Nasal spray protects mice from respiratory viruses, bacteria and allergens
By Stanford
University Medical Center
Edited by Sadie Harley, reviewed by Robert Egan
 |
| Bobby Jr. has a different idea about what to put up your nose |
In a new study in mice, they have developed a universal
vaccine formula that protects against a wide range of respiratory viruses,
bacteria and even allergens. The vaccine is delivered intranasally—such as
through a nasal spray—and provides broad protection in the lungs for several
months.
In the study, published in Science,
researchers show that vaccinated mice were protected against SARS-CoV-2 and
other coronaviruses, Staphylococcus aureus and Acinetobacter baumannii (common
hospital-acquired infections), and house dust mites (a common allergen).
In fact, the new vaccine has worked for a remarkably wide
spectrum of respiratory threats the researchers have tested, said Bali
Pulendran, Ph.D., the Violetta L. Horton Professor II and a professor of
microbiology and immunology who is the study's senior author. The lead author
of the study is Haibo Zhang, Ph.D., a postdoctoral scholar in Pulendran's lab.
If translated into humans, such a vaccine could replace
multiple jabs every year for seasonal respiratory infections and be on hand
should a new pandemic virus emerge.
Pie in the sky
The new vaccine is unlike any vaccine used today.
Since the 1790s, when the English physician Edward Jenner
coined the term vaccination (from the Latin vacca for cow) to refer to the use
of cowpox to inoculate against smallpox, all subsequent vaccines have relied on
the same fundamental principle: antigen specificity. That is, the vaccine
mimics a distinctive component of the pathogen—the spike proteins that cover
SARS-CoV-2, for example—to prepare the immune system to recognize and react
quickly to the real pathogen.
"That's been the paradigm of vaccinology for the last
230 years," Pulendran said.
But antigen-specific vaccines fail when a pathogen mutates
or when new pathogens emerge. That's why there's a new COVID-19 booster and flu
shot every year.
"It's becoming increasingly clear that many pathogens
are able to quickly mutate. Like the proverbial leopard that changes its spots,
a virus can change the antigens on its surface," Pulendran said.
Most attempts at a so-called universal vaccine have the
modest goal of inducing immunity against an entire family of virus—all
coronaviruses or all flu viruses, for example—usually by mimicking
evolutionarily conserved viral components that are less likely to mutate. A
truly universal vaccine that can counter diverse pathogens was a pie-in-the-sky
idea.
"We were interested in this idea because it sounded a
bit outrageous," Pulendran said. "I think nobody was seriously
entertaining that something like this could ever be possible."
Integrated immunity
The new vaccine doesn't try to mimic any part of a pathogen;
instead, it mimics the signals that
immune cells use to communicate with each other during an infection. This novel
strategy integrates the two branches of immunity—innate and adaptive—creating a
feedback loop that sustains a broad immune response.
The adaptive immune system is the workhorse of current
vaccines. It produces specialized agents, like antibodies and T cells, that
target specific pathogens and remember them for years to come.
The innate immune system, which deploys within minutes of a
new infection, has received less attention because it typically lasts only a
few days before ceding the spotlight to the adaptive immune system. It was seen
as the warm-up act for the main show.
But Pulendran's team was intrigued by the versatility of the
innate immune system, which consists of generalists (such as dendritic cells,
neutrophils and macrophages) that destroy anything deemed a pathogen.
"What's remarkable about the innate system is that it
can protect against a broad range of different microbes," Pulendran said.
Innate immunity is short-lived, but provides something
approaching universal protection.
There have long been hints that innate immunity can last
longer in certain circumstances. The most-studied example is the Bacillus
Calmette-Guerin tuberculosis vaccine, which is given to some 100
million newborns every year.
Epidemiological and clinical studies have shown that it can
decrease infant mortality from other infections, suggesting that the
cross-protection could last months. But the phenomenon was inconsistent and the
mechanism mysterious.
In 2023, Pulendran's team published a study in
mice elucidating the mechanism. Like other vaccines, the tuberculosis vaccine
induced both an innate and adaptive immune response in the mice, but unusually,
the innate response was sustained for several months.
