A Yale School of Medicine research team led by Akiko Iwasaki, PhD, recently found that local vaccines administered with a nasal spray were more effective in protecting mice against influenza than vaccines that are injected into the muscle, the way standard flu shots are done. Iwasaki, who is Waldemar Von Zedtwitz Professor of Immunobiology and professor of molecular, cellular, and developmental biology and of epidemiology (microbial diseases), discusses her new research, which was published December 10 in Science Immunology.
People have been getting flu shots for 40 years or more, and more recently COVID-19 vaccinations, but your research suggests that a nasal vaccine may be a more effective approach to stopping respiratory virus. What did you find?
Akiko Iwasaki: We found that local mucosal immunity that's established by intranasal vaccination elicits a much more robust and cross reactive, cross protective immunity than a conventional vaccine that uses intramuscular injection. And the way we got to this knowledge is that we were comparing different routes of vaccine administration and found that only after the intranasal vaccination, there are these antibodies that are secreted into the mucosa known as IgA. And this IgA coats the mucus membrane and mucus surface and protects the host by preventing the virus from entering the body. So it's like putting the guard outside of the door instead of inside the door where antibodies normally work, inside the body.
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What is special about mucosal linings as a system for delivery as opposed to delivering a vaccine systemically through injection?
Iwasaki: Essentially there are really two compartments of the immune system. One is the systemic circular compartment where T cells and B cells and antibodies circulate and survey for infection. And an entirely different compartment is the mucosal compartment where you can immunize and induce immune responses within those particular mucosal surfaces. That allows for local immune response to be elicited. So antibody T cells and B cells are now focused in that particular mucosal membrane. And because they're right there at the right place where the pathogen enters, they can act much more quickly and much more effectively and more broadly across different variants of viruses.
This study focused on influenza virus, but might your findings be applicable to SARS-CoV-2, the virus that causes COVID?
Iwasaki: Yes, absolutely. This study is really understanding the basics of the immune system and how it works within the mucosal tissue. And we can apply nasal vaccine strategy to any other virus, including SARS-CoV-2. And that's essentially what we're doing. We have a study that we're writing up to be able to publish soon where we are combining some of the mucosal strategy to elicit local immunity against SARS-CoV-2, essentially to establish this cross protective, long-lasting immunity within the respiratory mucosa.
Universal flu vaccine is a goal in society and the scientific community. Does this research on nasal flu vaccination help us get there?
Iwasaki: I think mucosal vaccines will provide us with the tool to develop the universal flu vaccine, or maybe universal coronavirus vaccine, and [vaccines for] many other respiratory infections. This research is supported through a National Institutes of Health mechanism to develop universal flu vaccine. The reason for the promise of the mucosal vaccine is that it provides local immunity and the fact that this IgA, which is a dimer (a structure consisting of two identical components) of an antibody, has four binding sites instead of two binding sites. And so it allows that antibody to bind to surfaces of the virus even after a little bit of mutations accumulate. It’s much more resistant to variations on the viral surface. So I think combined with that, with the right kind of immunogen, we should be able to achieve the goal of universal flu vaccines or universal viral vaccines of other types.
Would a nasal vaccine need to be delivered more often than an injected vaccine, or is there a mechanism by which the protection lasts?
Iwasaki: The beauty of the local mucosal vaccine is that not only does it provide protection acutely, but also it’s a long-lasting immunity. What happens is that these T cells and B cells come into that mucosal surface and they remain there and they become what’s known as tissue-resident memory cells.
What work had been done at Yale, whether in your lab or elsewhere, to set the stage for nasal vaccines against viruses?
Iwasaki: There were just many, many findings over the years. It's not something that we just came up with overnight. My lab started 21 years ago trying to understand how herpes simplex virus infects the host and how we can manipulate the immune system to block that process. So we have this “prime and pull” strategy to be able to block primary infection as well as potentially therapeutic vaccines against existing genital herpes. Other applications include a vaccination strategy with a cervical cancer vaccine. We have a collaboration with Dr. Alessandro Santin here at Yale, where we are using that strategy to establish immune response within the cervix of women who have pre-cancerous lesions with HPV.
For those two viruses, presumably it isn’t an intranasal approach.
Iwasaki: With the genital herpes and the cervical cancer vaccine, the mucosal immunity is in the genital mucosa. The application is obviously through different routes, but the concept is the same.
Is there anything else you want to add?
Iwasaki: I think that the mucosal vaccine will supplement and complement the existing vaccines against COVID, and it might help people who are afraid to take the needle because the nasal vaccine is basically going to be a spray. So you just take it as nasal spray and it's a little bit less scary. So hopefully that will increase the number of people who want to vaccinate themselves.