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.
The Crucial Role of the Little-Known Panels
<p>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.</p><p>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.</p><p>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. </p><p>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. </p><p>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. </p><p>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 <em>Data Monitoring Committees in Clinical Trials, </em>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.</p><p>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.</p><p>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.</p><p>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.</p><p>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. </p><p>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.</p><p>"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." </p>Building Trust: More Transparency
<p>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.</p><p>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.)</p><p>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."</p><p>Weijer, for his part, thinks DSMBs should disclose <em>all</em> 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?"</p><p>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.</p><p>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."</p>The Biggest Challenge for a COVID-19 Vaccine
As scientists race to develop a safe and effective vaccine, companies and governments must figure out how to distribute affordable doses all over the world as fast as possible.
Although no one has conducted a survey on the topic, it's safe to say that a single hope unites much of humanity at the present moment: the prospect of a vaccine for COVID-19, which has infected more than 9 million people worldwide, killed nearly 500,000, and sent the global economy into a tailspin since it first appeared in China last December.
"We've never delivered something to every corner of the world before."
Scientists are racing to make that vision a reality. As of this writing, 11 vaccine candidates are in clinical trials and over 100 others are in preclinical development, in a dozen countries. Pointing to new technology and compressed testing protocols, experts predict a winner could emerge in 12 to 18 months—a fraction of the four years it took to develop the previous record-holder, the mumps vaccine, in the 1960s. Teams at Oxford University and Boston-based Moderna Therapeutics say they could have a product ready even sooner, if the formulas they're testing prove safe and effective. A just-announced White House initiative, Operation Warp Speed, aims to fast-track multiple candidates, with the goal of delivering 100 million doses in November and another 200 million by January 2021.
These timetables could prove wildly over-optimistic. But even if the best-case scenario comes true, and a viable COVID-19 vaccine emerges this fall, a gargantuan challenge remains: getting the shot to everyone who needs it. Epidemiologists figure that at least 70 percent of Earth's population—or 5.6 billion people—would have to be inoculated to achieve "herd immunity," in which each person who catches the disease passes it to less than one other individual. "In order to stop the pandemic, we need to make the vaccine available to almost every person on the planet," Microsoft co-founder Bill Gates blogged in April, as his foundation pledged $300 million to the effort. "We've never delivered something to every corner of the world before."
The difficulties are partly logistical, partly political, and largely a combination of the two. Overcoming those obstacles will require unprecedented cooperation among national governments, international organizations, and profit-minded corporations—in an era when nationalist rivalries are rampant and global leadership is up for grabs.
That may be tougher than developing the vaccine itself.
Logistical Conundrums
Manufacturing and distributing billions of vaccine doses would be a daunting task even in the most harmonious of times. Take the packaging problem. The vaccines under development range from old-school (based on inactivated or weakened viruses) to cutting-edge (using snippets of RNA or DNA to train the immune system to attack the invader). Some may work better than others for different patient groups—the young versus the elderly, for example. All, however, must be stored in vials and administered with syringes.
Among the handful of U.S. companies that manufacture such products, many must import the special glass tubing for vials, as well as the polypropylene for syringe barrels and the rubber or silicone for stoppers and plungers. These materials are commonly sourced from China and India, where lockdowns and export bans restrict supply. Rick Bright, the ousted director of the federal Biomedical Advanced Research and Development Authority (BARDA), claims he was ignored when he warned the Trump Administration that a medical-glass shortage was looming before the coronavirus crisis hit; securing enough to vaccinate 300 million Americans, he told Congress in May, could take up to two years.
Getting the vaccine to poorer countries presents further hurdles. To begin with, there's refrigeration. Inactivated or live vaccines must be kept between 2 and 8 degrees Centigrade (or 35 to 46 degrees Fahrenheit); RNA vaccines typically require much colder temperatures—as low as -80 degrees. This makes storage and transport challenging in parts of the world that lack reliable electricity. DNA vaccines don't need cold storage, but (like RNA vaccines) they remain experimental. They've never been approved to treat any human disease.
Tracking vaccine distribution is another conundrum for low- to-middle-income countries. "Supply chain management is really about information," explains Rebecca Weintraub, assistant professor of global health and social medicine at Harvard Medical School and director of the Better Evidence project at Harvard's Ariadne Labs. "It's about leveraging data to determine demand, predict behavior, and understand the flow of the product itself." Systems for collecting and analyzing such data can be hard to find in poorer regions, she notes. What's more, many people in those areas lack any type of ID card, making it difficult to know who has or hasn't received a vaccine.
