A spritz instead of a jab? Future COVID-19 vaccines may go up your nose.

The current batch of COVID-19 vaccines effectively prevents severe disease and death and offers substantial protection against the variants. But the authorized vaccines are not 100 percent effective at blocking all infections. To address this deficit, scientists are exploring new ways of delivering vaccines that yield stronger and more durable immunity against SARS-CoV-2. One promising approach might be to trade a jab in the arm for a spritz up the nose.

Over the past several months, as some manufacturers are preparing booster shots to deliver a third dose, a handful of promising studies have revealed the effectiveness of intranasal vaccines in mice, ferrets, hamsters, and non-human primates. Further along are six candidate COVID-19 vaccines, administered as nasal sprays, that are currently in phase 1 clinical trials. And, just this week, at the meeting of the American Society for Virology, Meissa Vaccines announced that a single dose of their intranasal COVID-19 vaccine candidate showed promising results in non-human primates. If these vaccines come to market, immunologists say that might offer better protection because they more closely resemble the way the virus naturally infects us—through the mucous membranes of the nose and upper airways. And immunologists say this makes a difference in the immune response.

“If you want to generate a sustainable, long-lasting immune response, you want to vaccinate locally,” says José Ordovas-Montañes, a Harvard University immunologist who studies immunity in the gut and nasal mucosal tissues. Ordovas-Montañes says that when we get a jab in the arm, we are inducing immunity on a systemic, body-wide scale where our antibodies and T cells will distribute themselves around the blood vessels. While that might sound good, this approach is “sub-optimal” because the immune cells are “distracted” and not focused on the location where the virus enters the body. A shot up the nose, on the other hand, provides a big boost of immunity in the upper respiratory tract and potentially the lungs, eliciting a local antibody response and T cell response. This enables immune cells to apprehend and destroy the pathogen on arrival.

“I think the big benefit is that you generate immunity at the site of infection,” says Donna Farber, an immunologist at Colombia University. “That’s where you need the immunity, where the virus is coming in.”

A shot in the arm is like vaccinating us from the inside out. We generate immunity throughout the body, and some of those antibodies trickle into the airways and nasal passages. But the nasal spray works the other way around, boosting the site of infection first and the rest of the body second. “You basically get a two for one,” says Paul McCray, a pediatric pulmonologist at the University of Iowa.

McCray and colleagues published a paper this month in Science Advances showing that mice and ferrets are protected from severe diseases after just one dose of an intranasal vaccine. They will be launching a clinical trial later this month for 80 healthy adults ages 18 to 75 years at three sites around the U.S.

A more practical vaccine

Vaccines that target the mucous membranes aren’t new. There are many oral vaccines that are approved to combat infections such as polio and cholera. The idea is that they will prime the mucosal tissues of the intestinal tract in much the same way as intranasal vaccines prime the respiratory tract. In many cases, like in the live attenuated oral polio vaccine, these vaccines work better than the shot. But intranasal vaccines remain rare in the vaccine landscape overall. Many are hoping that the pandemic will change that.

“COVID has really accelerated the development of some things that were always right in front of us hiding in plain sight,” says David Curiel, a gene therapy researcher at Washington University in St. Louis. Earlier this year, he published a study showing a robust response after a dose of an intranasal vaccine in non-human primates. He points out that another benefit to developing these kinds of vaccines is that they could be easier to administer, especially around the world in places that do not have well-established healthcare systems. 

The current batch of approved vaccines are highly efficacious, but there aren’t enough doses to vaccinate everyone in the world, and the pandemic is far from over, especially in India and several countries throughout Africa and South America. Forgoing the needle, something that could be in short supply, would be advantageous. The COVID-19 vaccines may mark a new era in mucosal immunity.

Where does our immunity live?

When the immune system is discussed, most people think about blood. Immune cells are often described as mini watchers that patrol the blood vessels looking for invaders. But, over the past decade or more, understanding of the immune system has evolved and researchers now know that many immune cells reside in the tissues.

More than 95 percent of T cells, for example, take up permanent residence in the tissues and organs, with distinct populations dwelling in the skin, gut, brain, liver, and lung. Natural killer cells, which are related to B and T cells, spend their lives in the uterus remodeling the tissue during pregnancy. There are even some immune cells, called microglia, that live in the brain and never journey into the blood vessels. Instead, they migrate to the central nervous system early in embryogenesis and stay there for the remainder of the organism’s life.

These tissue-specific immune cells can work to our advantage when it comes to vaccines because they not only remember the pathogen but also where it first invaded the body.

The immune system has developed an elegant way of doing this called “immune imprinting,” says Ulrich von Andrian, an immunology professor at Harvard. Von Andrian was the first to demonstrate, in mice, how the immune system keeps track of where a particular pathogen entered the body.

The immune system is alerted to new threats when specialized cells, called “antigen-presenting cells,” such as macrophages, pick up little bits and pieces of the virus around the body and present them to the T cells. This process is called “T cell education,” and it is the immune system’s version of an intelligence briefing. It takes place in the lymph nodes, where all the lymph fluids drain, along with the cells and bits of viruses. These little training centers are located throughout the body, and as anyone who has gotten very sick and experienced a swollen lymph node can attest, they are particularly abundant in the neck, armpit, and the groin. Von Andrian showed in his seminal experiment that the intelligence briefing not only contains info about the specific threat, but also the location where it was first spotted.

In an experiment from his lab back in 2003, T cells were removed from mice and put into different petri dishes, where they were mixed with antigen-presenting cells from lymph nodes, skin, and the gut. After about a week in the petri dish, the T cells were injected back into the mice. The T cells that were educated with antigen-presenting cells from the gut, immediately swarmed back into the gut. Like a homing pigeon that flies great distances to get back home, these cells had an innate sense of where to go. They remained there for a long time, standing guard for an invasion.

Von Andrian says that the lymph nodes teach the T-cells how to migrate back to the part of the body where they first encountered the pathogen. The lymph nodes closest to the nasal tissues reside in the neck; and the lymph nodes connected to the arm, where vaccine shots are administered, are “in a different part of town.”

“When you get an infection, you get it in your mucosal surfaces in your nasal cavity, and you prime your T cells and your entire immune system in your upper respiratory tract, which means these cells are going to stay there, become resident, and act like a sentinel defense,” says Marcus Buggert, an immunologist and T cell researcher at the Karolinska Institute in Sweden. “If you vaccinate yourself in the arm, you won't induce that type of T cell response.”