A combination of new prefusion mRNA and protein vaccines enhances neutralizing antibodies and protection against respiratory syncytial virus.

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.