Weintraub and two coauthors published an article in April in the Harvard Business Review, suggesting solutions to these and other developing-world problems: solar direct-drive refrigerators, app-based data-capture systems, biometric digital IDs. But such measures—not to mention purchasing adequate supplies of vaccine—would require massive funding.
And that's where the logistical begins to overlap with the political.
Global Access Versus "Vaccine Nationalism"
An array of institutions have already begun laying the groundwork for achieving worldwide, equitable access to COVID-19 vaccines. In February, the World Bank and the Norway-based Coalition for Epidemic Preparedness Innovations (CEPI) cohosted a global consultation on funding vaccine development and manufacturing. In late April, the World Health Organization (WHO), in collaboration with dozens of governments, nonprofits, and industry leaders, launched a program called the Access to COVID-19 Tools Accelerator to expedite such efforts.
Soon afterward, the European Union, along with six countries and the Bill and Melinda Gates Foundation, held a Coronavirus Global Response telethon that raised $8 billion to support Gavi, the Vaccine Alliance—a public-private partnership that subsidizes immunization in low-income countries. The United States and Russia, however, chose not to participate.
This snub by the world's remaining superpower and one of its principal challengers worried many observers. "I am concerned about what I call vaccine nationalism," CEPI executive director Richard Hatchett told the Los Angeles Times. "That's the tension between obligations elected leaders will feel to protect the lives of their citizens" versus the imperative for global sharing.
Some signs point to a possible rerun of the hoarding that accompanied the 2009 H1N1 influenza pandemic, when wealthy nations bought up virtually all vaccine supplies—denying them to poorer countries, and sometimes to one another. Operation Warp Speed has declared an "America First" policy for any vaccine arising from its efforts. Pharma giant Sanofi recently suggested that it would take a similar approach, since the U.S. was first to fund the company's COVID-19 research. (Sanofi's CEO backtracked after officials in France, where the firm is headquartered, protested.) The Oxford group, which is partnering with British-based drug maker AstraZeneca, intends to prioritize Great Britain.
Yet momentum is building for more generous strategies as well. In May, over 100 current and former world leaders, along with prominent economists and public health experts, issued an open letter calling for a "people's vaccine" for COVID-19, which would be patent-free, distributed globally, and available to all countries free of charge. At the WHO's annual World Health Assembly, all 194 member states accepted a resolution urging that vaccines for the disease be made available as a "global public good"—though the U.S. dissociated itself from a clause proposing a patent pool to keep costs down, which it argued might disincentivize "innovators who will be essential to the solutions the whole world needs."
Gavi, for its part, plans to launch a mechanism designed to encourage those innovators while promoting accessibility: an advance market commitment, in which countries pledge to purchase a vaccine, with no money down. Future contributions will be based on the value of the product to their health systems and their ability to pay.
"It's essential to realize that a threat anywhere is a threat everywhere."
A few private-sector players are stepping up, too. U.S.-based Johnson & Johnson, which has received nearly half a billion dollars from the federal government for COVID-19 vaccine research, has promised to provide up to 900 million doses on a not-for-profit basis, if its trials pan out. Other companies have agreed to produce vaccines on a "cost-plus" basis, with a smaller-than-usual profit margin.
How Sharing Can Pay Off
No one knows how all this will work out if and when a vaccine becomes available. (Another wild card: Trump has announced that he is cutting U.S. ties to the WHO over its alleged favoritism toward China, which could hobble the agency's ability to coordinate distribution -- though uncertainty remains about the process of withdrawal and reversing course may still be possible.) To public health experts, however, it's clear that ensuring accessibility is not just a matter of altruism.
"A historic example is smallpox," Rebecca Weintraub observes. "When it kept getting reintroduced into high-income countries from low-income countries, the rich countries realized it was worth investing in the vaccine for countries that couldn't afford it." After a two-decade campaign led by the WHO, the last case of this ancient scourge was diagnosed in 1977.
Conversely, vaccine nationalism doesn't just hurt poor countries. During the H1N1 pandemic, which killed an estimated 284,000 people worldwide, production problems led to shortages in the United States. But Australia stopped a domestic manufacturer from exporting doses to the U.S until all Aussies had been immunized.
Such considerations, Weintraub believes, might help convince even the most reluctant rich-country leaders that an accessible vaccine—if deployed in an epidemiologically targeted way—would serve both the greater good and the national interest. "I suspect the pressures put on our politicians to act globally will be significant," she says.
