Correlates of protection and disease in experimental human respiratory syncytial virus infection

Abstract

Understanding of respiratory syncytial virus (RSV) disease and vaccine development has been hampered by an incomplete understanding of the immune mechanisms of protection and disease in humans. Reinfection with antigenically similar strains of RSV occurs throughout life, and observational studies of natural infection do not permit analysis of events in the pre-symptomatic phase of disease. Experimental infection of healthy adults with a standardised inoculum was therefore used to study RSV upper respiratory tract (URT) disease. Pre-existing humoral immunity was assessed locally and systemically, and dynamics of URT symptoms, viral load and nasal mediators were analysed to identify factors involved in symptomatic infection. Forty subjects were enrolled of whom 24 developed infection and 17 exhibited typical cold-like features. Peak symptoms and viral load occurred on days 7 and 8 respectively. Pre-inoculation RSV-specific nasal IgA was most clearly associated with resistance to infection, but infection-boosted levels waned after 6 months. The frequency of acute IgG and IgA antibody secreting cells increased after infection and virus-specific IgG⁺ memory B cells (MBC) incremented around 4-fold. By contrast, IgA⁺ MBC were undetectable pre- and post- infection whereas influenza-specific IgG⁺ and IgA⁺ cells were found at comparable frequencies in convalescent blood from patients recovered from H1N1 influenza, suggesting a specific defect in IgA memory after RSV infection. Nasal viral load correlated with levels of nasal IFN-γ, CXCL10, MIG, TNF and IL-6. Subjects exhibiting early pre-symptomatic IFN-α responses showed reduced symptom scores and lower overall viral loads. Lifelong susceptibility to RSV infection thus reflects a specific defect in IgA memory to RSV, the cause of which needs to be determined. Symptomatic disease results from a failure of innate immune control of RSV replication in the pre-symptomatic stages of infection during the first 48 hrs of viral encounter. Viral replication leads to epithelial injury and inflammation reflected by a number of inflammatory mediators in nasal secretions. Mucosally-delivered vaccines could overcome the IgA memory defect and induce durable protection, which might be enhanced by inducing local IFN-α immediately after viral exposure.