A skin patch to treat peanut allergies teaches the body to tolerate the nuts
Ever since he was a baby, Sharon Wong’s son Brandon suffered from rashes, prolonged respiratory issues and vomiting. In 2006, as a young child, he was diagnosed with a severe peanut allergy.
"My son had a history of reacting to traces of peanuts in the air or in food,” says Wong, a food allergy advocate who runs a blog focusing on nut free recipes, cooking techniques and food allergy awareness. “Any participation in school activities, social events, or travel with his peanut allergy required a lot of preparation.”
Peanut allergies affect around a million children in the U.S. Most never outgrow the condition. The problem occurs when the immune system mistakenly views the proteins in peanuts as a threat and releases chemicals to counteract it. This can lead to digestive problems, hives and shortness of breath. For some, like Wong’s son, even exposure to trace amounts of peanuts could be life threatening. They go into anaphylactic shock and need to take a shot of adrenaline as soon as possible.
Typically, people with peanut allergies try to completely avoid them and carry an adrenaline autoinjector like an EpiPen in case of emergencies. This constant vigilance is very stressful, particularly for parents with young children.
“The search for a peanut allergy ‘cure’ has been a vigorous one,” says Claudia Gray, a pediatrician and allergist at Vincent Pallotti Hospital in Cape Town, South Africa. The closest thing to a solution so far, she says, is the process of desensitization, which exposes the patient to gradually increasing doses of peanut allergen to build up a tolerance. The most common type of desensitization is oral immunotherapy, where patients ingest small quantities of peanut powder. It has been effective but there is a risk of anaphylaxis since it involves swallowing the allergen.
"By the end of the trial, my son tolerated approximately 1.5 peanuts," Sharon Wong says.
DBV Technologies, a company based in Montrouge, France has created a skin patch to address this problem. The Viaskin Patch contains a much lower amount of peanut allergen than oral immunotherapy and delivers it through the skin to slowly increase tolerance. This decreases the risk of anaphylaxis.
Wong heard about the peanut patch and wanted her son to take part in an early phase 2 trial for 4-to-11-year-olds.
“We felt that participating in DBV’s peanut patch trial would give him the best chance at desensitization or at least increase his tolerance from a speck of peanut to a peanut,” Wong says. “The daily routine was quite simple, remove the old patch and then apply a new one. By the end of the trial, he tolerated approximately 1.5 peanuts.”
How it works
For DBV Technologies, it all began when pediatric gastroenterologist Pierre-Henri Benhamou teamed up with fellow professor of gastroenterology Christopher Dupont and his brother, engineer Bertrand Dupont. Together they created a more effective skin patch to detect when babies have allergies to cow's milk. Then they realized that the patch could actually be used to treat allergies by promoting tolerance. They decided to focus on peanut allergies first as the more dangerous.
The Viaskin patch utilizes the fact that the skin can promote tolerance to external stimuli. The skin is the body’s first defense. Controlling the extent of the immune response is crucial for the skin. So it has defense mechanisms against external stimuli and can promote tolerance.
The patch consists of an adhesive foam ring with a plastic film on top. A small amount of peanut protein is placed in the center. The adhesive ring is attached to the back of the patient's body. The peanut protein sits above the skin but does not directly touch it. As the patient sweats, water droplets on the inside of the film dissolve the peanut protein, which is then absorbed into the skin.
The peanut protein is then captured by skin cells called Langerhans cells. They play an important role in getting the immune system to tolerate certain external stimuli. Langerhans cells take the peanut protein to lymph nodes which activate T regulatory cells. T regulatory cells suppress the allergic response.
A different patch is applied to the skin every day to increase tolerance. It’s both easy to use and convenient.
“The DBV approach uses much smaller amounts than oral immunotherapy and works through the skin significantly reducing the risk of allergic reactions,” says Edwin H. Kim, the division chief of Pediatric Allergy and Immunology at the University of North Carolina, U.S., and one of the principal investigators of Viaskin’s clinical trials. “By not going through the mouth, the patch also avoids the taste and texture issues. Finally, the ability to apply a patch and immediately go about your day may be very attractive to very busy patients and families.”
