Single-cycle respiratory syncytial virus infection induces robust adaptive immune responses and reduces disease severity in mice

Abstract

Abstract Respiratory syncytial virus (RSV) is the leading cause of severe respiratory tract infection in infants and young children. However, despite extensive efforts, there remains no licensed RSV vaccine. Recently, a recombinant infectious RSV strain lacking the gene for the matrix (M) protein (M-null RSV) was developed as a potential vaccine candidate. The M protein is required for reassembly of the virion following infection and gene expression within a host cell. Infection with M-null RSV produces viral proteins but does not result in the generation of infectious virus progeny resulting in a single-cycle infection. To determine its immunogenicity in vivo, mice were infected with either M-null RSV or a wild-type (WT) RSV. M-null RSV-infected mice exhibited significantly reduced lung viral titers, weight loss, and pulmonary dysfunction compared to mice given WT RSV. Remarkably, M-null RSV infection induced CD4 and CD8 T cell responses in the lung and airways of similar magnitude to that of a WT RSV infection at acute time-points. Germinal center B cell numbers and serum antibody levels were also similar between M-null and WT RSV-infected mice. M-null RSV infection also generated robust memory immune responses. A substantial proportion of B cells, CD4 T cells, and CD8 T cells remained within the lung tissue of M-null RSV-infected mice 30 days post-infection. Importantly, RSV-specific memory CD8 T cells expressing CD69 and CD103, the canonical markers of tissue resident memory, were also generated by M-null RSV infection. Given the reduced disease severity and robust immune responses developed following single-cycle infection, M-null RSV may be an effective vaccine candidate.