Mucosal CD8+ T cell responses induced by an MCMV based vaccine vector confer protection against influenza challenge

• Published in: PLoS pathogens 2019-09, Vol.15 (9), p.e1008036-e1008036
• Main Authors: Zheng, Xiaoyan, Oduro, Jennifer D, Boehme, Julia D, Borkner, Lisa, Ebensen, Thomas, Heise, Ulrike, Gereke, Marcus, Pils, Marina C, Krmpotic, Astrid, Guzmán, Carlos A, Bruder, Dunja, Čičin-Šain, Luka
• Format: Article
• Language: English
• Subjects: Administration, Intranasal; Amino Acid Sequence; Analysis; Animals; Antigenic determinants; Antigens; Artificial chromosomes; Biology and life sciences; CD8 antigen; CD8-Positive T-Lymphocytes - immunology; Cell Line; Cell-mediated immunity; Chemokines; Chemokines - biosynthesis; Clinical medicine; Cytokines; Cytomegalovirus; Cytotoxicity; Disease control; Ebola virus; Epitopes; Epitopes, T-Lymphocyte - administration & dosage; Epitopes, T-Lymphocyte - genetics; Epitopes, T-Lymphocyte - immunology; Female; Gene Products, env - administration & dosage; Gene Products, env - genetics; Gene Products, env - immunology; Genes; Genetic Vectors; Health aspects; House mouse; Human behavior; Humans; IE2 protein; Immunity; Immunity, Mucosal; Immunization; Immunological memory; Immunology; Infection; Infections; Inflammation; Influenza; Influenza A; Influenza A Virus, H1N1 Subtype - genetics; Influenza A Virus, H1N1 Subtype - immunology; Influenza vaccines; Influenza Vaccines - administration & dosage; Influenza Vaccines - genetics; Influenza Vaccines - immunology; Influenza, Human - immunology; Influenza, Human - prevention & control; Kinases; Latent infection; Lung - immunology; Lung - virology; Lung diseases; Lungs; Lymphocytes; Lymphocytes T; Major histocompatibility complex; Medicine and health sciences; Mice; Mice, Inbred BALB C; Mucosal immunity; Muromegalovirus - genetics; Muromegalovirus - immunology; NIH 3T3 Cells; Peptide Fragments - administration & dosage; Peptide Fragments - genetics; Peptide Fragments - immunology; Peptides; Prevention; Product development; Research and Analysis Methods; Respiratory Mucosa - immunology; Respiratory Mucosa - virology; Supervision; T cells; Vaccination; Vaccines; Vaccines, Synthetic - administration & dosage; Vaccines, Synthetic - genetics; Vaccines, Synthetic - immunology; Viral infections; Viral vaccines; Virology; Viruses; γ-Interferon
• ISSN: 1553-7374; 1553-7366; 1553-7374
• DOI: 10.1371/journal.ppat.1008036

Cytomegalovirus (CMV) is a ubiquitous β-herpesvirus that establishes life-long latent infection in a high percentage of the population worldwide. CMV induces the strongest and most durable CD8+ T cell response known in human clinical medicine. Due to its unique properties, the virus represents a promising candidate vaccine vector for the induction of persistent cellular immunity. To take advantage of this, we constructed a recombinant murine CMV (MCMV) expressing an MHC-I restricted epitope from influenza A virus (IAV) H1N1 within the immediate early 2 (ie2) gene. Only mice that were immunized intranasally (i.n.) were capable of controlling IAV infection, despite the greater potency of the intraperitoneally (i.p.) vaccination in inducing a systemic IAV-specific CD8+ T cell response. The protective capacity of the i.n. immunization was associated with its ability to induce IAV-specific tissue-resident memory CD8+ T (CD8TRM) cells in the lungs. Our data demonstrate that the protective effect exerted by the i.n. immunization was critically mediated by antigen-specific CD8+ T cells. CD8TRM cells promoted the induction of IFNγ and chemokines that facilitate the recruitment of antigen-specific CD8+ T cells to the lungs. Overall, our results showed that locally applied MCMV vectors could induce mucosal immunity at sites of entry, providing superior immune protection against respiratory infections.