Can Radical Transparency Overcome Resistance to COVID-19 Vaccines?

Secretive panels of independent experts called Data Safety and Monitoring Boards examine clinical trials' data for safety and efficacy.
When historians look back on the COVID-19 pandemic, they may mark November 9, 2020 as the day the tide began to turn. That's when the New York-based pharmaceutical giant Pfizer announced that clinical trials showed its experimental vaccine, developed with the German firm BioNTech, to be 90 percent effective in preventing the disease.
A week later, Massachusetts biotech startup Moderna declared its vaccine to be 95 percent effective. By early December, Great Britain had begun mass inoculations, followed—once the Food and Drug Administration gave the thumbs-up—by the United States. In this scenario, the worst global health crisis in a century was on the cusp of resolution.
Yet future chroniclers may instead peg November 9 as the day false hope dawned. That could happen if serious safety issues, undetected so far, arise after millions of doses are administered. Experts consider it unlikely, however, that such problems alone (as opposed to the panic they might spark) would affect enough people to thwart a victory over the coronavirus. A more immediate obstacle is vaccine hesitancy—the prospect that much of the populace will refuse to roll up their sleeves.
To achieve "herd immunity" for COVID-19 (the point at which a vaccine reduces transmission rates enough to protect those who can't or won't take it, or for whom it doesn't work), epidemiologists estimate that up to 85 percent of the population will have to be vaccinated. Alarmingly, polls suggest that 40 to 50 percent of Americans intend to decline, judging the risks to be more worrisome than those posed by the coronavirus itself.
COVID vaccine skeptics occupy various positions on a spectrum of doubt. Some are committed anti-vaxxers, or devotees of conspiracy theories that view the pandemic as a hoax. Others belong to minority groups that have historically been used as guinea pigs in unethical medical research (for horrific examples, Google "Tuskegee syphilis experiment" or "Henrietta Lacks"). Still others simply mistrust Big Pharma and/or Big Government. A common fear is that the scramble to find a vaccine—intensified by partisan and profit motives—has led to corner-cutting in the testing and approval process. "They really rushed," an Iowa trucker told The Washington Post. "I'll probably wait a couple of months after they start to see how everyone else is handling it."
The COVID crisis has spurred calls for secretive Data Safety and Monitoring Boards to come out of the shadows.
The consensus among scientists, by contrast, is that the process has been rigorous enough, given the exigency of the situation, that the public can feel reasonably confident in any vaccine that has earned the imprimatur of the FDA. For those of us who share that assessment, finding ways to reassure the hesitant-but-persuadable is an urgent matter.
Vax-positive public health messaging is one obvious tactic, but a growing number of experts say it's not enough. They prescribe a regimen of radical transparency throughout the system that regulates research—in particular, regarding the secretive panels that oversee vaccine trials.
The Crucial Role of the Little-Known Panels
Like other large clinical trials involving potentially high-demand or controversial products, studies of COVID-19 vaccines in most countries are supervised by groups of independent observers. Known in the United States as data safety and monitoring boards (DSMBs), and elsewhere as data monitoring committees, these panels consist of scientists, clinicians, statisticians, and other authorities with no ties to the sponsor of the study.
The six trials funded by the federal program known as Operation Warp Speed (including those of newly approved Moderna and frontrunner AstraZeneca) share a DSMB, whose members are selected by the National Institutes of Health; other companies (including Pfizer) appoint their own. The panel's job is to monitor the safety and efficacy of a treatment while the trial is ongoing, and to ensure that data is being collected and analyzed correctly.
Vaccine studies are "double-blinded," which means neither the participants nor the doctors running the trial know who's getting the real thing and who's getting a placebo. But the DSMB can access that information if a study volunteer has what might be a serious side effect—and if the participant was in the vaccine group, the board can ask that the trial be paused for further investigation.
The DSMB also checks for efficacy at pre-determined intervals. If it finds that the vaccine group and the placebo group are getting sick at similar rates, the panel can recommend stopping the trial due to "futility." And if the results look overwhelmingly positive, the DSMB can recommend that the study sponsor apply for FDA approval before the scheduled end of the trial, in order to hurry the product to market.
