripps Research Translational Institute. As with data from a similar antibody, developed by Eli Lilly, he warned that the data so far should not be enough for the Food and Drug Administration to grant an emergency use authorization.   “This doesn’t cut it, but it’s moving in the right direction, that’s for sure,” Topol said. In a notable finding, the data seem to show that the antibody had a bigger effect in patients who tested positive for SARS-CoV-2 but had not created high levels of their own antibodies against the virus. In this group, even a lower dose of the Regeneron antibodies seemed to result in patients getting better faster.

The data add to the early results from Eli Lilly, which showed a reduction in virus levels for patients at some doses and a tantalizing hint that the treatment might help keep patients out of the hospital.  Monoclonal antibodies are synthetic versions of one of the immune system’s own weapons against invaders. From the start of the pandemic, some experts have been most hopeful about this technology to create new medicines to fight SARS-CoV-2, the virus that causes Covid-19. But that potential could be limited by the ability to manufacture large quantities of the treatments. Regeneron has reached an agreement with Roche, the Swiss drug giant, to increase its production capacity. Experts said longer studies, which are ongoing, will be needed to really know if the antibody treatments make patients better. “We are highly encouraged by the robust and consistent nature of these initial data, as well as the emerging well-tolerated safety profile, and we have begun discussing our findings with regulatory authorities while continuing our ongoing trials,” said George Yancopoulos, Regeneron’s chief scientific officer. 

The data are from a 275-patient portion of Regeneron’s study testing REGN-COV2 in patients who have tested positive for Covid-19 but who are not in the hospital. Patients received either placebo, 2.4 grams of REGN-COV2, or 8 grams of REGN-COV2. (The antibody cocktail is delivered intravenously.) Those who received the high dose saw viral levels decrease by 0.60 log10 copies of the virus per milliliter compared to placebo after seven days, a result that was statistically significant. In the lower dose, there was a 0.23 log10 reduction, which was not statistically significant. Regeneron did not give the total amount of virus detected in its press release. At the beginning of the study, Regeneron tested patients not only to see if they had SARS-CoV-2, but also to see if they created their own antibodies against the virus. The company found that 45% of patients had created antibodies, 41% had not, and 14% had unclear results. Those without antibodies had higher levels of virus in swabs from their noses from the start. And those who had created their own antibodies got better much faster. Patients with their own antibodies in the placebo group saw symptoms disappear in seven days, while in those whom antibodies were not detected, it took 13 days for symptoms to go away. Giving the patients Regeneron’s synthetic antibody had a far greater effect on the amount of virus detected in those who did not have an antibody response before treatment. There was a reduction of 0.6 log10 copies/mL in the patients who received the high dose, and 0.51 in those who received the low dose, both of them statistically significant. The reductions were also greater in patients who had higher levels of virus. And in those patients who did not have detectable antibodies at the study’s outset, Regeneron’s antibody cocktail improved symptoms. In this group, symptoms were alleviated in 13 days on placebo, eight days in the high-dose group, and six days in the low-dose group.  Among the 275 patients for whom data are being reported, 50% were Hispanic, 14% were African American, and the rest of the racial breakdown was not disclosed. On average, they were 45 years old. Forty-nine percent of participants were male and 51% were female...

Regeneron's Press Release:

https://investor.regeneron.com/news-releases/news-release-details/regenerons-regn-cov2-antibody-cocktail-reduced-viral-levels-and 

Lilly, which is developing the drug with the biotechnology firm Abcellera, tested three doses of its antibody against placebo. A drug being developed by Eli Lilly helped sick patients rid their systems of the virus that causes Covid-19 sooner and may have prevented them from landing in the hospital, according to newly released data. The drug is what is known as a monoclonal antibody, which experts view as being among the most likely technologies to help treat Covid-19. It’s a manufactured version of the antibodies that the body uses as part of its response to a virus.  “This is a good start,” said Eric Topol, the director and founder of the Scripps Research Translational Institute. “A lot is pinned not only on Lilly but on the whole family of these [monoclonal antibodies], because even though they’re expensive and they’re not going to make a gajillion doses, they could make a big difference in the whole landscape of the pandemic.” Lilly, which is developing the drug with the biotechnology firm Abcellera, tested three doses of its antibody against placebo in a trial enrolling about 450 patients recently diagnosed with mild to moderate Covid-19. The middle dose, 2,800 mg, met the trial’s primary goal of significantly reducing patients’ levels of SARS-CoV-2 after 11 days. But other doses of the drug did not meet that goal, including a higher dose of 7,000 mg and a lower one of 700 mg. That could raise the risk that the benefit was due to chance, because normally one expects a medicine to become more effective as the dose increases, known as a dose response.

