Location! Location! Location! Redirecting the Vaccine Package

As you may recall from your clinic visits, most immunizations are given as an intramuscular (“into the muscle”) injection. Yet, most disease-causing microbes infect the mucosal surfaces, notably the respiratory tract and urogenital tract (Figure 1). Contagious microbes such as SARS-CoV-2, HIV, and influenza still present a significant burden to public health. Therefore, despite the tremendous success of current vaccines, the scientific community continues to strive for better vaccination strategies. 

In a recent study published in Science Immunology, Oh and colleagues explore whether delivering the mucosal vaccines at the site of natural infection can improve vaccine protections. They use the influenza virus to evaluate the benefits of intranasal (“into the nose”) vaccine delivery in mice.

Figure 1. The mucosal immune system. The mucosal surfaces consist primarily of respiratory, gastrointestinal, and urogenital tracts. Image created with BioRender.com

Vaccines create immune memories

History has shown that immunizations prevented millions of deaths caused by harmful microbes. Vaccines safely introduce the immune system to a weakened form or a component of the microbe. Following the immunization, the adaptive immune system memorizes these modified microbes in the form of memory B and T cells. Upon exposure to the memorized microbe, memory B cells secrete antibodies, which are proteins that bind specifically to their target. On the other hand, memory T cells may either directly kill the microbes or stimulate other immune cells to join the fight.

Interestingly, some memory cells establish residence at the site of immunization, while others patrol around the body. Therefore, understanding the unique function of these resident immune cells is critical to revealing the benefits of mucosal vaccination.

Not all memories are created equal

Antibodies come in many different flavors, each can result in distinct immune functions. Among these antibody flavors, IgA is the expert at defending mucosal barriers such as the respiratory tract. However, the researchers found that only flu-specific IgA developed in the lung of intranasally exposed mice, whereas the intraperitoneally (“into the abdomen”) exposed mice only had non-specific IgA that are naturally present in the lung (Figure 2). 

Figure 2. Routes of immunization administration. The researchers expose the mice to flu virus either intranasally or intraperitoneally. Image created with BioRender.com

The scientists then interrogate the source of these IgA-secreting cells using a laboratory technique called parabiosis (Figure 3), where a healthy mouse is surgically fused to an intranasally infected mouse. These fused mice thereby share the same blood circulation, which allows the free exchange of antibodies. Nonetheless, there were more flu-specific IgA in the lung of intranasally exposed mice. This observation suggests that these flu-specific IgAs are produced locally in the lung only during intranasal infection.

Figure 3: Parabiosis. Surgically conjoined mice share the same circulatory system, which enables free exchange of circulating cells and proteins. Image created with BioRender.com

Intranasal vaccine may reduce viral transmission

So far, the researchers observed flu-specific IgA in the lung after an intranasal exposure to the whole flu virus. However, it is important to investigate whether these IgAs can also be induced by intranasal flu vaccines. The researchers put this question to the test by immunizing mice with just a flu protein, which is a much more safe and suitable vaccine than the real virus itself!

After the immunization, the mice were exposed to the real virus to assess the vaccine protection. The intranasally immunized mice experienced the least weight loss and recovered fastest compared to their intraperitoneally immunized and unimmunized counterparts. 

Surprisingly, when the researchers examined the mouse lungs, they discovered that the flu viruses were unable to reproduce in these intranasally immunized mice. This observation, known as sterilizing immunity, revealed an invaluable advantage for intranasal vaccine. The sterilizing immunity is a groundbreaking advance because no viral replication means no transmission (imagine how valuable that would be in the COVID-19 pandemic!).

Intranasal vaccine offers stronger protection against variants

 As we have learned in the past few years, the emergence of viral variants presents another important consideration in vaccine designs. When the immunized mice were exposed to a new variant of the flu, the intranasally immunized mice generated the variant-specific IgA more rapidly compared to the other routes of immunization. This advantage of intranasal immunization was also evident in the better survival of these mice after exposure to viral variants. 

This flu model of vaccination revealed compelling evidence for intranasal vaccination. If these findings are translatable to humans, they may revolutionize vaccination by enhancing the vaccine’s protection against transmission and viral variants. These advantages have promising implications especially in the current era of the COVID-19 pandemic.


Journal article: Oh, J. E., Song, E., Moriyama, M., Wong, P., Zhang, S., Jiang, R., Strohmeier, S., Kleinstein, S. H., Krammer, F., & Iwasaki, A. (2021). Intranasal priming induces local lung-resident B cell populations that secrete protective mucosal antiviral IgA. Science Immunology, 6(66), 1–12. https://doi.org/10.1126/sciimmunol.abj5129

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