With this kind of inside dope and high-level influence, DSMBs could easily become targets for outside pressure. That's why, since the 1980s, their membership has typically been kept secret.
During the early days of the AIDS crisis, researchers working on HIV drugs feared for the safety of the experts on their boards. "They didn't want them to be besieged and harassed by members of the community," explains Susan Ellenberg, a professor of biostatistics, medical ethics and health policy at the University of Pennsylvania, and co-author of Data Monitoring Committees in Clinical Trials, the DSMB bible. "You can understand why people would very much want to know how things were looking in a given trial. They wanted to save their own lives; they wanted to save their friends' lives." Ellenberg, who was founding director of the biostatistics branch of the AIDS division at the National Institute of Allergy and Infectious Diseases (NIAID), helped shape a range of policies designed to ensure that DSMBs made decisions based on data and nothing else.
Confidentiality also shields DSMB members from badgering by patient advocacy groups, who might urge that a drug be presented for approval before trial results are conclusive, or by profit-hungry investors. "It prevents people from trying to pry out information to get an edge in the stock market," says Art Caplan, a bioethicist at New York University.
Yet the COVID crisis has spurred calls for DSMBs to come out of the shadows. One triggering event came in March 2020, when the FDA approved hydroxychloroquine for COVID-19—a therapy that President Donald J. Trump touted, despite scant evidence for its efficacy. (Approval was rescinded in June.) If the agency could bow to political pressure on these medications, critics warned, it might do so with vaccines as well. In the end, that didn't happen; the Pfizer approval was issued well after Election Day, despite Trump's goading, and most experts agree that it was based on solid science. Still, public suspicion lingers.
Another shock came in September, after British-based AstraZeneca announced it was pausing its vaccine trial globally due to a "suspected adverse rection" in a volunteer. The company shared no details with the press. Instead, AstraZeneca's CEO divulged them in a private call with J.P. Morgan investors the next day, confirming that the volunteer was suffering from transverse myelitis, a rare and serious spinal inflammation—and that the study had also been halted in July, when another volunteer displayed neurological symptoms. STAT News broke the story after talking to tipsters.
Although both illnesses were found to be unrelated to the vaccine, and the trial was restarted, the incident had a paradoxical effect: while it confirmed for experts that the oversight system was working, AstraZeneca's initial lack of candor added to many laypeople's sense that it wasn't. "If you were seeking to undermine trust, that's kind of how you would go about doing it," says Charles Weijer, a bioethicist at Western University in Ontario, who has helped develop clinical trial guidelines for the World Health Organization.
Both Caplan and Weijer have served on many DSMBs; they believe the boards are generally trustworthy, and that those overseeing COVID vaccine trials are performing their jobs well. But the secrecy surrounding these groups, they and others argue, has become counterproductive. Shining a light on the statistical sausage-makers would help dispel doubts about the finished product.
"I'm not suggesting that any of these companies are doing things unethically," Weijer explains. "But the circumstances of a global pandemic are sufficiently challenging that perhaps they ought to be doing some things differently. I believe it would be trust-producing for data monitoring committees to be more forthcoming than usual."
Building Trust: More Transparency
Just how forthcoming is a matter of debate. Caplan suggests that each COVID vaccine DSMB reveal the name of its chair; that would enable the scientific community, as well as the media and the general public, to get a sense of the integrity and qualifications of the board as a whole while preserving the anonymity of the other members.
Indeed, when Operation Warp Speed's DSMB chair, Richard Whitley, was outed through a website slip-up, many observers applauded his selection for the role; a professor of pediatrics, microbiology, medicine and neurosurgery at the University of Alabama at Birmingham, he is "an exceptionally experienced and qualified individual," Weijer says. (Reporters with ProPublica later identified two other members: Susan Ellenberg and immunologist William Makgoba, known for his work on the South African AIDS Vaccine Initiative.)