In a statement, Lilly said the problem may have stemmed from how the study chose to assess how much virus was detectable after 11 days. Most patients, including those who received placebo, had almost no virus at that time point. The company said that an analysis at day three showed the lower viral levels among those who received the antibody. In a more tantalizing finding, the medicine also appeared to reduce patients’ odds of ending up in the hospital. Just 1.7% of patients who received the drug, called LY-CoV555, eventually went to the emergency room or were hospitalized, compared with 6% of those who took placebo. That amounts to 72% relative reduction in risk. Those hospitalization data, though, are from a small number of patients, again increasing the odds that the finding won’t hold up with further study. Five of 302 patients on LY-CoV555 were hospitalized, compared to nine of 150 patients who received placebo. Lilly declined to confirm the difference is statistically significant, citing the need for full publication of the results.

“This is extremely exciting, and maybe a pivotal moment in the fight against Covid-19, said Daniel Skovronsky, Lilly’s chief scientific officer. “I think this should give us confidence that neutralizing antibodies are going to be an important part of the solution for ours and other companies, and that  we will win the fight against Covid-19 through medicine and innovation.” Skovronsky noted that studies of the antibody began only six months ago, and said that, although two doses missed on the 11-day endpoint, the antibody’s impact on symptoms and hospitalization gave him confidence in the result. He said that Lilly will share the results with regulators such as the Food and Drug Administration, and hoped to have discussions about a possible emergency use authorization (EUA). “We will be discussing with regulators what the appropriate next steps are,” Skovronsky said. “So, of course, those discussions will include additional clinical trials as well as other options such as EUA. It’s a small dataset for sure, we we have 450 patients in this data set, but the magnitude of the impact on a hard end point years is very exciting and potentially meaningful for patients.”..

Company's Release available in this site (Sept. 16, 2020):

https://investor.lilly.com/node/43721/pdf

University of Pittsburgh School of Medicine scientists have isolated the smallest biological molecule to date that completely and specifically neutralizes the SARS-CoV-2 virus, which is the cause of COVID-19. This antibody component, which is 10 times smaller than a full-sized antibody, has been used to construct a drug — known as Ab8 — for potential use as a therapeutic and prophylactic against SARS-CoV-2. The researchers report today (September 14, 2020) in the journal Cell that Ab8 is highly effective in preventing and treating SARS-CoV-2 infection in mice and hamsters. Its tiny size not only increases its potential for diffusion in tissues to better neutralize the virus, but also makes it possible to administer the drug by alternative routes, including inhalation. Importantly, it does not bind to human cells — a good sign that it won’t have negative side-effects in people. Ab8 was evaluated in conjunction with scientists from the University of North Carolina at Chapel Hill (UNC) and University of Texas Medical Branch (UTMB) at Galveston, as well as the University of British Columbia and University of Saskatchewan.

“Ab8 not only has potential as therapy for COVID-19, but it also could be used to keep people from getting SARS-CoV-2 infections,” said co-author John Mellors, M.D., chief of the Division of Infectious Diseases at UPMC and Pitt. “Antibodies of larger size have worked against other infectious diseases and have been well tolerated, giving us hope that it could be an effective treatment for patients with COVID-19 and for protection of those who have never had the infection and are not immune.” The tiny antibody component is the variable, heavy chain (VH) domain of an immunoglobulin, which is a type of antibody found in the blood. It was found by “fishing” in a pool of more than 100 billion potential candidates using the SARS-CoV-2 spike protein as bait. Ab8 is created when the VH domain is fused to part of the immunoglobulin tail region, adding the immune functions of a full-size antibody without the bulk. Abound Bio, a newly formed UPMC-backed company, has licensed Ab8 for worldwide development. Dimiter Dimitrov, Ph.D., senior author of the Cell publication and director of Pitt’s Center for Antibody Therapeutics, was one of the first to discover neutralizing antibodies for the original SARS coronavirus in 2003. In the ensuing years, his team discovered potent antibodies against many other infectious diseases, including those caused by MERS-CoV, dengue, Hendra and Nipah viruses. The antibody against Hendra and Nipah viruses has been evaluated in humans and approved for clinical use on a compassionate basis in Australia.

