Vaccine development for respiratory syncytial virus

Abstract

Respiratory syncytial virus (RSV) is an important and ubiquitous respiratory pathogen for which no vaccine is available notwithstanding more than 50 years of effort. It causes the most severe disease at the extremes of age and in settings of immunodeficiency. Although RSV is susceptible to neutralizing antibody, it has evolved multiple mechanisms of immune evasion allowing it to repeatedly infect people despite relatively little genetic diversity. Recent breakthroughs in determining the structure and antigenic content of the fusion (F) glycoprotein in its metastable untriggered prefusion form (pre-F) and the stable rearranged postfusion form (post-F) have yielded vaccine strategies that can induce potent neutralizing antibody responses and effectively boost pre-existing neutralizing activity. In parallel, novel live-attenuated and chimeric virus vaccine candidates and other novel approaches to deliver vaccine antigens have been developed. These events and activities have aroused optimism and a robust pipeline of potential vaccine products that promise to provide a means to reduce the public health burden of RSV infection.

Figure 1

Antigenic sites on the RSV F. Prefusion and postfusion RSV F (pre-F and post-F) structures are shown as molecular surfaces, with N-linked glycans modeled as sticks and the viral membrane represented as a gray disc. There are two pre-F-specific antigenic sites (Ø and V) and two sites that are present on both conformations (II and IV). Antibodies against site III generally bind tighter to the pre-F conformation, whereas antibodies against site I bind tighter to the post-F conformation. The neutralization sensitivity of each antigenic site is directly related to exclusive or preferential binding to the pre-F conformation. The most potent monoclonal antibodies (mAbs) bind to the apex of the pre-F trimer at sites Ø and V, and mAbs to those sites compete with antibodies that account for the large majority of neutralizing activity in human sera. Images prepared by Morgan S. Gilman, PhD, Department of Biochemistry and Cell Biology, Giesel School of Medicine at Dartmouth.