Caplan would also like to see more details of the protocols DSMBs are using to make decisions, such as the statistical threshold for efficacy that would lead them to seek approval from the FDA. And he wishes the NIH would spell out specific responsibilities for these monitoring boards. "They don't really have clear, government-mandated charters," he notes. For example, there's no requirement that DSMBs include an ethicist or patient advocate—both of which Caplan considers essential for vaccine trials. "Rough guidelines," he says, "would be useful."
Weijer, for his part, thinks DSMBs should disclose all their members. "When you only disclose the chair, you leave questions unanswered," he says. "What expertise do [the others] bring to the table? Are they similarly free of relevant conflicts of interest? And it doesn't answer the question that will be foremost on many people's minds: are these people in the pocket of pharma?"
Weijer and Caplan both want to see greater transparency around the trial results themselves. Because the FDA approved the Pfizer and Moderna vaccines with emergency use authorizations rather than full licensure, which requires more extensive safety testing, these products reached the market without the usual paper trail of peer-reviewed publications. The same will likely be true of any future COVID vaccines that the agency greenlights. To add another level of scrutiny, both ethicists suggest, each company should publicly release its data at the end of a trial. "That offers the potential for academic groups to go in and do an analysis," Weijer explains, "to verify the claims about the safety and efficacy of the vaccine." The point, he says, is not only to ensure that the approval was justified, but to provide evidence to counter skeptics' qualms.
Caplan may differ on some of the details, but he endorses the premise. "It's all a matter of trust," he says. "You're always watching that, because a vaccine is only as good as the number of people who take it."
Probiotic bacteria can be engineered to fight antibiotic-resistant superbugs by releasing chemicals that kill them.
In 1945, almost two decades after Alexander Fleming discovered penicillin, he warned that as antibiotics use grows, they may lose their efficiency. He was prescient—the first case of penicillin resistance was reported two years later. Back then, not many people paid attention to Fleming’s warning. After all, the “golden era” of the antibiotics age had just began. By the 1950s, three new antibiotics derived from soil bacteria — streptomycin, chloramphenicol, and tetracycline — could cure infectious diseases like tuberculosis, cholera, meningitis and typhoid fever, among others.
Today, these antibiotics and many of their successors developed through the 1980s are gradually losing their effectiveness. The extensive overuse and misuse of antibiotics led to the rise of drug resistance. The livestock sector buys around 80 percent of all antibiotics sold in the U.S. every year. Farmers feed cows and chickens low doses of antibiotics to prevent infections and fatten up the animals, which eventually causes resistant bacterial strains to evolve. If manure from cattle is used on fields, the soil and vegetables can get contaminated with antibiotic-resistant bacteria. Another major factor is doctors overprescribing antibiotics to humans, particularly in low-income countries. Between 2000 to 2018, the global rates of human antibiotic consumption shot up by 46 percent.
In recent years, researchers have been exploring a promising avenue: the use of synthetic biology to engineer new bacteria that may work better than antibiotics. The need continues to grow, as a Lancetstudy linked antibiotic resistance to over 1.27 million deaths worldwide in 2019, surpassing HIV/AIDS and malaria. The western sub-Saharan Africa region had the highest death rate (27.3 people per 100,000).
Researchers warn that if nothing changes, by 2050, antibiotic resistance could kill 10 million people annually.
To make it worse, our remedy pipelines are drying up. Out of the 18 biggest pharmaceutical companies, 15 abandoned antibiotic development by 2013. According to the AMR Action Fund, venture capital has remained indifferent towards biotech start-ups developing new antibiotics. In 2019, at least two antibiotic start-ups filed for bankruptcy. As of December 2020, there were 43 new antibiotics in clinical development. But because they are based on previously known molecules, scientists say they are inadequate for treating multidrug-resistant bacteria. Researchers warn that if nothing changes, by 2050, antibiotic resistance could kill 10 million people annually.
The rise of synthetic biology
To circumvent this dire future, scientists have been working on alternative solutions using synthetic biology tools, meaning genetically modifying good bacteria to fight the bad ones.
