A new piece in the Atlantic sparked debate this week about the risk of ongoing COVID exposure to children as the country navigates toward the end of the pandemic. Brown University economist Emily Oster equated a child’s risk of serious illness from the coronavirus to that of their vaccinated grandmother. If grandma receives the Pfizer vaccine, her risk of serious illness is decreased by 95 percent. According to Oster, the condition of “being a child” aged 0-17 is 98 percent protective against hospitalization—so go ahead, plan that family summer vacation!
Oster cites no clinical or scientific experts in her piece, but some doctors were quick to respond that the comparisons are not equivalent (and also provide ready-made scripting for the “anti-vaxx” movement, which could claim that kids are already “basically vaccinated”).
But the article does bring up a real question that millions of families will soon face: what can we do when grandma and grandpa (and hopefully mom and dad) are vaccinated, but the kids are not? Given the pace of clinical trials, teens could be eligible for vaccination as soon as late summer, but COVID vaccines might not be approved for younger children until months later—and this generational vaccine divide will likely linger into 2022.
Undoubtedly children are at lower risk from COVID than adults, and likely transmit the disease less frequently (although much of the data supporting the latter comes from studies in schools, where social distancing and masking are enforced). And we’re not out of the woods yet: as COVID cases surge again in Michigan, schools there have seen a spike in outbreaks as well.
As families look at conflicting data and messages in the media, they need clear, coordinated guidance from state and federal officials to help them gauge safety as they navigate their second “pandemic summer”.
The national COVID indicators all continued to move in the right direction this week, with new cases down 16 percent, hospitalizations down 26 percent, and deaths (while still alarmingly high at more than 3,000 per day) down 6 percent from the week prior.
More good news: both nationally and globally, the number of people vaccinated against COVID now exceeds the total number of people infected with the virus, at least according to official statistics—the actual number of coronavirus infections is likely several times higher.
On the vaccine front, Johnson & Johnson filed with the Food and Drug Administration (FDA) for an Emergency Use Authorization for its single-dose COVID vaccine, which could become the third vaccine approved for use in the US following government review later this month. The J&J vaccine is reportedly 85 percent effective at preventing severe COVID disease, although it is less effective at preventing infection than the Pfizer and Moderna shots.
Elsewhere, TheLancet reported interim Phase III results for Russia’s Sputnik V vaccine trials, showing it to be 91 percent effective at preventing infection, and a new study found the Oxford-AstraZeneca vaccine to be 75 percent effective against the more-contagious UK virus variant.
Amid the positive vaccine news, the Biden administration moved to accelerate the vaccination campaign, invoking the Defense Production Act to boost production and initiating shipments directly to retail pharmacies. With the House and Senate starting the budget reconciliation process that could eventually lead to as much as $1.9T in stimulus funding, including billions more for vaccines and testing, it feels as though the tide may be finally turning in the battle against coronavirus.
While the key indicators are still worrisome—we’re only back to Thanksgiving-week levels of new cases—and emerging variants are cause for concern, it’s worth celebrating a week that brought more good news than bad.
Best to follow Dr. Fauci’s advice for this Super Bowl weekend, however: “Just lay low and cool it.”
Anti-inflammatory oral drug colchicine improved COVID-19 outcomes for patients with relatively mild cases, according to certain topline results from the COLCORONA trial announced in a brief press release.
Overall, the drug used for gout and rheumatic diseases reduced risk of death or hospitalizations by 21% versus placebo, which “approached statistical significance.”
However, there was a significant effect among the 4,159 of 4,488 patients who had their diagnosis of COVID-19 confirmed by a positive PCR test:
25% fewer hospitalizations
50% less need for mechanical ventilation
44% fewer deaths
If full data confirm the topline claims — the press release offered no other details, and did not mention plans for publication or conference presentation — colchicine would become the first oral drug proven to benefit non-hospitalized patients with COVID-19.
“Our research shows the efficacy of colchicine treatment in preventing the ‘cytokine storm’ phenomenon and reducing the complications associated with COVID-19,” principal investigator Jean-Claude Tardif, MD, of the Montreal Heart Institute, said in the press release. He predicted its use “could have a significant impact on public health and potentially prevent COVID-19 complications for millions of patients.”
Currently, the “tiny list of outpatient therapies that work” for COVID-19 includes convalescent plasma and monoclonal antibodies, which “are logistically challenging (require infusions, must be started very early after symptom onset),” tweeted Ilan Schwartz, MD, PhD, an infectious diseases researcher at the University of Alberta in Edmonton.
The COLCORONA findings were “very encouraging,” tweeted Martin Landray, MB ChB, PhD, of the Big Data Institute at the University of Oxford in England. His group’s RECOVERY trial has already randomized more than 6,500 hospitalized patients to colchicine versus usual care as one of the arms of the platform trial, though he did not offer any findings from that study.
“Different stage of disease so remains an important question,” he tweeted. “Maybe old drugs can learn new tricks!” Landray added, pointing to dexamethasone.
“I think this is an exciting time. Many groups have been pursuing lots of different questions related to COVID and its complications,” commented Richard Kovacs, MD, immediate past-president of the American College of Cardiology. “We’re now beginning to see the fruit of those studies.”
COLCORONA was conducted remotely, without in-person contact, with participants across Canada, the U.S., Europe, South America, and South Africa. It randomized participants double-blind to colchicine 0.5 mg or a matching placebo twice daily for the first 3 days and then once daily for the last 27 days.
