Respiratory syncytial virus infection remains a serious health problem, not only in infants but also in immunocompromised adults and the elderly. An effective and safe
vaccine is not available due to several obstacles: non-replicating
RSV vaccines may prime for excess Th2-type responses and enhanced respiratory disease (ERD) upon natural
RSV infection of
vaccine recipients. We previously found that inclusion of the
Toll-like receptor 4 (TLR4)
ligand monophosphoryl lipid A (MPLA) in reconstituted RSV membranes (
virosomes) potentiates
vaccine-induced immunity and skews immune responses toward a Th1-phenotype, without priming for ERD. As mucosal immunization is an attractive approach for induction of RSV-specific systemic and mucosal antibody responses and TLR
ligands could potentiate such responses, we explored the efficacy and safety of RSV-MPLA
virosomes administered intranasally (IN) to mice and cotton rats. In mice, we found that incorporation of MPLA in IN-administered RSV
virosomes increased both systemic
IgG and local
secretory-IgA (S-
IgA) antibody levels and resulted in significantly reduced lung viral titers upon live virus challenge. Also, RSV MPLA
virosomes induced more Th1-skewed responses compared to responses induced by FI-RSV. Antibody responses and Th1/Th2-
cytokine responses induced by RSV-MPLA
virosomes were comparable to those induced by live
RSV infection. By comparison,
formalin-inactivated RSV (FI-RSV) induced serum
IgG that inhibited viral shedding upon challenge, but also induced Th2-skewed responses. In cotton rats, similar effects of incorporation of MPLA in
virosomes were observed with respect to induction of systemic
antibodies and inhibition of lung viral shedding upon challenge, but mucosal sS-
IgA responses were only moderately enhanced. Importantly, IN immunization with RSV-MPLA
virosomes, like live
virus infection, did not lead to any signs of ERD upon live virus challenge of vaccinated animals, whereas IM immunization with FI-RSV did induce severe lung immunopathology under otherwise comparable conditions. Taken together, these data show that mucosally administered RSV-MPLA
virosomes hold promise for a safe and effective
vaccine against RSV.