Can mRNA Technology Hold The Allergy Cure We’ve All Been Waiting For?

Williesha Morris’ allergy saga kicked off in 2015 with a never-ending barrage of sinus infections. Her nose suddenly grew congested and stuffy — a searing pain radiating from her sinuses made daily tasks taxing. Whenever an episode struck, Morris would receive a script for antibiotics. They worked for a while — until they didn’t. Like clockwork, the aggravating congestion and debilitating pain would return within a few months.

“I was trying to figure out why I felt better outside than inside,” Morris, a 44-year-old resident of Tuscaloosa, Alabama, tells Inverse. “I didn’t understand what was going on.”

She initially thought it was a pollen allergy and met with an allergist. They did a skin prick test, where a doctor places a small amount of an allergen on the skin (usually the forearm or back), which is then pricked or scratched with a needle. It turned out Morris definitely had an allergy, just not to pollen — instead, the culprit turned out to be dust mites, microscopic insects related to ticks and spiders that commonly live in household dust.

Morris’ story isn’t unique. In the United States, allergic diseases — which also include eczema and asthma, among others — are the sixth leading cause of chronic illness. In fact, over 100 million people experience some sort of allergy every year. (About 20 million of those folks, like Morris, suffer from a dust mite allergy.)

And although rarely fatal, some conditions can turn serious. For instance, food allergies result in 30,000 emergency room visits, 2,000 hospitalizations, and 150 deaths annually.

To ease their sniffly and itchy woes, allergy sufferers have long turned to immunotherapies. These treatments aim to help the immune system unlearn those bad habits that trigger an overblown allergic reaction. Clinicians have used immunotherapy for over a century, but in recent years, researchers have made major strides in tackling allergies that were long believed to be incurable.

With ramped-up immunotherapies, vaccines, and even tiny capsules of mRNA, scientists hope that agonizing allergy symptoms and hit-or-miss therapies can become a thing of the past.

What exactly is an allergy?

Contrary to popular belief, allergies don’t just mean that your body rejects a certain type of food or pollen. Allergies actually involve a common type of immune reaction called a type one hypersensitivity. Here’s how it works: Some individuals develop an antibody to a specific protein that, once their immune system encounters it, sets off a specific cascade of symptoms, according to Maya Jerath, professor of medicine in the Division of Allergy and Immunology at the Washington University School of Medicine at St. Louis

“This can be itching, sneezing, wheezing, and also fall in your blood pressure, what we call shock or anaphylaxis,” Jerath tells Inverse.

This chain reaction typically begins with T cells, a type of white blood cell that’s essentially the quarterback of the immune system: It detects the enemy's formation and commands other cells to action. When T cells learn of an allergen, they produce a chemical alarm that riles up other immune cells.

The T cells prompt B cells to make a special antibody for the occasion called IgE, Edwin Kim, director of the UNC Food Allergy Initiative at the University of North Carolina School of Medicine, Chapel Hill, tells Inverse.

“That’s the stage we call sensitization — basically, the first seeing of the allergen and the creation of antibodies,” he explains. “Then in the next stage, those antibodies find their way onto the surface of cells called mast cells, eosinophils, [or basophils]. Once they’re parked around those cells, then they’re basically ready and waiting.”

So, if these IgE antibodies are sensitive to ragweed, a common environmental allergen, binding to the antibody will flip a switch on in the mast cells, eosinophils, and basophils and unleash a raging torrent of chemicals.

The most important of these chemicals is histamine, which dilates blood vessels and makes them more loosey-goosey. Histamine can contribute to allergic reaction symptoms like itching, swelling, and redness.

What causes allergies?

Genetics and environment are likely at play. It isn’t clear how much each contributes to the whole allergic calculus. Still, scientists suspect that one’s environment plays an outsized role.

“We do wonder if there are factors we’re changing in the environment that are driving up allergies,” Jerath says.

It could be shifts in food processing or farming that allow the proteins in plants to provoke more allergies or prompt more severe immune responses, she adds.

There’s growing evidence that the microbiome — the collection of tiny organisms living on and inside the human body — may also be involved in the development of allergies, Caroline Sokol, an allergist at Massachusetts General Hospital and an assistant professor at Harvard Medical School, tells Inverse.

“It’s not like humans have changed all that much genetically in the past 40 years,” says Sokol. “It is clear that the microbiome plays some sort of role.”

For example, researchers know that giving antibiotics to young infants can mess with the microbiome early in life and increase allergy risks.

“We don’t know why this is but it probably has something to do with the fact that in early life, the bugs living in our guts do an important job of educating our immune system about what we should and shouldn’t react to,” she says.

