(E) Guarded lung influenzaCspecific CD8+ T cells in mice 5 weeks after vaccination with 2015C2016 IIV or LAIV. of circulating T cells and neutralizing antibodies, which persisted long-term after vaccination. Interestingly, intranasal administration of IIV or injection of LAIV failed to elicit T cell responses or provide protection against viral contamination, demonstrating dual requirements for respiratory targeting and a live-attenuated strain to establish TRM. The Flupirtine maleate ability of LAIV to generate lung TRM capable of providing long-term protection against nonvaccine viral strains, as exhibited here, has important implications for protecting the population against emergent influenza pandemics by direct fortification of lung-specific immunity. Introduction Influenza virus is usually a severe, acute respiratory pathogen with the potential to generate novel strains capable of global pandemics. Current vaccines protect against disease by eliciting neutralizing antibodies to the strain-specific glycoproteins hemagglutinin (HA) and neuraminidase (NA). Such neutralizing antibodies are the correlate of protection by which current vaccines are assessed (1, 2). However, antigenic shift and drift drive alterations in these molecules, limiting protective efficacy of antibody responses and necessitating the annual production of new vaccines (2). Developing vaccines that provide universal protection to current and emerging influenza strains remains a major public health challenge. Influenza infection generates both lasting antibody and T cell responses (3). While antibody responses are strain dependent, virus-specific T cells identify epitopes derived from conserved internal viral proteins in both mice and humans (4C6) and have been shown to provide heterosubtypic, cross-strain protection in animal models (3, 7). Promoting T cellCmediated protection through vaccination, however, has remained elusive, and the precise subsets involved in protection are still being defined. We as well as others have recognized subsets of noncirculating, lung tissueCresident memory (TRM) CD4+ and CD8+ T cells generated following influenza contamination; these cells mediate enhanced viral clearance, survival to lethal challenge, and protection to heterosubtypic challenge (8C10). Establishment of TRM, which mediate protection against site-specific contamination, has also been explained in other tissues, including the skin, female reproductive tract, and brain (11C14). The Rabbit Polyclonal to 14-3-3 zeta protective capacities of TRM suggest that vaccination strategies targeting their generation and persistence may provide enhanced immunity compared with vaccines relying on circulating responses. However, functions for circulating versus tissue-localized immunity in vaccine-mediated protection remain undefined. Two classes of influenza vaccines are currently available: injectable inactivated influenza (IIV) vaccines and live-attenuated influenza (LAIV) vaccines administered i.n. Both generate HA-specific neutralizing antibodies and exhibit similar protection against influenza-like illness (1, 15C18), with LAIV more efficacious in children (19). Whether protective influenza-specific T cells are generated in humans following vaccination has been difficult to establish (20, 21). Moreover, it is not known whether influenza vaccines promote TRM development in humans or animal models. Here, we evaluated the capacity of currently used quadrivalent Fluzone IIV or FluMist LAIV vaccines to promote lung T cell responses and protective TRM. We found that vaccination with LAIV, but not IIV, elicited strong lung T cell responses, while IIV promoted primarily neutralizing antibody responses as observed by hemagglutination-inhibition assay (HAI). Importantly, LAIV but not IIV elicited the establishment of long-term, virus-specific lung TRM and provided heterosubtypic protection to nonvaccine Flupirtine maleate viral strains Flupirtine maleate much like previous influenza contamination. Vaccine-mediated lung T cell responses and protection required both the live-attenuated strain and respiratory targeting, revealing a requirement for site-specific productive contamination for establishing lung TRM. Our findings demonstrate that LAIV may be an effective strategy to generate influenza-specific lung TRM capable of cross-strain protection in a pandemic situation. Results Distinct localization of main responses generated from vaccination with IIV and LAIV. We compared main immune responses, including T cell and antibody responses, in mice vaccinated i.p. or s.c. with Fluzone IIV versus i.n. with FluMist LAIV. The injection routes (i.p. and s.c.) for IIV were chosen based on patterns of antigen drainage with i.p. immunization draining to the lung-draining, mediastinal lymph nodes (MedLN) (22, 23) and s.c. immunization at the base of the neck, draining to the axillary lymph nodes, much like intradeltoid injection in humans (24, 25). We observed increased numbers of CD3+ T cells in the.
