Existing vaccines are designed to protect against specific pathogens. However, respiratory viruses are highly diverse and mutate rapidly, limiting the effectiveness of conventional vaccines against respiratory infections.
To overcome this limitation, an international team of researchers developed a universal intranasal vaccine and tested it in mice. As a result, after four immunizations, the mice developed long-lasting antiviral immunity. Moreover, these mice tolerated infections with coronaviruses and bacterial pathogens significantly better than mice in the control group.
Study Rationale
Previous epidemiological studies have shown that some vaccines, such as BCG and the oral polio vaccine, can provide partial protection against unrelated infections. These effects are associated with the formation of trained innate immunity and changes in the interaction between innate and adaptive immune mechanisms. Together, these findings revealed a complex immune network formed within specific tissues. This phenomenon has been termed integrated organ immunity.
Another prerequisite was positive clinical experience with the BCG vaccine against respiratory viruses. However, BCG is administered intravenously, which increases risk and limits its widespread use due to the requirement for highly skilled medical personnel.
Therefore, researchers proposed harnessing the integrated immunity of the respiratory system to immunize mucosal surfaces and protect against airborne pathogens.
Study Details
The universal vaccine combined two types of proteins:
- The first – fragments of toll-like receptors, which are required to detect foreign particles.
- The second is the chicken protein ovalbumen, which is used to induce allergic responses in experimental models.
Researchers chose intranasal administration as the delivery method. Previous studies had shown that intranasal immunization provides more effective protection in the respiratory tract than intramuscular injection.
They then conducted a series of experiments to assess the resistance of vaccinated mice to various infections. One group received four immunizations at 7-day intervals. The second group received no treatment and served as the control.
In the first experiment, researchers evaluated the effectiveness of the universal vaccine against coronaviruses and influenza. They used three different coronaviruses (SARS-CoV, SARS-CoV-2, SCH014) and an H1N1 influenza strain. Mice were infected intranasally, and researchers monitored clinical progression, viral load, biochemical parameters, and changes in respiratory tissues.
They also assessed the duration of immune protection. The experiment was conducted at three time points after the final vaccination: 21 days, 42 days, and 3 months.
Vaccinated mice consistently tolerated infection significantly better than control mice:
- lost less weight;
- had lower viral load according to PCR analysis;
- showed less severe lung damage;
- had lower levels of lung inflammation.
In the next experiment, researchers infected mice with bacterial pathogens. These included Staphylococcus aureus, Streptococcus pneumoniae, and A. baumannii. Notably, A. baumannii causes a wide range of hospital-acquired infections, including meningitis, pneumonia, wound infections, bloodstream infections, and urinary tract infections.
First, an intranasal bacterial infection was used. The results were similar to those of the previous experiment – vaccinated mice showed reduced weight loss, lung damage, and lung bacterial load.
Then, researchers tested the effect of intranasal vaccination on bacterial infection during intravenous S. aureus infection. In this case as well, vaccinated mice showed milder disease – kidney damage was less severe, and bacterial load in the kidneys was lower.
In the next experiment, researchers tested the hypothesis that the universal vaccine could influence hypersensitivity-driven allergic responses. The rationale was as follows:
- The vaccine is based on TLR4 and TLR7 proteins.
- Activation of TLR4 and TLR7 triggers innate immune responses and cytokine production, promoting a Th1 response.
- Allergic hypersensitivity reactions are associated with a dominant Th2 response.
- Th1 and Th2 responses mutually regulate each other.
- Therefore, the vaccine could potentially reduce Th2 activity and suppress allergic responses.
To test this, asthma was induced in mice by exposure to house dust mites. This type of asthma represents a typical hypersensitivity-driven allergic disorder.
Immunization significantly alleviated allergic asthma – vaccinated mice showed markedly reduced lung mucus hypersecretion. Biochemical analysis also demonstrated reduced Th2 levels and decreased markers of allergic inflammation.
In the final series of experiments, researchers investigated the mechanisms by which the universal vaccine integrates innate and adaptive immunity to stimulate a coordinated immune response in the respiratory system.
First, they analyzed cellular changes in the lung immune landscape after immunization. Long-lived cells of both innate and adaptive immunity accumulated in the bronchi. The lifespan of these cells exceeded 3 months.
Next, researchers analyzed the genomes of these immune cells and lung epithelial cells. They observed increased activation of genes responsible for:
- detection of foreign particles in antigen-presenting cells;
- protection against pathogens in epithelial cells;
- degradation of foreign proteins in phagocytic cells.
They also observed enhanced signaling interactions between innate immune cells, adaptive immune cells, and bronchial epithelial cells.
In the final experiment, researchers observed the function of this integrated immune system during infection in vaccinated mice. Within the first hours after infection, immune cells were rapidly recruited to the bronchi. These cells then formed dense clusters resembling lymph node structures.
As a result, by day 3 post-infection, IgG antibodies were already produced in the lung tissue. These immune responses occurred alongside reduced levels of pro-inflammatory proteins associated with cytokine storm.
In the control group, such clustering of immune cells was not observed. Researchers concluded that the universal vaccine establishes an immune microenvironment in the lungs that promotes rapid antibody production, coordinates the intensity of the immune response, and limits tissue damage.
Conclusion
Intranasal administration of the universal vaccine provides long-lasting protection independent of pathogen type. The mechanism is based on the formation of lymph node–like structures in tissues that accelerate antibody production. Researchers suggest that this vaccine could be used in the early stages of a pandemic – before strain-specific vaccines become available.
Reference
Mucosal vaccination in mice provides protection from diverse respiratory threats
