Designing safe, effective nasal vaccines

 Most vaccines—and boosters—are injected directly into muscle tissue, usually in the upper arm, to kickstart the body's immune system in the fight against disease. But for respiratory diseases like COVID-19, it can be important to have protection right where the virus enters: the respiratory tract.

In a new study, Yale researchers have found that nasal vaccine boosters can trigger strong immune defenses in the respiratory tract, even without the help of immune-boosting ingredients known as adjuvants. The findings, researchers suggest, may offer critical insights into developing safer, more effective nasal vaccines in the future.

"Our study shows how a simple viral protein antigen can boost respiratory tract immune responses against viruses," said Akiko Iwasaki, Sterling Professor of Immunobiology at Yale School of Medicine (YSM) and senior author of the study. "These data imply that viral proteins in nasal spray may be used as a safe way to promote antiviral immunity at the site of viral entry."

The study was published today in the journal Nature Immunology. The first author is Dong-il Kwon, a postdoctoral fellow in Yale's Department of Immunobiology.

For the study, the researchers first injected mice with a traditional mRNA COVID-19 shot, which was injected directly into the muscle. Then, the team gave the mice a booster vaccine through the nose. The team specifically wanted to evaluate the effects of vaccine boosters that don't contain special ingredients known as adjuvants. Used in some vaccines, adjuvants help stimulate a stronger, longer-lasting immune response, but they can also have adverse effects like inflammation and swelling of facial nerves.

"We call this vaccine strategy 'prime and spike,' which is where the mice were intramuscularly primed with mRNA vaccines followed by a nasal boosting with unadjuvanted spike protein," said Kwon, who is a member of Iwasaki's lab.

The Yale-developed "prime and spike" vaccine approach jump-starts immune response in the respiratory system—the first part of the body infected by COVID-19. "Prime" refers to the process of administering a traditional intramuscular vaccine shot, while "spike" refers to a follow-up vaccination delivered to the nose—usually in the form of a spray containing coronavirus-derived spike proteins.

After the first shot, immune cells became primed in the lymph nodes of the mice. After the nasal booster, B cells from the lymph node migrated to the lungs and produced immunoglobulin A (IgA), an antibody that helps protect the nose and lungs from infection. Memory CD4+ helper T cells acted as natural adjuvants by recruiting B cells and helping them secrete IgA in the lung.

Only the nasal booster triggered this strong local immune response, the researchers found. Boosters given other ways, including intramuscular injection, didn't produce much IgA or activate immune cells in the lungs of the mice. When the researchers gave the mice a second nasal booster, their IgA levels increased even more in both the lungs and nasal passages.

"These findings help explain why nasal boosters do not require adjuvant to induce robust mucosal immunity at the respiratory mucosa and can be used to design safe and effective vaccines against respiratory virus pathogens," Kwon said.

Regular COVID-19 shots don't create much IgA in the nose and lungs. So, people can still get infected or pass it on, even if they're vaccinated. But this study shows that nasal boosters can trigger strong, long-lasting immune protection where respiratory diseases like COVID-19 first attack.

"Understanding how this safe and simple nasal booster promotes protective mucosal immunity will make it easier to develop this approach for human use in the near future," Iwasaki said.

Iwasaki is also a professor of dermatology and of molecular, cellular, and developmental biology in Yale's Faculty of Arts and Sciences, a professor of epidemiology (microbial diseases) at Yale School of Public Health, and an investigator at the Howard Hughes Medical Institute.

Other Yale authors include Tianyang Mao, a former graduate student who is now a postdoctoral fellow at the Broad Institute of MIT and Harvard; Benjamin Israelow, assistant professor of medicine (infectious diseases) at YSM; Keyla Santos Guedes de Sá, a postdoctoral associate; and Huiping Dong, a research assistant.

More information: Dong-il Kwon et al, Mucosal unadjuvanted booster vaccines elicit local IgA responses by conversion of pre-existing immunity in mice, Nature Immunology (2025). DOI: 10.1038/s41590-025-02156-0

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