Clinical trials are testing convalescent plasma — which contains antibodies from people who already had COVID-19 — as a treatment for those battling the infection, but there isn’t enough plasma for those who might need it, and it isn’t proven to work. That’s why Dimitrov and his team set out to isolate the gene for one or more antibodies that block the SARS-CoV-2 virus, which would allow for mass production. In February, Wei Li, Ph.D., assistant director of Pitt’s Center for Therapeutic Antibodies and co-lead author of the research, began sifting through large libraries of antibody components made using human blood samples and found multiple therapeutic antibody candidates, including Ab8, in record time. Then a team at UTMB’s Center for Biodefense and Emerging Diseases and Galveston National Laboratory, led by Chien-Te Kent Tseng, Ph.D., tested Ab8 using live SARS-CoV-2 virus. At very low concentrations, Ab8 completely blocked the virus from entering cells. With those results in hand, Ralph Baric, Ph.D., and his UNC colleagues tested Ab8 at varying concentrations in mice using a modified version of SARS-CoV-2. Even at the lowest dose, Ab8 decreased by 10-fold the amount of infectious virus in those mice compared to their untreated counterparts. Ab8 also was effective in treating and preventing SARS-CoV-2 infection in hamsters, as evaluated by Darryl Falzarano, Ph.D., and colleagues at the University of Saskatchewan. Sriram Subramaniam, Ph.D., and his colleagues at the University of British Columbia uncovered the unique way Ab8 neutralizes the virus so effectively by using sophisticated electron microscopic techniques.

Original study published in Cell (August 31, 2020):

https://doi.org/10.1016/j.cell.2020.09.007

Jill Horowitz stood outside the Quaker Ridge Shopping Center in New Rochelle, N.Y.—an early COVID-19 hotspot—in March, stopping shoppers as they walked into the grocery store. She handed them blue pamphlets soliciting volunteers for a Rockefeller University antibody research study. “I would say, ‘Would you like to help us find a cure?’” says Horowitz, executive director of strategic operations at Rockefeller’s Laboratory of Molecular Immunology. “I didn’t even have to mention coronavirus. This neighborhood was completely subsumed.”

Within weeks—and after receiving more than 2,000 phone calls from volunteers—the university had selected more than 100 participants who had recovered from COVID-19 or had come into contact with someone who had the disease, says Michel Nussenzweig, head of the laboratory. From participants’ blood samples, he and his team isolated more than a dozen potent antibodies that “neutralized,” or deactivated, SARS-CoV-2, the virus that causes COVID-19, in a lab dish. The study is one of a growing number showing the body produces antibodies against this deadly disease. The findings suggest that therapies based on these proteins could be a promising approach. But experts caution that such therapies must clear several hurdles before they can be deployed against COVID-19.

Our body naturally produces antibodies to help us fight infections. Many researchers believe that by isolating antibodies from people who have recovered from COVID-19 and then artificially reproducing them, we can develop therapies that could minimize symptoms and speed recovery from the disease. Some of the same scientists are also eyeing the prophylactic use of copied antibodies to stave off an infection in those who have not contracted the new coronavirus. (Therapies based on these so-called monoclonal antibodies are different from convalescent plasma treatments, which have also made headlines recently. In the latter, plasma is taken from people who have recovered from COVID-19 and transfused directly into those who are infected. The jury is still out on whether convalescent plasma is truly effective against the disease.)...

Research teams hunt antiviral “neuts” in blood of recovered COVID-19 patients, tweak existing antibodies or design new ones. One of the first people to be diagnosed with COVID-19 in the United States hopes a legacy of her nightmare—the antibodies it left in her blood—will lead to a drug that can help others infected with the novel coronavirus that has now killed more than 250,000 people worldwide. Early this year, the woman had just learned of the outbreak in Wuhan, China, when she flew to Beijing to celebrate the Lunar New Year with her elderly parents and extended family. A brother from Wuhan joined the gathering on 23 January, catching one of the last flights out before the city went into lockdown. Days later, her father developed a fever, but the family wasn’t concerned. “My dad always has some fever in the winter,” says the woman, a researcher who asked to be called Dr. X to protect her privacy.

