Department of Medical Microbiology, Molecular Virology Section, University Medical Center Groningen and University of Groningen, Groningen, The Netherlands.
PLoS One. 2013 Apr 8;8(4):e61287. doi: 10.1371/journal.pone.0061287. Print 2013.
RSV 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.
To 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.
We 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.
Incorporation 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.
Mucosal immunization with RSV-virosomes, supplemented with incorporated TLR2- and/or NOD2-ligands, represents a promising approach to induce effective and safe RSV-specific immunity.
呼吸道合胞病毒（RSV）感染仍然是新生儿和老年人的严重威胁。目前，尚无预防 RSV 感染的疫苗。黏膜 RSV 疫苗很有吸引力，因为它可以诱导黏膜和系统抗体，从而保护上呼吸道和下呼吸道。先前，我们报道了一种用于肌肉内注射的 RSV 病毒体疫苗，该疫苗具有内在的佐剂特性，由掺入的亲脂性 Toll 样受体 2（TLR2）配体介导。然而，尚未研究这种 RSV 病毒体疫苗候选物是否适合用于黏膜免疫策略，以及是否可以进一步加入其他先天受体配体（如 NOD2 配体）来增强疫苗的免疫原性和保护效力。
探索鼻腔内（IN）接种 RSV 病毒体疫苗，补充 TLR2 和/或 NOD2 配体，是否是诱导 RSV 特异性免疫的有效策略。
我们制备了携带 TLR2（Pam3CSK4）和/或 NOD2（L18-MDP）配体的 RSV 病毒体。我们使用 TLR2 和/或 NOD2 配体反应性的鼠和人细胞系在体外测试了这些病毒体的免疫增强特性，并通过评估 BALB/c 小鼠 IN 免疫接种后保护性抗体和细胞应答的诱导来进行体内研究。
在体外，Pam3CSK4 和/或 L18-MDP 的掺入增强了病毒体激活（抗原呈递）细胞的能力，这表现为 NF-κB 诱导。在体内，Pam3CSK4 掺入病毒体可增强血清 IgG 抗体应答和 IN 免疫后的黏膜抗体应答。虽然单独的 L18-MDP 无效，但将 L18-MDP 掺入携带 Pam3CSK4 的病毒体中可进一步增强黏膜抗体应答。最后，用佐剂化的病毒体（特别是 Pam3CSK4/L18-MDP 佐剂化的病毒体）进行 IN 免疫接种可保护小鼠免受 RSV 感染，而不会引发疾病加重。
黏膜接种 RSV 病毒体，补充掺入的 TLR2 和/或 NOD2 配体，是诱导有效和安全 RSV 特异性免疫的一种很有前途的方法。
