Abstract
Respiratory syncytial virus (RSV) causes high hospitalization and mortality in children and the elderly. RSV prefusion conformation-stabilized fusion (F) protein vaccines have been licensed for elderly and maternal vaccination. Nonetheless, a demand exists for an effective RSV vaccine in elderly and young children, avoiding vaccine-enhanced disease. We developed a new prefusion mRNA containing a prototype (DS-Cav1 pre-F) stabilizing and additional fusion domain mutations. The new pre-F mRNA vaccine, encapsulated in lipid nanoparticles (LNP), effectively induced neutralizing antibodies and a preferential Th1-type effector T cell response in mice. Remarkably, a combination of pre-F mRNA-LNP and pre-F protein elicited significantly higher titers of neutralizing antibodies against RSV A and B strains than either pre-F mRNA or protein vaccine alone. Pre-F mRNA and its combination with pre-F protein provided protection by clearing lung viral loads, preventing lung histopathology and inflammation, compared to the prototype pre-F protein. Combination pre-F mRNA and pre-F protein vaccination modulated balanced effector CD8 T cell responses after challenge. This study supports the idea that combining pre-F mRNA and pre-F protein vaccines would provide more effective humoral and balanced cellular immunity than either mRNA or protein vaccine alone.