Conserved T-cell epitopes of respiratory syncytial virus (RSV) delivered by recombinant live attenuated influenza vaccine viruses efficiently induce RSV-specific lung-localized memory T cells and augment influenza-specific resident memory T-cell responses

Highlights

• Two LAIV-RSV vaccine viruses induced RSV M2₈₂-specific effector memory CD8 T cells producing both IFNγ and TNFα cytokines.

• The inserted RSV epitopes did not affect influenza-specific CD4 Tem levels in the lungs of immunized mice.

• LAIV-RSV viruses induced RSV M2₈₂-specific lung-localized CD8 Tem cells expressing both CD69 and CD103 T_RM markers.

• The magnitude of RSV M2₈₂-specific CD8 Tem responses correlates with protection against RSV-induced lung pathology.

• The addition of RSV epitopes into the LAIV strain augmented CD69⁺CD103⁺ influenza-specific CD8 Tem responses in the lungs.

Abstract

Respiratory syncytial virus (RSV) can cause recurrent infection in people because it does not stimulate a long-lived immunological memory. There is an urgent need to develop a safe and efficacious vaccine against RSV that would induce immunological memory without causing immunopathology following natural RSV infection. We have previously generated two recombinant live attenuated influenza vaccine (LAIV) viruses that encode immunodominant T-cell epitopes of RSV M2 protein in the neuraminidase or NS1 genes. These chimeric vaccines afforded protection against influenza and RSV infection in mice, without causing pulmonary eosinophilia or inflammatory RSV disease. The current study assessed the formation of influenza-specific and RSV-specific CD4 and CD8 T-cell responses in the lungs of mice, with special attention to the lung tissue-resident memory T cell subsets (T_RM). The RSV epitopes did not affect influenza-specific CD4 effector memory T cell (Tem) levels in the lungs. The majority of these cells formed by LAIV or LAIV-RSV viruses had CD69⁺CD103^- phenotype. Both LAIV+NA/RSV and LAIV+NS/RSV recombinant viruses induced significant levels of RSV M2₈₂ epitope-specific lung-localized CD8 Tem cells expressing both CD69 and CD103 T_RM markers. Surprisingly, the CD69⁺CD103⁺ influenza-specific CD8 Tem responses were augmented by the addition of RSV epitopes, possibly as a result of the local microenvironment formed by the RSV-specific memory T cells differentiating to T_RM in the lungs of mice immunized with LAIV-RSV chimeric viruses. This study provides evidence that LAIV vector-based vaccination can induce robust lung-localized T-cell immunity to the inserted T-cell epitope of a foreign pathogen, without altering the immunogenicity of the viral vector itself.