GoKawiilThere have long been hints that innate immunity can last longer in certain circumstances. The most-studied example is the Bacillus Calmette-Guerin 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. 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 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 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 said.
“Fast forward two and a half years and we’ve shown that exactly what we had speculated is feasible in mice.”
Double whammy
The new vaccine, for now known as GLA-3M-052-LS+OVA, mimics the T cell signals that directly stimulate innate immune cells in the lungs. It also contains a harmless antigen, an egg protein called ovalbumin or OVA, which recruits T cells into the lungs to maintain the innate response for weeks to months.
In the study, mice were given a drop of the vaccine in their noses. Some recieved 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 — a sign of illness — and often death; their lungs were inflamed and full of virus. Vaccinated mice lost much less weight and all survived; their lungs were nearly clear of the virus.
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