Confirmation of infectious coronavirus retrieved from hospital air

Skeptics of the notion that the coronavirus spreads through the air — including many expert advisers to the World Health Organization — have held out for one missing piece of evidence: proof that floating respiratory droplets called aerosols contain live virus and not just fragments of genetic material.

Now a team of virologists and aerosol scientists has produced exactly that: confirmation of infectious virus in the air.

“This is what people have been clamoring for,” said Linsey Marr, an expert in airborne spread of viruses who was not involved in the work. “It’s unambiguous evidence that there is infectious virus in aerosols.”

A research team at the University of Florida succeeded in isolating live virus from aerosols collected at a distance of seven to 16 feet from patients hospitalized with COVID-19 — farther than the 6 feet recommended in social distancing guidelines.

The findings, posted online last week, have not yet been vetted by peer review but have already caused something of a stir among scientists. “If this isn’t a smoking gun, then I don’t know what is,” Marr tweeted last week.

But some experts said it still was not clear that the amount of virus recovered was sufficient to cause infection.

The research was exacting. Aerosols are minute by definition, measuring only up to 5 micrometers across; evaporation can make them even smaller. Attempts to capture these delicate droplets usually damage the virus they contain.

“It’s very hard to sample biological material from the air and have it be viable,” said Shelly Miller, an environmental engineer at the University of Colorado Boulder who studies air quality and airborne diseases.

“We have to be clever about sampling biological material so that it is more similar to how you might inhale it.”

Previous attempts were stymied at one step or another in the process. For example, one team tried using a rotating drum to suspend aerosols and showed that the virus remained infectious for up to three hours. But critics argued that those conditions were experimental and unrealistic.

Other scientists used gelatin filters or plastic or glass tubes to collect aerosols over time. But the force of the air shrank the aerosols and sheared the virus. Another group succeeded in isolating live virus but did not show that the isolated virus could infect cells.

In the new study, researchers devised a sampler that uses pure water vapor to enlarge the aerosols enough that they can be collected easily from the air. Rather than leave these aerosols sitting, the equipment immediately transfers them into a liquid rich with salts, sugar and protein, which preserves the pathogen.

“I’m impressed,” said Robyn Schofield, an atmospheric chemist at Melbourne University in Australia, who measures aerosols over the ocean. “It’s a very clever measurement technique.”

As editor of the journal Atmospheric Measurement Techniques, Schofield is familiar with the options available but said she had not seen any that could match the new one.

The researchers had previously used this method to sample air from hospital rooms. But in those attempts, other floating respiratory viruses grew faster, making it difficult to isolate the coronavirus.

This time, the team collected air samples from a room in a ward dedicated to COVID-19 patients at the University of Florida Health Shands Hospital. Neither patient in the room was subject to medical procedures known to generate aerosols, which the WHO and others have contended are the primary source of airborne virus in a hospital setting.

The team used two samplers, one about 7 feet from the patients and the other about 16 feet from them. The scientists were able to collect virus at both distances and then to show that the virus they had plucked from the air could infect cells in a lab dish.

The genome sequence of the isolated virus was identical to that from a swab of a newly admitted symptomatic patient in the room.

The room had six air changes per hour and was fitted with efficient filters, ultraviolet irradiation and other safety measures to inactivate the virus before the air was reintroduced into the room.

That may explain why the researchers found only 74 virus particles per liter of air, said John Lednicky, the team’s lead virologist at the University of Florida. Indoor spaces without good ventilation — such as schools — might accumulate much more airborne virus, he said.

But other experts said it was difficult to extrapolate from the findings to estimate an individual’s infection risk.

“I’m just not sure that these numbers are high enough to cause an infection in somebody,” said Angela Rasmussen, a virologist at Columbia University in New York.

“The only conclusion I can take from this paper is you can culture viable virus out of the air,” she said. “But that’s not a small thing.”

Several experts noted that the distance at which the team found virus is much farther than the 6 feet recommended for physical distancing.

“We know that indoors, those distance rules don’t matter anymore,” Schofield said. It takes about five minutes for small aerosols to traverse the room even in still air, she added.

The 6-foot minimum is “misleading, because people think they are protected indoors and they’re really not,” she said.

That recommendation was based on the notion that “large ballistic cannonball-type droplets” were the only vehicles for the virus, Marr said. The more distance people can maintain, the better, she added.