Participants were ages 40 and older, not hospitalized at the time of enrollment, and had at least one risk factor for COVID-19 complications: age 70-plus, obesity, diabetes, uncontrolled hypertension, known asthma or chronic obstructive pulmonary disease, known heart failure, known coronary disease, fever of ≥38.4°C (101.12°F) within the last 48 hours, dyspnea at presentation, or certain blood cell abnormalities.
It had been planned as a 6,000-patient trial, but whether it was stopped for efficacy at a preplanned interim analysis or for some other reason was not spelled out in the press release. Whether the PCR-positive subgroup was preplanned also wasn’t clear. Key details such as confidence intervals, adverse effects, and subgroup results were omitted as well.
While a full manuscript is reportedly underway, “we don’t know enough to bring this into practice yet,” argued Kovacs.
Some physicians also warned about the potential for misuse of the findings and attendant risks.
Dhruv Nayyar, MD, of the University of Toronto, tweeted that he has already had “patients inquiring why we are not starting colchicine for them. Science by press release puts us in a difficult position while providing care. I just want to see the data.”
Angela Rasmussen, MD, a virologist with the Georgetown Center for Global Health Science and Security’s Viral Emergence Research Initiative in Washington, agreed, tweeting:“When HCQ [hydroxychloroquine] was promoted without solid data, there was at least one death from an overdose. We don’t need people self-medicating with colchicine.”
As was the case with hydroxychloroquine before the papers proved little efficacy in COVID-19, Kovacs told MedPage Today: “We always get concerned when these drugs are repurposed that we might see an unintended run on the drug and lessen the supply.”
Citing the well-known diarrheal side effect of colchicine, infectious diseases specialist Edsel Salvana, MD, of the University of Pittsburgh and University of the Philippines in Manila, tweeted a plea for use only in the trial-proven patient population with confirmed COVID-19 — not prophylaxis.
The dose used was on par with that used in cardiovascular prevention and other indications, so the diarrhea incidence would probably follow the roughly 10% rate seen in the COLCOT trial, Kovacs suggested.
In the clinic, too, there are some cautions. As Elin Roddy, MD, a respiratory physician at Shrewsbury and Telford Hospital NHS Trust in England, tweeted: “Lots of drug interactions with colchicine potentially — statins, macrolides, diltiazem — we have literally been running up to the ward to cross off clarithromycin if RECOVERY randomises to colchicine.”
I had been staring her in the eyes, as she had ordered, but when a doctor on my other side began jabbing me with a needle, I started to turn my head. “Don’t look at it,” the first doctor said. I obeyed.
This was in early August in New Orleans, where I had signed up to be a participant in the clinical trial for the Pfizer-BioNTech COVID-19 vaccine. It was a blind study, which meant I was not supposed to know whether I had gotten the placebo or the real vaccine. I asked the doctor if I would really been able to tell by looking at the syringe. “Probably not,” she answered, “but we want to be careful. This is very important to get right.”
I became a vaccine guinea pig because, in addition to wanting to be useful, I had a deep interest in the wondrous new roles now being played by RNA, the genetic material that is at the heart of new types of vaccines, cancer treatments and gene-editing tools. I was writing a book on the Berkeley biochemist Jennifer Doudna. She was a pioneer in determining the structure of RNA, which helped her and her doctoral adviser figure out how it could be the origin of all life on this planet. Then she and a colleague invented an RNA-guided gene-editing tool, which won them the 2020 Nobel Prize in Chemistry.
The tool is based on a system that bacteria use to fight viruses. Bacteria develop clustered repeated sequences in their DNA, known as CRISPRs, that can remember dangerous viruses and then deploy RNA-guided scissors to destroy them. In other words, it’s an immune system that can adapt itself to fight each new wave of viruses—just what we humans need. Now, with the recently approved Pfizer-BioNTech vaccine and a similar one from Moderna being slowly rolled out across the U.S. and Europe, RNA has been deployed to make a whole new type of vaccine that will, when it reaches enough people, change the course of the pandemic.
Up until last year, vaccines had not changed very much, at least in concept, for more than two centuries. Most have been modeled on the discovery made in 1796 by the English doctor Edward Jenner, who noticed that many milkmaids were immune to smallpox. They had all been infected by a form of pox that afflicts cows but is relatively harmless to humans, and Jenner surmised that the cowpox had given them immunity to smallpox. So he took some pus from a cowpox blister, rubbed it into scratches he made in the arm of his gardener’s 8-year-old son and then (this was in the days before bioethics panels) exposed the kid to smallpox. He didn’t become ill.
Before then, inoculations were done by giving patients a small dose of the actual smallpox virus, hoping that they would get a mild case and then be immune. Jenner’s great advance was to use a related but relatively harmless virus. Ever since, vaccinations have been based on the idea of exposing a patient to a safe facsimile of a dangerous virus or other germ. This is intended to kick the person’s adaptive immune system into gear. When it works, the body produces antibodies that will, sometimes for many years, fend off any infection if the real germ attacks.
One approach is to inject a safely weakened version of the virus. These can be good teachers, because they look very much like the real thing. The body responds by making antibodies for fighting them, and the immunity can last a lifetime. Albert Sabin used this approach for the oral polio vaccine in the 1950s, and that’s the way we now fend off measles, mumps, rubella and chicken pox.
At the same time Sabin was trying to develop a vaccine based on a weakened polio virus, Jonas Salk succeeded with a safer approach: using a killed or inactivated virus. This type of vaccine can still teach a person’s immune system how to fight off the live virus but is less likely to cause serious side effects. Two Chinese companies, Sinopharm and Sinovac, have used this approach to develop vaccines for COVID-19 that are now in limited use in China, the UAE and Indonesia.
