title: A recombinant anchorless respiratory syncytial virus (RSV) fusion (F) protein/monophosphoryl lipid A (MPL) vaccine protects against RSV-induced replication and lung pathology.
abstract: We previously demonstrated that the severe cytokine storm and pathology associated with RSV infection following intramuscular vaccination of cotton rats with FI-RSV Lot 100 could be completely abolished by formulating the vaccine with the mild TLR4 agonist and adjuvant, monophosphoryl lipid A (MPL). Despite this significant improvement, the vaccine failed to blunt viral replication in the lungs. Since MPL is a weak TLR4 agonist, we hypothesized that its adjuvant activity was mediated by modulating the innate immune response of respiratory tract resident macrophages. Therefore, we developed a new vaccine preparation with purified, baculovirus expressed, partially purified, anchorless RSV F protein formulated with synthetic MPL that was administered to cotton rats intranasally, followed by an intradermal boost. This novel formulation and heterologous "prime/boost" route of administration resulted in decreased viral titers compared to that seen in animals vaccinated with F protein alone. Furthermore, animals vaccinated by this route showed no evidence of enhanced lung pathology upon RSV infection. This indicates that MPL acts as an immune modulator that protects the host from vaccine-enhanced pathology, and reduces RSV replication in the lower respiratory tract when administered by a heterologous prime/boost immunization regimen.
authors.affiliation: Sigmovir Biosystems, Inc., Rockville, MD 20850, United States. Electronic address: j.blanco@sigmovir.com.
authors.forename: Jorge C G
authors.initials: JC
authors.lastname: Blanco
authors.affiliation: Sigmovir Biosystems, Inc., Rockville, MD 20850, United States.
authors.forename: Marina S
authors.initials: MS
authors.lastname: Boukhvalova
authors.affiliation: Sigmovir Biosystems, Inc., Rockville, MD 20850, United States.
authors.forename: Lioubov M
authors.initials: LM
authors.lastname: Pletneva
authors.affiliation: Department of Microbiology and Immunology, University of Maryland, Baltimore, MD 21201, United States.
authors.forename: Kari Ann
authors.initials: KA
authors.lastname: Shirey
authors.affiliation: Department of Microbiology and Immunology, University of Maryland, Baltimore, MD 21201, United States.
authors.forename: Stefanie N
authors.initials: SN
authors.lastname: Vogel
mesh_terms: D000276:Adjuvants, Immunologic / Q000494:pharmacology; D000281:Administration, Intranasal; D000818:Animals; D057134:Antibodies, Neutralizing / Q000097:blood; D000914:Antibodies, Viral / Q000097:blood; D008050:Lipid A / Q000031:analogs & derivatives / Q000276:immunology; D008168:Lung / Q000473:pathology* / Q000821:virology; D051381:Rats; D011994:Recombinant Proteins / Q000276:immunology; D018357:Respiratory Syncytial Virus Infections / Q000517:prevention & control*; D022261:Respiratory Syncytial Virus Vaccines / Q000276:immunology*; D012136:Respiratory Syncytial Viruses / Q000502:physiology*; D051197:Toll-Like Receptor 4 / Q000819:agonists; D014760:Viral Fusion Proteins / Q000276:immunology*; D014779:Virus Replication
chemical_list: D000276:Adjuvants, Immunologic; D057134:Antibodies, Neutralizing; D000914:Antibodies, Viral; C526850:F protein, human respiratory syncytial virus; D008050:Lipid A; D011994:Recombinant Proteins; D022261:Respiratory Syncytial Virus Vaccines; D051197:Toll-Like Receptor 4; D014760:Viral Fusion Proteins; C048436:monophosphoryl lipid A
keywords: Cotton rat; F-protein; FI-RSV; MPL; RSV