From the time life evolved on earth around 3.8 billion years ago, bacteria have engaged in biological warfare. They constantly strategize new methods to combat each other by synthesizing toxic proteins that kill competition.
For example, Escherichia coli produces bacteriocins or toxins to kill other strains of E.coli that attempt to colonize the same habitat. Microbes like E.coli (which are not all pathogenic) are also naturally present in the human microbiome. The human microbiome harbors up to 100 trillion symbiotic microbial cells. The majority of them are beneficial organisms residing in the gut at different compositions.
The chemicals that these “good bacteria” produce do not pose any health risks to us, but can be toxic to other bacteria, particularly to human pathogens. For the last three decades, scientists have been manipulating bacteria’s biological warfare tactics to our collective advantage.
In the late 1990s, researchers drew inspiration from electrical and computing engineering principles that involve constructing digital circuits to control devices. In certain ways, every cell in living organisms works like a tiny computer. The cell receives messages in the form of biochemical molecules that cling on to its surface. Those messages get processed within the cells through a series of complex molecular interactions.
Synthetic biologists can harness these living cells’ information processing skills and use them to construct genetic circuits that perform specific instructions—for example, secrete a toxin that kills pathogenic bacteria. “Any synthetic genetic circuit is merely a piece of information that hangs around in the bacteria’s cytoplasm,” explains José Rubén Morones-Ramírez, a professor at the Autonomous University of Nuevo León, Mexico. Then the ribosome, which synthesizes proteins in the cell, processes that new information, making the compounds scientists want bacteria to make. “The genetic circuit remains separated from the living cell’s DNA,” Morones-Ramírez explains. When the engineered bacteria replicates, the genetic circuit doesn’t become part of its genome.
Highly intelligent by bacterial standards, some multidrug resistant V. cholerae strains can also “collaborate” with other intestinal bacterial species to gain advantage and take hold of the gut.
In 2000, Boston-based researchers constructed an E.coli with a genetic switch that toggled between turning genes on and off two. Later, they built some safety checks into their bacteria. “To prevent unintentional or deleterious consequences, in 2009, we built a safety switch in the engineered bacteria’s genetic circuit that gets triggered after it gets exposed to a pathogen," says James Collins, a professor of biological engineering at MIT and faculty member at Harvard University’s Wyss Institute. “After getting rid of the pathogen, the engineered bacteria is designed to switch off and leave the patient's body.”
Overuse and misuse of antibiotics causes resistant strains to evolve
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Seek and destroy
As the field of synthetic biology developed, scientists began using engineered bacteria to tackle superbugs. They first focused on Vibrio cholerae, whichin the 19th and 20th century caused cholera pandemics in India, China, the Middle East, Europe, and Americas. Like many other bacteria, V. cholerae communicate with each other via quorum sensing, a process in which the microorganisms release different signaling molecules, to convey messages to its brethren. Highly intelligent by bacterial standards, some multidrug resistant V. choleraestrains can also “collaborate” with other intestinal bacterial species to gain advantage and take hold of the gut. When untreated, cholera has a mortality rate of 25 to 50 percent and outbreaks frequently occur in developing countries, especially during floods and droughts.
Sometimes, however, V. cholerae makes mistakes. In 2008, researchers at Cornell University observed that when quorum sensing V. cholerae accidentally released high concentrations of a signaling molecule called CAI-1, it had a counterproductive effect—the pathogen couldn’t colonize the gut.
So the group, led byJohn March, professor of biological and environmental engineering, developed a novel strategy to combat V. cholerae. They genetically engineered E.coli toeavesdrop on V. cholerae communication networks and equipped it with the ability to release the CAI-1 molecules. That interfered with V. cholerae progress.Two years later, the Cornell team showed that V. cholerae-infected mice treated with engineered E.coli had a 92 percent survival rate.
These findings inspired researchers to sic the good bacteria present in foods like yogurt and kimchi onto the drug-resistant ones.
