A team at Stanford Medicine’s Pulendran Lab has developed a nasal spray vaccine that protects mice against a broad range of respiratory threats — including coronaviruses, bacteria and allergens — for at least three months, according to a Feb. 19 paper published in “Science.”

The paper suggests that a vaccine formulation could one day replace multiple seasonal shots for respiratory infections — a step toward a universal vaccine.

Rather than mimicking a specific pathogen, which has been the typical paradigm of vaccines in the past 230 years, the new vaccine used in the study — known as GLA-3M-052-LS+OVA — works by activating the body’s innate immune system, a rapid but often short-lived line of defense that can fight a broad range of threats. 

Bali Pulendran, the paper’s communication author and director of Stanford Medicine’s Institute for Immunology, Transplantation and Infection, says the vaccine’s key innovation lies in “integrated organ immunity,” which uses a harmless egg protein to recruit T cells into the lungs, keeping innate immune cells alert for as long as six months.

“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 primed innate response reduced viral levels in the lungs by 700-fold. In addition, any pathogen that slipped through the first line of defense of innate immunity was then met with an adaptive immune response in as little as three days — compared to a typical two-week period in unvaccinated mice.

“What has been most striking is how robustly this approach works — not only in the data presented in the paper, but also in the overall health and behavior of the vaccinated mice after infection compared with unvaccinated controls,” said Haibo Zhang, lead author and post-doctoral scholar in the Institute for Immunity, Transplantation, and Infection of Stanford Medicine.

Zhang traced the project’s origins to her doctoral research on innate immune signaling and discussions with Pulendran about integrated organ immunity. The concept, formally introduced in 2024, proposed that innate and adaptive immune cells can form a self-sustaining protective network within an organ like the lung. 

“This framework has become the conceptual foundation for our ‘universal vaccine’ strategy,” Zhang said.

Mark Davis, professor of microbiology and immunology at Stanford Medicine, called the work “a paradigm shift in how thinking about vaccines has broadened from a focus only on specific vaccines [to] the realization that mobilizing the less specific innate immune system could give us short term, but critical protection.”

Since the development of the first smallpox vaccine in the 1790s, all vaccines have relied on the same principle: teaching the immune system to recognize a specific pathogen.

“That’s been the paradigm of vaccinology for the last 230 years,” Pulendran said in an interview with Stanford Medicine’s news center. “We were interested in this idea because it sounded a bit outrageous. I think nobody was seriously entertaining that something like this could ever be possible.”

In an email to The Daily, Davis highlighted the vaccine’s potential relevance to future pandemics. “In the critical first months of a virulent new pandemic, before a specific vaccine was available, a universal vaccine like the one in this paper could significantly blunt the early stages of a [SARS- CoV-2] like infection,” he wrote. 

While the study is currently limited to mice, Pulendran outlined next steps to advance the vaccine, which include toxicology studies and phased dose increases. 

The team plans to collaborate with Imperial College London and Emory University in follow-up studies. 

Pulendran expressed confidence in Stanford’s role in further advancing future research on the vaccine. “In the last 15 years or so, I think Stanford has led the way in the human immune system,” he said. 

In the best-case scenario, Pulendran estimates a universal respiratory vaccine could be available in five to seven years. “We [at Stanford] are incredibly well poised to take this to the clinic and to run with it,” he said.