Respiratory Syncytial Virus Escape from Immunization

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DESCRIPTION: (Adapted from Applicant's Abstract) Respiratory syncytial virus (RSV) is the most common viral agent of lower respiratory tract infections of infants and causes repeat infections throughout life. RSV antigenic variability may contribute to the ability of RSV to cause repeated infections. RSV is also a cause of significant morbidity and mortality in bone marrow transplant (BTM) patients. Neutralizing antibodies to RSV may be pre-existing in and/or may be passively administered to BMT patients. It is hypothesized that due to selective pressure by antibody RSV will accumulate changes in the F and G proteins during prolonged replication in immunocompromised patients. Sequential RSV isolates from BMT patients will be monitored for the development of F and/or G protein genetic changes that are associated with resistance to antibody may result in impaired fitness for replication. Therefore the antibody resistant viruses will be characterized as to their fitness for replication in cell culture and in animals (Aim 2). The ability of the mutant viruses to evade passive immunity in animals will also be determined (Aim 3). In a clinical trial BMT patients with RSV pneumonia will receive therapy with a humanized F monoclonal antibody (palivizumab). This will result in the replication of RSV in the presence of an antibody that is known to select for escape mutants. Thus, palivizumab escape mutants will be selected in cell culture (Aim 4) and characterized as to fitness and capacity to evade passive immunity in the manner described for the human derived viruses. These experiments will define the extent to which RSV becomes resistant to antibodies during prolonged replication in immunocompromised host. In addition, the likelihood that resistant viruses derived in cell culture will maintain normal fitness for replication and escape passive immunity in animals will be determined. These studies will provide evidence from humans and from animals as to the clinical challenges that antibody resistant viruses may pose to the current passive immunization approaches against RSV.