Universal Nasal Spray Vaccine Shows Promise Against Respiratory Illnesses in Mice

A potential new vaccine, delivered as a nasal spray, could offer broad protection against a range of respiratory illnesses – and the protection may last for months, according to early research in mice. The experimental vaccine aims to train the immune system to respond to a wide variety of viruses, bacteria, and even allergens, offering a potential “one-stop” solution for seasonal respiratory protection.

The quest for a universal respiratory vaccine – one that shields against multiple pathogens – has long been a goal in medical research. Scientists at Stanford Medicine believe they’ve taken a significant step forward with a novel approach that differs fundamentally from traditional vaccine strategies. Published in the journal Science in February, the study details how the vaccine protected mice against SARS-CoV-2 and other coronaviruses, as well as common bacterial infections like Staphylococcus aureus and Acinetobacter baumannii, and even house dust mite allergens.

A Shift in Vaccine Philosophy

Current vaccines largely rely on “antigen-specificity,” meaning they target specific parts of a pathogen to trigger an immune response. As immunologist Professor Bali Pulendran of Stanford Medicine explains, this approach has limitations. “Antigen-specific vaccines fail when a pathogen mutates or new pathogens emerge – the reason for regular booster shots against viruses like SARS-CoV-2 or influenza.” The rapid mutation rate of many viruses means vaccines can quickly become less effective, necessitating frequent updates.

Most attempts at universal vaccines focus on targeting conserved parts of viruses – elements that change less frequently. However, the Stanford team’s approach is more ambitious. Instead of mimicking a pathogen, this new vaccine attempts to replicate the signals that immune cells use to communicate during an infection. This novel strategy aims to integrate both branches of the immune system – the innate and the adaptive – creating a feedback loop that sustains a broad immune response.

The adaptive immune system, responsible for the long-term memory of infections, is the foundation of most current vaccines. It produces specialized tools like antibodies and T-cells to target specific pathogens. The innate immune system, which acts as a first responder, is typically short-lived. Pulendran’s team focused on harnessing the versatility of the innate immune system, which uses generalist cells (like dendritic cells, neutrophils, and macrophages) to attack anything identified as a threat. “The remarkable thing about the innate system is that it can protect against a wide variety of microbes,” Pulendran notes. While short-lived, innate immunity offers a nearly universal defense.

Long-Lasting, Cross-Protective Immunity

Evidence suggests that innate immunity can persist longer under certain circumstances. The BCG vaccine against tuberculosis, administered to approximately 100 million newborns annually, provides one example. Epidemiological and clinical studies have shown it can reduce infant mortality from other infections, suggesting a cross-protective effect lasting for months. However, the mechanism behind this phenomenon remained a mystery for a long time.

In 2023, Pulendran’s team published research clarifying this mechanism. Like other vaccines, the tuberculosis vaccine triggered both innate and adaptive immune responses in mice. Surprisingly, the innate immune response in their study persisted for several months. The researchers discovered that T-cells recruited to the lungs as part of the adaptive immune response were sending signals to the innate immune system. Stanford Medicine researchers found that these T-cells delivered a crucial signal to maintain innate immune system activation, lasting up to three months – far longer than the typical few days to a week.

While activated, this innate immune response protected mice from SARS-CoV-2 and other coronavirus infections. The team identified the signals sent by the T-cells as cytokines, which activate Toll-like receptors (TLRs) on innate immune cells.

A Vaccine with a Two-Pronged Approach

The new vaccine, currently designated GLA-3M-052-LS+OVA, mimics the T-cell signals that directly stimulate innate immune cells in the lungs. It also includes a harmless antigen, a protein called ovalbumin (OVA), to attract T-cells to the lungs and sustain the innate immune response for weeks to months.

In the study, mice received a single drop of the vaccine into their noses, with some receiving multiple doses a week apart. Subsequently, each mouse was exposed to a specific respiratory virus. After three doses, the mice were protected against SARS-CoV-2 and other coronaviruses for at least three months.

Unvaccinated mice exposed to these viruses experienced significant weight loss and often died, with inflamed lungs full of virus. Vaccinated mice lost less weight, all survived, and their lungs remained largely virus-free. The vaccine delivered a “double hit” to the virus, according to Pulendran: the prolonged innate immune response reduced the viral load in the lungs by 700-fold. Any viruses that bypassed this initial defense were met with a rapid adaptive immune response in the lungs.

“The lung’s immune system is so vigilant that it can launch typical adaptive immune responses – virus-specific T-cells and antibodies – within just three days. That’s an exceptionally short timeframe,” Pulendran observed. “It typically takes two weeks in an unvaccinated mouse.”

Encouraged by the vaccine’s ability to ward off various viral infections, the researchers expanded their testing to bacterial respiratory infections, S. Aureus and A. Baumannii. Vaccinated mice were protected against these pathogens for approximately three months as well. “Then we asked ourselves, ‘What else could get into the lungs?’” The answer, naturally, was allergens.

The researchers exposed mice to a house dust mite protein. Unvaccinated mice exhibited a strong Th2 response and mucus buildup in their airways. The vaccine suppressed the Th2 response, and the airways of vaccinated mice remained clear.

From Lab to Clinic: What’s Next?

“I think we’ve developed a universal vaccine against a variety of respiratory diseases,” Pulendran concludes. The research team hopes to begin testing the vaccine in humans soon, starting with a Phase I safety study, followed by a larger study to assess efficacy if the initial results are promising. Pulendran estimates that two doses of a nasal spray could be sufficient to protect people.

With adequate funding, a universal respiratory vaccine could be available in five to seven years. It could serve as a crucial defense against future pandemics and simplify seasonal vaccinations, Pulendran believes. As reported by Ärztezeitung, the potential impact on public health is significant.

“Imagine getting a nasal spray in the fall that protects you from all respiratory viruses, including SARS-CoV-2, influenza, respiratory syncytial virus, and the common cold, as well as bacterial pneumonia and spring allergies,” says Pulendran. “That would revolutionize medicine.”

It’s crucial to remember that this research is still in its early stages, and the results observed in mice may not translate directly to humans. Further research and clinical trials are essential to determine the safety and effectiveness of this novel vaccine approach.