title: Establishment of memory CD8+ T cells with live attenuated influenza virus across different vaccination doses.
abstract: FluMist has been used in children and adults for more than 10 years. As pre-existing CD8+ T cell memory pools can provide heterologous immunity against distinct influenza viruses, it is important to understand influenza-specific CD8+ T cell responses elicited by different live attenuated influenza virus (LAIV) regimens. In this study, we immunized mice intranasally with two different doses of live-attenuated PR8 virus (PR8 ts, H1N1), low and high, and then assessed protective efficacy by challenging animals with heterosubtypic X31-H3N2 virus at 6 weeks post-vaccination. Different LAIV doses elicited influenza-specific CD8+ T cell responses in lungs and spleen, but unexpectedly not in bronchoalveolar lavage. Interestingly, the immunodominance hierarchy at the acute phase after immunization varied depending on the LAIV dose; however, these differences disappeared at 6 weeks post-vaccination, resulting in generation of comparable CD8+ T cell memory pools. After vaccination with either dose, sufficient numbers of specific CD8+ T cells were generated for recall and protection of mice against heterosubtypic H1N1→H3N2 challenge. As a result, immunized mice displayed reduced weight loss, diminished inflammatory responses and lower viral titres in lungs, when compared to unvaccinated animals. Interestingly, the higher dose led to enhanced viral clearance on day 5 post-challenge, though this was not associated with increased CD8+ T cell responses, but with higher levels of non-neutralizing antibodies against the priming virus. Our study suggests that, while different LAIV doses result in distinct immune profiles, even a low dose produces sufficient protective CD8+ T cell memory against challenge infection, though the high dose results in more rapid viral clearance and reduced inflammation.
authors.affiliation: Department of Microbiology and Immunology, University of Melbourne at the Peter Doherty Institute for Infection and Immunity, Parkville, VIC 3010, Australia.
authors.forename: Zhongfang
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Department of Microbiology and Immunology, University of Melbourne at the Peter Doherty Institute for Infection and Immunity, Parkville, VIC 3010, Australia.
authors.forename: Lukasz
authors.initials: L
authors.lastname: Kedzierski
authors.affiliation: Department of Microbiology and Immunology, University of Melbourne at the Peter Doherty Institute for Infection and Immunity, Parkville, VIC 3010, Australia.
authors.forename: Simone
authors.initials: S
authors.lastname: Nuessing
authors.affiliation: Department of Microbiology and Immunology, University of Melbourne at the Peter Doherty Institute for Infection and Immunity, Parkville, VIC 3010, Australia.
authors.forename: Brendon Yew Loong
authors.initials: BYL
authors.lastname: Chua
authors.affiliation: Department of Microbiology and Immunology, University of Melbourne at the Peter Doherty Institute for Infection and Immunity, Parkville, VIC 3010, Australia.
authors.forename: Sergio M
authors.initials: SM
authors.lastname: Quiñones-Parra
authors.affiliation: Division of Basic Biomedical Sciences, Sanford School of Medicine, University of South Dakota, Vermillion, SD, USA.
authors.forename: Victor C
authors.initials: VC
authors.lastname: Huber
authors.affiliation: Department of Microbiology and Immunology, University of Melbourne at the Peter Doherty Institute for Infection and Immunity, Parkville, VIC 3010, Australia.
authors.forename: David C
authors.initials: DC
authors.lastname: Jackson
authors.affiliation: Department of Immunology, St Jude Children's Research Hospital, Memphis, TN, USA.
authors.forename: Paul G
authors.initials: PG
authors.lastname: Thomas
authors.affiliation: Department of Microbiology and Immunology, University of Melbourne at the Peter Doherty Institute for Infection and Immunity, Parkville, VIC 3010, Australia.
authors.forename: Katherine
authors.initials: K
authors.lastname: Kedzierska
mesh_terms: D000818:Animals; D000914:Antibodies, Viral / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D006801:Humans; D007156:Immunologic Memory; D053118:Influenza A Virus, H1N1 Subtype / Q000235:genetics / Q000276:immunology*; D053122:Influenza A Virus, H3N2 Subtype / Q000235:genetics / Q000276:immunology*; D007252:Influenza Vaccines / Q000008:administration & dosage* / Q000276:immunology; D007251:Influenza, Human / Q000276:immunology* / Q000517:prevention & control / Q000821:virology; D008168:Lung / Q000821:virology; D051379:Mice; D008810:Mice, Inbred C57BL; D014613:Vaccines, Attenuated / Q000008:administration & dosage* / Q000276:immunology
chemical_list: D000914:Antibodies, Viral; D007252:Influenza Vaccines; D014613:Vaccines, Attenuated