Stanford Medicine researchers and collaborators have developed a universal vaccine candidate that studies in mice suggest protects against a wide range of respiratory viruses, bacteria, and even allergens. Unlike any vaccine used today, the new vaccine, delivered intranasally, was found to provide broad protection in the lungs for several months. The novel vaccination strategy integrates the two branches of immunity—innate and adaptive—creating a feedback loop that sustains a broad immune response.
The research team, headed by Bali Pulendran, PhD, the Violetta L. Horton Professor II, director of the Institute for Immunity, Transplantation and Infection, and a professor of pathology, microbiology and immunology at Stanford University, demonstrated that vaccinated mice were protected against SARS-CoV-2 and other coronaviruses, Staphylococcus aureus and Acinetobacter baumannii (common hospital-acquired infections), and house dust mite allergen. Pulendran said the new vaccine has worked for a remarkably wide spectrum of respiratory threats that the researchers tested. Speaking to GEN, Pulendran emphasized that the reported work is preclinical, and the team’s goal is to translate their research carefully and responsibly. “If it ultimately proves safe and effective in humans, the potential impact could be transformative: simplifying seasonal vaccination and improving readiness for emerging respiratory threats,” Pulendran said.
Senior author Pulendran, together with first author Haibo Zhang, PhD, a postdoctoral scholar in Pulendran’s lab, and colleagues, reported on their work in Science, in a paper titled “Mucosal vaccination in mice provides protection from diverse respiratory threats,” in which they stated that their results “… reveal a class of “universal vaccines” against diverse respiratory threats.”
Since the 1790s, when Edward Jenner coined the term vaccination (from the Latin vacca for cow), in reference to the use of cowpox to inoculate against smallpox, all subsequent vaccines have relied on the same fundamental principle, which is 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.
Urgent need for a broadly protective vaccine
However, antigen-specific vaccines fail when a pathogen mutates or when new pathogens emerge. “Traditional vaccines target specific pathogens, limiting their scope against diverse respiratory threats,” the authors wrote. 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,” Pulendran added. “Like the proverbial leopard that changes its spots, a virus can change the antigens on its surface.” The authors further noted, “There is, therefore, an urgent need for the development of a broadly protective, clinically applicable vaccine targeting diverse airborne viruses and bacteria to enhance pandemic preparedness and strengthen global health security.”
The team’s newly developed 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. And, as Pulendran explained to GEN, this is, conceptually, a very different approach to that of the dominant “antigen-specific” paradigm that has “guided vaccinology” for 230 years since Jenner. “… here the strategy is to recreate key immune communication signals in the lung that sustain a heightened, protective state, while still engaging adaptive immunity to help maintain that state over time,” GEN was told. The reason this hasn’t been a mainstream approach, Pulendran further noted, is that “… (i) the field has historically prioritized antigen specificity as the central organizing principle for both efficacy and regulatory pathways, and (ii) it has been challenging to achieve broad innate protection in a way that is durable and localized—i.e., without unacceptable systemic inflammation.”
A pie-in-the-sky idea?
Most attempts at a universal vaccine may have the challenging 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 adaptive immune system is the workhorse of current vaccines. It produces specialized agents, such as 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.
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. Innate immunity is short-lived but provides something approaching universal protection. “What’s remarkable about the innate system is that it can protect against a broad range of different microbes,” Pulendran pointed out.
There have long been hints that innate immunity can last longer in certain circumstances. The most-studied example is the Bacillus Calmette-Guérin (BCG) 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. The findings from such studies, together “… reveal a complex, tissue-localized immune network involving the concerted action of the adaptive and innate immune systems along with structural cells—a phenomenon we have termed “integrated organ immunity,” the investigators stated.
Sustained innate response
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 noted. 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 (TLRs), on innate immune cells.
“Integrated organ immunity”
“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 commented. “Our prior BCG work helped clarify a plausible mechanism for durable, lung-localized “antigen-agnostic” protection, through the dynamic interplay of the adaptive and innate immune systems (which we termed “integrated organ immunity“), which in turn made a rational synthetic approach feasible,” Pulendran further noted to GEN.
In their newly reported paper in Science, the investigators said they “… hypothesized that a mucosal vaccine that delivers TLR ligands alongside an antigen could exploit the dynamic interplay between the adaptive and innate immune systems to stimulate integrated organ immunity and protect against diverse pathogens in vivo.” Pulendran added, “Fast forward two and a half years and we’ve shown that exactly what we had speculated is feasible in mice.”
