Respiratory syncytial virus (RSV) is the most important pathogen causing severe lower respiratory tract infection (LRTI) in infants. RSV causes LRTI in 20-30% of infants and hospitalizes approximately 1% of the winter infant cohort in the USA. RSV is a universal infectious disease of infants for which no vaccine is available. Development of an RSV vaccine for infants has been impeded by previous experience in the 1960s with a formalin inactivated vaccine candidate which not only was not protective, but also led to enhanced RSV disease and deaths in vaccinees subsequently exposed to wild type RSV. Live attenuated vaccines (LAVs), the basis for other licensed childhood vaccines, have not led to enhanced disease in animals or RSV nave infants. To date, the challenge with LAV candidates has been striking the right balance between sufficient and stable attenuation and preservation of immunity. To address these challenges, we propose evaluating our live-attenuated vaccine candidate (MV-012-968). This candidate was engineered to achieve the necessary balance by codon deoptimization of the NS1, NS2, and G genes together with enhanced expression of the pre-fusion conformation of the F protein through the deletion of the SH gene and by incorporation of novel pre-F stability amino acids. We submit that the balance between attenuation and immunogenicity will be demonstrated by tolerability of the intranasal vaccine among seronegative infants (ultimate target population) and by induction of neutralizing antibody responses capable of preventing serious lower respiratory tract RSV infection in the target population. This application is intended to support the first step in the overall clinical development program of the MV-012-968 vaccine, by supporting activities leading to the initiation of the first-in-man Phase 1a evaluation of the vaccine in seropositive adults and children in the United States. Specific activities to be supported in this application will include the development of the clinical protocol, informed consent forms, diary cards, case report forms, investigator?s brochure, statistical analysis plan, clinical monitoring and data management plans and necessary study manuals. A subset of these documents will be included in the planned IND submission regarding the Phase 1a study. The proposed activities are essential to the design of and readiness for a Phase 1a study of the novel, attenuated, intranasal RSV vaccine, intended to protect young infants from serious RSV disease.
In 2015 respiratory syncytial virus (RSV) was estimated to cause 3.2 million hospitalization and approximately 59,600 deaths in children below the age of 5 years worldwide. There is currently no approved RSV vaccine. A Phase 1 study is being planned to evaluate the safety and immunogenicity of a promising live attenuated RSV vaccine that elicit a high level of protective RSV neutralizing antibodies despite heavy attenuation in the cotton rat model.