Your risk for allergy may even start well before you’re exposed to the outside world, Michael Nelson, chief of the University of Virginia School of Medicine’s Division of Asthma, Allergy and Immunology, tells Inverse. While chilling in the womb, exposure to potential allergens can impact the immune system.

“We’re still trying to sort out some of those factors by looking at high-risk cohorts from infants of parents with allergic disease,” he says.

An old treatment with new tricks

So if allergies result from a hyperactive immune system, how do we go about calming it down? People could try to avoid the allergen altogether, which is easier said than done (as anyone with an allergy can attest).

Doctors can also attempt to tackle the symptoms head-on. For example, antihistamines can relieve sneezing, itchy eyes, and a runny nose. But these two approaches offer more of a short-term bandage than a long-term fix.

That’s where immunotherapy comes in. With this approach, people receive increasing doses of allergens over time in an effort to desensitize the immune system. The goal: encountering even a puff of pollen or a shred of peanut without setting off reactions.

Depending on the type of allergen, clinicians can deliver immunotherapy in a few ways. For example, for seasonal, indoor, or insect sting allergies, patients typically receive a shot of allergen right under the skin (called subcutaneous immunotherapy), says Kim of UNC. Typically, people must receive a jab once or three times a week — during what’s called the buildup phase, which can last anywhere from around three to 10 months. This is followed by a maintenance phase, where people get a monthly shot for three to five years (or potentially longer).

Scientists are looking into new (and potentially more effective) ways to deliver immunotherapy.

These techniques currently come with downsides. Subcutaneous immunotherapy can prove dangerous for food allergies because of the risk of anaphylaxis, Sokol says. In these cases, oral immunotherapy may offer a safer alternative. It operates the same way as the shot, except patients eat small quantities of the food allergen. The FDA has only approved one treatment for food allergies, which can help temper an allergic response to peanuts if a child ever comes into inadvertent contact. Still, this isn’t a cure.

But now, scientists are looking into new (and potentially more effective) ways to deliver immunotherapy. For example, patients could receive a patch containing a teensy amount of allergens for about 24 hours, then move on to patches with larger and larger doses. (One for peanut allergies called Viaskin is currently in clinical trials.)

Compared to today’s methods, this route could prove more convenient because it can be self-administered. It may also come with fewer side effects compared to current therapies for food allergies.

There’s also intranasal (up into the nose), sublingual (under the tongue), and most recently, intralymphatic immunotherapy — where clinicians inject the allergen into the lymph nodes in the groin.

“There’s some excitement out there for intralymphatic,” says Kim. Ideally, immunotherapy bypasses the parts of the immune system that causes hypersensitivity. With the intralymphatic technique, researchers aim for the to go straight to the T cells and other important immune cells to spur tolerance to an allergen.

A couple of recent studies investigating intralympathic immunotherapy found that, at least for a few patients, as little as three injections induced long-term changes to their immune system — essentially curing them of their allergy, Kim says. But these effects need to be confirmed in larger studies.

The future of immunotherapies

Scientists are also looking into new packages to deliver these allergens into the body to make them safer and more powerful. Some groups suggest tiny materials called nanoparticles, which have also been researched for Covid-19 vaccines.

Current early-stage ideas include coating an allergen in gold nanoparticles for sublingual immunotherapy, or creating vaccine-like treatments that encase bits of mRNA-encoding proteins associated with egg or peanut allergies.

For these types of therapies, researchers want patients to develop tolerance in the liver — this organ is regularly bombarded with foreign invaders and contains cells that train the immune system, says Fernanda Young, a research clinician at the National Institutes of Allergy and Infectious Diseases.

But one major problem with these vaccine-esque immunotherapies, says Sokol of MGH, is figuring out a way to target the regulatory arm of the immune system (the one promoting tolerance) while avoiding its inflammatory side and activating the allergy.

During an allergic response, people respond to multiple proteins of an allergen, says Young. The difficulty is finding just the right bit of that allergen (or allergens) to base a vaccine on.

Ultimately, it's difficult for allergy immunotherapies to offer long-lasting benefits. Only a small percentage of people actually manage to develop tolerance; most remain on immunotherapy throughout their entire lives. So researchers need to find out what makes those folks different and how various routes of immunotherapy or the particular allergens used factor into that.

To help with her dust allergy, Williesha Morris received shots. But she couldn’t stick with it — driving to the doctor’s office proved time-consuming, not to mention expensive. (For those without health insurance, allergy shots can be thousands of dollars; even for people with insurance, the weekly copay can add up.) She eventually stopped going altogether. Now, she manages her dust mite allergies with nasal filters in her nostrils, which she wears all day.

But if today’s research pans out, people like Morris could find quicker, safer, and more permanent relief for their symptoms.

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