The new vaccine, designated GLA-3M-052-LS+OVA, mimics the T cell signals that directly stimulate innate immune cells in the lungs. It also contains the harmless antigen, an egg protein ovalbumin (OVA), which recruits T cells into the lungs to maintain the innate response for weeks to months. “We evaluated an intranasal vaccine combining the TLR4 agonist GLA and the TLR7/8 agonist 3M-052-LS with ovalbumin (OVA), selected to provide a defined antigen and broad innate stimulation,” the scientists said.
As part of their newly reported 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 and often death; their lungs were inflamed and full of virus. In contrast, vaccinated mice lost much less weight and all survived; their lungs were nearly clear of the virus.
A “double whammy” vaccine
The vaccine is a “double whammy” against viral infection, Pulendran pointed out. The prolonged innate response lowers the amount of virus in the lungs about 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.”
Encouraged by the vaccine’s ability to fend off different types of viral infection, the researchers expanded their testing to see whether the vaccine could protect against the bacterial respiratory infections Staphylococcus aureus and Acinetobacter baumannii. The results confirmed that vaccinated mice were protected against these pathogens for about three months. “… vaccinated mice showed durable protection against bacterial infection with Staphylococcus aureus and Acinetobacter baumannii as indicated by lower lung bacterial loads at least three months-post vaccinations,” the authors stated. Pulendran added, “Then we thought, ‘What else could go in the lung?’ Allergens.”
Protection against bacteria, viruses, and allergic asthma
The team 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. The team found that unvaccinated mice showed a strong Th2 response and accumulated mucus in their airways. The vaccine quelled the Th2 response, and vaccinated mice maintained clear airways. “Importantly, in addition to broad protection against respiratory viruses and bacteria, we show that vaccination can prevent allergic asthma, extending the scope of integrated organ immunity–based interventions into allergic disease,” the scientists stated.
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. “I think what we have is a universal vaccine against diverse respiratory threats,” Pulendran said. The researchers hope to progress their research with a view to testing a vaccine in humans, 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. “Given that two to four intranasal doses conferred protection in mice, future optimization to two doses and use of user-friendly devices such as nasal sprays may enable practical deployment in humans,” the team suggested.
The researchers are currently evaluating multiple related vaccine candidates in mice, varying in composition, dose, schedule, and formulation, GEN was told. “Based on comparative preclinical data—including durability, breadth of protection—we will select the most promising candidate to advance. This will include optimization of the nasal delivery method/device and assessment of manufacturability and stability,” Pulendran said.
Development pathway
Once a lead candidate is selected, the researchers will undertake formal toxicology studies, “with particular attention to local tolerability in the nasal and lung compartments and careful profiling of inflammatory and immune activation signatures,” alongside preclinical studies to assess breadth and durability of protection across respiratory pathogens. “We will further define the immune features associated with durable, lung-localized protection, with an emphasis on identifying biomarkers that could be monitored in Phase I trials to guide dose and schedule selection,” Pulendran explained to GEN. “The timeline to IND is highly dependent on securing dedicated funding, completing lead-candidate selection, scaling manufacturing, and conducting formal GLP toxicology studies. At present, we are actively exploring funding mechanisms to support these IND-enabling activities.… Broadly, a multi-year path to first-in-human studies is realistic, with the more optimistic timelines contingent on the availability of substantial resources.”
A truly universal vaccine
In the best case scenario, with enough funding, Pulendran estimates a universal respiratory vaccine might be available in five to seven years. This could represent a bulwark against new pandemics and simplify seasonal vaccinations. “This could serve as an early pandemic countermeasure, providing broad protection before strain-matched vaccines are available,” they wrote. “Outside pandemic settings, seasonal administration could protect against influenza, common cold viruses, RSV, and other respiratory threats—ultimately paving the way toward a truly universal vaccine.”
Pulendran said, “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. That would transform medical practice.” Speaking to GEN, Pulendran added, “One of the attractive features is that the core “innate-activating/tissue-conditioning” concept is platform-like, and in principle could be paired rapidly with a new pathogen antigen to tailor adaptive responses. That said, even with a platform, the preclinical and regulatory requirements for a new product (or a substantially modified product) still dictate timelines. In a true emergency, development can be accelerated, but it is best to describe timelines qualitatively rather than committing to a specific number of months.”
When asked about the potential to expand the platform beyond the lung, Pulendran said, “The broader concept—durable, localized protection through coordinated innate–adaptive ‘integrated organ immunity’—could potentially be adapted to other mucosal or tissue sites (e.g., upper airway, gut), but it would require site-appropriate delivery approaches, optimization of safety/tolerability, and validation that the same type of durable, beneficial immune state can be induced without pathology.”
