A virosomal respiratory syncytial virus vaccine adjuvanted with monophosphoryl lipid A provides protection against viral challenge without priming for enhanced disease in cotton rats

BACKGROUND: Non‐replicating respiratory syncytial virus (RSV) vaccine candidates could potentially prime for enhanced respiratory disease (ERD) due to a T‐cell‐mediated immunopathology, following RSV infection. Vaccines with built‐in immune response modifiers, such as Toll‐like receptor (TLR) ligands, may avoid such aberrant imprinting of the immune system. METHODS: We developed reconstituted RSV envelopes (virosomes) with incorporated TLR4 ligand, monophosphoryl lipid A (RSV‐MPLA virosomes). Immune responses and lung pathology after vaccination and challenge were investigated in ERD‐prone cotton rats and compared with responses induced by live virus and formaldehyde‐inactivated vaccine (FI‐RSV), a known cause of ERD upon RSV challenge. RESULTS: Vaccination with RSV‐MPLA virosomes induced higher levels of virus‐neutralizing antibodies than FI‐RSV or live virus infection and provided protection against infection. FI‐RSV, but not RSV‐MPLA virosomes, primed for increases in expression of Th2 cytokines IL‐4, IL‐5, IL‐13, and Th1 cytokine IL‐1b, 6 hour–5 days after infection. By contrast, RSV‐MPLA virosomes induced IFN‐γ transcripts to similar levels as induced by live virus. Animals vaccinated with FI‐RSV, but not RSV‐MPLA virosomes showed alveolitis, with prominent neutrophil influx and peribronchiolar and perivascular infiltrates. CONCLUSION: These results show that RSV‐MPLA virosomes represent a safe and immunogenic vaccine candidate that warrants evaluation in a clinical setting.