Local B cell immunity and durable memory after live-attenuated influenza intranasal vaccination of humans

Seasonal influenza vaccines are most frequently delivered as intramuscular inactivated vaccines, which elicit systemic responses against the immunodominant hemagglutinin (HA) head domain. An intranasally administered, live-attenuated influenza vaccine designed to stimulate mucosal immunity, FluMist, is the sole intranasal vaccine approved in the United States. However, FluMist has lower systemic immunogenicity and efficacy in adults compared with intramuscular formulations. In this study, human mucosal and systemic immunity were examined after seasonal intramuscular or intranasal vaccination. Nasopharyngeal swabs of adenoid tissue were used to longitudinally sample the upper airway. FluMist induced substantial increases in upper respiratory tract IgG⁺ and IgA⁺ HA-specific memory B cells, which displayed an activated CD27⁺CD21^- phenotype. H1, H3, and influenza B virus HA-specific memory B cells were all detected in the upper airway after intranasal immunization, remained elevated at 6 months postvaccination, and were associated with the presence of circulating T follicular helper (cT_FH) cells. Recently activated upper airway memory B cells were not readily detected in intramuscular vaccinees, despite the elevation of systemic antibodies and circulating HA-specific memory B cells. Thus, despite minimal immune responses detected in circulation, adults vaccinated with the live-attenuated influenza vaccine generate substantial local antigen-specific memory B cell responses. These findings have implications for improving influenza vaccines and for mucosal vaccination against other respiratory pathogens.