Another traditional approach is to inject a subunit of the virus, such as one of the proteins that are on the virus’s coat. The immune system will then remember these, allowing the body to mount a quick and robust response when it encounters the actual virus. The vaccine against the hepatitis B virus, for example, works this way. Using only a fragment of the virus means that they are safer to inject into a patient and easier to produce, but they are often not as good at producing long-term immunity. The Maryland-based biotech Novavax is in late-stage clinical trials for a COVID-19 vaccine using this approach, and it is the basis for one of the two vaccines already being rolled out in Russia.
The plague year of 2020 will be remembered as the time when these traditional vaccines were supplanted by something fundamentally new:genetic vaccines, which deliver a gene or piece of genetic code into human cells. The genetic instructions then cause the cells to produce, on their own, safe components of the target virus in order to stimulate the patient’s immune system.
For SARS-CoV-2—the virus that causes COVID-19—the target component is its spike protein, which studs the outer envelope of the virus and enables it to infiltrate human cells. One method for doing this is by inserting the desired gene, using a technique known as recombinant DNA, into a harmless virus that can deliver the gene into human cells. To make a COVID vaccine, a gene that contains instructions for building part of a coronavirus spike protein is edited into the DNA of a weakened virus like an adenovirus, which can cause the common cold. The idea is that the re-engineered adenovirus will worm its way into human cells, where the new gene will cause the cells to make lots of these spike proteins. As a result, the person’s immune system will be primed to respond rapidly if the real coronavirus strikes.
This approach led to one of the earliest COVID vaccine candidates, developed at the aptly named Jenner Institute of the University of Oxford. Scientists there engineered the spike-protein gene into an adenovirus that causes the common cold in chimpanzees, but is relatively harmless in humans.
The lead researcher at Oxford is Sarah Gilbert. She worked on developing a vaccine for Middle East respiratory syndrome (MERS) using the same chimp adenovirus. That epidemic waned before her vaccine could be deployed, but it gave her a head start when COVID-19 struck. She already knew that the chimp adenovirus had successfully delivered into humans the gene for the spike protein of MERS. As soon as the Chinese published the genetic sequence of the new coronavirus in January 2020, she began engineering its spike-protein gene into the chimp virus, waking each day at 4 a.m.
Her 21-year-old triplets, all of whom were studying biochemistry, volunteered to be early testers, getting the vaccine and seeing if they developed the desired antibodies. (They did.) Trials in monkeys conducted at a Montana primate center in March also produced promising results.
Bill Gates, whose foundation provided much of the funding, pushed Oxford to team up with a major company that could test, manufacture and distribute the vaccine. So Oxford forged a partnership with AstraZeneca, the British-Swedish pharmaceutical company. Unfortunately, the clinical trials turned out to be sloppy, with the wrong doses given to some participants, which led to delays. Britain authorized it for emergency use at the end of December, and the U.S. is likely to do so in the next two months.
Johnson & Johnson is testing a similar vaccine that uses a human adenovirus, rather than a chimpanzee one, as the delivery mechanism to carry a gene that codes for making part of the spike protein. It’s a method that has shown promise in the past, but it could have the disadvantage that humans who have already been exposed to that adenovirus may have some immunity to it. Results from its clinical trial are expected later this month.
In addition, two other vaccines based on genetically engineered adenoviruses are now in limited distribution: one made by CanSino Biologics and being used on the military in China and another named Sputnik V from the Russian ministry of health.
There is another way to get genetic material into a human cell and cause it to produce the components of a dangerous virus, such as the spike proteins, that can stimulate the immune system. Instead of engineering the gene for the component into an adenovirus, you can simply inject the genetic code for the component into humans as DNA or RNA.
Let’s start with DNA vaccines. Researchers at Inovio Pharmaceuticals and a handful of other companies in 2020 created a little circle of DNA that coded for parts of the coronavirus spike protein. The idea was that if it could get inside the nucleus of a cell, the DNA could very efficiently churn out instructions for the production of the spike-protein parts, which serve to train the immune system to react to the real thing.
The big challenge facing a DNA vaccine is delivery.How can you get the little ring of DNA not only into a human cell but into the nucleus of the cell? Injecting a lot of the DNA vaccine into a patient’s arm will cause some of the DNA to get into cells, but it’s not very efficient.
Some of the developers of DNA vaccines, including Inovio, tried to facilitate the delivery into human cells through a method called electroporation, which delivers electrical shock pulses to the patient at the site of the injection. That opens pores in the cell membranes and allows the DNA to get in. The electric pulse guns have lots of tiny needles and are unnerving to behold. It’s not hard to see why this technique is unpopular, especially with those on the receiving end. So far, no easy and reliable delivery mechanism has been developed for getting DNA vaccines into the nucleus of human cells.
That leads us to the molecule that has proven victorious in the COVID vaccine race and deserves the title of TIME magazine’s Molecule of the Year: RNA. Its sibling DNA is more famous. But like many famous siblings, DNA doesn’t do much work. It mainly stays bunkered down in the nucleus of our cells, protecting the information it encodes. RNA, on the other hand, actually goes out and gets things done. The genes encoded by our DNA are transcribed into snippets of RNA that venture out from the nucleus of our cells into the protein-manufacturing region. There, this messenger RNA (mRNA) oversees the assembly of the specified protein. In other words, instead of just sitting at home curating information, it makes real products.
