In 2023, Pulendran’s team published a study in rats clarifying the mechanism. Like other vaccines, the tuberculosis vaccine induced both innate and adaptive immune responses in mice, but unusually, the innate response persisted for several months. The researchers found that T cells recruited to the lungs as part of the adaptive response were sending signals to keep innate immune cells active.
“Those T cells were providing an important signal to maintain activation of the innate system, which normally lasts a few days or a week, but in this case, it could last up to 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 hypothesized that since we now know how the tuberculosis vaccine is mediating its cross-protective effects, it would be possible to create a synthetic vaccine, perhaps a nasal spray, that has the right combination of Toll-like receptor stimuli and certain antigens to deliver T cells to the lungs,” Pulendran said.
“Fast forward two and a half years and we showed that what we had predicted was possible in mice.”
double kill
The new vaccine, now known as GLA-3M-052-LS+OVA, mimics T cell signals that directly stimulate innate immune cells in the lungs. It also contains a harmless antigen, egg protein called ovalbumin or OVA, which recruits T cells to the lungs to sustain the innate response for weeks to months.
In the study, rats were given a drop of the vaccine in their nose. Some were given multiple doses a week apart. Each mouse was then exposed to one type of respiratory virus. Three doses of the vaccine gave mice protection against SARS-CoV-2 and other coronaviruses for at least three months.
In unvaccinated mice, these viruses caused dramatic weight loss – a sign of disease – and often death; His lungs were swollen and full of virus. The vaccinated mice lost little weight and all survived; His lungs were almost free from the virus.
Pulendran said the vaccine is a “double whammy” against the viral infection. The prolonged innate response reduces the amount of virus in the lungs by 700-fold. And viruses that escape this initial protection face a rapid adaptive response in the lungs.
“The lung immune system is so prepared and so alert that it can launch specific adaptive responses – virus-specific T cells and antibodies – in just three days, which is an exceptionally short time,” Pulendran said. “Typically, it takes two weeks in an unvaccinated mouse.”
Surprised by the vaccine’s ability to prevent a variety of viral infections, the researchers expanded their testing to the bacterial respiratory infections Staphylococcus aureus and Acinetobacter baumannii. Vaccinated mice also remained protected from them for about three months.
“Then we thought, ‘What else could get into the lungs?'” Pulendran said. “Allergies.”
They exposed mice to proteins derived from house dust mites, a common trigger for allergic asthma. Allergic reactions are caused by a type of immune response known as a Th2 response. Unvaccinated mice showed a strong Th2 response and mucus accumulated in their airways. The vaccine silenced the Th2 response and the airways of the vaccinated mice remained clear.
“I think we have a universal vaccine against various respiratory threats,” Pulendran said.
Researchers hope to test the vaccine in humans, first in a Phase I safety trial, then, if successful, in a larger trial in which vaccinated people are exposed to infection. Pulendran believes that two doses of the nasal spray will be enough to provide protection to humans.
In the best case scenario, with adequate funding, Pulendran estimates that a universal respiratory vaccine could be available in five to seven years. This could be a protective shield against new pandemics and simplify seasonal vaccinations.
“Imagine taking 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 allergies,” Pulendran said. “He will change the practice of medicine.”
Researchers from Emory University School of Medicine, the University of North Carolina at Chapel Hill, Utah State University and the University of Arizona contributed to this work.
The study was supported by the National Institutes of Health (grant AI167966), Violetta L. Funding came from the Horton Professor Endowment, the Soffer Fund Endowment, and Open Philanthropy.
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