Stanford Medicine researchers and collaborators have produced an intranasal liposomal vaccine that protected mice against multiple respiratory viruses, bacteria, and even allergens in a single formulation, marking a significant advance toward a universal respiratory vaccine. The study, published in the journal Science, combined innate immune activators with a model antigen delivered directly to the nasal lining, where most airborne pathogens first take hold. If the approach survives the difficult leap from animal models to human trials, it could reshape how the world defends against seasonal flu, coronaviruses, and future pandemic threats.
How a Nasal Spray Trained Mice to Fight Nearly Everything
Traditional vaccines work by teaching the immune system to recognize a specific pathogen. That precision is also a limitation: a flu shot designed for one strain offers little help against a novel coronavirus, and vice versa. The Stanford-led team took a different route. Their intranasal liposomal formulation pairs two toll-like receptor agonists, TLR4 and TLR7/8 ligands, with a model antigen. Rather than priming the body to hunt one target, the combination supercharges innate immunity at the mucosal surface of the nose, creating a broad defensive barrier that does not depend on recognizing a single virus.
In mouse experiments, the formulation produced broad protection against multiple respiratory viruses, including SARS-CoV-2 and other coronaviruses, as well as bacteria such as Staphylococcus. That protection proved durable, lasting at least approximately 3 months in the animals tested. Bali Pulendran, the Stanford immunologist who led the work, described the underlying mechanism as a “two-bulwark system”: an initial mucosal barrier limits pathogen entry at the nose, while a second layer of innate immune activation generates non-selective pathogen protection deeper in the airways. The dual mechanism helps explain why the vaccine worked against such a wide range of threats in the same experiment.
Parallel Nasal Vaccine Strategies Show Similar Promise
The Stanford study is not an isolated result. Several independent research groups have been converging on the same basic insight: delivering immune-stimulating material directly to the nasal mucosa can trigger both local and systemic defenses that injected vaccines often miss. A separate peer-reviewed study in mice demonstrated that an albumin-fused antigen delivered intranasally used FcRn-mediated transport across the mucosal barrier to generate protective systemic and mucosal antibody responses in models for both SARS-CoV-2 and influenza A. Another team showed that an RBD-Fc mucosal vaccine provided variant-proof protection against SARS-CoV-2 in both mice and hamsters, a stronger translational signal than mice-only data.
These parallel efforts matter because they suggest the nasal delivery concept is not a one-off curiosity tied to a single lab’s formulation. Different antigen designs, different adjuvant strategies, and different animal models are all pointing in the same direction: mucosal immunity activated at the point of pathogen entry can block infection more broadly than a needle in the arm. The convergence strengthens the scientific case, even as each individual study remains limited to animal data and will need to be validated in carefully designed human trials that can capture both safety and real-world effectiveness.
Early Human Trials Are Already Underway
The gap between promising mouse results and a product that works in people is notoriously wide in vaccine development. But several nasal vaccine candidates have already entered early-stage human testing, signaling that regulators and funders see enough potential to justify the risk. The U.S. National Institutes of Health has launched a Phase 1 trial of an intranasal COVID-19 candidate called MPV/S-2P, with an enrollment target of 60 adults. Investigators are assessing safety as well as immune responses in blood and nasal samples, reflecting a shift away from judging vaccines solely by circulating antibody levels and toward a more complete picture of mucosal protection.
On the influenza side, early clinical work is also building a foundation for broader respiratory protection. A Phase 1 study of the intranasal vaccine Ad4-H5-VTN found it to be safe and capable of producing neutralizing antibodies that persisted for years after a single dose, along with evidence of local mucosal responses. In parallel, the NIH has opened a trial of the universal influenza candidate FluMos-v1, which is designed to protect against multiple strains and has advanced into human testing through an early-stage study of its safety and immunogenicity. Together, these efforts illustrate how intranasal delivery and broad-spectrum antigen design are moving from theoretical ideas into concrete clinical programs.
Why the Mouse-to-Human Gap Still Looms Large
For all the excitement, a clear-eyed reading of the evidence demands caution. Every result described in the Stanford Science paper comes from mice, and the history of vaccine development is full of candidates that performed well in rodents but failed in human trials. Mice have shorter, simpler nasal passages, different distributions of immune cells, and far less microbial diversity in their airways than people do, all of which can influence how a nasal vaccine is absorbed and how long its effects last. Reporting in Nature on the Stanford findings underscored these translation challenges, emphasizing that even strong protection in mice does not guarantee meaningful efficacy in humans, particularly when the goal is to block many different pathogens with a single formulation.
Durability is another major unknown. The roughly three-month protection window observed in mice is encouraging for an animal with a lifespan of about two years, but it offers limited guidance for human dosing schedules that might need to span years or even decades. The “two-bulwark” mechanism described by the Stanford team (a rapid innate barrier at the nasal surface followed by broader activation deeper in the airways) remains a hypothesis that must be tested directly in human tissue and in clinical trials. Researchers will also have to watch for safety signals unique to the nose and lungs, such as excessive inflammation or tolerance issues from repeatedly stimulating innate pathways. Until those questions are answered, the vision of a universal nasal spray or vaccine that shields people from a wide swath of respiratory threats will remain an intriguing, but still unproven, possibility rather than an imminent public-health tool.
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*This article was researched with the help of AI, with human editors creating the final content.
