Small hydrophobic protein of respiratory syncytial virus as a novel vaccine antigen.

Abstract

Human respiratory syncytial virus (HRSV) is the leading cause of lower respiratory tract infections and associated hospitalizations of infants worldwide [1]. HRSV infects the epithelium of the lung and actively initiates the shedding of infected cells without inducing major cytopathology [2]. When these infected cells are not efficiently cleared by macrophages or T cells, they form clumps that can obstruct the very narrow airways of young infants [3]. Possibly the most intriguing features of HRSV are its ability to infect young infants in the presence of maternal neutralizing antibodies and its ability to reinfect throughout life [4,5]. As such HRSV is also associated with excess morbidity and mortality in elderly people [6]. Why is it that the natural immune responses poorly protect against reinfection with HRSV? First, HRSV evades innate immune responses [7]. In addition, most HRSV infections are restricted to the upper respiratory tract, a site that is poorly accessed by circulating, potentially virus-neutralizing IgG. There is some evidence to suggest that HRSV-neutralizing antibodies inversely correlate with severity of HRSV disease [8–10]. In line with this, prophylactic use of a monoclonal HRSV-neutralizing antibody reduces HRSV-associated hospitalizations of high-risk infants by approximately 50% [11]. However, epidemiological and controlled HRSV challenge studies showed that infants and even healthy adults with high levels of serum antibodies directed against the neutralizing HRSV antigens F and G, remained susceptible to HRSV infection [8,9]. With these observations and the fact that very young infants are an important target group, it is not surprising that decades of HRSV research has not yet resulted in an effective vaccine. As HRSV neutralizing antibodies can provide a degree of protection, most subunit vaccine developments aim at inducing such antibodies. HRSV F and G are the major surface proteins and are known to display neutralizing epitopes [12]. Recently, important progress has been made in developing RSV F and G subunit vaccines, including the breakthrough of the production of recombinant HRSV F protein that is stabilized in its prefusion conformation [13]. Compared to post fusion F, immunization with prefusion F induces higher HRSV-neutralizing antibodies in mice and in nonhuman primates. In addition, antibodies directed against the conserved cysteine noose of the HRSV G proteins, that contain a CX3C motif, were shown to inhibit protein G-CX3CR interaction and reduce HRSV replication and disease [14]. Taking into account the partial immunity evoked by recurrent natural infections, it remains to be seen whether HRSV subunit vaccines solely based on the F and/or G proteins will be able to provide strong long-living immunity. Small hydrophobic protein of respiratory syncytial virus as a novel vaccine antigen