Brandon Wong displaying origami figures he folded at an Origami Convention in 2022
Sharon Wong
Clinical trials
Results from DBV's phase 3 trial in children ages 1 to 3 show its potential. For a positive result, patients who could not tolerate 10 milligrams or less of peanut protein had to be able to manage 300 mg or more after 12 months. Toddlers who could already tolerate more than 10 mg needed to be able to manage 1000 mg or more. In the end, 67 percent of subjects using the Viaskin patch met the target as compared to 33 percent of patients taking the placebo dose.
“The Viaskin peanut patch has been studied in several clinical trials to date with promising results,” says Suzanne M. Barshow, assistant professor of medicine in allergy and asthma research at Stanford University School of Medicine in the U.S. “The data shows that it is safe and well-tolerated. Compared to oral immunotherapy, treatment with the patch results in fewer side effects but appears to be less effective in achieving desensitization.”
The primary reason the patch is less potent is that oral immunotherapy uses a larger amount of the allergen. Additionally, absorption of the peanut protein into the skin could be erratic.
Gray also highlights that there is some tradeoff between risk and efficacy.
“The peanut patch is an exciting advance but not as effective as the oral route,” Gray says. “For those patients who are very sensitive to orally ingested peanut in oral immunotherapy or have an aversion to oral peanut, it has a use. So, essentially, the form of immunotherapy will have to be tailored to each patient.” Having different forms such as the Viaskin patch which is applied to the skin or pills that patients can swallow or dissolve under the tongue is helpful.
The hope is that the patch’s efficacy will increase over time. The team is currently running a follow-up trial, where the same patients continue using the patch.
“It is a very important study to show whether the benefit achieved after 12 months on the patch stays stable or hopefully continues to grow with longer duration,” says Kim, who is an investigator in this follow-up trial.
"My son now attends university in Massachusetts, lives on-campus, and eats dorm food. He has so much more freedom," Wong says.
The team is further ahead in the phase 3 follow-up trial for 4-to-11-year-olds. The initial phase 3 trial was not as successful as the trial for kids between one and three. The patch enabled patients to tolerate more peanuts but there was not a significant enough difference compared to the placebo group to be definitive. The follow-up trial showed greater potency. It suggests that the longer patients are on the patch, the stronger its effects.
They’re also testing if making the patch bigger, changing the shape and extending the minimum time it’s worn can improve its benefits in a trial for a new group of 4-to-11 year-olds.
The future
DBV Technologies is using the skin patch to treat cow’s milk allergies in children ages 1 to 17. They’re currently in phase 2 trials.
As for the peanut allergy trials in toddlers, the hope is to see more efficacy soon.
For Wong’s son who took part in the earlier phase 2 trial for 4-to-11-year-olds, the patch has transformed his life.
“My son continues to maintain his peanut tolerance and is not affected by peanut dust in the air or cross-contact,” Wong says. ”He attends university in Massachusetts, lives on-campus, and eats dorm food. He still carries an EpiPen but has so much more freedom than before his clinical trial. We will always be grateful.”
Inside Scoop: How a DARPA Scientist Helped Usher in a Game-Changing Covid Treatment
Amy Jenkins was in her office at DARPA, a research and development agency within the Department of Defense, when she first heard about a respiratory illness plaguing the Chinese city of Wuhan. Because she's a program manager for DARPA's Biological Technologies Office, her colleagues started stopping by. "It's really unusual, isn't it?" they would say.
At the time, China had a few dozen cases of what we now call COVID-19. "We should maybe keep an eye on that," she thought.
Early in 2020, still just keeping watch, she was visiting researchers working on DARPA's Pandemic Prevention Platform (P3), a project to develop treatments for "any known or previously unknown infectious threat," within 60 days of its appearance. "We looked at each other and said, 'Should we be doing something?'" she says.
For projects like P3, groups of scientists—often at universities and private companies—compete for DARPA contracts, and program managers like Jenkins oversee the work. Those that won the P3 bid included scientists at AbCellera Biologics, Inc., AstraZeneca, Duke University, and Vanderbilt University.
At the time Jenkins was talking to the P3 performers, though, they didn't have evidence of community transmission. "We would have to cross that bar before we considered doing anything," she says.