On 28 January, her brother also developed a fever. The next day, on her scheduled flight home, a nervous Dr. X wore a mask, brought disinfectant wipes and cleaned everything she touched, and didn’t accept any food or drinks from flight attendants. “I treated myself as a potential infectious source.” Her husband picked her up at the airport, wearing a mask. With the car windows rolled down, they drove to an emergency room to request a coronavirus test. “I didn’t have a fever, so they didn’t really take me seriously,” she says. But coincidentally, her brother texted as she waited to be seen: He had COVID-19. So she received a test. Days later, after she quarantined herself, developed mild COVID-19 symptoms, and then re­bounded,, the result came back positive....

Regeneron's therapy is part of a class of treatments known as monoclonal antibodies, which are made to act as immune cells that scientists hope can fight infections. The Food and Drug Administration on Saturday granted an emergency use authorization for Regeneron’s Covid-19 antibody treatment, the experimental therapy given to President Donald Trump when he contracted the coronavirus in October. Regeneron submitted an emergency use application that month after preclinical studies showed that the therapy, called REGN-COV2, reduced the amount of virus and associated damage in the lungs of non-human primates. The company said trial data also shows the drug reduces medical visits in patients with mild-to-moderate Covid-19. “The FDA remains committed to advancing the nation’s public health during this unprecedented pandemic. Authorizing these monoclonal antibody therapies may help outpatients avoid hospitalization and alleviate the burden on our health care system,” said FDA Commissioner Stephen M. Hahn. Regeneron’s therapy is part of a class of treatments known as monoclonal antibodies, which are made to act as immune cells that scientists hope can fight infections. Monoclonal antibody treatments gained widespread attention after news that Trump received Regeneron’s antibody cocktail. As Trump’s health improved, he touted it as a “cure.” But Regeneron’s CEO, Dr. Leonard Schleifer, has stressed that more testing is required.

“Some people don’t know how to define therapeutic. I view it different. It’s a cure,” Trump said in a video posted Oct. 7 on Twitter. “For me, I walked in. I didn’t feel good. A short 24 hours later, I was feeling great. I wanted to get out of the hospital. And that’s what I want for everybody. I want everybody to be given the same treatment as your president because I feel great.” Regeneron’s authorization comes after the FDA announced on Nov. 9 that it had authorized Eli Lilly’s antibody treatment – called bamlanivimab –for people newly infected with Covid and are at risk of developing a severe form of the disease. Officials said the treatment shouldn’t be used for hospitalized patients because there is no data to show the drug is helpful at that stage of the disease. The authorization will expand the number of drugs at doctors’ disposal to fight the virus, which continues to rapidly spread across the United States and other parts of the world. Before the authorization, people could only get the drug as part of an FDA program that gives some patients limited access to investigational medical products. Gilead Sciences’ antiviral drug remdesivir is the first and only fully approved treatment in the U.S. for Covid.

FDA Authorization Letter (Nov. 21, 2020):

https://www.fda.gov/media/143891/download

A study of a drug that mutes the body’s immune response found that it did not prevent the deaths of people with moderate COVID-19, dealing a blow to a once-popular hypothesis about treatments for the disease. In some people with severe COVID-19, the immune system launches an excessive inflammatory response, suggesting a link between grave illness and an overly vigorous immune defence against SARS-CoV-2. The link is bolstered by the association between high levels of a protein called IL-6, which stimulates the immune system, and both death and the need for ventilation in people with COVID-19.

John Stone at the Massachusetts General Hospital in Boston and his colleagues tried to dampen inflammation in people with COVID-19 by treating them with the drug tocilizumab, which interferes with IL-6 activity (J. H. Stone et al. N. Engl. J. Med. https://doi.org/ffjp; 2020). But in a randomized, controlled trial of 243 people with moderate disease, the team found no statistically significant reduction in deaths or the need for ventilation among those who received tocilizumab compared with those who didn’t. The study does not rule out the possibility that a larger trial with more statistical power could uncover a benefit.

