Abstract
Respiratory syncytial virus (RSV) and human metapneumovirus (HMPV) are paramyxoviruses that are responsible for substantial human health burden, particularly in children and the elderly. The fusion (F) glycoproteins are major targets of the neutralizing antibody response and studies have mapped dominant antigenic sites in F. Here we grafted a major neutralizing site of RSV F, recognized by the prophylactic monoclonal antibody palivizumab, onto HMPV F, generating a chimeric protein displaying epitopes of both viruses. We demonstrate that the resulting chimeric protein (RPM-1) is recognized by both anti-RSV and anti-HMPV F neutralizing antibodies indicating that it can be used to map the epitope specificity of antibodies raised against both viruses. Mice immunized with the RPM-1 chimeric antigen generate robust neutralizing antibody responses to MPV but weak or no cross-reactive recognition of RSV F, suggesting that grafting of the single palivizumab epitope stimulates a comparatively limited antibody response. The RPM-1 protein provides a new tool for characterizing the immune responses resulting from RSV and HMPV infections and provides insights into the requirements for developing a chimeric subunit vaccine that could induce robust and balanced immunity to both virus infections.
Highlights
Respiratory syncytial virus (RSV) and human metapneumovirus (HMPV) are respiratory viruses that cause widespread morbidity within the human population second only to influenza virus [1]
The antibody stabilizes the native conformation of the free peptide (Fig 1B) into the helix-turn-helix motif that is nearly identical to the conformation observed in the native RSV and HMPV F proteins
Recently developed approaches appear promising and the potential for developing a pan-pneumovirus vaccine to both RSV and HMPV is attractive conceptually, as RSV and HMPV together are responsible for a majority of respiratory disease in children and the elderly after influenza virus
Summary
Respiratory syncytial virus (RSV) and human metapneumovirus (HMPV) are respiratory viruses that cause widespread morbidity within the human population second only to influenza virus [1]. RSV is the most common cause of bronchiolitis and pneumonia in infants worldwide and impacts the elderly and others with weakened immune systems, leading to hundreds of thousands of hospitalizations and millions of hospital visits yearly in the US [2,3,4]. Similar to RSV, HMPV infections are associated with a significant burden of hospitalizations and hospital visits in young children, as well as in the elderly [6, 7]. A humanized murine monoclonal antibody (palivizumab) has been developed for the prophylactic treatment of infants at high risk for RSV infection [8, 9]. A second generation, affinity-matured variant of palivizumab has been generated (motavizumab) [10, 11], it has not been approved for therapeutic use
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