A new study led by University of Toronto researchers has shown that immune cells in the gut follow an atypical pathway to produce antibodies that provide long-term protection against viruses.
The findings , which were published today in the journal Cell, could help guide the development of better vaccines for respiratory viruses like influenza, SARS-CoV-2 and bird flu.
While COVID-19 and flu vaccines reduce the risk of severe complications of illness, they are less effective at preventing infections at the outset. To protect against infection, a vaccine must activate a strong immune response at the places where a virus typically gains entry — the nose, mouth and airways. This so-called mucosal immunity relies on an antibody called IgA, which is concentrated in the mucous membranes lining your respiratory and digestive tracts and secreted through bodily fluids like saliva and tears.
"If you could make a mucosal immune response that's durable, that's the Holy Grail because then you're blocking entry of the virus," says Jen Gommerman, the study's senior author and a professor and chair of immunology at U of T's Temerty Faculty of Medicine.
"If you block entry, then you're not going to get infected and you're not going to transmit the virus."
One of the biggest challenges in developing a mucosal vaccine has been figuring out how to create a long-lasting IgA response.
Gommerman says that previous research, including a 2020 study from her group in collaboration with Anne-Claude Gingras, have shown that even though natural infections with viruses like SARS-CoV-2 do generate a local immune response, those responses fade quickly.
"When we looked at the key IgA antibody that protects us against infection, those antibody levels really don't last," she says.
At the same time, researchers also knew that a long-lasting, vaccine-induced IgA response was possible.
"We know that oral vaccination against rotavirus and polio gives you lifelong immunity, so we hypothesized that maybe there was something about the oral route and the small intestine that could allow for a long-lived IgA response," says Gommerman.
To test their hypothesis, the research team, led by postdoctoral fellow Kei Haniuda, turned to a mouse model of rotavirus infection with the goal of better understanding how virus-specific IgA immune responses are generated.
They found that while the gut IgA response depends on crosstalk between two types of immune cells, T cells and B cells, it skips a key step where parts of the virus are first presented to T cells, thereby allowing for a faster IgA antibody response. Moreover, the IgA produced in response to the virus were protective and lasted for at least 200 days after the initial infection.
"The IgA response was shockingly long lived," says Gommerman.
"Despite the virus being cleared within about 10 days, the response continued to improve over time, so you end up having IgA antibodies that are very, very good at recognizing rotavirus."
She thinks there may be something unique about the gut environment — for example, its anatomy and rich microbial community — that enables it to generate such a durable and effective immune response. These findings support the potential of oral vaccination as a strategy to protect against respiratory viruses, but Gommerman notes that there are also significant hurdles to creating an oral vaccine.
Building on this work, she recently submitted a funding application to pursue the development of an oral vaccine against highly pathogenic avian influenza, or bird flu.
Her lab is also exploring a complementary approach using the microbiome to make current flu and COVID-19 vaccines — which are delivered by injection — more "mucosal-friendly" and hopefully leading to a stronger IgA response.
"We learned how the immune cells get activated, how we can detect them and what signals are critical for their development," says Gommerman.
"We can now apply that knowledge to developing better vaccines."