U.S. regulators Wednesday approved the first drug for the treatment of Ebola. The Food and Drug Administration OK'd the drug developed by Regeneron Pharmaceuticals for treating adults and children with the Zaire Ebola virus strain, the most deadly of six known types. It typically kills 60% to 90% of patients. The drug was one of four tested during an outbreak in Congo that killed nearly 2,300 people before it ended in June. Survival was significantly better in study participants given Regeneron’s Inmazeb or a second experimental drug. The study was ended ahead of schedule last year so all patients could get access to those drugs. Regeneron’s treatment is a combination of three antibodies that work by killing the virus. It’s given once by IV. “When you have three drugs that bind to the (virus), there’s a low probability that the virus can evade all of them,” said Leah Lipsich, who heads Regeneron’s global program for infectious diseases. She said that should help prevent the virus from becoming resistant to the drug.

Seeking U.S. approval first is a common strategy for drugmakers developing treatments for diseases mainly found in the tropics and in developing countries. The FDA’s action will make it easier for Regeneron to get approval or allow emergency use during outbreaks in African countries, where the approval process is not straightforward, Lipsich said. The study in Congo involved 681 people, who were give one of four treatments. After four weeks, about a third of those who got Regeneron’s drug had died. Results were about the same for a second drug. But about half had died among the groups given one of the other two drugs, ZMapp or remdesivir. Gilead Science’s remdesivir is now being used as a treatment for coronavirus. Ebola is very contagious and is spread mainly through contact with body fluids from infected people. Symptoms include fever, muscle pain, vomiting, kidney and liver damage, and sometimes internal and external bleeding. The FDA approved the first vaccine for Ebola last December. The U.S. government, which helped fund the approved drug’s development, will buy thousands of doses over the next six years to go into the Strategic National Stockpile. Ebola cases are rare in the U.S., but occasionally are diagnosed in travelers returning from areas with an outbreak.

FDA release (Oct. 14, 2020):

https://www.fda.gov/news-events/press-announcements/fda-approves-first-treatment-ebola-virus

AstraZeneca’s long-acting antibody (LAAB) combination, AZD7442, will advance into two Phase III clinical trials in more than 6,000 participants at sites in and outside the US that are due to begin in the next weeks. The LAABs have been engineered with AstraZeneca’s proprietary half-life extension technology to increase the durability of the therapy for six to 12 months following a single administration. The combination of two LAABs is also designed to reduce the risk of resistance developed by the SARS-CoV-2 virus. The Company has received support of around $486m from the US Government for the development and supply of AZD7442 under an agreement with the Biomedical Advanced Research and Development Authority (BARDA), part of the Office of the Assistant Secretary for Preparedness and Response at the US Department of Health and Human Services, and the Department of Defense Joint Program Executive Office for Chemical, Biological, Radiological and Nuclear Defense.

One trial will evaluate the safety and efficacy of AZD7442 to prevent infection for up to 12 months, in approximately 5,000 participants. The second trial will evaluate post-exposure prophylaxis and pre-emptive treatment in approximately 1,100 participants. AstraZeneca is planning additional trials to evaluate AZD7442 in approximately 4,000 patients for the treatment of COVID-19. AstraZeneca plans to supply up to 100,000 doses starting towards the end of 2020 and the US Government can acquire up to an additional one million doses in 2021 under a separate agreement. Pascal Soriot, Chief Executive Officer, said: “This agreement with the US Government will help accelerate the development of our long-acting antibody combination which has the potential to provide immediate and long-lasting effect in both preventing and treating COVID-19 infections. We will be evaluating the LAAB combination in different settings from prophylaxis, to outpatient treatment to hospitalisation, with a focus on helping the most vulnerable people.”

LAABs mimic natural antibodies and have the potential to treat and prevent disease progression in patients already infected with the virus, as well as to be given as a preventative intervention prior to exposure to the virus. A LAAB combination could be complementary to vaccines as a prophylactic agent, e.g. for people for whom a vaccine may not be appropriate or to provide added protection for high-risk populations. It could also be used to treat people who have been infected. Today’s agreement builds on previous funding of more than $25m from US government agencies BARDA and the Defense Advanced Research Projects Agency for the discovery and evaluation of the monoclonal antibodies, as well as the Phase I clinical trial started in August 2020 to assess safety, tolerability and pharmacokinetics of AZD7442 in healthy individuals.

