BACKGROUND
Respiratory Syncytial Virus (RSV) is the single largest viral cause of pediatric bronchiolitis and pneumonia, with a high worldwide mortality, and there is no safe and effective vaccine. Ever since the encounter with vaccine-enhanced disease (VED) during a formalin-inactivated RSV vaccination trial in the 1960s, it has been enormously challenging to impart both sufficient safety and efficacy in a single vaccine. RSV contains a negative-sense, single-stranded RNA genome that expresses eleven known proteins from ten genes. Of these, the fusion (F) protein is a transmembrane (surface) glycoprotein that contains important antigenic epitopes of human RSV and that is essential for virus infectivity. As such, F protein appears to be critical for induction of neutralizing anti-RSV antibodies. Recently, it has been recognized that the viral fusion (F) protein is unstable and readily shifts to the post-fusion conformation during purification or vaccine preparation. As a result, a large proportion of vaccine-induced antibodies (Abs) target the post-fusion form, which is functionally obsolete.
For RSV-naïve children, live-attenuated vaccines are an important focus, because inactivated and subunit vaccines are poor at inducing cell-mediated immunity which can contribute to VED, whereas live vaccines never induce VED. Moreover, live vaccines can induce broad systemic and local immunity. Thus, for RSV-naïve individuals a live vaccine approach is an attractive option, provided the vaccine itself is sufficiently safe and cannot revert to a more aggressive phenotype. To successfully vaccinate RSV-naïve children there is a need to develop a prefusion F candidate that provides a balanced immune response without causing VED.
SUMMARY OF TECHNOLOGY
OSU inventors have developed a novel vaccine candidate which expresses a prefusion-stabilized form of F (FPRE) from a live-attenuated but self-limited virus, and thereby providing a sustainable platform for a balanced immune response needed for protection of RSV naïve children. Whereas stabilization of FPRE renders it nonfunctional and a virus solely expressing FPRE is not viable, our investigators have overcome these challenges by developing a complementation system that allows generation of infectious F-deleted or F-compromised viruses from cDNA in baculovirus GP64-expressing cells. Due to replacement of functional F with trans-complemented GP64, the pseudotyped viruses are infectious but self-limited and cannot spread beyond initially infected cells, thus constituting a safe and attractive, single-cycle, live-attenuated platform.
By applying the above concept, our researchers have produced and characterized novel live-attenuated RSV prototype vaccines in a mouse model. These vaccines lack a functional F protein and express instead pre-fusion stabilized F, and hence are live but self-limited after vaccination. Despite being self-limited, the vaccines were shown to induce both strong humoral and cell-mediated immunity which protected the lungs from pathology induced by a wild-type RSV challenge. Thus, the pre-F single cycle vaccines combine a strong safety and immunogenicity profile, and have excellent potential to exceed previous formulations in inducing a broadly efficacious yet safe immune response for the RSV- naïve target population.
POTENTIAL AREAS OF APPLICATION
- A novel live-attenuated RSV vaccine candidate which is both safe and efficacious
- Prevention of human RSV outbreaks through immunization of infants, young children and elderly
COMMERCIAL OPPORTUNITY
Respiratory syncytial virus infection represents the major cause of hospitalization of infants in the US with up to 120,000 annual RSV admissions. Causing as many as 200,000 annual infant deaths worldwide, RSV has an estimated >$3 billion cost associated with management of RSV infection in infants and children. Palivizumab has been the only RSV-specific treatment on the market with peak sales of >$1.1 billion in 2010.
STAGE OF DEVELOPMENT