The world soon leapt far over that bar. By the time Jenkins and her team decided P3 should be doing something—with their real work beginning in late February--it was too late to prevent this pandemic. But she could help P3 dig into the chemical foundations of COVID-19's malfeasance, and cut off its roots. That work represents, in fact, her roots.
In late February 2020, DARPA received a single blood sample from a recovered COVID-19 patient, in which P3 researchers could go fishing for antibodies. The day it arrived, Jenkins's stomach roiled. "We get one shot," she thought.
Fighting the Smallest Enemies
Jenkins, who's in her early 40s, first got into germs the way many 90s kids did: by reading The Hot Zone, a novel about a hemorrhagic fever gone rogue. It wasn't exactly the disintegrating organs that hooked her. It was the idea that "these very pathogens that we can't even see can make us so sick and bring us to our knees," she says. Reading about scientists facing down deadly disease, she wondered, "How do these things make you so sick?"
She chased that question in college, majoring in both biomolecular science and chemistry, and later became an antibody expert. Antibodies are proteins that hook to a pathogen to block it from attaching to your cells, or tag it for destruction by the rest of the immune system. Soon, she jumped on the "monoclonal antibodies" train—developing synthetic versions of these natural defenses, which doctors can give to people to help them battle an early-stage infection, and even to prevent an infection from taking root after an exposure.
Jenkins likens the antibody treatments to the old aphorism about fishing: Vaccines teach your body how to fish, but antibodies simply give your body the pesca-fare. While that, as the saying goes, won't feed you for a lifetime, it will last a few weeks or months. Monoclonal antibodies thus are a promising preventative option in the immediate short-term when a vaccine hasn't yet been given (or hasn't had time to produce an immune response), as well as an important treatment weapon in the current fight. After former president Donald Trump contracted COVID-19, he received a monoclonal antibody treatment from biotech company Regeneron.
As for Jenkins, she started working as a DARPA Biological Technologies Office contractor soon after completing her postdoc. But it was a suit job, not a labcoat job. And suit jobs, at first, left Jenkins conflicted, worried about being bored. She'd give it a year, she thought. But the year expired, and bored she was not. Around five years later, in June 2019, the agency hired her to manage several of the office's programs. A year into that gig, the world was months into a pandemic.
The Pandemic Pivot
At DARPA, Jenkins inherited five programs, including P3. P3 works by taking blood from recovered people, fishing out their antibodies, identifying the most effective ones, and then figuring out how to manufacture them fast. Back then, P3 existed to help with nebulous, future outbreaks: Pandemic X. Not this pandemic. "I did not have a crystal ball," she says, "but I will say that all of us in the infectious diseases and public-health realm knew that the next pandemic was coming."
Three days after a January 2020 meeting with P3 researchers, COVID-19 appeared in Seattle, then began whipping through communities. The time had come for P3 teams to swivel. "We had done this," she says. "We had practiced this before." But would their methods stand up to something unknown, racing through the global population? "The big anxiety was, 'Wow, this was real,'" says Jenkins.
While facing down that realness, Jenkins was also managing other projects. In one called PREPARE, groups develop "medical countermeasures" that modulate a person's genetic code to boost their bodies' responses to threats. Another project, NOW, envisions shipping-container-sized factories that can make thousands of vaccine doses in days. And then there's Prometheus—which means "forethought" in Greek, and is the name of the god who stole fire and gave it to humans. Wrapping up as COVID ramped up, Prometheus aimed to identify people who are contagious—with whatever—before they start coughing, and even if they never do.
All of DARPA's projects focus on developing early-stage technology, passing it off to other agencies or industry to put it into operation. The orientation toward a specific goal appealed to Jenkins, as a contrast to academia. "You go down a rabbit hole for years at a time sometimes, chasing some concept you found interesting in the lab," she says. That's good for the human pursuit of knowledge, and leads to later applications, but DARPA wants a practical prototype—stat.
"Dual-Use" Technologies
That desire, though, and the fact that DARPA is a defense agency, present philosophical complications. "Bioethics in the national-security context turns all the dials up to 10+," says Jonathan Moreno, a medical ethicist at the University of Pennsylvania.