The Milken Institute’s COVID-19 Treatment and Vaccine Tracker tracks the development of treatments and vaccines for COVID-19 (coronavirus). Explore the latest updates on the urgent race to develop a COVID-19 vaccine.

FasterCures, a center of the Milken Institute, has curated one of the most detailed and complete databases of treatments and vaccines for COVID-19. The database tracks over 500 therapeutics and prophylactics generated from publicly-available information from validated sources. The database is searchable, and information can be filtered by multiple criteria, including among others the stage of the therapy or vaccine, type of product, developer, and sponsors of clinical trials. Each entry contains important information such as dates and key milestones of each vaccine or therapy, and links to clinical trials and key research publications.

When visiting the site ensure you click on the spreadsheet link to access the searchable and filter options of the database tracker

Available at https://covid-19tracker.milkeninstitute.org/

U.S. President Donald Trump has received a promising but experimental COVID-19 drug still in clinical trials, according to a White House statement released Friday afternoon, following his diagnosis with the disease. Sean Conley, the President’s personal physician, wrote in a memo that he treated Trump with an eight-gram dose of Regeneron’s experimental antibody cocktail. Trump has also received zinc, vitamin D, aspirin, melatonin and a heartburn drug thought to help fight COVID-19. Regeneron on Tuesday announced promising results related to its monoclonal antibodies—drugs that mimic the human body’s natural immune response. When the body detects an infection, it deploys proteins called antibodies to help fight it off. Monoclonal antibodies essentially kickstart that process with synthetic proteins. In preliminary results from a trial of 275 non-hospitalized COVID-19 patients who were treated with either the antibody cocktail or a placebo, Regeneron’s cocktail reduced the amount of virus in patients’ systems and helped alleviate their symptoms, the company says. The therapy worked particularly well for patients whose immune systems failed to mount a natural response to SARS-CoV-2, the virus that causes COVID-19, according to Regeneron’s results.

While those are promising results, they have yet to be peer-reviewed, and Regeneron’s therapy has not yet been cleared by the U.S. Food and Drug Administration. After the trial’s findings were released, executives said they planned to “rapidly” discuss them with the FDA, CNBC reports. Regeneron has enrolled participants for a larger study to confirm and build upon the results of its first trial. Trump is “fatigued but in good spirits” following his diagnosis with COVID-19, Conley wrote in his memo. He has reportedly experienced mild symptoms so far. First Lady Melania Trump, who also tested positive for the coronavirus, has a headache and mild cough, according to the memo. Trump is being taken to Walter Reed National Military Medical Center for a “few days,” the Associated Press reported late Friday afternoon.

A mix of ultrapotent antibodies from recovered COVID-19 patients has been shown to recognize and lock down the infection machinery of the pandemic coronavirus and keep it from entering cells. Each of the antibody types performs these overlapping tasks slightly differently. Low doses of these antibodies, individually or as a cocktail, were also shown to protect hamsters from infection when exposed to the coronavirus by preventing it from replicating in their lungs. An advantage of such cocktails is that they might also prevent the natural mutant forms of the virus that arose during this pandemic to escape treatment. As some variants in the infection machinery have already been discovered during the coronavirus pandemic, using a mix of antibodies allows for neutralization of a broad spectrum of such viral variants. In addition to preventing virus entry into host cells, the presence of the antibodies also seems to set off the infection-fighting actions of other immune cells, which arrive to clear out the virus. "We believe that leveraging multiple, distinct, complementary mechanisms of action could provide additional benefits for clinical applications," the researchers noted.

The researchers determined how the antibodies worked on a molecular level through cryo-electron microscopy studies of the resulting changes in the configuration of the virus infection machinery. Besides directly preventing interactions with the host receptor, one of the two discovered antibodies locks the infection machinery in an inactive conformation, meaning it could not fuse with the host membrane on the surface of the cell. If unable to fuse, the coronavirus cannot break in and deliver its RNA to commandeer the cell.  The findings of this research are reported Sept. 24 in a rapid release paper in Science. Here is the paper. The senior authors were Dr. Katja Fink of Vir Biotechnology and Dr. David Veesler, associate professor of biochemistry at the University of Washington School of Medicine. Veesler has studied the molecular structure and infection mechanisms of a variety of coronaviruses and other viruses. The lead authors were M. Alejandra Tortorici of the UW Department of Biochemistry and the Institut Pasteur in Paris, and Martina Beltramello of Humab BioMed, a subsidiary of Vir Biotechnology in Switzerland. Researchers from Washington University in St Louis, Rega Institute in Belgium, the University of Milan, Italy, and the University of Texas in Dallas also collaborated on the research.