Three years later in 2011, Singapore-based scientists engineered E.coli to detect and destroy Pseudomonas aeruginosa, an oftendrug-resistant pathogen that causes pneumonia, urinary tract infections, and sepsis. Once the genetically engineered E.coli found its target through its quorum sensing molecules, it then released a peptide, that could eradicate 99 percent of P. aeruginosa cells in a test-tube experiment. The team outlined their work in a Molecular Systems Biology study.
“At the time, we knew that we were entering new, uncharted territory,” says lead author Matthew Chang, an associate professor and synthetic biologist at the National University of Singapore and lead author of the study. “To date, we are still in the process of trying to understand how long these microbes stay in our bodies and how they might continue to evolve.”
More teams followed the same path. In a 2013 study, MIT researchers also genetically engineered E.coli to detect P. aeruginosa via the pathogen’s quorum-sensing molecules. It then destroyed the pathogen by secreting a lab-made toxin.
Probiotics that fight
A year later in 2014, a Nature study found that the abundance of Ruminococcus obeum, a probiotic bacteria naturally occurring in the human microbiome, interrupts and reduces V.cholerae’s colonization— by detecting the pathogen’s quorum sensing molecules. The natural accumulation of R. obeumin Bangladeshi adults helped them recover from cholera despite living in an area with frequent outbreaks.
The findings from 2008 to 2014 inspired Collins and his team to delve into how good bacteria present in foods like yogurt and kimchi can attack drug-resistant bacteria. In 2018, Collins and his team developed the engineered probiotic strategy. They tweaked a commonly found bacteria in yogurt called Lactococcus lactis.
Engineered bacteria can be trained to target pathogens when they are at their most vulnerable metabolic stage in the human gut. --José Rubén Morones-Ramírez.
More scientists followed with more experiments. So far, researchers have engineered various probiotic organisms to fight pathogenic bacteria like Staphylococcus aureus (leading cause of skin, tissue, bone, joint and blood infections) and Clostridium perfringens (which causes watery diarrhea) in test-tube and animal experiments. In 2020, Russian scientists engineered a probiotic called Pichia pastoris to produce an enzyme called lysostaphin that eradicated S. aureus in vitro. Another 2020 study from China used an engineered probiotic bacteria Lactobacilli casei as a vaccine to prevent C. perfringens infection in rabbits.
In a study last year, Ramírez’s group at the Autonomous University of Nuevo León, engineered E. coli to detect quorum-sensing molecules from Methicillin-resistant Staphylococcus aureus or MRSA, a notorious superbug. The E. coli then releases a bacteriocin that kills MRSA. “An antibiotic is just a molecule that is not intelligent,” says Ramírez. “On the other hand, engineered bacteria can be trained to target pathogens when they are at their most vulnerable metabolic stage in the human gut.”
Collins and Timothy Lu, an associate professor of biological engineering at MIT, found that engineered E. coli can help treat other conditions—such as phenylketonuria, a rare metabolic disorder, that causes the build-up of an amino acid phenylalanine. Their start-up Synlogic aims to commercialize the technology, and has completed a phase 2 clinical trial.
Circumventing the challenges
The bacteria-engineering technique is not without pitfalls. One major challenge is that beneficial gut bacteria produce their own quorum-sensing molecules that can be similar to those that pathogens secrete. If an engineered bacteria’s biosensor is not specific enough, it will be ineffective.
Another concern is whether engineered bacteria might mutate after entering the gut. “As with any technology, there are risks where bad actors could have the capability to engineer a microbe to act quite nastily,” says Collins of MIT. But Collins and Ramírez both insist that the chances of the engineered bacteria mutating on its own are virtually non-existent. “It is extremely unlikely for the engineered bacteria to mutate,” Ramírez says. “Coaxing a living cell to do anything on command is immensely challenging. Usually, the greater risk is that the engineered bacteria entirely lose its functionality.”
