Enhanced neutralizing antibodies and protection against RSV by new pre-fusion mRNA and subunit protein combination vaccines in mice.

Human respiratory syncytial virus (RSV) causes high hospitalizations and mortality in children and elderly. RSV pre-fusion stabilized protein vaccines have been licensed for elderly and maternal vaccination. Nonetheless, there exists an urgent demand for a safer and effective RSV vaccine in elderly and young children, avoiding vaccine-enhanced disease. We developed a new pre-fusion mRNA construct (F1d-dcmTM) containing additional mutations as well as prototype pre-fusion stabilizing mutations (DS-Cav1). New pre-fusion F1d-dcmTM mRNA encapsulated in lipid nanoparticles (LNP) was found to be more effective in inducing neutralizing antibodies after vaccination of mice than prototype DS-Cav1 Pre-fusion protein. Remarkably, we found that combined F1d-dcmTM mRNA-LNP and Pre-fusion protein vaccination elicited significantly higher amounts of RSV neutralizing antibodies in mice than those by either vaccine alone. After challenge of vaccinated mice with RSV, F1d-dcmTM mRNA-LNP and combination group with pre-fusion protein provided effective protection by clearing lung viral loads, preventing lung histopathology and inflammation, and inducing balanced T cell responses, compared to those by prototype pre-fusion protein. These new RSV pre-fusion mRNA vaccine construct and a strategy of combined vaccination would provide safer and more effective protection than current prototype RSV pre-fusion subunit vaccine.