Scientists including Sydney Brenner at Cambridge and James Watson at Harvard first identified and isolated mRNA molecules in 1961. But it was hard to harness them to do our bidding, because the body’s immune system often destroyed the mRNA that researchers engineered and attempted to introduce into the body. Then in 2005, a pair of researchers at the University of Pennsylvania, Katalin Kariko and Drew Weissman, showed how to tweak a synthetic mRNA molecule so it could get into human cells without being attacked by the body’s immune system.
When the COVID-19 pandemic hit a year ago, two innovative young pharmaceutical companies decided to try to harness this role played by messenger RNA: the German company BioNTech, which formed a partnership with the U.S. company Pfizer; and Moderna, based in Cambridge, Mass. Their mission was to engineer messenger RNA carrying the code letters to make part of the coronavirus spike protein—a string that begins CCUCGGCGGGCA … —and to deploy it in human cells.
BioNTech was founded in 2008 by the husband-and-wife team of Ugur Sahin and Ozlem Tureci, who met when they were training to be doctors in Germany in the early 1990s. Both were from Turkish immigrant families, and they shared a passion for medical research, so much so that they spent part of their wedding day working in the lab. They founded BioNTech with the goal of creating therapies that stimulate the immune system to fight cancerous cells. It also soon became a leader in devising medicines that use mRNA in vaccines against viruses.
In January 2020, Sahin read an article in the medical journal Lancet about a new coronavirus in China. After discussing it with his wife over breakfast, he sent an email to the other members of the BioNTech board saying that it was wrong to believe that this virus would come and go as easily as MERS and SARS. “This time it is different,” he told them.
BioNTech launched a crash project to devise a vaccine based on RNA sequences, which Sahin was able to write within days, that would cause human cells to make versions of the coronavirus’s spike protein. Once it looked promising, Sahin called Kathrin Jansen, the head of vaccine research and development at Pfizer. The two companies had been working together since 2018 to develop flu vaccines using mRNA technology, and he asked her whether Pfizer would want to enter a similar partnership for a COVID vaccine. “I was just about to call you and propose the same thing,” Jansen replied. The deal was signed in March.
By then, a similar mRNA vaccine was being developed by Moderna, a much smaller company with only 800 employees. Its chair and co-founder, Noubar Afeyan, a Beirut-born Armenian who immigrated to the U.S., had become fascinated by mRNA in 2010, when he heard a pitch from a group of Harvard and MIT researchers. Together they formed Moderna, which initially focused on using mRNA to try to develop personalized cancer treatments, but soon began experimenting with using the technique to make vaccines against viruses.
In January 2020, Afeyan took one of his daughters to a restaurant near his office in Cambridge to celebrate her birthday. In the middle of the meal, he got an urgent text message from the CEO of his company, Stéphane Bancel, in Switzerland. So he rushed outside in the freezing temperature, forgetting to grab his coat, to call him back.
Bancel said that he wanted to launch a project to use mRNA to attempt a vaccine against the new coronavirus. At that point, Moderna had more than 20 drugs in development but none had even reached the final stage of clinical trials. Nevertheless, Afeyan instantly authorized him to start work. “Don’t worry about the board,” he said. “Just get moving.” Lacking Pfizer’s resources, Moderna had to depend on funding from the U.S. government. Anthony Fauci, head of the National Institute of Allergy and Infectious Diseases, was supportive. “Go for it,” he declared. “Whatever it costs, don’t worry about it.”
It took Bancel and his Moderna team only two days to create the RNA sequences that would produce the spike protein, and 41 days later, it shipped the first box of vials to the National Institutes of Health to begin early trials. Afeyan keeps a picture of that box on his cell phone.
An mRNA vaccine has certain advantages over a DNA vaccine, which has to use a re-engineered virus or other delivery mechanism to make it through the membrane that protects the nucleus of a cell. The RNA does not need to get into the nucleus. It simply needs to be delivered into the more-accessible outer region of cells, the cytoplasm, which is where proteins are constructed.
The Pfizer-BioNTech and Moderna vaccines do so by encapsulating the mRNA in tiny oily capsules, known as lipid nanoparticles.Moderna had been working for 10 years to improve its nanoparticles.This gave it one advantage over Pfizer-BioNTech: its particles were more stable and did not have to be stored at extremely low temperatures.
By November, the results of the Pfizer-BioNTech and Moderna late-stage trials came back with resounding findings: both vaccines were more than 90% effective. A few weeks later, with COVID-19 once again surging throughout much of the world, they received emergency authorization from the U.S. Food and Drug Administration and became the vanguard of the biotech effort to beat back the pandemic.
The ability to code messenger RNA to do our bidding will transform medicine. As with the COVID vaccines, we can instruct mRNA to cause our cells to make antigens—molecules that stimulate our immune system—that could protect us against many viruses, bacteria, or other pathogens that cause infectious disease. In addition, mRNA could in the future be used, as BioNTech and Moderna are pioneering, to fight cancer. Harnessing a process called immunotherapy, the mRNA can be coded to produce molecules that will cause the body’s immune system to identify and kill cancer cells.
RNA can also be engineered, as Jennifer Doudna and others discovered, to target genes for editing. Using the CRISPR system adapted from bacteria, RNA can guide scissors-like enzymes to specific sequences of DNA in order to eliminate or edit a gene. This technique has already been used in trials to cure sickle cell anemia. Now it is also being used in the war against COVID. Doudna and others have created RNA-guided enzymes that can directly detect SARS-CoV-2 and eventually could be used to destroy it.
More controversially, CRISPR could be used to create “designer babies” with inheritable genetic changes. In 2018, a young Chinese doctor used CRISPR to engineer twin girls so they did not have the receptor for the virus that causes AIDS. There was an immediate outburst of awe and then shock. The doctor was denounced, and there were calls for an international moratorium on inheritable gene edits. But in the wake of the pandemic, RNA-guided genetic editing to make our species less receptive to viruses may someday begin to seem more acceptable.
