Neutralizing epitopes on the respiratory syncytial virus fusion glycoprotein

Highlights

• X-ray crystal structures of prefusion and postfusion RSV F have been determined.

• Antibodies specific for the prefusion conformation are extremely potent.

• Select antibodies neutralize both RSV and human metapneumovirus.

• Structure-based vaccine design has produced promising immunogens.

Respiratory syncytial virus (RSV) is a leading cause of pneumonia and bronchiolitis, but despite decades of research a safe and effective vaccine has remained elusive. The viral fusion glycoprotein (RSV F) plays an obligatory role in the entry process and is the major target of neutralizing antibodies, making it an attractive target for vaccine development. This review will summarize the recently determined structures of RSV F in the prefusion and postfusion conformations and describe the location and properties of neutralizing epitopes on RSV F, including the newly identified prefusion-specific epitopes. The influence of these findings on vaccine development will also be discussed, with a focus on the rational design and optimization of vaccine antigens.

Introduction

Respiratory syncytial virus (RSV) is a leading cause of lower respiratory tract diseases such as pneumonia and bronchiolitis [1]. It is an extremely infectious paramyxovirus, infecting almost all children within their first two years of life [2]. The very young are most susceptible to severe disease, and in the U.S. the peak age of hospitalization is 1–2 months of age [3, 4]. In a recent analysis of global mortality, it was estimated that RSV is responsible for 6.7% of all deaths for children between 1 month and 1 year of age [5]. RSV infection elicits neutralizing antibodies and an effective T cell response, but immunity to the virus wanes over time, leading to reinfections throughout life [6]. Although disease severity is mild for older children and healthy adults, RSV causes substantial morbidity and mortality in elderly people [7, 8].

An effective RSV vaccine is urgently needed, and more than 40 are currently in development covering a broad range of modalities, including live-attenuated and protein subunit vaccines [9, 10]. Of the three proteins on the virion surface, only the fusion glycoprotein (RSV F) is absolutely required for infection, and it is the main target of neutralizing antibodies in human sera [11••, 12]. RSV F is also the target of palivizumab, a monoclonal antibody that passively protects infants from severe disease [13]. Therefore, the elicitation of potent, neutralizing antibodies against RSV F is a major goal for most vaccine developers [14].

In the last few years, there have been new developments in RSV research that have significantly advanced our understanding of the structure, antigenicity, and immunogenicity of RSV F. These include the elucidation of the X-ray crystal structures of RSV F in the prefusion and postfusion conformations, the isolation of extremely potent neutralizing antibodies that target novel epitopes, and the rational design of vaccine antigens. The goal of this review is to summarize these recent advances and highlight how this knowledge is being used to inform vaccine development.