The researchers discovered that T cells recruited to the
lungs as part of the adaptive response were sending signals to the innate
immune cells to keep them active.
"Those T cells were providing a critical signal to keep
the activation of the innate system, which typically lasts for a few days or a
week, but in this case, it could last for three months," Pulendran said.
The researchers showed that as long as the innate response
remained active, the mice were protected against SARS-CoV-2 and other
coronavirus infections. They identified the signals sent by T cells as cytokines that
activate pathogen-sensing receptors, known as toll-like receptors, on innate
immune cells.
"In that paper, we speculated that since we now know
how the tuberculosis vaccine is mediating its cross-protective effects, it
would be possible to make a synthetic vaccine, perhaps a nasal spray, that has
the right combination of toll-like receptor stimuli and some antigen to get the
T cells into the lungs," Pulendran said.
"Fast forward two and a half years and we've shown that
exactly what we had speculated is feasible in mice."
Double whammy
The new vaccine, for now known as GLA-3M-052-LS+OVA, mimics
the T cell signals that directly stimulate innate immune cells in the lungs. It
also contains a harmless antigen, an egg protein called ovalbumin or OVA, which
recruits T cells into the lungs to maintain the innate response for weeks to
months.
In the study, mice were given a drop of the vaccine in their
noses. Some received multiple doses, given a week apart. Each mouse was then
exposed to one type of respiratory virus. With three doses of the vaccine, mice
were protected against SARS-CoV-2 and other coronaviruses for at least three
months.
In unvaccinated mice, these viruses caused dramatic weight
loss—a sign of illness—and often death; their lungs were inflamed and full of
virus. Vaccinated mice lost much less weight and all survived; their lungs were
nearly clear of the virus.
The vaccine is a "double whammy" against viral
infection, Pulendran said. The prolonged innate response lowers the amount of
virus in the lungs by 700-fold. And viruses that slip through this initial
defense are met with a swift adaptive response in the lungs.
"The lung immune system is so ready and so alert that
it can launch the typical adaptive responses—virus-specific T cells and
antibodies—in as little as three days, which is an extraordinarily short length
of time," Pulendran said. "Normally, in an unvaccinated mouse, it
takes two weeks."
Amazed by the vaccine's ability to fend off different types
of viral infections, the researchers expanded their testing to bacterial
respiratory infections, Staphylococcus aureus and Acinetobacter baumannii. The
vaccinated mice were protected against these, too, for about three months.
"Then we thought, 'What else could go in the
lung?'" Pulendran said. "Allergens."
They exposed the mice to a protein from house dust mites, a
common trigger for allergic asthma. Allergic reactions are caused by a type of
immune response known as Th2 response. Unvaccinated mice showed a strong Th2
response and mucus accumulation in their airways. The vaccine quelled
the Th2 response and vaccinated mice maintained clear airways.
"I think what we have is a universal vaccine against
diverse respiratory threats," Pulendran said.
The researchers hope to test the vaccine in humans next,
first in a Phase I safety trial, then, if successful, in a larger trial in
which vaccinated people are exposed to infections. Pulendran thinks two doses
of a nasal spray would be enough to provide protection in humans.
In the best case scenario, with enough funding, Pulendran
estimates a universal respiratory vaccine might be available in five to seven
years. It could be a bulwark against new pandemics and simplify seasonal
vaccinations.
"Imagine getting a nasal spray in the fall months that
protects you from all respiratory viruses including COVID-19, influenza,
respiratory syncytial virus and the common cold, as well as bacterial pneumonia
and early spring allergens," Pulendran said. "That would transform
medical practice."
Researchers from Emory University School of Medicine, the
University of North Carolina at Chapel Hill, Utah State University and the
University of Arizona contributed to the work.
Publication details
Haibo Zhang et al, Mucosal vaccination in mice provides
protection from diverse respiratory threats, Science (2026). DOI:
10.1126/science.aea1260. www.science.org/doi/10.1126/science.aea1260
Journal information: Science