Efficient therapeutic options are needed to control the spread of SARS-CoV-2 that has caused more than 978,000 fatalities worldwide. While the world awaits approved vaccines, pharmaceuticals to prevent or treat infections from the pandemic coronavirus are being sought that might be quicker to develop and test. These might both address the gap until vaccines are widely distributed, and still be needed for use after vaccines are available. "Our results pave the way to implement antibody cocktails for prophylaxis or therapy that might have the advantage of circumventing or limiting the emergence of viral escape mutants," the researchers noted. The antibody cocktail in their study needs to undergo trials in humans to determine safety and effectiveness.

Original study published in Science (Sept. 24, 2020):

https://doi.org/10.1126/science.abe3354

The world's largest randomised trial of potential medicines for COVID-19 is to add Regeneron's experimental antiviral antibody cocktail REGN-COV2 to the drugs it is testing in patients hospitalised with the disease. The UK RECOVERY trial, which has been testing a range of potential COVID-19 treatments since it began in April, will compare the effects of adding REGN-COV2 - a lab-manufactured monoclonal antibody - to standard care. “This is the first drug actually designed for this disease,” said Martin Landray, a professor of medicine & epidemiology at Oxford University who is co-leading the trial. “There are lots of good reasons for thinking this might be really quite a powerful treatment,” he told Reuters in an interview. The addition of Regeneron’s drug to the RECOVERY trial comes amid growing hopes that monoclonal antibodies may emerge as effective ways to treat COVID-19.  Until now, the RECOVERY trial had mostly been studying whether existing drugs could be re-purposed to tackle the new disease, and it has already found answers on a number of them.

In June and September, trial results showed that widely used steroids such as dexamethasone and hydrocortisone were able to reduce death rates among severely-ill COVID-19 patients.  Also in June, RECOVERY trial results showed that the anti-malarial drug hydroxychloroquine, once touted by U.S. President Donald Trump as a potential “game changer” in the pandemic, was of no benefit in treating COVID-19 patients.  Regeneron’s REGN-COV2 cocktail, which the company is already testing in late-stage clinical trials in people, combines one Regeneron-made antibody and a second antibody isolated from people who have recovered after being infected with COVID-19.  The combination is designed to bind to the spike protein used by the new coronavirus to gain access to human cells, limiting the virus’s ability to escape.  Regeneron developed the biological drug before linking up with Roche ROG.S to expand its manufacturing capacity in hopes of meeting global demand, should the medicine prove effective. Regeneron would handle U.S. sales, with Roche selling the medicine around the world.

Landray said his team had secured enough supply of the drug so that up to “several thousand” patients could be given it in the trial and compared with several thousand controls. “Given that the second phase (of COVID-19 infections in the UK) seems to be coming now, it is a really good time to be starting this,” he said. The United States already has a $450 million deal for the cocktail in place, under the terms of which Regeneron will sell it around 70,000 to 300,000 potential treatment doses or 420,000 to 1.3 million prevention doses of REGN-COV2. Data is due later this month, Regeneron has said.  Alongside Regeneron, Eli Lilly LLY.N, working with biotech firm AbCellera, is seen as a leading contender in the antibody race. In August it started testing whether its antibody can prevent COVID-19 infections in nursing homes. A separate trial testing the compound on recently diagnosed COVID patients may yield initial data in September or shortly after. GlaxoSmithKline GSK.L and partner Vir Biotechnology VIR.O also began testing an experimental antibody on newly diagnosed COVID-19 patients late last month. AstraZeneca AZN.L is for now testing its antibody-based cocktail on healthy volunteers for tolerability.