Throughout human history, we have been subjected to wave after wave of viral and bacterial plagues. One of the earliest known was the Babylon flu epidemic around 1200 B.C. The plague of Athens in 429 B.C. killed close to 100,000 people, the Antonine plague in the 2nd century killed 5 million, the plague of Justinian in the 6th century killed 50 million, and the Black Death of the 14th century took almost 200 million lives, close to half of Europe’s population.
The COVID-19 pandemic that killed more than 1.8 million people in 2020 will not be the final plague. However, thanks to the new RNA technology, our defenses against most future plagues are likely to be immensely faster and more effective. As new viruses come along, or as the current coronavirus mutates, researchers can quickly recode a vaccine’s mRNA to target the new threats. “It was a bad day for viruses,” Moderna’s chair Afeyan says about the Sunday when he got the first word of his company’s clinical trial results. “There was a sudden shift in the evolutionary balance between what human technology can do and what viruses can do. We may never have a pandemic again.”
The invention of easily reprogrammable RNA vaccines was a lightning-fast triumph of human ingenuity, but it was based on decades of curiosity-driven research into one of the most fundamental aspects of life on planet earth: how genes are transcribed into RNA that tell cells what proteins to assemble. Likewise, CRISPR gene-editing technology came from understanding the way that bacteria use snippets of RNA to guide enzymes to destroy viruses. Great inventions come from understanding basic science. Nature is beautiful that way.
Dr. Megan Ranney has learned a lot about Covid-19 since she began treating patients with the disease in the emergency department in February.
But there’s one question she still can’t answer: What makes some patients so much sicker than others?
Advancing age and underlying medical problems explain only part of the phenomenon, said Ranney, who has seen patients of similar age, background and health status follow wildly different trajectories.
“Why does one 40-year-old get really sick and another one not even need to be admitted?” asked Ranney, an associate professor of emergency medicine at Brown University.
In some cases, provocative new research shows, some people — men in particular — succumb because their immune systems are hit by friendly fire. Researchers hope the finding will help them develop targeted therapies for those patients.
In an international study in Science, 10 percent of nearly 1,000 Covid-19 patients who developed life-threatening pneumonia had antibodies that disable key immune system proteins called interferons. These antibodies — known as autoantibodies, because they attack the body itself — weren’t found at all in 663 people with mild or asymptomatic Covid-19 infections. Only four of 1,227 healthy patients had the autoantibodies. The study was led by the Covid Human Genetic Effort, which includes 200 research centers in 40 countries.
“This is one of the most important things we’ve learned about the immune system since the start of the pandemic,” said Dr. Eric Topol, executive vice president for research at Scripps Research in San Diego, who wasn’t involved in the new study. “This is a breakthrough finding.”
In a second Science study by the same team, the authors found that an additional 3.5 percent of critically ill patients had mutations in genes that control the interferons involved in fighting viruses. Given that the body has 500 to 600 of those genes, it’s possible that researchers will find more mutations, said Qian Zhang, lead author of the second study.
Interferons serve as the body’s first line of defense against infection, sounding the alarm and activating an army of virus-fighting genes, said virologist Angela Rasmussen, an associate research scientist at the Center for Infection and Immunity at Columbia University’s Mailman School of Public Health.
“Interferons are like a fire alarm and a sprinkler system all in one,” said Rasmussen, who wasn’t involved in the new studies.
Lab studies show that interferons are suppressed in some people with Covid-19, perhaps by the virus itself.
Interferons are particularly important for protecting the body against new viruses, such as the coronavirus, which the body has never encountered, said Zhang, a researcher at Rockefeller University’s St. Giles Laboratory of Human Genetics of Infectious Diseases.
When infected with the novel coronavirus, “your body should have alarms ringing everywhere,” Zhang said. “If you don’t get the alarm out, you could have viruses everywhere in large numbers.”
Significantly, patients didn’t make autoantibodies in response to the virus. Instead, they appeared to have had them before the pandemic even began, said Paul Bastard, the antibody study’s lead author, who is also a researcher at Rockefeller University.
For reasons that researchers don’t understand, the autoantibodies never caused a problem until patients were infected with Covid-19, Bastard said. Somehow, the coronavirus, or the immune response it triggered, appears to have set them in motion.
“Before Covid, their condition was silent,” Bastard said. “Most of them hadn’t gotten sick before.”
Bastard said he now wonders whether autoantibodies against interferon also increase the risk from other viruses, such as influenza. Among patients in his study, “some of them had gotten flu in the past, and we’re looking to see if the autoantibodies could have had an effect on flu.”
Scientists have long known that viruses and the immune system compete in a sort of arms race, with viruses evolving ways to evade the immune system and even suppress its response, said Sabra Klein, a professor of molecular microbiology and immunology at the Johns Hopkins Bloomberg School of Public Health.
Antibodies are usually the heroes of the immune system, defending the body against viruses and other threats. But sometimes, in a phenomenon known as autoimmune disease, the immune system appears confused and creates autoantibodies. This occurs in diseases such as rheumatoid arthritis, when antibodies attack the joints, and Type 1 diabetes, in which the immune system attacks insulin-producing cells in the pancreas.
Although doctors don’t know the exact causes of autoimmune disease, they’ve observed that the conditions often occur after viral infections. Autoimmune diseases are more common as people age.
