Abstract
Efforts to develop a vaccine for respiratory syncytial virus (RSV) have primarily focused on the RSV fusion protein. The pre-fusion conformation of this protein induces the most potent neutralizing antibodies and is the focus of recent efforts in vaccine development. Following the first identification of mutations in the RSV F protein (DS-Cav1 mutant protein) that stabilized the pre-fusion conformation, other mutant stabilized pre-fusion F proteins have been described. To determine if there are differences in alternate versions of stabilized pre-fusion F proteins, we explored the use, as vaccine candidates, of virus-like particles (VLPs) containing five different pre-fusion F proteins, including the DS-Cav1 protein. The expression of these five pre-F proteins, their assembly into VLPs, their pre-fusion conformation stability in VLPs, their reactivity with anti-F monoclonal antibodies, and their induction of immune responses after the immunization of mice, were characterized, comparing VLPs containing the DS-Cav1 pre-F protein with VLPs containing four alternative pre-fusion F proteins. The concentrations of anti-F IgG induced by each VLP that blocked the binding of prototype monoclonal antibodies using two different soluble pre-fusion F proteins as targets were measured. Our results indicate that both the conformation and immunogenicity of alternative VLP associated stabilized pre-fusion RSV F proteins are different from those of DS-Cav1 VLPs.
Highlights
Respiratory syncytial virus (RSV) is a significant human pathogen but, despite decades of effort, no licensed vaccines exist
The reported instability of DS-Cav1 F could negatively impact immune responses to the F protein, so we characterized immune responses to four alternative mutation stabilized pre-fusion F proteins. We examined their expression and assembly into virus-like particles (VLPs), the stability of the pre-fusion conformation in VLPs, the reactivity of VLP associated pre-F proteins with anti-F monoclonal antibodies, and their induction of neutralizing antibodies following the immunization of mice
Our results indicate that VLPs expressing different versions of stabilized pre-fusion respiratory syncytial virus (RSV) F proteins can differentially impact immunogenicity
Summary
Respiratory syncytial virus (RSV) is a significant human pathogen but, despite decades of effort, no licensed vaccines exist. RSV infections can result in severe respiratory disease in the very young, the elderly, and immunocompromised populations. This virus is a common cause of severe acute lower respiratory track disease in infants and young children worldwide [1]. Infections of this population in the US frequently result in hospitalization and in developing countries, the infections cause significant mortality [1,2]. It is estimated that the virus results in 11,000 to 17,000 elderly deaths per year in the US and ten times that number of RSV associated hospitalizations [7]. The world population over the age of 60 is forecast to reach 2.1 billion, more than 20% of the population, by 2050
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