Enhanced immune responses and protection by vaccination with respiratory syncytial virus fusion protein formulated with CpG oligodeoxynucleotide and innate defense regulator peptide in polyphosphazene microparticles.
Although respiratory syncytial virus (RSV) is the leading cause of serious respiratory tract disease in children, to date no RSV vaccine is available. To produce an effective subunit vaccine, a truncated secreted version of the F protein (ΔF) was expressed in mammalian cells, purified and shown to form trimers. The ΔF protein was then formulated with a CpG oligodeoxynucleotide (ODN) and an innate defense regulator (IDR) peptide in polyphosphazene microparticles (ΔF-MP). Mice immunized either intramuscularly (IM) or intranasally (IN) with ΔF-MP developed significantly higher levels of virus-neutralizing antibodies in the sera and lungs, as well as higher numbers of IFN-γ secreting cells than mice immunized with the ΔF protein alone. In contrast, the IM delivered ΔF induced high production of IL-5 while the IN delivered ΔF did not elicit a measurable immune response. After RSV challenge, essentially no virus and no evidence of immunopathology were detected in mice immunized with ΔF-MP regardless of the route of delivery. While the mice immunized IM with ΔF alone also showed reduced virus replication, they developed enhanced levels of pulmonary IgE, IL-4, IL-5, IL-13 and eotaxin, as well as eosinophilia after challenge. The level of protection induced by the ΔF-MP formulation was equivalent after IM and IN delivery. The efficacy and safety of the ΔF-MP formulation was confirmed in cotton rats, which also developed enhanced immune responses and were fully protected from RSV challenge after vaccination with ΔF-MP. In conclusion, formulation of recombinant ΔF with CpG ODN and IDR peptide in polyphosphazene microparticles should be considered for further evaluation as a safe and effective vaccine against RSV.
VIDO-Intervac, University of Saskatchewan, Saskatoon, SK S7N 5E3, Canada.
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Garlapati
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Garg
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Brownlie
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Latimer
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Simko
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Hancock
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Babiuk
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Gerdts
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Potter
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van Drunen Littel-van den Hurk
D000276:Adjuvants, Immunologic / Q000494:pharmacology*; D000818:Animals; D000914:Antibodies, Viral / Q000097:blood; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D002460:Cell Line; D005260:Female; D006801:Humans; D007113:Immunity, Innate; D007073:Immunoglobulin E / Q000097:blood; D018793:Interleukin-13 / Q000097:blood; D015847:Interleukin-4 / Q000097:blood; D015848:Interleukin-5 / Q000097:blood; D008168:Lung / Q000276:immunology / Q000473:pathology / Q000821:virology; D051379:Mice; D008807:Mice, Inbred BALB C; D009838:Oligodeoxyribonucleotides / Q000494:pharmacology*; D009943:Organophosphorus Compounds / Q000276:immunology / Q000494:pharmacology*; D011108:Polymers / Q000494:pharmacology*; D051381:Rats; D011994:Recombinant Proteins; D018357:Respiratory Syncytial Virus Infections / Q000276:immunology* / Q000517:prevention & control; D022261:Respiratory Syncytial Virus Vaccines / Q000008:administration & dosage* / Q000276:immunology; D012136:Respiratory Syncytial Viruses / Q000276:immunology; D014611:Vaccination; D014760:Viral Fusion Proteins / Q000276:immunology*; D014779:Virus Replication
D000276:Adjuvants, Immunologic; D000914:Antibodies, Viral; C408982:CPG-oligonucleotide; D018793:Interleukin-13; D015848:Interleukin-5; D009838:Oligodeoxyribonucleotides; D009943:Organophosphorus Compounds; D011108:Polymers; D011994:Recombinant Proteins; D022261:Respiratory Syncytial Virus Vaccines; D014760:Viral Fusion Proteins; C108974:poly(phosphazene); D015847:Interleukin-4; D007073:Immunoglobulin E