Other analysts share her guarded optimism. Kelly Moore, who teaches health policy at Vanderbilt University Medical Center, oversaw Tennessee's immunization programs for more than a decade, and later became a member of the Sabin-Aspen Vaccine Science & Policy Group—a panel of international experts that in 2019 released a report titled "Accelerating the Development of a Universal Influenza Vaccine." The 117-page document provided a road map toward a long-sought goal: creating a flu shot that doesn't need to be reformulated each year to target changing viral strains.
"One lesson we learned was that it's crucial to deploy financial resources in a systematic way to support coordination among laboratories that would typically be competitors," Moore says. And that, she adds, is happening with COVID-19, despite nationalist frictions: scientists from Sanofi joining forces with those at rival GSK; researchers at other companies allying with teams at government laboratories; university labs worldwide sharing data across borders. "I have been greatly encouraged to see the amount of global collaboration involved in this enterprise. Partners are working together who would normally never be partners."
For Moore, whose 77-year-old mother survived a bout with the disease, the current pandemic has hit close to home. "It's essential to realize that a threat anywhere is a threat everywhere," she says. "Morally and ethically, we have a tremendous obligation to ensure that the most vulnerable have access to an affordable vaccine, irrespective of where they live."
[Editor's Note: This article was originally published on June 8th, 2020 as part of a standalone magazine called GOOD10: The Pandemic Issue. Produced as a partnership among LeapsMag, The Aspen Institute, and GOOD, the magazine is available for free online. For this reprinting of the article, we have updated the latest statistics on COVID-19 and related global news.]
CORRECTION: A sentence about DNA vaccines incorrectly stated that they require cold storage, like RNA vaccines. The error has been fixed.
Researchers Are Testing a New Stem Cell Therapy in the Hopes of Saving Millions from Blindness
NIH researchers in Kapil Bharti's lab work toward the development of induced pluripotent stem cells to treat dry age-related macular degeneration.
Of all the infirmities of old age, failing sight is among the cruelest. It can mean the end not only of independence, but of a whole spectrum of joys—from gazing at a sunset or a grandchild's face to reading a novel or watching TV.
The Phase 1 trial will likely run through 2022, followed by a larger Phase 2 trial that could last another two or three years.
The leading cause of vision loss in people over 55 is age-related macular degeneration, or AMD, which afflicts an estimated 11 million Americans. As photoreceptors in the macula (the central part of the retina) die off, patients experience increasingly severe blurring, dimming, distortions, and blank spots in one or both eyes.
The disorder comes in two varieties, "wet" and "dry," both driven by a complex interaction of genetic, environmental, and lifestyle factors. It begins when deposits of cellular debris accumulate beneath the retinal pigment epithelium (RPE)—a layer of cells that nourish and remove waste products from the photoreceptors above them. In wet AMD, this process triggers the growth of abnormal, leaky blood vessels that damage the photoreceptors. In dry AMD, which accounts for 80 to 90 percent of cases, RPE cells atrophy, causing photoreceptors to wither away. Wet AMD can be controlled in about a quarter of patients, usually by injections of medication into the eye. For dry AMD, no effective remedy exists.
Stem Cells: Promise and Perils
Over the past decade, stem cell therapy has been widely touted as a potential treatment for AMD. The idea is to augment a patient's ailing RPE cells with healthy ones grown in the lab. A few small clinical trials have shown promising results. In a study published in 2018, for example, a University of Southern California team cultivated RPE tissue from embryonic stem cells on a plastic matrix and transplanted it into the retinas of four patients with advanced dry AMD. Because the trial was designed to test safety rather than efficacy, lead researcher Amir Kashani told a reporter, "we didn't expect that replacing RPE cells would return a significant amount of vision." Yet acuity improved substantially in one recipient, and the others regained their lost ability to focus on an object.
Therapies based on embryonic stem cells, however, have two serious drawbacks: Using fetal cell lines raises ethical issues, and such treatments require the patient to take immunosuppressant drugs (which can cause health problems of their own) to prevent rejection. That's why some experts favor a different approach—one based on induced pluripotent stem cells (iPSCs). Such cells, first produced in 2006, are made by returning adult cells to an undifferentiated state, and then using chemicals to reprogram them as desired. Treatments grown from a patient's own tissues could sidestep both hurdles associated with embryonic cells.
