Stanford scientists develop nasal spray vaccine that protects mice from viruses, bacteria, allergens

A universal vaccine breakthrough in mice

Stanford Medicine researchers have developed a nasal spray vaccine that protected mice against a wide range of respiratory viruses, bacteria, and allergens. The study, published November 19th in Science, shows the vaccine provides broad protection in the lungs for at least three months.

In tests, vaccinated mice were shielded from SARS-CoV-2, other coronaviruses, and the bacteria Staphylococcus aureus and Acinetobacter baumannii. The vaccine also prevented allergic reactions to house dust mites. Senior author Bali Pulendran called it a "universal vaccine against diverse respiratory threats."

If it works in humans, such a vaccine could replace annual shots for flu and COVID-19 and be ready for future pandemics. Lead author Haibo Zhang is a postdoctoral scholar in Pulendran's lab.

How the new vaccine works

This vaccine breaks from 230 years of established science. Since Edward Jenner's smallpox vaccine, all vaccines have relied on antigen specificity—mimicking a unique part of a pathogen, like a virus's spike protein, to train the immune system.

"That’s been the paradigm of vaccinology," Pulendran said. The problem is that pathogens mutate, making those specific targets obsolete. This is why new COVID-19 and flu boosters are needed regularly.

Instead of mimicking a pathogen, this new formula mimics the signals immune cells use to communicate. It creates a feedback loop between the body's two immune branches:

• Adaptive immunity: The targeted, memory-based system current vaccines use.
• Innate immunity: The rapid, generalist first responders that attack anything foreign.

The innate system is powerful but short-lived. Pulendran's team found a way to keep it active for months.

The tuberculosis vaccine clue

The research was inspired by the Bacillus Calmette-Guérin (BCG) tuberculosis vaccine. Given to about 100 million newborns yearly, it has been shown to reduce infant deaths from other infections, suggesting months of cross-protection.

In a 2023 study, Pulendran's team discovered why. The BCG vaccine recruits T cells to the lungs. Those T cells then send signals—cytokines that activate pathogen-sensing toll-like receptors—telling innate immune cells to stay active.

"In that paper, we speculated that... it would be possible to make a synthetic vaccine, perhaps a nasal spray," Pulendran said. "Fast forward two and a half years and we’ve shown that exactly what we had speculated is feasible in mice."

Stunning results across threats

The experimental vaccine, called GLA-3M-052-LS+OVA, contains those T cell signals and a harmless egg protein (ovalbumin) to recruit T cells into the lungs. Mice received it as a nasal drop.

With three doses, mice were protected from coronaviruses for three months. Unvaccinated mice lost dramatic weight, often died, and had virus-filled lungs. Vaccinated mice survived with nearly clear lungs.

The vaccine acts as a "double whammy," Pulendran said. The prolonged innate response reduces viral load in the lungs by 700-fold. Any virus that gets past it triggers an adaptive response in just three days, compared to two weeks in an unprepared mouse.

The team then tested it against bacterial infections and a common allergen. The protection held for about three months in each case, suppressing the harmful immune response to dust mites.

The path to a human vaccine

The researchers plan to test the vaccine in humans, starting with a Phase I safety trial. If successful, a larger trial would expose vaccinated volunteers to infections. Pulendran believes two nasal spray doses could provide human protection.

With sufficient funding, he estimates a universal respiratory vaccine could be available in five to seven years. It could fundamentally change how we handle respiratory illness.

"Imagine getting a nasal spray in the fall months that protects you from all respiratory viruses... as well as bacterial pneumonia and early spring allergens," Pulendran said. "That would transform medical practice."

Researchers from Emory University, the University of North Carolina at Chapel Hill, Utah State University, and the University of Arizona contributed. Funding came from the National Institutes of Health and several endowments.