Thousands of Vaccine Volunteers Got a Dummy Shot. Should They Get the Real Deal Now?
The highly anticipated rollout of a COVID-19 vaccine poses ethical considerations: When will trial volunteers who got a placebo be vaccinated? And how will this affect the data in those trials?
It's an issue that vaccine manufacturers and study investigators are wrestling with as the Food and Drug Administration is expected to grant emergency use authorization this weekend to a vaccine developed by Pfizer and the German company BioNTech. Another vaccine, produced by Moderna, is nearing approval in the United States.
The most vulnerable—health care workers and nursing home residents—are deemed eligible to receive the initial limited supply in accordance with priority recommendations from the Centers for Disease Control and Prevention (CDC).
With health care workers constituting an estimated 20 percent of trial participants, this question also comes to the fore: "Is it now ethically imperative that we offer them the vaccine, those who have had placebo?" says William Schaffner, an infectious diseases physician at Vanderbilt University and an adviser to the CDC's immunization practices committee.
When a "gold-standard" measure becomes available, participants in the placebo group "would ordinarily be notified" of the strong public health recommendation to opt for immunization, says Johan Bester, interim assistant dean for biomedical science education and director of bioethics at the University of Nevada, Las Vegas School of Medicine.
"If a treatment or prevention exists that we know works, it is unethical to withhold it from people who would benefit from it just to answer a research question." This moral principle poses a quandary for ethicists and physicians alike, as they ponder possible paths to proceed with vaccination amid ongoing trials. Rigorous trials are double-blinded—neither the participants nor the investigators know who received the actual vaccine and who got a dummy injection.
"The intent of these trials is to follow these folks for up to two years," says Marci Drees, infection prevention officer and hospital epidemiologist for ChristianaCare in Wilmington, Delaware. At a minimum, she adds, researchers would prefer to monitor participants for six months.
"You can still follow safety over a long-term period of time without actually continuing to have a placebo group for comparison."
But in the midst of a pandemic, that may not be feasible. Prolonged exposure to the highly contagious and lethal virus could have dire consequences.
To avoid compromising the integrity of the blinded data, "there are some potentially creative solutions," Drees says. For instance, trial participants could receive the opposite of what they initially got, whether it was the vaccine or the placebo.
One factor in this decision-making process depends on when a particular trial is slated to conclude. If that time is approaching, the risk of waiting would be lower than if the trial is only halfway in progress, says Eric Lofgren, an epidemiologist at Washington State University who has studied the impact of COVID-19 in jails and at in-person sporting events.
Sometimes a study concludes earlier than the projected completion date. "All clinical trials have a data and safety monitoring board that reviews the interim results," Lofgren says. The board may halt a trial after finding evidence of harm, or when a treatment or vaccine has proven to be "sufficiently good," rendering it unethical to deprive the placebo group of its benefits.
The initial months of a trial are most crucial for assessing a vaccine's safety. Differences between the trial groups would be illuminating if fewer individuals who got the active vaccine contracted the virus and developed symptoms when compared to the placebo recipients. After that point, in vaccine-administered participants, "you can still follow safety over a long-term period of time without actually continuing to have a placebo group for comparison," says Dial Hewlett Jr., medical director for disease control at the Westchester County Department of Health in New York.
Even outside of a trial, safety is paramount and any severe side effects that occur will be closely monitored and investigated through national reporting networks. For example, regulators in the U.K. are investigating several rare but serious allergic reactions to the Pfizer vaccine given on Tuesday. The FDA has asked Pfizer to track allergic reactions in its safety monitoring plan, and some experts are proposing that Pfizer conduct a separate study of the vaccine on people with a history of severe allergies.
As the FDA eventually grants authorization to multiple vaccines, more participants are likely to leave trials and opt to be vaccinated. It is important that enough participants choose to stay in ongoing trials, says Nicole Hassoun, professor of philosophy at the State University of New York at Binghamton, where she directs the Global Health Impact program to extend medical access to the poor.