In yet another unexpected finding, 94 percent of patients in the study with the autoantibodies were men. About 12.5 percent of men with life-threatening Covid-19 pneumonia had autoantibodies against interferon, compared with 2.6 percent of women.
“I’ve been studying sex differences in viral infections for 22 years, and I don’t think anybody who studies autoantibodies thought this would be a risk factor for Covid-19,” Klein said.
The study might help explain why men are more likely than women to become critically ill with Covid-19 and die, Klein said.
“You see significantly more men dying in their 30s, not just in their 80s,” she said.
Akiko Iwasaki, a professor of immunobiology at the Yale School of Medicine, noted that several genes involved in the immune system’s response to viruses are on the X chromosome.
Women have two copies of this chromosome — along with two copies of each gene. That gives women a backup in case one copy of a gene becomes defective, Iwasaki said.
Men, however, have only one copy of the X chromosome. So if there is a defect or a harmful gene on the X chromosome, they have no other copy of the gene to correct the problem, Iwasaki said.
Bastard noted that one woman in the study who developed autoantibodies has a rare genetic condition in which she has only one X chromosome.
Women more likely to be ‘long-haulers’
Scientists have struggled to explain why men have a higher risk of hospitalization and death from Covid-19. When the disease first appeared in China, experts speculated that men suffered more from the virus because they are much more likely to smoke than Chinese women.
Researchers quickly noticed that men in Spain were also more likely to die of Covid-19, however, even though men and women there smoke at about the same rate, Klein said.
Experts have hypothesized that men might be put at higher risk by being less likely to wear masks in public than women and more likely to delay seeking medical care, Klein said.
But behavioral differences between men and women provide only part of the answer. Scientists say it’s possible that the hormone estrogen may somehow protect women, while testosterone may put men at greater risk. Interestingly, recent studies have found that obesity poses a much greater risk to men with Covid-19 than to women, Klein said.
Yet women have their own form of suffering from Covid-19.
Studies show that women are four times more likely to experience long-term Covid-19 symptoms, lasting weeks or months, including fatigue, weakness and a kind of mental confusion known as “brain fog,” Klein said.
As women, “maybe we survive it and are less likely to die, but then we have all these long-term complications,” she said.
After reading the studies, Klein said she would like to learn whether patients who become severely ill from other viruses, such as influenza, also harbor genes or antibodies that disable interferon.
“There’s no evidence for this in flu,” Klein said. “But we haven’t looked. Through Covid-19, we may have uncovered a very novel mechanism of disease, which we could find is present in a number of diseases.”
To be sure, scientists say the new study solves only part of the mystery of why patient outcomes can vary so greatly.
Researchers say it’s possible that some patients are protected by previous exposure to other coronaviruses. Patients who get very sick also may have inhaled higher doses of the virus, such as from repeated exposure to infected co-workers.
Screening patients for autoantibodies against interferons could help predict which patients are more likely to become very sick, said Bastard, who is also affiliated with the Necker Hospital for Sick Children in Paris. Testing takes about two days. Hospitals in Paris can now screen patients on request from a doctor, he said.
Although only 10 percent of patients with life-threatening Covid-19 have autoantibodies, “I think we should give the test to everyone who is admitted,” Bastard said. Otherwise, “we wouldn’t know who is at risk for a severe form of the disease.”
Bastard said he hopes his findings will lead to new therapies that save lives. He noted that the body manufactures many types of interferons. Giving patients a different type of interferon — one not disabled by their genes or autoantibodies — might help them fight off the virus.
In fact, a pilot study of 98 patients published Thursday in the Lancet Respiratory Medicine journal found benefits from an inhaled form of interferon. In the industry-funded British study, hospitalized Covid-19 patients randomly assigned to receive interferon beta-1a were more than twice as likely as others to recover enough to resume their regular activities.
Researchers need to confirm the findings in a much larger study, said Dr. Nathan Peiffer-Smadja, a researcher at Imperial College London who wasn’t involved in the study but wrote an accompanying editorial. Future studies should test patients’ blood for genetic mutations and autoantibodies against interferon to see whether they respond differently from others.
Peiffer-Smadja said inhaled interferon may work better than an injected form of the drug because it’s delivered directly to the lungs. While injected versions of interferon have been used for years to treat other diseases, the inhaled version is still experimental and not commercially available.
And doctors should be cautious about interferon for now, because a study led by the World Health Organization found no benefit to an injected form of the drug in Covid-19 patients, Peiffer-Smadja said. In fact, there was a trend toward higher mortality rates in patients given interferon, although the finding could have been due to chance. Giving interferon later in the course of disease could encourage a destructive immune overreaction called a cytokine storm, in which the immune system does more damage than the virus.
Around the world, scientists have launched more than 100 clinical trials of interferons, according to clinicaltrials.gov, a database of research studies from the National Institutes of Health.
Until larger studies are completed, doctors say, Bastard’s findings are unlikely to change how they treat Covid-19.
Dr. Lewis Kaplan, president of the Society of Critical Care Medicine, said he treats patients according to their symptoms, not their risk factors.
“If you are a little sick, you get treated with a little bit of care,” Kaplan said. “You are really sick, you get a lot of care. But if a Covid patient comes in with hypertension, diabetes and obesity, we don’t say: ‘They have risk factors. Let’s put them in the ICU.'”
In Thursday’s second and final Presidential debate, former Vice President Joe Biden warned that a “dark winter” lies ahead in the coronavirus pandemic, and with cases, hospitalizations, and deaths on the rise across the country, it now appears that we are headed into a “third wave” of infections that may prove worse than both the initial onset of COVID on the coasts and the summertime spike in the Sun Belt.