However, the biggest challenge is bringing the curative bacteria to consumers. Pharmaceutical companies aren’t interested in antibiotics or their alternatives because it’s less profitable than developing new medicines for non-infectious diseases. Unlike the more chronic conditions like diabetes or cancer that require long-term medications, infectious diseases are usually treated much quicker. Running clinical trials are expensive and antibiotic-alternatives aren’t lucrative enough.
“Unfortunately, new medications for antibiotic resistant infections have been pushed to the bottom of the field,” says Lu of MIT. “It's not because the technology does not work. This is more of a market issue. Because clinical trials cost hundreds of millions of dollars, the only solution is that governments will need to fund them.” Lu stresses that societies must lobby to change how the modern healthcare industry works. “The whole world needs better treatments for antibiotic resistance.”
Meet Dr. Renee Wegrzyn, the first Director of President Biden's new health agency, ARPA-H
Today's podcast guest, Dr. Renee Wegrzyn, directs ARPA-H, a new agency formed last year to spearhead health innovations. Time will tell if ARPA-H will produce advances on the level of its fellow agency, DARPA.
In today’s podcast episode, I talk with Renee Wegrzyn, appointed by President Biden as the first director of a health agency created last year, the Advanced Research Projects Agency for Health, or ARPA-H. It’s inspired by DARPA, the agency that develops innovations for the Defense department and has been credited with hatching world-changing technologies such as ARPANET, which became the internet.
Time will tell if ARPA-H will lead to similar achievements in the realm of health. That’s what President Biden and Congress expect in return for funding ARPA-H at 2.5 billion dollars over three years.
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How will the agency figure out which projects to take on, especially with so many patient advocates for different diseases demanding moonshot funding for rapid progress?
I talked with Dr. Wegrzyn about the opportunities and challenges, what lessons ARPA-H is borrowing from Operation Warp Speed, how she decided on the first ARPA-H project that was announced recently, why a separate agency was needed instead of reforming HHS and the National Institutes of Health to be better at innovation, and how ARPA-H will make progress on disease prevention in addition to treatments for cancer, Alzheimer’s and diabetes, among many other health priorities.
Dr. Wegrzyn’s resume leaves no doubt of her suitability for this role. She was a program manager at DARPA where she focused on applying gene editing and synthetic biology to the goal of improving biosecurity. For her work there, she received the Superior Public Service Medal and, in case that wasn’t enough ARPA experience, she also worked at another ARPA that leads advanced projects in intelligence, called I-ARPA. Before that, she ran technical teams in the private sector working on gene therapies and disease diagnostics, among other areas. She has been a vice president of business development at Gingko Bioworks and headed innovation at Concentric by Gingko. Her training and education includes a PhD and undergraduate degree in applied biology from the Georgia Institute of Technology and she did her postdoc as an Alexander von Humboldt Fellow in Heidelberg, Germany.
Dr. Wegrzyn told me that she’s “in the hot seat.” The pressure is on for ARPA-H especially after the need and potential for health innovation was spot lit by the pandemic and the unprecedented speed of vaccine development. We'll soon find out if ARPA-H can produce gamechangers in health that are equivalent to DARPA’s creation of the internet.
Show links:
ARPA-H - https://arpa-h.gov/
Dr. Wegrzyn profile - https://arpa-h.gov/people/renee-wegrzyn/
Dr. Wegrzyn Twitter - https://twitter.com/rwegrzyn?lang=en
President Biden Announces Dr. Wegrzyn's appointment - https://www.whitehouse.gov/briefing-room/statement...
Leaps.org coverage of ARPA-H - https://leaps.org/arpa/
ARPA-H program for joints to heal themselves - https://arpa-h.gov/news/nitro/ -
ARPA-H virtual talent search - https://arpa-h.gov/news/aco-talent-search/
Dr. Renee Wegrzyn was appointed director of ARPA-H last October.
Matt Fuchs is the editor-in-chief of Leaps.org and Making Sense of Science. He is also a contributing reporter to the Washington Post and has written for the New York Times, Time Magazine, WIRED and the Washington Post Magazine, among other outlets. Follow him @fuchswriter.