Abstract
IntroductionRSV infection remains a serious threat to newborns and the elderly. Currently, there is no vaccine available to prevent RSV infection. A mucosal RSV vaccine would be attractive as it could induce mucosal as well as systemic antibodies, capable of protecting both the upper and lower respiratory tract. Previously, we reported on a virosomal RSV vaccine for intramuscular injection with intrinsic adjuvant properties mediated by an incorporated lipophilic Toll-like receptor 2 (TLR2) ligand. However, it has not been investigated whether this virosomal RSV vaccine candidate would be suitable for use in mucosal immunization strategies and if additional incorporation of other innate receptor ligands, like NOD2-ligand, could further enhance the immunogenicity and protective efficacy of the vaccine.ObjectiveTo explore if intranasal (IN) immunization with a virosomal RSV vaccine, supplemented with TLR2 and/or NOD2-ligands, is an effective strategy to induce RSV-specific immunity.MethodsWe produced RSV-virosomes carrying TLR2 (Pam3CSK4) and/or NOD2 (L18-MDP) ligands. We tested the immunopotentiating properties of these virosomes in vitro, using TLR2- and/or NOD2-ligand-responsive murine and human cell lines, and in vivo by assessing induction of protective antibody and cellular responses upon IN immunization of BALB/c mice.ResultsIncorporation of Pam3CSK4 and/or L18-MDP potentiates the capacity of virosomes to activate (antigen-presenting) cells in vitro, as demonstrated by NF-κB induction. In vivo, incorporation of Pam3CSK4 in virosomes boosted serum IgG antibody responses and mucosal antibody responses after IN immunization. While L18-MDP alone was ineffective, incorporation of L18-MDP in Pam3CSK4-carrying virosomes further boosted mucosal antibody responses. Finally, IN immunization with adjuvanted virosomes, particularly Pam3CSK4/L18-MDP-adjuvanted-virosomes, protected mice against infection with RSV, without priming for enhanced disease.ConclusionMucosal immunization with RSV-virosomes, supplemented with incorporated TLR2- and/or NOD2-ligands, represents a promising approach to induce effective and safe RSV-specific immunity.
Highlights
Respiratory Syncytial Virus (RSV) infection remains a serious threat to newborns and the elderly
We previously reported on the feasibility of inclusion of lipophilic Toll-like receptor (TLR)-ligand adjuvants (i.e. Toll-like receptor 2 (TLR2)-ligand Pam3CSK4 and TLR4ligand Monophosphoryl Lipid A; MPLA) in RSV virosomes and demonstrated that such adjuvant-supplemented virosomes have the capacity to induce protective antibodies after parenteral administration to mice or cotton rats, without priming for enhanced disease [11,12]
We found that a TLR9 ligand (i.e. CpG DNA), alone or co-formulated with a NOD2 ligand (i.e. L18MDP), could boost mucosal and systemic antibody responses to admixed inactivated RSV whole virions upon IN administration to mice [8]
Summary
RSV infection remains a serious threat to newborns and the elderly. Currently, there is no vaccine available to prevent RSV infection. We reported on a virosomal RSV vaccine for intramuscular injection with intrinsic adjuvant properties mediated by an incorporated lipophilic Toll-like receptor 2 (TLR2) ligand. It has not been investigated whether this virosomal RSV vaccine candidate would be suitable for use in mucosal immunization strategies and if additional incorporation of other innate receptor ligands, like NOD2-ligand, could further enhance the immunogenicity and protective efficacy of the vaccine. New candidate RSV vaccines should induce Th1-skewed immune responses with induction of protective systemic and mucosal antibodies without priming for enhanced pathology upon natural infection. Mucosal vaccines that include TLR-ligands for activation of innate receptors could be promising in this respect
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