Developing a PIV5-based human metapneumovirus (HMPV) vaccine

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ABSTRACT In this Phase I SBIR application, we propose to develop an intranasal, parainfluenza virus 5 (PIV5)-based human metapneumovirus (HMPV) vaccine. HMPV is one of the leading causes of acute respiratory infections (ARIs) in children, immunocompromised individuals, and the elderly. Illness ranges from asymptomatic infection to severe bronchiolitis and pneumonia, with 90-100% of children infected between the ages of 5-10 years old. No licensed HMPV vaccine is available and there is an unmet medical need to develop a safe and effective HMPV vaccine. PIV5 is a safe delivery vector for intranasal immunization. The PIV5-vectored COVID-19 vaccine (CVXGA1) and respiratory syncytial virus (RSV, a leading cause of lower respiratory tract infection in infants and elderly) vaccine are currently in Phase 1 clinical testing. Preclinical data for PIV5-based RSV candidate vaccines have shown excellent immunogenicity, protection, and safety profiles in various animal models, including the cotton rat model, demonstrating lack of vaccine-induced enhanced disease observed following formalin-inactivated RSV vaccination. In this grant proposal, we will produce two PIV5-based HMPV candidate vaccine constructs, one in the W3A strain with the SH gene deleted (W3A!SH-HMPV-F) and another in the canine parainfluenza virus (CPI) vaccine strain (CPI-HMPV-F) to compare their replication in vitro, antigen expression in vitro, immunogenicity, and protection against HMPV challenge infection in a mouse model. The novelty of the vaccine proposed in this Phase I SBIR application relates to: 1) the use of a chimeric HMPV F protein containing the PIV5 F cytoplasmic tail to potentially increase HMPV F antigen exposure on the virion surface 2) a needle-free intranasal delivery method in a safe, highly immunogenic viral vector and 3) the ability to induce mucosal immunity, which is necessary for protecting against respiratory pathogens. Once the PIV5-vectored HMPV vaccine is demonstrated to be immunogenic in the mouse model, the Phase II SBIR proposal will focus on preclinical studies needed for entering Phase 1 clinical trials with the final goal of generating a bivalent PIV5- vectored RSV and HMPV vaccine which would provide protection against the two leading causes of lower respiratory tract infections in infants and elderly.