While developing antibody treatments to stem a pandemic seems straightforwardly good, all biological research—especially that backed by military money—requires evaluating potential knock-on applications, even those that might come from outside the entity that did the developing. As Moreno put it, "Albert Einstein wasn't thinking about blowing up Hiroshima." Particularly sensitive are so-called "dual-use" technologies—those tools that could be used for both benign and nefarious purposes, or are of interest to both the civilian and military worlds.
Moreno takes Prometheus itself as an example of "dual-use" technology. "Think about somebody wearing a suicide vest. Instead of a suicide vest, make them extremely contagious with something. The flu plus Ebola," he says. "Send them someplace, a sensitive environment. We would like to be able to defend against that"—not just tell whether Uncle Fred is bringing asymptomatic COVID home for Christmas. Prometheus, Jenkins says, had safety in mind from the get-go, and required contenders to "develop a risk mitigation plan" and "detail their strategy for appropriate control of information."
To look at a different program, if you can modulate genes to help healing, you probably know something (or know someone else could infer something) about how to hinder healing. Those sorts of risks are why PREPARE researchers got their own "ethical, legal, and social implications" panel, which meets quarterly "to ensure that we are performing all research and publications in a safe and ethical manner," says Jenkins.
DARPA as a whole, Moreno says, is institutionally sensitive to bioethics. The agency has ethics panels, and funded a 2014 National Academies assessment of how to address the "ethical, legal, and societal issues" around technology that has military relevance. "In the cases of biotechnologies where some of that research brushes up against what could legitimately be considered dual-use, that in itself justifies our investment," says Jenkins. "DARPA deliberately focuses on safety and countermeasures against potentially dangerous technologies, and we structure our programs to be transparent, safe, and legal."
Going Fishing
In late February 2020, DARPA received a single blood sample from a recovered COVID-19 patient, in which P3 researchers could go fishing for antibodies. The day it arrived, Jenkins's stomach roiled. "We get one shot," she thought.
As scientists from the P3-funded AbCellera went through the processes they'd practiced, Jenkins managed their work, tracking progress and relaying results. Soon, the team had isolated a suitable protein: bamlanivimab. It attaches to and blocks off the infamous spike proteins on SARS-CoV-2—those sticky suction-cups in illustrations. Partnering with Eli Lilly in a manufacturing agreement, the biotech company brought it to clinical trials in May, just a few months after its work on the deadly pathogen began, after much of the planet became a hot zone.
On November 10—Jenkins's favorite day at the (home) office—the FDA provided Eli Lilly emergency use authorization for bamlanivimab. But she's only mutedly screaming (with joy) inside her heart. "This pandemic isn't 'one morning we're going to wake up and it's all over,'" she says. When it is over, she and her colleagues plan to celebrate their promethean work. "I'm hoping to be able to do it in person," she says. "Until then, I have not taken a breath."
Everyone Should Hear My COVID Vaccine Experience
On December 18th, 2020, I received my first dose of the Pfizer mRNA vaccine against SARS-CoV-2. On January 9th, 2021, I received my second. I am now a CDC-card-carrying, fully vaccinated person.
The build-up to the first dose was momentous. I was scheduled for the first dose of the morning. Our vaccine clinic was abuzz with excitement and hope, and some media folks were there to capture the moment. A couple of fellow emergency physicians were in the same cohort of recipients as I; we exchanged virtual high-fives and took a picture of socially distanced hugs. It was, after all, the closest thing we'd had to a celebration in months.
I walked in the vaccine administration room with anticipation – it was tough to believe this moment was truly, finally here. I got a little video of my getting the shot, took my obligate vaccine selfie, waited in the observation area for 15 minutes to ensure I didn't have a reaction, and then proudly joined 1000s of fellow healthcare workers across the country in posting #ThisIsMyShot on social media. "Here we go, America!"
The first shot, though, didn't actually do all that much for me. It hurt less than a flu shot (which, by the way, doesn't hurt much). I had virtually no side effects. I also knew that it did not yet protect me. The Pfizer (and Moderna) data show very clearly that although the immune response starts to grow 10-12 days after the first shot, one doesn't reach full protection against COVID-19 until much later.
