Stanford Medicine researchers have developed an experimental nasal spray vaccine that protected mice against SARS‑CoV‑2, influenza, and Streptococcus pneumoniae (a cause of bacterial pneumonia) with a single dose, with protection lasting at least three months in the study. The formulation, called GLA-3M-052-LS+OVA, pairs two immune-stimulating compounds with a model antigen delivered in liposomes directly to the airways. If the approach translates to humans, it could reshape how public health systems prepare for respiratory threats, but the work is still preclinical and significant hurdles remain before human trials.
How Two Immune Triggers Create Broad Protection
The Stanford team built the nasal spray around a simple but unconventional idea: instead of training the immune system to recognize one specific virus, prime the lungs to fight almost anything that invades them. The formulation combines a TLR4 agonist called GLA with a TLR7/8 agonist called 3M-052, both packaged in liposomes alongside ovalbumin, a well-studied protein antigen. Together, these two innate immune stimulants and the T-cell-recruiting antigen align with what researchers have described as integrated organ immunity, a concept in which innate, adaptive, and structural cells in lung tissue cooperate to sustain a heightened defensive state. The term “universal” here does not mean the vaccine targets every pathogen individually. It means the protection is antigen-agnostic, turning the respiratory tract into a hostile environment for a wide range of invaders.
That GLA and 3M-052 pairing has a track record in earlier preclinical work. A liposomal combination of the same two compounds previously drove balanced systemic and mucosal immune responses, including mucosal IgA, in mice. Separately, formulated 3M-052 protected animals against high-dose H5N1 influenza challenge and broadened antibody responses in studies that explicitly noted the potential for synergistic formulations with GLA. The new nasal spray essentially merges those two lines of research into a single intranasal delivery system, betting that simultaneous activation of two distinct toll-like receptor pathways at the mucosal surface will produce stronger and longer-lasting local immunity than either compound alone.
What the Mouse Data Actually Show
In the study, mice that received the intranasal liposomal formulation were protected against multiple respiratory threats for at least three months after a single administration. The protection extended across SARS-CoV-2 variants, influenza strains, and Streptococcus pneumoniae, the bacterium responsible for a large share of community-acquired pneumonia worldwide. Experimental controls in which individual components were removed saw immunity wane, suggesting the multi-component strategy contributed to the durability of the response. The formulation also reduced allergic responses in the airways in mouse experiments, an unexpected finding noted in coverage of the work.
The three-month durability finding echoes earlier mechanistic work from the same research group. A prior study showed that BCG vaccination could confer non-specific protection lasting about three months in mice against SARS-CoV-2 variants and influenza by mapping a CD4-positive T cell and interferon-gamma feedback loop that maintained innate antiviral states in the lungs. The new nasal spray appears to activate a similar feedback circuit more efficiently and through a targeted formulation rather than a live bacterial vaccine. That distinction matters because a defined chemical formulation is far easier to standardize, manufacture, and regulate than a live organism like BCG.
Pneumonia Protection Draws on Separate Evidence
The headline claim that the spray blocks pneumonia rests on the mouse challenge data from the Science paper, but supporting evidence comes from independent research lines as well. The TLR7/8 agonist 3M-052 has separately been shown to boost pneumococcal vaccine responses in rhesus macaques, increasing serotype-specific antibody titers and functional opsonophagocytic killing with large magnitude effects compared to the standard PCV13 conjugate vaccine alone. That primate data provides a bridge between mouse experiments and potential human relevance, though it involved an injected formulation rather than a nasal spray.
A separate proof-of-concept study demonstrated that an intranasal influenza-vectored vaccine expressing pneumococcal surface protein A could protect mice against both influenza and Streptococcus pneumoniae, including heterosubtypic influenza protection and broad pneumococcal antibody binding with complement deposition. Taken together, these studies suggest that intranasal delivery of immune-stimulating compounds can generate meaningful defense against bacterial lung infections, not just viral ones. The Stanford formulation’s ability to cover both categories in a single dose, without requiring pathogen-specific antigens beyond the model protein ovalbumin, is what sets it apart from earlier dual-target approaches.
Expert Caution on the Road to Human Use
Outside immunologists have flagged real concerns about translating this approach from mice to people. Independent experts who reviewed the findings raised critical caveats about safety trade-offs of sustained innate activation in human airways, where chronic inflammation could cause tissue damage or exacerbate conditions like asthma. The mouse immune system tolerates aggressive innate stimulation more readily than the human respiratory tract, and three months of heightened immune alertness in human lungs is an untested proposition. No regulatory body has weighed in publicly on the formulation, and no human or large-animal safety data for the combined intranasal GLA–3M-052 liposomes are yet available.
Additional commentary has underscored how unusual the proposed strategy is within the broader vaccine landscape. Reporting in Nature has emphasized that most respiratory vaccines aim to elicit targeted antibody and T cell responses against defined viral or bacterial antigens, whereas this nasal spray leans heavily on innate immune training and tissue-level reprogramming. The Nature news coverage frames the work as an experimental vaccine platform and not a regulatory endorsement. That distinction reinforces the message that, for now, the nasal spray remains an intriguing but early-stage concept.
What Comes Next for “Universal” Respiratory Vaccines
For the Stanford formulation to move toward human testing, several technical and regulatory milestones will need to be cleared. Researchers must first generate detailed toxicology data in at least one large-animal model, probing whether repeated or high-dose intranasal administration of GLA–3M-052 liposomes causes local tissue damage, alters lung function, or triggers systemic inflammation. Manufacturing questions also loom: liposomal formulations can be sensitive to temperature and shear stress, so scaling up production while preserving particle size, adjuvant ratios, and stability will be critical. Regulators are likely to ask for extensive characterization of how long the induced “integrated organ immunity” persists and whether it can be reversed or modulated if adverse effects emerge.
At the same time, public health agencies and funders will have to weigh the potential benefits of a broadly protective, single-dose nasal spray against the costs and uncertainties of developing such a novel platform. If future studies confirm that a single intranasal administration can protect against diverse respiratory viruses and bacteria for several months, the technology could be deployed seasonally in high-risk settings such as nursing homes, crowded workplaces, or regions facing emerging outbreaks. But any move in that direction will depend on rigorous human data showing that the immune training seen in mice can be reproduced safely in people, without tipping the delicate balance between protection and pathology in the lungs.
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*This article was researched with the help of AI, with human editors creating the final content.