She's hopeful that younger participants and individuals without underlying medical conditions will make that determination. But the departure of too many participants at high risk for the virus would make it more difficult to evaluate the vaccine's safety and efficacy in those populations, Hassoun says, while acknowledging, "We can't have the best of both worlds."
Once a safe and effective vaccine is approved in the United States, "it would not be ethically appropriate to do placebo trials to test new vaccines."
One solution would entail allowing health care workers to exit a trial after a vaccine is approved, even though this would result in "a conundrum when the next group of people are brought forward to get the vaccine—whether they're people age 65 and older or they're essential workers, or whoever they are," says Vanderbilt physician Schaffner, who is a former board member of the Infectious Diseases Society of America. "All of a sudden, you'll have an erosion of the volunteers who are in the trial."
For now, one way or another, experts agree that current and subsequent trials should proceed. There is a compelling reason to identify additional vaccines with potentially greater effectiveness but with fewer side effects or less complex delivery methods that don't require storage at extremely low temperatures.
"Continuing with existing vaccine trials and starting others remains important," says Nir Eyal, professor and director of Rutgers University's Center for Population-Level Bioethics in New Brunswick, New Jersey. "We still need to tell how much proven vaccines block infections and how long their duration lasts. And populations around the world need vaccines that are easier to store and deliver, or simply cheaper."
But once a safe and effective vaccine is approved in the United States, "it would not be ethically appropriate to do placebo trials to test new vaccines," says bioethicist Bester at the University of Nevada, Las Vegas School of Medicine. "One possibility if a new vaccine emerges, is to test it against existing vaccines."
In a letter sent to trial volunteers in November, Pfizer and BioNTech committed to establishing "a process that would allow interested participants in the placebo group who meet the eligibility criteria for early access in their country to 'cross-over' to the vaccine group." The trial plans to continue monitoring all subjects regardless of whether people in the placebo group cross over, Pfizer said in a presentation to the FDA today. After Pfizer has collected six months of safety data, in April 2021, it plans to ask the FDA for full approval of the vaccine.
In the meantime, the company pledged to update volunteers as they obtain more input from regulatory authorities. "Thank you again for making a difference by being a part of this study," they wrote. "It is only through the efforts of volunteers like you that reaching this important milestone and developing a potential vaccine against COVID-19 is possible."
CORRECTION: An earlier version of this article mistakenly stated that the FDA would be granting emergency "approval" to the Pfizer/BioNTech vaccine, rather than "emergency use authorization." We regret the error.
DNA- and RNA-based electronic implants may revolutionize healthcare
Implantable electronic devices can significantly improve patients’ quality of life. A pacemaker can encourage the heart to beat more regularly. A neural implant, usually placed at the back of the skull, can help brain function and encourage higher neural activity. Current research on neural implants finds them helpful to patients with Parkinson’s disease, vision loss, hearing loss, and other nerve damage problems. Several of these implants, such as Elon Musk’s Neuralink, have already been approved by the FDA for human use.
Yet, pacemakers, neural implants, and other such electronic devices are not without problems. They require constant electricity, limited through batteries that need replacements. They also cause scarring. “The problem with doing this with electronics is that scar tissue forms,” explains Kate Adamala, an assistant professor of cell biology at the University of Minnesota Twin Cities. “Anytime you have something hard interacting with something soft [like muscle, skin, or tissue], the soft thing will scar. That's why there are no long-term neural implants right now.” To overcome these challenges, scientists are turning to biocomputing processes that use organic materials like DNA and RNA. Other promised benefits include “diagnostics and possibly therapeutic action, operating as nanorobots in living organisms,” writes Evgeny Katz, a professor of bioelectronics at Clarkson University, in his book DNA- And RNA-Based Computing Systems.
While a computer gives these inputs in binary code or "bits," such as a 0 or 1, biocomputing uses DNA strands as inputs, whether double or single-stranded, and often uses fluorescent RNA as an output.