The findings should also push people to heed precautions for airborne transmission like improved ventilation, said Seema Lakdawala, a respiratory virus expert at the University of Pittsburgh.

“We all know that this virus can transmit by all these modes, but we’re only focusing on a small subset,” Lakdawala said.

She and other experts noted one strange aspect of the new study. The team reported finding just as much viral RNA as they did infectious virus, but other methods generally found about 100-fold more genetic matter.

“When you do nasal swabs or clinical samples, there is a lot more RNA than infectious virus,” Lakdawala said.

Lednicky has received emails and phone calls from researchers worldwide asking about that finding. He said he would check his numbers again to be sure.

But ultimately, he added, the exact figures may not matter. “We can grow the virus from air — I think that should be the important take-home lesson,” he said.

https://www.chicagotribune.com/nation-world/ct-nw-nyt-coronavirus-hospital-air-20200811-2fruaob6gvdpfodmph6tcvhpq4-story.html

Eloxx Pharma restarts mid-stage cystic fibrosis study in the U.S.

Eloxx Pharmaceuticals (NASDAQ:ELOX) jumps 9% premarket in reaction to the resumption of enrollment in its Phase 2 clinical trial for ELX-02 in cystic fibrosis in the U.S. which was temporarily paused in response to the COVID-19 pandemic.

On June 17, enrollment resumed in a Phase 2 cystic fibrosis trial in Europe and Israel too.

“Our highest priority is to complete the Phase 2 proof of concept clinical trial program and report top line data as soon as possible,” said Dr. Gregory Williams, CEO of Eloxx.

https://seekingalpha.com/news/3604543-eloxx-pharma-restarts-mid-stage-cystic-fibrosis-study-in-u-s

EyeGate Pharma rallies on development path for conjunctivitis treatment

Thinly traded nano cap EyeGate Pharmaceuticals (NASDAQ:EYEG) jumps 67% premarket on light volume in reaction to its announcement that the FDA has clarified a development path for MoxiGel, a combination of its Ocular Bandage Gel and an antibiotic, for the potential treatment of bacterial conjunctivitis.

An IND is on tap for H1 2021.

Ocular Bandage Gel, based on a modified form of the natural polymer hyaluronic acid, is designed to stay on the corneal surface longer.

https://seekingalpha.com/news/3604474-eyegate-pharma-rallies-67-on-development-path-for-conjunctivitis-treatment

FDA accepts Regeneron application for evinacumab for cholesterol disorder

Under Priority Review status, the FDA accepts for review Regeneron Pharmaceuticals’ (NASDAQ:REGN) marketing application seeking approval of evinacumab as an adjunct to other lipid-lowering therapies for the treatment of patients with homozygous familial hypercholesterolemia (HoFH), a rare inherited disorder characterized by abnormally high levels of cholesterol in the blood.

The agency’s action date is February 11, 2021.

Evinacumab is a fully human monoclonal antibody that binds to a protein called ANGPTL3 that plays a key role in lipoprotein metabolism via inhibiting two enzymes called lipoprotein lipase and endothelial lipase. It is also being tested in patients with refractory hypercholesterolemia and severe hypertriglyceridemia.

https://seekingalpha.com/news/3604491-fda-accepts-regeneron-application-for-evinacumab-for-inherited-cholesterol-disorder

Pfizer/BioNTech Covid vax continues to show strong effect in early-stage study

August 12, 2020

Data from an ongoing Phase 1/2 clinical trial evaluating three dose levels of Pfizer (NYSE:PFE) and collaboration partner BioNTech SE’s (NASDAQ:BNTX) COVID-19 vaccine candidate BNT162b1 in healthy volunteers showed an acceptable safety profile and dose-dependent increases in glycoprotein receptor-binding domain (RBD)-binding IgG concentrations and SARS-CoV-2 neutralizing antibody titers. The data, just published in the journal Nature, was generated on the first two dose levels, 10 µg and 30 µg. The highest dose of 100 µg was only administered once due to increased reactogenicity and the absence of a significant incremental immunogenicity effect compared to the 30 µg dose.

1.6-fold to 4.6-fold increases on geometric mean neutralizing antibody titers after the second dose were observed.