New research indicates that human immune system cells are storing information about the coronavirus so they can fight it off again. To the immune system, not all germs are equally memorable. But our body’s cells seem to be seriously studying up on the coronavirus. Scientists who have been monitoring immune responses to the virus are now starting to see encouraging signs of strong, lasting immunity, even in people who developed only mild symptoms of Covid-19, a flurry of new studies suggests. Disease-fighting antibodies, as well as immune cells called B cells and T cells that are capable of recognizing the virus, appear to persist months after infections have resolved — an encouraging echo of the body’s enduring response to other viruses. “Things are really working as they’re supposed to,” said Deepta Bhattacharya, an immunologist at the University of Arizona and an author on one of the new studies, which has not yet been peer-reviewed. Although researchers cannot forecast how long these immune responses will last, many experts consider the data a welcome indication that the body’s most studious cells are doing their job — and will have a good chance of fending off the coronavirus, faster and more fervently than before, if exposed to it again. “This is exactly what you would hope for,” said Marion Pepper, an immunologist at the University of Washington and an author on another of the new studies, which is currently under review at the journal Nature. “All the pieces are there to have a totally protective immune response.”

Protection against reinfection cannot be fully confirmed until there is proof that most people who encounter the virus a second time are actually able to keep it at bay, Dr. Pepper said. But the findings could help quell recent concerns over the virus’s ability to dupe the immune system into amnesia, leaving people vulnerable to repeat bouts of disease. Researchers have yet to find unambiguous evidence that coronavirus reinfections are occurring, especially within the few months that the virus has been rippling through the human population. The prospect of immune memory “helps to explain that,” Dr. Pepper said. In discussions about immune responses to the coronavirus, much of the conversation has focused on antibodies — Y-shaped proteins that can latch onto the surfaces of pathogens and block them from infecting cells. But antibodies represent just one wing of a complex and coordinated squadron of immune soldiers, each with their own unique modes of attack. Viruses that have already invaded cells, for instance, are cloaked from antibodies, but are still vulnerable to killer T cells, which force infected cells to self-destruct. Another set of T cells, nicknamed “helpers,” can coax B cells to mature into antibody-making machines. (Yet another sector of the immune system assails pathogens within minutes of their arrival, while sending out signals called cytokines to mobilize forces from elsewhere in the body. Some evidence suggests that severe cases of Covid-19 may stem from this early process going awry.) Antibodies also come with an expiration date: Because they are inanimate proteins and not living cells, they can’t replenish themselves, and so disappear from the blood just weeks or months after they are produced. Hordes of antibodies appear shortly after a virus has breached the body’s barriers, then wane as the threat dissipates. Most of the B cells that produce these early antibodies die off as well. But even when not under siege, the body retains a battalion of longer-lived B cells that can churn out virus-fighting antibodies en masse, should they prove useful again. Some patrol the bloodstream, waiting to be triggered anew; others retreat into the bone marrow, generating small amounts of antibodies that are detectable years, sometimes decades, after an infection is over. Several studies, including those led by Dr. Bhattacharya and Dr. Pepper, have found antibodies capable of incapacitating the coronavirus lingering at low levels in the blood months after people have recovered from Covid-19. “The antibodies decline, but they settle in what looks like a stable nadir,” which is observable about three months after symptoms start, Dr. Bhattacharya said. “The response looks perfectly durable.”...

SARS-CoV-2 is a newly emerged coronavirus responsible for the current COVID-19 pandemic that has resulted in more than 3.7 million infections and 260,000 deaths as of 6 May 202o. Vaccine and therapeutic discovery efforts are paramount to curb the pandemic spread of this zoonotic virus. The SARS-CoV-2 spike (S) glycoprotein promotes entry into host cells and is the main target of neutralizing antibodies.

Here we describe multiple monoclonal antibodies targeting SARS-CoV-2 S identified from memory B cells of an individual who was infected with SARS-CoV in 2003. One antibody, named S309, potently neutralizes SARS-CoV-2 and SARS-CoV pseudoviruses as well as authentic SARS-CoV-2 by engaging the S receptor-binding domain. Using cryo-electron microscopy and binding assays, we show that S309 recognizes a glycan-containing epitope that is conserved within the sarbecovirus subgenus, without competing with receptor attachment.

Antibody cocktails including S309 along with other antibodies identified here further enhanced SARS-CoV-2 neutralization and may limit the emergence of neutralization-escape mutants. These results pave the way for using S309- and S309-containing antibody cocktails for prophylaxis in individuals at high risk of exposure or as a post-exposure therapy to limit or treat severe disease.

Published in Nature (May 18, 2020): 

https://doi.org/10.1038/s41586-020-2349-y