Abstract
Infection with Respiratory Syncytial Virus (RSV) causes both upper and lower respiratory tract disease in humans, leading to significant morbidity and mortality in both young children and older adults. Currently, there is no licensed vaccine available, and therapeutic options are limited. During the infection process, the type I viral fusion (F) glycoprotein on the surface of the RSV particle rearranges from a metastable prefusion conformation to a highly stable postfusion form. In people naturally infected with RSV, most potent neutralizing antibodies are directed to the prefusion form of the F protein. Therefore, an engineered RSV F protein stabilized in the prefusion conformation (DS-Cav1) is an attractive vaccine candidate. Long-term stability at 4°C or higher is a desirable attribute for a commercial subunit vaccine antigen. To assess the stability of DS-Cav1, we developed assays using D25, an antibody which recognizes the prefusion F-specific antigenic site Ø, and a novel antibody 4D7, which was found to bind antigenic site I on the postfusion form of RSV F. Biophysical analysis indicated that, upon long-term storage at 4°C, DS-Cav1 undergoes a conformational change, adopting alternate structures that concomitantly lose the site Ø epitope and gain the ability to bind 4D7.
Highlights
Respiratory Syncytial Virus (RSV) infections are common and generally cause mild, cold-like symptoms in healthy adults and older children
To assess the stability of DS-Cav1 stored at 4°C, we have developed assays using antibodies that can discriminate between the prefusion and postfusion forms of RSV F
Based on the crystal structures of the prefusion and postfusion RSV F proteins [13, 21], we identified 368 surface-exposed residues, and each was individually mutated to an alanine to generate a comprehensive mutant RSV F expression library
Summary
Respiratory Syncytial Virus (RSV) infections are common and generally cause mild, cold-like symptoms in healthy adults and older children. In premature babies, infants, older adults and immunocompromised individuals, RSV can lead to more severe lower respiratory tract disease, causing pneumonia or bronchiolitis, and may be life-threatening [1,2,3,4]. There is no vaccine available to prevent RSV infection or disease. Passive prophylaxis with palivizumab (Synagis1), is approved for use in a subset of preterm infants that are at greatest risk for developing severe RSV-induced lung disease. Palivizumab is a humanized monoclonal antibody that binds one of the RSV surface-exposed.
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