So when, two days after my first shot, I headed back to work in the emergency department, I kept wondering "Will this be the day that I get sick? Wouldn't that be ironic!" Although I never go without an N95 during patient care, it just takes one slip – scratching one's eyes, eating lunch in a break room that an infected colleague had just been in – to get ill. Ten months into this pandemic, it is so easy to get fatigued, to make a small error just one time.
Indeed, I had a few colleagues fall ill in between their first and second shots; one was hospitalized. This was not surprising, but still sad, given how close they had come to escaping infection.
Scientifically speaking, one doesn't need to feel bad to develop an immune response. Emotionally, though, I welcomed the symptoms as proof positive that I would be protected.
This time period felt a little like we had our learner's permit for driving: we were on our way to being safe, but not quite there yet.
I also watched, with dismay, our failures as a nation at timely distribution of the vaccine. On December 18th, despite the logistical snafus that many of us had started to highlight, it was still somewhat believable that we would at least distribute (if not actually administer) 20 million doses by the New Year. But by December 31, my worst fears about the feds' lack of planning had been realized. Only 14 million doses had gone to states, and fewer than 3 million had been administered. Within the public health and medical community, we began to debate how to handle the shortages and slow vaccination rates: should we change prioritization schemes? Get rid of the second dose, in contradiction to what our FDA had approved?
Let me be clear: I really, really, really wanted my second dose. It is what is supported by the data. After living this long at risk, it felt frankly unfair that I might not get fully protected. I waited with trepidation, afraid that policies would shift before I got it in my arm.
At last, my date for my second shot arrived.
This shot was a little less momentous on the outside. The vaccine clinic was much more crowded, as we were now administering first doses to more people, as well as providing the second dose to many. There were no high fives, no media, and I took no selfies. I finished my observation period without trouble (as did everyone else vaccinated the same day, as is typical for these vaccines). I walked out the door planning to spend a nice afternoon outdoors with my kids.
Within 15 minutes, though, the very common side effects – reported by 80% of people my age after the second dose – began to appear. First I got a headache (like 52% of people my age), then body aches (37%), fatigue (59%), and chills (35%). I felt "foggy", like I was fighting something. Like 45% of trial participants who had received the actual vaccine, I took acetaminophen and ibuprofen to stave off the symptoms. There is some minimal evidence from other vaccines that pre-treatment with these anti-inflammatories may reduce antibodies, but given that half of trial participants took these medications, there's no reason to make yourself suffer if you develop side effects. Forty-eight hours later, just in time for my next shift, the side effects magically cleared. Scientifically speaking, one doesn't need to feel bad to develop an immune response. Emotionally, though, I welcomed the symptoms as proof positive that I would be protected.
My reaction was truly typical. Although the media hype focuses on major negative reactions, they are – statistically speaking – tremendously rare: fewer than 11/million people who received the Pfizer vaccine, and 3/million who received the Moderna vaccine, developed anaphylaxis; of these, all were treated, and all are fine. Compare this with the fact that approximately 1200/million Americans have died of this virus. I'll choose the minor, temporary, utterly treatable side effects any day.
Now, more than 14 days after my second dose, the data says that my chance of getting really sick is, truly, infinitesimally low. I don't have to worry that each shift will put me into the hospital. I feel emotionally lighter, and a little bit like I have a secret super-power.
But I also know that we are not yet home free.
I may have my personal equivalent of Harry Potter's invisibility cloak – but we don't yet know whether it protects those around me, at all. As Dr. Fauci himself has written, while community spread is high, there is still a chance that I could be a carrier of infection to others. So I still wear my N95 at work, I still mask in public, and I still shower as soon as I get home from a shift and put my scrubs right in the washing machine to protect my husband and children. I also won't see my parents indoors until they, too, have been vaccinated.
At the end of the day, these vaccines are both amazing and life-changing, and not. My colleagues are getting sick less often, now that many of us are a week or more out from our second dose. I can do things (albeit still masked) that would simply not have been safe a month ago. These are small miracles, for which I am thankful. But like so many things in life, they would be better if shared with others. Only when my community is mostly vaccinated, will I breathe easy again.
My deepest hope is that we all have – and take - the chance to get our shots, soon. Because although the symbolism and effect of the vaccine is high, the experience itself was … not that big a deal.