The companies first reported preliminary data from the trial on July 1. The highest neutralizing titers reported then were 1.8x (10 µg) and 2.8x (30 µg).

https://seekingalpha.com/news/3604515-pfizer-biontech-covidminus-19-vaccine-continues-to-show-strong-effect-in-early-stage-study

Antibody drugs may be among best weapons against Covid. Will they matter?

From the moment Covid-19 emerged as a threat, one approach to making drugs to treat or prevent the disease seemed to hold the most promise: They’re known as monoclonal antibodies.

Now, scientists are on the brink of getting important data that may indicate whether these desperately needed therapies could be safe and effective. Clinical trials involving a pair of antibodies developed by Regeneron Pharmaceuticals will read out early results in September. A separate effort from Eli Lilly could yield data later in the fall.

Despite experts’ eagerness to see the data, however, there remains a debate over just how significant a role any antibody treatment might play in changing the course of the pandemic.

“A lot of smart people who understand immunology and virology think antibodies will work,” said Robert Nelsen, an investor at ARCH Venture Partners who is invested in Vir Biotechnology, which will start tests of its own Covid-19 antibody study this month.

Scott Gottlieb, the former commissioner of the Food and Drug Administration, is less sure antibody treatments will be significant factors in bringing the pandemic under control. Even though the development efforts have been proceeding extraordinarily fast by normal standards, the U.S. has spent billions of dollars purchasing vaccines in advance, but has done far less to shore up capacity for antibody drugs.

“We may have missed a window to scale the manufacturing of antibody drugs that could have been an important bridge to a vaccine and a hedge in the event vaccines are delayed or don’t work,” Gottlieb, a fellow at the American Enterprise Institute and board member for Pfizer and other health care companies, told STAT. “These drugs had the ability to perhaps meaningfully change the contours of this epidemic, and we just won’t have enough doses to realize that goal.”

Monoclonal antibodies are antibodies — the kind that the body produces to neutralize invading viruses — that have been genetically engineered into new medicines.

In 1975, two researchers, Georges J.F. Köhler and César Milstein, developed the method for mass-producing them by fusing antibody-producing cells from mice with cancer cells. They shared the Nobel Prize in physiology or medicine in 1984. The first monoclonal antibody drug, for kidney transplant patients, was approved in 1986. Today, Humira, an antibody from AbbVie that treats a host of immune-related diseases, is the pharmaceutical industry’s top-selling product, generating $15 billion in sales last year.

Regeneron has produced several monoclonal antibodies since being founded in 1988, including Praluent for high cholesterol, Libtayo for a type of cancer, and Dupixent for severe eczema. In 2014, the technology was also used to develop an effective treatment for Ebola.

As the Covid pandemic hit, Regeneron’s chief scientific officer, George Yancopoulos, assigned Christos Kyratsous, a confident, Porsche-driving scientist with a dry sense of humor, to lead a team that would search for an antibody. In early February, a non-infectious fragment of genetic code of the novel coronavirus arrived at the company’s research laboratories in Tarrytown, N.Y., from China, and the company has used this starting material to produce hundreds of virus-neutralizing antibodies using genetically engineered mice, along with blood taken from survivors of Covid-19.

But getting antibodies into people has taken time. “I tragically right now have a 91-year-old aunt who’s trapped in a nursing home where right now there’s a coronavirus outbreak,” Yancopoulos said in April. “And I just wish I could get them our [drug] today. It’s just not ready.”

Other companies are advancing their own efforts. For years, AbCellera, a Vancouver-based biotech, had been working with the National Institutes of Health and the U.S. Department of Defense to game out the response to future pandemics. In February, the NIH’s National Institute of Allergy and Infectious Diseases sent the company a sample of blood from a patient who had recovered from Covid-19. AbCellera inserted the sample into a credit-card-sized device that isolates the B cells that make antibodies, and used it to find more than 550 antibodies that might work against the virus.

Adaptive Biotechnologies, AbbVie, and AstraZeneca have also rushed forward with their own antibody efforts.

Regeneron’s antibodies — REGN10933 and REGN10987 — both target the “spike” protein on the virus’ surface that helps it invade cells, but individually, each drug binds to the protein at a different, non-overlapping location. This “cocktail” approach aims to increase the chance that the virus can be neutralized without escaping. It’s the same multidrug strategy used successfully to treat other viral diseases such as HIV and hepatitis C. Regeneron refers to the dual antibody regimen as REGN-COV2.

