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As the SARS-CoV-2 virus spreads, it changes. This has helped him get through our firewalls, the immunity that vaccines create or leave behind after we recover from an infection. For this reason we are well into the third year of the pandemic in the midst of another wave of Covid-19 caused by the most immune-preventable variant yet, BA.5. And more variants are coming.
As vaccine makers try to update first-generation shots in hopes of improving our protection for the fall, other scientists are taking a different approach, making vaccines that are administered via nasal spray or pills that have more immune defenders on the front lines of the body: the lining of the mouth, nose and throat.
“The hope is to boost the defenses right in the nose so the virus can’t even replicate in the nose,” said Dr. Ellen Foxman, an immunobiologist at the Yale School of Medicine. “And then someone who has a really effective mucosal vaccine can’t even really support virus replication or make viruses that can infect other people.
If it works, there is hope that mucosal immunity could slow the development of new coronavirus variants and finally bring the Covid-19 pandemic under control.
There’s still a long way to go, however, and many scientists say the approach needs a cash injection to accelerate the pace of development, similar to the billions of dollars expended by Operation Warp Speed, the first generation of Covid-19 vaccines in record time.
An old approach meets new technology
Most are based on the oldest types of vaccine technology, using killed or weakened versions of a virus or bacterium to teach the body how to recognize and fight when a real infection is underway.
Because of these actual pathogens, some people cannot use these types of vaccines. Exposing certain groups — including pregnant women and those with compromised immune systems — to weakened viruses themselves is risky.
None have met the goal of preventing transmission of infection, but that may be because they haven’t received the same investment as injectable vaccines, says Ed Lavelle, an immunologist at Trinity College Dublin.
“What hasn’t really happened with mucosal vaccines are huge technological advances that happened with injectable vaccines even before Covid,” Lavelle said.
But that could change soon.
Can nasal spray vaccines slow down new variants?
More than a dozen nasal spray vaccines against Covid-19 are being tested worldwide. Many are using novel technologies, such as providing instructions on how harmless trojan viruses make the coronavirus spike protein. Others want to use the mRNA technology that has been so successful with the injectable vaccines in the form of a nasal spray.
One company, Vaxart, has even made a tablet that delivers instructions on how to make parts of the new coronavirus to the gut, which then builds immunity “in the tube”.
“What we found is that if you did oral immunization, you inhibited this breakthrough’s ability to infect other animals,” said Sean Tucker, Vaxart’s chief scientific officer.
The Vaxart tablet, which is about the size and shape of an aspirin, uses an adenovirus – the same delivery system used by Johnson & Johnson and AstraZeneca’s Covid vaccines – to carry instructions for making parts of the SARS-CoV virus. 2 spikes deliver protein to the intestinal cells, which stimulates the release of antibodies in the nose and mouth.
In an early study of 35 participants, 46% had a rise in nasal antibodies after taking the tablet vaccine. Those that did seemed to provide a broad spectrum of immunity to a range of types of coronavirus, and they seemed to maintain that protection for about a year. That may take a little longer than injectable vaccines, although more research is needed to confirm these results.
Tucker is presenting these early findings at the Seattle conference on Monday. He says they will also be published as a preprint study in the coming days.
A Phase 2 trial of a pill with a slightly different formulation, involving nearly 900 participants, is also underway, Tucker says. It should be completed next summer.
Most of the mucosal vaccines in development are designed to be given as a liquid spray or nasal spray, and many are intended to be used as a booster shot in people who have received a full baseline series of Covid-19 vaccines.
“I don’t see them as nasal vaccines. I think of them as nasal boosters,” said Jennifer Gommerman, an immunologist at the University of Toronto who specializes in tissue-specific immunity.
That’s important, Gommerman says, because nasal vaccines — like FluMist — haven’t really worked well.
The next generation of vaccines will be something different, she says. You will build on the body-wide immunity created by gunfire; You’ll just direct it up your nose and down your throat where it’s needed most, she says.
“But here we’re actually talking about something else, where we’re talking about building on top of the systemic immunity that was induced by a vaccine against three mRNA shots, and then training that systemic immunity to go to the upper airway to boost it.” through the nose,” Gommerman says.
Only the group that received the injection followed by the nasal spray developed robust immunity to the Covid-19 virus.
“This approach, which we have demonstrated in the mouse model, provides 100% protection against a lethal dose of SARS-CoV-2 infection and dramatically reduces viral loads in the nose and lungs,” Iwasaki said.
Rely on IgA antibodies
Mucosal vaccines also target a slightly different part of the immune system than shots.
Injections cause the body to make antibodies against the virus that causes Covid-19. Most of these are Y-shaped proteins called IgG antibodies that are programmed to recognize and block specific parts of the SARS-CoV-2 virus along its tips, the parts of the virus that attach to our cells and infect them.
A much smaller fraction of these are IgA antibodies, and they look like two Ys joined together at their tails and turned sideways, making them look more like a dog bone, Gommerman says.
Like bouncers in a bar, IgA antibodies are the primary immune molecules that stand guard in the mucosa.
These molecules are more powerful than IgG antibodies. They have four arms instead of two, and they’re special because they’re less picky about what to latch on to than IgG antibodies.
“They might be a bit more promiscuous in the way they recognize different variants. And that’s obviously a plus,” Gommerman said.
Syringes raise IgA antibodies in the nose for a short time, but the hope is that mucosal vaccines will really increase the population of these sentinels and help them stay active longer.
“Whether they will be able to confer full sterilizing immunity is a very big challenge,” Gommerman said. “But we should be working now to slow human-to-human transmission because this virus keeps mutating and then fools our immune system and goes through that mucosal layer.
“This is a very contagious virus now,” she said.
Iwasaki says she would like to move her vaccine from animal research to human clinical trials.
“We’re still at the stage where we’re kind of struggling to raise money, even make the vaccine for human use, because it’s millions of dollars, and we’re not sitting on that kind of money for the research lab.” , she said: “So not yet.”