Adamala’s research focuses on developing such biocomputing systems using DNA, RNA, proteins, and lipids. Using these molecules in the biocomputing systems allows the latter to be biocompatible with the human body, resulting in a natural healing process. In a recent Nature Communications study, Adamala and her team created a new biocomputing platform called TRUMPET (Transcriptional RNA Universal Multi-Purpose GatE PlaTform) which acts like a DNA-powered computer chip. “These biological systems can heal if you design them correctly,” adds Adamala. “So you can imagine a computer that will eventually heal itself.”
The basics of biocomputing
Biocomputing and regular computing have many similarities. Like regular computing, biocomputing works by running information through a series of gates, usually logic gates. A logic gate works as a fork in the road for an electronic circuit. The input will travel one way or another, giving two different outputs. An example logic gate is the AND gate, which has two inputs (A and B) and two different results. If both A and B are 1, the AND gate output will be 1. If only A is 1 and B is 0, the output will be 0 and vice versa. If both A and B are 0, the result will be 0. While a computer gives these inputs in binary code or "bits," such as a 0 or 1, biocomputing uses DNA strands as inputs, whether double or single-stranded, and often uses fluorescent RNA as an output. In this case, the DNA enters the logic gate as a single or double strand.
If the DNA is double-stranded, the system “digests” the DNA or destroys it, which results in non-fluorescence or “0” output. Conversely, if the DNA is single-stranded, it won’t be digested and instead will be copied by several enzymes in the biocomputing system, resulting in fluorescent RNA or a “1” output. And the output for this type of binary system can be expanded beyond fluorescence or not. For example, a “1” output might be the production of the enzyme insulin, while a “0” may be that no insulin is produced. “This kind of synergy between biology and computation is the essence of biocomputing,” says Stephanie Forrest, a professor and the director of the Biodesign Center for Biocomputing, Security and Society at Arizona State University.
Biocomputing circles are made of DNA, RNA, proteins and even bacteria.
Evgeny Katz
The TRUMPET’s promise
Depending on whether the biocomputing system is placed directly inside a cell within the human body, or run in a test-tube, different environmental factors play a role. When an output is produced inside a cell, the cell's natural processes can amplify this output (for example, a specific protein or DNA strand), creating a solid signal. However, these cells can also be very leaky. “You want the cells to do the thing you ask them to do before they finish whatever their businesses, which is to grow, replicate, metabolize,” Adamala explains. “However, often the gate may be triggered without the right inputs, creating a false positive signal. So that's why natural logic gates are often leaky." While biocomputing outside a cell in a test tube can allow for tighter control over the logic gates, the outputs or signals cannot be amplified by a cell and are less potent.
TRUMPET, which is smaller than a cell, taps into both cellular and non-cellular biocomputing benefits. “At its core, it is a nonliving logic gate system,” Adamala states, “It's a DNA-based logic gate system. But because we use enzymes, and the readout is enzymatic [where an enzyme replicates the fluorescent RNA], we end up with signal amplification." This readout means that the output from the TRUMPET system, a fluorescent RNA strand, can be replicated by nearby enzymes in the platform, making the light signal stronger. "So it combines the best of both worlds,” Adamala adds.
These organic-based systems could detect cancer cells or low insulin levels inside a patient’s body.
The TRUMPET biocomputing process is relatively straightforward. “If the DNA [input] shows up as single-stranded, it will not be digested [by the logic gate], and you get this nice fluorescent output as the RNA is made from the single-stranded DNA, and that's a 1,” Adamala explains. "And if the DNA input is double-stranded, it gets digested by the enzymes in the logic gate, and there is no RNA created from the DNA, so there is no fluorescence, and the output is 0." On the story's leading image above, if the tube is "lit" with a purple color, that is a binary 1 signal for computing. If it's "off" it is a 0.
