The best Covid-19 vaccines are really, really effective. Better than many flu vaccines. Better than some hepatitis-B vaccines. Better than the measles vaccines, in many cases.
But even the messenger-RNA vaccines aren’t perfect. They started out being around 95-percent effective at preventing serious illness from older forms of Covid. But there’s ample evidence they lose effectiveness with time and in the face of new, more dangerous variants of the SARS-CoV-2 virus such as Delta and Omicron.
To make the vaccines more durable over time, a team of scientists at Yale is exploring a creative new approach to administering doses. The mRNA vaccines from Pfizer and Moderna are designed for “parenteral” or “intramuscular” administration — that is, injections to the arm. That’s typical of most vaccines.
But according to the Yale team — which includes noted immunobiologist Akiko Iwasaki, research resident Benjamin Golman-Israelow and other researchers spread across several departments and the school of medicine — a Covid-19 vaccine might work better if it’s administered directly on the part of the body where the novel-coronavirus tends to first take hold: the nasal passage with its sticky “mucosal” tissue.
“It’s like having a guard in front of the castle instead of behind the gate,” Golman-Israelow said.
A traditional parenteral injection into the muscles delivers a vaccine to the bloodstream which spreads it throughout the body and elicits a broad response from antibodies and T-cells. These vaccines are the proverbial jacks-of-all-trades … and masters of none. Broad instead of specific.
When it comes to the current Covid vaccines, the immune response in the nose and throat is weaker than it could be, according to the Yale researchers. “Currently approved parenteral vaccines induce robust systemic immunity, but poor immunity at the respiratory mucosa,” they wrote in a new study that appeared online late last month and is currently going through the peer-review process.
A more specific approach that matches vaccine strategy with virus type — a nasal vaccine for a respiratory virus — could confer stronger and more lasting immunity, they theorize. It works by taking advantage of our immune system’s ability to produce highly specific antibodies and T-cells — not only in response to particular viruses, but also where each virus attacks us.
“Our immune system is designed to react in a special way to a pathogen it sees in the respiratory tract or gut in comparison to a pathogen it might see on the skin, for example,” explained Kenneth Palmer, an infectious-diseases expert at the University of Louisville.
“While the intranasal vaccines are late to the party, they provide a different kind of local protection that could have a very beneficial impact,” said Paul McCray, a University of Iowa pediatric pulmonologist who is working on his own nasal-spray Covid vaccine.
There have been a few other nasal-spray vaccines, including popular flu-vaccine Flumist. Other research teams including McCray’s are working on Covid sprays — as well as some in Russia and India — but in the West, the Yale scientists are showing some of the best early results. Their new spray can “elicit mucosal immune memory within the respiratory tract,” they wrote.
There’s a problem, however. It could take a long time to fully develop a mucus-only vaccine for Covid. It would have to go through large-scale human trials over a period of many months — years, even — before the developers could approach health regulators for emergency approval.
To speed things along, Iwasaki, Golman-Israelow and the other Yale scientists are developing the spray vaccine strictly as a booster for the existing mRNA vaccines.
The Yale team is, in a sense, partially piggybacking on a vaccine that the U.S. Food and Drug Administration has already authorized for widespread use. “There might be a lower bar to getting into human studies if they’re working with something that’s already approved,” Palmer said.
The idea is to get your first two prime doses of mRNA as injections, then follow up later with a spray booster. The Yale scientists call it the “Prime and Spike” approach.
That’s a reference to the initial “prime” injections that are the first part of a full course of vaccine, and the spike protein that the novel coronavirus uses to grab onto and infect our cells. A fragment of that spike is the key ingredient in the experimental spray.
“We show that Prime and Spike induces robust T-resident memory cells, B-resident memory cells and [immunoglobulin A] at the respiratory mucosa, boosts systemic immunity and completely protects mice with partial immunity from lethal SARS-CoV-2 infection,” Iwasaki, Golman-Israelow and their colleagues wrote.
As a bonus, a spray booster like the kind the Yale team is investigating might encounter less resistance than an injected booster. While many hardcore anti-vaxxers are motivated by misinformation or ideology, less strident vaccine hesitancy is sometimes associated with the unpleasant sensation of getting a shot — “people being frightened of needles,” as Palmer explains.
And since it’s so easy to use, it’s theoretically possible to develop a booster spray people can take at home. That “may make distribution easier,” Golman-Israelow says. And besides, any logistical hassle might be worth it if the spray booster offers better and more lasting protection — and is less scary, to boot.
The next step for the Yale team is to wrap up animal trials then test Prime and Spike on people and, if it still works and proves it’s safe, team up with a manufacturer to produce it–and ask regulators to greenlight it.
That could take months under the best of circumstances. But with the COVID pandemic entering its third year, a new booster that deploys months from now — or even in 2023 — is still pretty useful.
Correction: A previous version of this article states Paul McCray is an immunologist. He is a pediatric pulmonologist.