Yesterday more than 71,600 new cases were reported nationwide, nearing a late-July record. Thirteen states hit record-high hospitalizations this week, measured by weekly averages, most in the Midwest and Mountain West. Several Northeastern states, which had previously brought the spread of the virus under control, also experienced substantial increases in infections, leading schools in Boston to suspend all in-person instruction. Of particular concern is hospital capacity, which is already being strained in the more rural areas now being hit by COVID cases. With infection spikes more geographically widespread than in earlier waves, fewer medical workers are available to lend support to hospitals in other states, leading to concerns about hospital staffing as admissions rise.
As hospitalizations increase, so too will demand for therapeutics to help shorten the course and moderate the impact of COVID. This week, Gilead Sciences’ antiviral drug remdesivir, previously available under an Emergency Use Authorization (EUA) from the federal government, became the first drug to win full approval from the Food and Drug Administration (FDA) to treat patients hospitalized with COVID-19. The approval was based on clinical studies that showed that remdesivir can reduce recovery time, and also includes use for pediatric COVID patients under the age of 11.
Meanwhile, the FDA cleared AstraZeneca to resume US clinical trials of its coronavirus vaccine, which had been suspended for a month following an adverse patient event. It’s widely expected that one or more drug companies will submit their vaccine candidates for EUA sometime next month, although new polling data released this week indicates that the American public is growing more skeptical in their willingness to take an early vaccine against the virus, with only 58 percent of respondents saying they would get the shot when it first becomes available, down from 69 percent in August. (Only 43 percent of Black respondents say they would get the vaccine, compared to 59 percent of Whites—a racial divide that reveals deep distrust based on the history of inequities in the US healthcare system.)
In many respects, the coming month will surely prove to be a pandemic turning point, revealing the magnitude of the next wave of COVID, the direction of US public health policy, the prospects for reliable therapeutics, and the timing of a safe and effective vaccine. We’ll soon know whether we are, indeed, headed for a winter of darkness.
One of the most perplexing elements of the novel coronavirus is its variability. It’s common knowledge that while many infected people will experience mild symptoms, those who are older, male and have underlying chronic disease are at much higher risk of severe disease and death.
Two recent papers published in Science provide some of themost compelling evidence behind the impaired immune response seen in severely affected patients—and a potential link to the gender disparities in outcomes.
Both papers are centered on the role of Type I interferon, an immune protein that provides a first line of defense in viral illness.
The first studyanalyzed the DNA of over 650 patients with severe COVID to assess mutations in the genes that code for interferon-1. Some 3.5 percent of patients with life-threatening COVID carried mutations, but these were found in none of the control patients who only had mild disease.
The second paperevaluated the presence of antibodies to the patient’s own interferon, finding that 14 percent of patients with severe disease had these “auto-antibodies”, which are extremely rare in the general population. Interestingly, 12.5 percent of severely ill men had the antibodies, compared to just 2.6 percent of women with severe disease. Previous work linked poor interferon response to the X chromosome, highlighting the potential increased risk for men.
Taken together, these studies indicate that impaired Type I interferon could contribute to 1 in 7 severe COVID cases. Scientists are hopeful this work could lead to new diagnostics that estimate a patient’s risk of poor outcomes. This growing body of work, with new insights published every week in Science and other journals, underscores the rapid advances being made in understanding and treating this novel and complex disease.
Along with the many political and public health questions raised by President Trump’s recent and very public bout with COVID-19 is the issue of when the public might have access to the same monoclonal antibody therapy that he received from doctors last week.
Having seen the President tout the benefits of Regeneron’s experimental antibody cocktail, COVID patients have reportedly been asking physicians about participating in clinical trials of the therapy, which is only available on a “compassionate use” basis outside of ongoing studies.
On Wednesday, Regeneronannounced it had submitted a request to the US Food and Drug Administration (FDA) for an Emergency Use Authorization (EUA) for the treatment, claiming that early data from ongoing trials showed promise in moderating coronavirus symptoms.
Eli Lilly, which is developing a similar antibody therapy, also announced plans to apply for an EUA, saying its drug has shown the ability to reduce hospitalizations among those infected with the virus.
The US government has already paid Regeneron $450M to access up to 300,000 doses of the therapy, and on Friday a spokesman for the Department of Health and Human Services (HHS) said the government would acquire up to a million doses from Regeneron and Eli Lilly by the end of the year, which it will allocate to hospitals in a similar approach to the way it has distributed Gilead Science’s antiviral drug remdesivir, which the President was also given last week.
News on the availability of potentially effective therapies to mitigate the impact of COVID-19 is welcome, particularly as thetimeline for COVID vaccines appears to be lengthening.
In guidance released this week, the FDA said it would require pharmaceutical companies to submit two months’ worth of data on vaccine safety and efficacy after patients received their final dose, as part of the EUA application process. The data requirement effectively means that, despite repeated promises from the White House, none of the vaccine candidates being developed will be available before the November 3rd Presidential election.
The head of the government’s vaccine program said separately this week that he expects data on vaccines being developed by Pfizer and Moderna to be available by December. As many have predicted, it will take months beyond that for a safe and effective vaccine to be distributed and administered to a majority of Americans.
Challenges will abound: ensuring sufficient manufacturing capacity, managing a complex supply chain, setting up specialized distribution and vaccination centers, and tracking those vaccinated (especially if two shots will be required). A massive public education campaign will also be needed to overcome vaccine hesitancy and ensure widespread immunization. And all of that will take time, and money.