The first look at Regeneron’s data will provide results on the ability of REGN-COV2 to reduce the amount of SARS-CoV-2 virus in patients compared to placebo. Safety and other data will also be announced.

Outcomes data will come later. For the study of hospitalized Covid-19 patients, Regeneron hopes to show that the treatment can improve clinical status based on a seven-point scale ranging from hospital discharge to death. In between, the scoring system measures changes in the use of supplemental oxygen or mechanical ventilation. In the study of ambulatory Covid-19 patients, REGN-COV2 is designed to speed recovery and prevent the disease from getting worse. Unlike Regeneron, Eli Lilly and AbCellera have chosen not to use a cocktail approach, starting instead by testing a single antibody. Data from its study, however, being conducted with the NIH, aren’t expected to be released until October or November.

“Reducing the theoretical risk of escape mutations has a real cost, and the real cost is manufacturing, meaning you will have less doses available, meaning fewer people will be treated in this critical time period,” Lilly Chief Scientific Officer Daniel Skovronsky told STAT during a recent event. “So my view is we go for a single antibody, which means that we can treat twice as many people if it works.”

The Lilly antibody, called LY-CoV555, will be investigated in a placebo-controlled clinical trial of approximately 300 patients hospitalized with mild to moderate Covid-19. An initial efficacy assessment based on symptoms improvement, including the need for supplemental oxygen, will be conducted five days following the injections of LY-CoV555 or placebo. If these initial results show a benefit for the Lilly antibody, the study will be expanded to enroll another 700 patients, including people with severe cases of Covid-19.

Recently published animal data suggest these antibody treatments may work in humans. Monkeys exposed to SARS-CoV-2 followed one day later with injections of the Regeneron cocktail cleared the virus faster than monkeys treated with a placebo. Damage to the lungs, including cases of pneumonia, was reduced but not eliminated in the monkeys treated with the cocktail compared to the placebo group. The monkey study was released via a preprint server, meaning the data had not yet been peer-reviewed or published in a journal.

In a research note, SVB Leerink analyst Geoff Porges called the monkey data “quite encouraging,” but he also cautioned it may not be curative in humans on its own, citing the inconclusive pneumonia results and the challenge of treating patients early, before they might have symptoms.

“If clinical development for the antibody cocktails is successful, we believe it would be most likely to complement the existing standard of care and antiviral therapies such as remdesivir, rather than displacing antivirals,” said Porges.

Nelsen, the investor at ARCH Venture Partners, said: “If you treat people who are very sick, you may not see anything. If you treat people earlier, you will probably see what you saw in the monkeys: a significant reduction in virus, which doesn’t necessarily mean a reduction in morbidity and mortality, but it should. What you really want to do is prevent the progression of the disease.”

Vir, the biotech firm that Nelsen backed, will start a clinical trial of its lead antibody candidate VIR-7831 later this month, seeking to show that it can prevent hospitalization due to Covid-19. A second antibody candidate, VIR-7832, will advance into a clinical trial later this year. Both drugs are designed to bind to a location on the spike protein that creates a high barrier to resistance. In preclinical studies, the antibodies also recruit immune cells to help kill other cells already infected by the virus, Vir said.

Similar to vaccines, antibody treatments are also being developed to prevent Covid-19 infection, particularly in people who are at high risk and who might have been exposed to the virus through close contact with an already infected person.

“Once someone has come into contact with some of the disease, it’s too late for an active vaccine,” Lilly’s Skovronsky said. “But a passive immunization like our antibody could be valuable. When you think about the populations that are suffering the most, it’s the elderly, it’s the immunocompromised, it’s patients in nursing homes and long-term care facilities.”

Lilly and NIAID are conducting a 2,400-patient Phase 3 study to test whether its treatment can keep nursing home patients from developing Covid-19. The antibody will be given to patients and staff at places where there has been an infection to see if it can stop them from developing the disease. To conduct the study, Lilly is deploying a fleet of recreational vehicles that can be used prepare study drug and do lab work, as well as pull trailers that can be used as on-site infusion clinics.

