In the realm of medical advancements, a universal vaccine that can protect against any pathogen has long been a Holy Grail — and about as elusive as a mythological vessel.

But Stanford Medicine researchers and collaborators have taken an astonishing step forward in that quest, surprising even themselves. 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 to publish Feb. 19 in Science, researchers showed 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, PhD, 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, PhD, 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.

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.”

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.”

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 recieved 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 Hil...

Healthcare Hygiene magazine

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