While still in research, TRUMPET and other biocomputing systems promise significant benefits to personalized healthcare and medicine. These organic-based systems could detect cancer cells or low insulin levels inside a patient’s body. The study’s lead author and graduate student Judee Sharon is already beginning to research TRUMPET's ability for earlier cancer diagnoses. Because the inputs for TRUMPET are single or double-stranded DNA, any mutated or cancerous DNA could theoretically be detected from the platform through the biocomputing process. Theoretically, devices like TRUMPET could be used to detect cancer and other diseases earlier.
Adamala sees TRUMPET not only as a detection system but also as a potential cancer drug delivery system. “Ideally, you would like the drug only to turn on when it senses the presence of a cancer cell. And that's how we use the logic gates, which work in response to inputs like cancerous DNA. Then the output can be the production of a small molecule or the release of a small molecule that can then go and kill what needs killing, in this case, a cancer cell. So we would like to develop applications that use this technology to control the logic gate response of a drug’s delivery to a cell.”
Although platforms like TRUMPET are making progress, a lot more work must be done before they can be used commercially. “The process of translating mechanisms and architecture from biology to computing and vice versa is still an art rather than a science,” says Forrest. “It requires deep computer science and biology knowledge,” she adds. “Some people have compared interdisciplinary science to fusion restaurants—not all combinations are successful, but when they are, the results are remarkable.”
In today’s podcast episode, Leaps.org Deputy Editor Lina Zeldovich speaks about the health and ecological benefits of farming crickets for human consumption with Bicky Nguyen, who joins Lina from Vietnam. Bicky and her business partner Nam Dang operate an insect farm named CricketOne. Motivated by the idea of sustainable and healthy protein production, they started their unconventional endeavor a few years ago, despite numerous naysayers who didn’t believe that humans would ever consider munching on bugs.
Yet, making creepy crawlers part of our diet offers many health and planetary advantages. Food production needs to match the rise in global population, estimated to reach 10 billion by 2050. One challenge is that some of our current practices are inefficient, polluting and wasteful. According to nonprofit EarthSave.org, it takes 2,500 gallons of water, 12 pounds of grain, 35 pounds of topsoil and the energy equivalent of one gallon of gasoline to produce one pound of feedlot beef, although exact statistics vary between sources.
Meanwhile, insects are easy to grow, high on protein and low on fat. When roasted with salt, they make crunchy snacks. When chopped up, they transform into delicious pâtes, says Bicky, who invents her own cricket recipes and serves them at industry and public events. Maybe that’s why some research predicts that edible insects market may grow to almost $10 billion by 2030. Tune in for a delectable chat on this alternative and sustainable protein.
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Further reading:
More info on Bicky Nguyen
https://yseali.fulbright.edu.vn/en/faculty/bicky-n...
The environmental footprint of beef production
https://www.earthsave.org/environment.htm
https://www.watercalculator.org/news/articles/beef-king-big-water-footprints/
https://www.frontiersin.org/articles/10.3389/fsufs.2019.00005/full
https://ourworldindata.org/carbon-footprint-food-methane
Insect farming as a source of sustainable protein
https://www.insectgourmet.com/insect-farming-growing-bugs-for-protein/
https://www.sciencedirect.com/topics/agricultural-and-biological-sciences/insect-farming
Cricket flour is taking the world by storm
https://www.cricketflours.com/
https://talk-commerce.com/blog/what-brands-use-cricket-flour-and-why/
Lina Zeldovich has written about science, medicine and technology for Popular Science, Smithsonian, National Geographic, Scientific American, Reader’s Digest, the New York Times and other major national and international publications. A Columbia J-School alumna, she has won several awards for her stories, including the ASJA Crisis Coverage Award for Covid reporting, and has been a contributing editor at Nautilus Magazine. In 2021, Zeldovich released her first book, The Other Dark Matter, published by the University of Chicago Press, about the science and business of turning waste into wealth and health. You can find her on http://linazeldovich.com/ and @linazeldovich.