An immunodominance-based Pan-Pneumovirus vaccine for protection against RSV and hMPV

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The goal of this research project is to further the development of a pan-Pneumovirus vaccine and to test our hypothesis that a chimeric Pneumovirus fusion (F) protein vaccine displaying immunodominant epitopes of respiratory syncytial virus (RSV) and human metapneumovirus (hMPV) will induce broad protection against both viruses. RSV and hMPV are widely prevalent agents of childhood viral respiratory infection, causing thousands of deaths and hundreds of thousands of hospitalizations each year. There are currently no approved vaccines to elicit protective antibodies against either virus, and no specific treatment options are available. The F glycoproteins of RSV and hMPV have been well-studied as targets of neutralizing antibodies, and several vaccine candidates for RSV are in clinical trials. We have developed a novel vaccine candidate (RHMS-1) encompassing immunodominant epitopes of both RSV and hMPV F proteins and verified its protective efficacy in mouse and cotton rat models. The rationale for pursuing a chimeric vaccine candidate is based on several factors, including focusing the immune response to only those epitopes that elicit potent neutralizing antibodies rather than less potent or non-neutralizing epitopes to improve protection, reducing vaccine escape compared to previous chimeric vaccines incorporating a single epitope, and the assessment of the first chimeric vaccine candidate beyond the mouse model. Additionally, we will determine immune correlates of protection for hMPV infection in a nonhuman primate model. These critical studies will provide a wealth of immunologic information in highly relevant, pre-clinical models that will guide an evidence-based path toward the optimization of a safe and effective pan-Pneumovirus vaccine. Our research will substantially advance the field by developing a vaccine for protection against the two leading causes of acute lower respiratory tract infection in children. As the pre-fusion RSV F protein has already demonstrated safety and the ability to elicit an effective immune response, we will build upon this success to extend this vaccine for protection against hMPV. In Aim 1, we will computationally stabilize and redesign our vaccine candidate, RHMS-1, using Rosetta to enhance protein stability and immunogenicity, and the best candidates will be rapidly screened in mice as both protein subunit and mRNA-lipid nanoparticle vaccines. In Aim 2, we will conduct structural and epitope analysis of our top vaccine candidate to verify the epitopes on RHMS are similar to RSV F and hMPV F proteins. In Aim 3, we will determine the protective efficacy of the top candidate RHMS vaccine in cotton rat and African Green Monkey models of RSV and hMPV infection. Our proposal is both conceptually and practically innovative as we are designing and testing novel vaccine candidates for protection against two important respiratory pathogens, and we are challenging current paradigms in the field by providing a single antigen for dual-virus protection. Furthermore, the innovation of the team is very high, as this proposal brings together diverse investigators and several state of the art technologies.