The results of studies by researchers at Yale University have demonstrated how intranasal vaccination can provide broad-based protection against heterologous respiratory viruses in mice, while systemic immunization, which used an injection to elicit body-wide protection, does not. The studies, focused on protecting against influenza infection, demonstrated that intranasal, but not systemic immunization induced IgA secretion from antibody secreting cells (ASCs) in the lung mucosa, which protected against a secondary challenge with either the same, or a different strain of the flu virus. Reporting on their studies in Science Immunology, the authors, headed by Yale’s Akiko Iwasaki, PhD, the Waldemar Von Zedtwitz professor of immunobiology, stated. “Our results show that local but not systemic immunization with influenza virus induces IgA secretion from resident ASCs in the lung mucosa, which provides robust protection and cross-protection against secondary challenge with influenza virus.” As Iwasaki further noted, “The best immune defense happens at the gate, guarding against viruses trying to enter.”

The findings also suggest that an immune response to the rapidly mutating SARS-CoV-2 virus might be found right at the door to our lungs, Iwasaki further suggested. The Yale team is currently testing nasal vaccine strains against COVID strains in animal models. Their published paper is titled, “Intranasal priming induces local lung-resident B cell populations that secrete protective mucosal antiviral IgA.” Co-first authors of the study were Yale’s Ji Eun Oh, PhD, Eric Song, PhD, and Miyu Moriyama, PhD.

Mucosal surfaces are continuously exposed to various types of pathogens and toxins, the authors wrote, and mucous membranes contain their own immune defense system that combat air- or foodborne pathogens. “There are several defense mechanisms at the mucosal barriers including innate defense such as mucus, antimicrobial peptides, natural antibodies, and the epithelial layer, as well as adaptive immune defense through the participation of various immune cells and effector mechanisms.”

When challenged, these barrier tissues produce B cells, which in turn secrete immunoglobin A antibodies. Unlike vaccines that elicit a system-wide immune response, IgA antibodies work locally on mucosal surfaces found in the nose, stomach, and lungs.

While the protective role of IgA-producing cells had been well established in combatting intestinal pathogens, Iwasaki’s lab wondered if triggering an IgA response might also produce a localized immune defense against respiratory viruses. “Secretory immunoglobulin A (IgA) is a predominant Ig isotype at mucosal surfaces whose epithelial cells express polymeric Ig receptor capable of transporting dimeric IgA to the lumen,” the team noted. “Although the role of IgA in intestinal mucosa has been extensively studied, the cell types responsible for secreting the IgA that protects the host against pathogens in the lower respiratory tract are less clear.”

Working with researchers at Icahn School of Medicine at Mount Sinai, the Yale researchers tested a protein-based vaccine that was designed to jump-start an IgA immune response, administering it to mice through either an injection, as is commonly done with systemic immunizations, or intranasally. They then exposed mice to multiple strains of influenza viruses.

They found that those animals that had received vaccine intranasally were much better protected against respiratory influenza than those that received injections. Nasal vaccines, but not the systemic shot, also induced antibodies that protected the animals against a variety of flu strains, not just against the strain the vaccine was meant to protect against. “Our results show that local but not systemic immunization with influenza virus induces IgA secretion from resident ASCs in the lung mucosa, which provides robust protection and cross-protection against secondary challenge with influenza virus.”

While both vaccine injections and nasal vaccines increased levels of antibodies in the blood of mice, only the nasal vaccine enabled IgA secretion into the lungs, where respiratory viruses need to lodge to infect the host, Iwasaki said.

If the nasal vaccines prove to be safe and efficient in humans, Iwasaki envisions them being used in conjunction with current vaccines and boosters that work system-wide in order to add immune system reinforcements at the source of infection.

As the authors concluded, “In summary, our data demonstrate that IgA-producing cells form in the lung after intranasal immunization and contribute to protection against challenge with homologous and heterologous influenza virus infection. Insights gained from our current study may be useful in designing new vaccines against other respiratory virus infections.”