At least hypothetically. Today, the only stem cell therapies approved by the U.S. Food and Drug Administration (FDA) are umbilical cord-derived products for various blood and immune disorders. Although scientists are probing the use of embryonic stem cells or iPSCs for conditions ranging from diabetes to Parkinson's disease, such applications remain experimental—or fraudulent, as a growing number of patients treated at unlicensed "stem cell clinics" have painfully learned. (Some have gone blind after receiving bogus AMD therapies at those facilities.)
Last December, researchers at the National Eye Institute in Bethesda, Maryland, began enrolling patients with dry AMD in the country's first clinical trial using tissue grown from the patients' own stem cells. Led by biologist Kapil Bharti, the team intends to implant custom-made RPE cells in 12 recipients. If the effort pans out, it could someday save the sight of countless oldsters.
That, however, is what's technically referred to as a very big "if."
The First Steps
Bharti's trial is not the first in the world to use patient-derived iPSCs to treat age-related macular degeneration. In 2013, Japanese researchers implanted such cells into the eyes of a 77-year-old woman with wet AMD; after a year, her vision had stabilized, and she no longer needed injections to keep abnormal blood vessels from forming. A second patient was scheduled for surgery—but the procedure was canceled after the lab-grown RPE cells showed signs of worrisome mutations. That incident illustrates one potential problem with using stem cells: Under some circumstances, the cells or the tissue they form could turn cancerous.
"The knowledge and expertise we're gaining can be applied to many other iPSC-based therapies."
Bharti and his colleagues have gone to great lengths to avoid such outcomes. "Our process is significantly different," he told me in a phone interview. His team begins with patients' blood stem cells, which appear to be more genomically stable than the skin cells that the Japanese group used. After converting the blood cells to RPE stem cells, his team cultures them in a single layer on a biodegradable scaffold, which helps them grow in an orderly manner. "We think this material gives us a big advantage," Bharti says. The team uses a machine-learning algorithm to identify optimal cell structure and ensure quality control.
It takes about six months for a patch of iPSCs to become viable RPE cells. When they're ready, a surgeon uses a specially-designed tool to insert the tiny structure into the retina. Within days, the scaffold melts away, enabling the transplanted RPE cells to integrate fully into their new environment. Bharti's team initially tested their method on rats and pigs with eye damage mimicking AMD. The study, published in January 2019 in Science Translational Medicine, found that at ten weeks, the implanted RPE cells continued to function normally and protected neighboring photoreceptors from further deterioration. No trace of mutagenesis appeared.
Encouraged by these results, Bharti began recruiting human subjects. The Phase 1 trial will likely run through 2022, followed by a larger Phase 2 trial that could last another two or three years. FDA approval would require an even larger Phase 3 trial, with a decision expected sometime between 2025 and 2028—that is, if nothing untoward happens before then. One unknown (among many) is whether implanted cells can thrive indefinitely under the biochemically hostile conditions of an eye with AMD.
"Most people don't have a sense of just how long it takes to get something like this to work, and how many failures—even disasters—there are along the way," says Marco Zarbin, professor and chair of Ophthalmology and visual science at Rutgers New Jersey Medical School and co-editor of the book Cell-Based Therapy for Degenerative Retinal Diseases. "The first kidney transplant was done in 1933. But the first successful kidney transplant was in 1954. That gives you a sense of the time frame. We're really taking the very first steps in this direction."
Looking Ahead
Even if Bharti's method proves safe and effective, there's the question of its practicality. "My sense is that using induced pluripotent stem cells to treat the patient from whom they're derived is a very expensive undertaking," Zarbin observes. "So you'd have to have a very dramatic clinical benefit to justify that cost."
Bharti concedes that the price of iPSC therapy is likely to be high, given that each "dose" is formulated for a single individual, requires months to manufacture, and must be administered via microsurgery. Still, he expects economies of scale and production to emerge with time. "We're working on automating several steps of the process," he explains. "When that kicks in, a technician will be able to make products for 10 or 20 people at once, so the cost will drop proportionately."
Meanwhile, other researchers are pressing ahead with therapies for AMD using embryonic stem cells, which could be mass-produced to treat any patient who needs them. But should that approach eventually win FDA approval, Bharti believes there will still be room for a technique that requires neither fetal cell lines nor immunosuppression.
And not only for eye ailments. "The knowledge and expertise we're gaining can be applied to many other iPSC-based therapies," says the scientist, who is currently consulting with several companies that are developing such treatments. "I'm hopeful that we can leverage these approaches for a wide range of applications, whether it's for vision or across the body."