Respiratory Syncytial Virus: Targeting the G Protein Provides a New Approach for an Old Problem

Abstract

Respiratory syncytial virus (RSV) is a major cause of lower respiratory tract infection (LRTI) annually affecting >2 million children in the United States <5 years old. In the elderly (>65 years old), RSV results in ∼175,000 hospitalizations annually in the United States with a worldwide incidence of ∼34 million. There is no approved RSV vaccine, and treatments are limited. Recently, a phase 3 trial in the elderly using a recombinant RSV F protein vaccine failed to meet its efficacy objectives, namely, prevention of moderate-to-severe RSV-associated LRTI and reduced incidence of acute respiratory disease. Moreover, a recent phase 3 trial evaluating suptavumab (REGN2222), an antibody to RSV F protein, did not meet its primary endpoint of preventing medically attended RSV infections in preterm infants. Despite these setbacks, numerous efforts targeting the RSV F protein with vaccines, antibodies, and small molecules continue based on the commercial success of a monoclonal antibody (MAb) against the RSV F protein (palivizumab). As the understanding of RSV biology has improved, the other major coat protein, the RSV G protein, has reemerged as an alternative target reflecting progress in understanding its roles in infecting bronchial epithelial cells and in altering the host immune response. In mouse models, a high-affinity, strain-independent human MAb to the RSV G protein has shown potent direct antiviral activity combined with the alleviation of virus-induced immune system effects that contribute to disease pathology. This MAb, being prepared for clinical trials, provides a qualitatively new approach to managing RSV for populations not eligible for prophylaxis with palivizumab.

Epidemiology and genetic variability of respiratory syncytial virus in Portugal, 2014–2018

“…Symptomatic supportive care and Palivizumab are currently available options to RSV disease clinical management, which reduce the symptoms and severity, decreasing hospitalization rate but not mortality [15][16][17][18]. Fortunately, RSV vaccines are progressing in phase III clinical trials and could be available in the coming years [19], being G protein suggested as a plausible target [20]. Therefore, ongoing global surveillance and characterization of circulating RSV strains are required for evidence-based vaccination policies.…”

Structures of respiratory syncytial virus G antigen bound to broadly neutralizing antibodies

“…Because these vaccines contained RSV F immunogen in its post-fusion conformation, one emerging approach is focused on the generation of RSV F immunogens that are stabilized in the pre-fusion conformation, as revealed by X-ray crystallographic studies (8). Additionally, RSV G is increasingly recognized as a critical target (9), yet its development as a vaccine antigen has been hindered by its dense and heterogeneous N- and O-glycosylation in the highly-variable mucin-like regions and a paucity of information correlating specific molecular structure with biological activity.…”

Conformational Flexibility in Respiratory Syncytial Virus G Neutralizing Epitopes

“…In humans, anti-G antibodies are associated with lower clinical disease severity scores, despite an abundance in sera more than 30 times lower than anti-F antibodies (8). Thus, the RSV G protein is increasingly recognized as an important target for RSV vaccine and therapeutic antibody development (22). RSV G is a type II membrane protein containing two mucin-like regions coated with 30 to 40 O-linked glycans and 3 to 5 N-linked glycans ( Fig.…”