Regeneron and NIAID are also conducting a prevention study in 2,000 healthy adults who are household contacts with an individual with a positive Covid-19 test.  Will it be possible to manufacture enough antibody? Regeneron said it is “in active discussions with other parties” that can add additional manufacturing capacity.

The big determinant of how fast answers will emerge will be the speed at which doctors can enroll patients in these studies, said Anita Kohli, the director of clinical research at Arizona Clinical Trials and an investigator for both Regeneron and Eli Lilly. This, she said, is harder than it sounds, especially for patients who are not so sick that they are in the hospital. “I think some of the recruitment is more difficult, because you’re recruiting sick people,” she said. “Sick people want to eat chicken soup and stay at home and not go to the clinical trials center.”

One problem is that diagnostic tests are taking a long time to come back. Doctors are supposed to enroll patients in the studies within five or six days of the onset of symptoms. If testing takes two weeks to come back, patients often recover before they are enrolled. Kohli’s center has begun to test patients for Covid in the hopes that some will volunteer to be in studies.

“Vaccines are not going to work for everybody,” she said. “People are still going to get sick, there’s no two ways about it. And we’ve got to have a treatment.”

The problem, she said, is that patients are not being made aware of clinical trials for therapeutics soon enough.

“People have not been directed toward clinical trials, or are not thinking about them,” she said.” I think that’s what we need to change here. It’s not that they aren’t very exciting, they are very exciting. They just aren’t talked about enough.”

https://www.statnews.com/2020/08/11/antibody-drugs-could-be-one-of-the-best-weapons-against-covid-19-but-will-they-matter/

Brazilian state in talks with Russia to make COVID-19 vaccine

Brazil’s Parana state is in talks to produce a COVID-19 vaccine approved by Russia despite not having completed mass clinical trials, but it was unclear if the state’s research institute would get regulatory approval in Brazil.

Tuesday’s announcement by the Parana Technology Institute (Tecpar) took Brazil’s regulators and health experts by surprise, with some raising doubts about the institute’s capacity to produce large volumes of a new vaccine from scratch.

The Parana government said in a statement that Governor Ratinho Júnior was set to meet the Russian ambassador to Brazil on Wednesday to discuss the terms of an agreement.

With the world’s biggest coronavirus outbreak outside the United States, Brazil has become a hub for mass clinical trials of potential vaccines. Brazilian officials have vowed to start producing British and Chinese vaccines within a year, but experts warn it may take at least twice as long.

Moscow’s decision to grant approval for its vaccine before completing clinical trials has raised concerns among some experts. About 10% of clinical trials are successful.

Moscow on Tuesday hailed its breakthrough, after less than two months of human testing, as evidence of Russia’s scientific prowess.

Russian business conglomerate Sistema has said it expects mass production by the end of the year.

Any production arrangement in Brazil would require approval by health regulator Anvisa. The agency said it had not yet received a request to authorize the Russian vaccine and that it could not comment on its safety or effectiveness before receiving data from the laboratory responsible for development.

Ivo Bucaresky, a former Anvisa director, urged caution, given the speed of the Russian vaccine’s development and incomplete testing.

“I would be afraid of Russia’s vaccine,” Bucaresky said in a telephone interview. “The Russian government was very bold, if not to say irresponsible, to put out a vaccine that had hardly been tested to vaccinate its population,” he added.

Two other former senior Anvisa officials told Reuters they did not believe Tecpar had the capability to mass produce the vaccine. One of them, a former head of the agency, said Tecpar now produces only one vaccine – to protect animals against rabies. Both sources requested anonymity to speak frankly.

The Parana government dismissed the concerns, stressing in its statement that Tecpar has the “technical capacity to participate in the process.”

Former Brazilian Health Minister Luiz Henrique Mandetta said political pressure to be the first with a vaccine was prevailing over scientific caution. But he said Parana had the technical ability to produce a vaccine and Brazil had clear requirements for testing before approval.

Besides, he told Reuters, “if Russia vaccinates 150 million of its citizens, that should be a good thermometer.”

Brazil has reported more than 3 million cases of the novel coronavirus as President Jair Bolsonaro urges a reopening of the economy. The death toll passed 100,000 this weekend.

https://www.reuters.com/article/us-health-coronavirus-brazil/brazilian-state-in-talks-with-russia-to-make-covid-19-vaccine-idUSKCN2571VX