President Trump’s recent and unfortunate illness underscores the importance of paying equal attention to the development of therapies and treatments—which are essentially a holding maneuver to get us through the coming winter and spring, and eventually to the promise of immunity that lies beyond.
The COVID-19 pandemic is rife with scientific and medical uncertainty, including debates about the ethics of using experimental treatments.
The big picture: As the global pandemic continues, the tension between providing the best available care for patients and performing trials to determine whether that care is effective risks complicating the medical response.
The big question: Is it unethical to withhold a possible treatment from someone who instead receives a placebo, or to continue to administer that treatment without having collected data on whether it works?
Driving the news: President Trump received an experimental monoclonal antibody cocktail via expanded access or “compassionate use,” which allows someone to access a treatment outside of a clinical trial before it is approved, provided their doctor, the drug company and the FDA agree.
Experts say his subsequent claims of the treatment being a cure risks reducing enrollment in clinical trials, flooding companies with requests for access to a limited number of doses andcreating false hope for patients.
“It’s important that we not say the president got access to a beneficial experimental intervention because we don’t know if it is beneficial or if there are adverse events associated with it,“ says Alex John London, director of the Center for Ethics and Policy at Carnegie Mellon University.
He and other ethicists say the president’s treatment highlights a broader question about the ethical obligation doctors have to the science needed to determine if those treatments are effective.
Between the lines: Offering patients experimental COVID-19 drugs via emergency use authorizations, expanded access programs and compassionate use can slow needed clinical trials.
Researchers have struggled to enroll people in clinical trials in which they may receive a placebo if patients can access a drug directly.
One example: “There’s been some hiccups with the expanded access use for convalescent plasma, because it was something that precluded people from enrolling in a randomized control trial, so it took longer, and we still don’t quite know how well convalescent plasma works,” says Amesh Adalja, an infectious disease physician and senior scholar at the Johns Hopkins Center for Health Security.
More than 100,000 COVID-19 patients at almost 2,800 U.S. hospitals received convalescent plasma from people who survived the virus and developed antibodies to it.
“It’s easy for people to say you enrolled 100,000 people, there should have been a trial. But a small number of those 2,800 hospitals would have been capable of doing those trials,” says the Mayo Clinic’s Michael Joyner, who leads the program.
There are now smaller trials taking place to answer questions about the effectiveness of plasma in treating the disease in different stages.
But if this happens again, Joyner says programs at academic medical centers should be peeled off earlier to form clinical trials run in parallel.
The gold standard for determining whether a treatment works is through randomized controlled trials in which people are randomly assigned to receive a treatment or to be in a control group.
In the uncertainty and urgency of a pandemic, some physicians argue randomizing people to receive a placebo goes against physicians’ ethics and that it is better to do something to help patients than do nothing.
“That’s a false dichotomy because the question is, what should we do?” says London.
From a doctor’s perspective, it’s important to weigh the collective value of theearly drug data and the individual needs of the patient, Adalja says.
“I do think you have to be extra careful when you’re thinking about drugs that you don’t have strong randomized control trial data for, or the data is incomplete or inconclusive,” he adds.
“What people have to ask themselves is what constitutes evidence or proof and where do you want to make the bets in a pandemic?” says Joyner.
“There is a moral, legal and public health obligation to do those trials before people use those products,” says Alison Bateman-House, a professor of medical ethics at NYU’s Grossman School of Medicine who co-chairs an international working group on pre-approval access to treatments.
She says she understands the emotional pull on doctors to help patients whose health is quickly deteriorating, “but it is not evidence-based medicine.”
“There is no ethical obligation to give anyone an unproven substance.”
— Alison Bateman-House, NYU Grossman School of Medicine
In a forthcoming paper, London argues that when medical professionals don’t have the knowledge they need to treat patients, it is their responsibility “to band together and run studies to get evidence to discharge [their] very ancient medical obligation.”
Medical ethics should be updated to include a responsibility to learn in the face of uncertainty, says London, who was part of a committee that called for research to be incorporated into the response to the Ebola outbreak in West Africa in 2014.
The U.K.’s large randomized RECOVERY trial is based in part on the Ebola experience, says London. “Because of it, we know dexamethasone is effective and hydroxychloroquine is not.”
What to watch: How the FDA’s handling of treatments during the pandemic influences other drugs and diseases once the pandemic ends.
The bottom line: “Medicine doesn’t have a good handle on uncertainty, and that is a problem,” says London.
Although COVID-19 cases, hospitalizations, and deaths are rising, there is also some positive news on the horizon, according to Joseph Allen of Harvard T.H. Chan School of Public Health.
In a July 14, 2020 Washington Post op-ed, Allen, assistant professor of exposure assessment science and director of the Healthy Buildings program, wrote that progress is being made in treatments, testing, and vaccines, and that there’s growing agreement about ways to curb the spread of infection.
Among positive developments, Allen cited:
Therapeutic treatments, such as cloned antibodies, are showing to be effective both to treat and prevent COVID-19.
Rapid, low-cost saliva tests for COVID-19 are being developed and could be a game-changer.
Universal mask-wearing is catching on.
Consensus has emerged that airborne spread of the coronavirus is happening, and the World Health Organization and other organizations are now recommending the use of healthy building strategies such as higher ventilation, better filtration, and the use of air-cleaning devices.
Several studies suggest that past exposure to common-cold coronaviruses may help protect some people from COVID-19 infection.
Vaccine trials seem to be working and drug makers have said they may be able to deliver doses as early as October.
“For the first time in history, nearly every scientist in the world is focused on the same problem,” Allen wrote. “This is starting to pay real dividends.”