title: Mammalian Cell-Derived Respiratory Syncytial Virus-Like Particles Protect the Lower as well as the Upper Respiratory Tract.
abstract: Globally, Respiratory Syncytial Virus (RSV) is a leading cause of bronchiolitis and pneumonia in children less than one year of age and in USA alone, between 85,000 and 144,000 infants are hospitalized every year. To date, there is no licensed vaccine. We have evaluated vaccine potential of mammalian cell-derived native RSV virus-like particles (RSV VLPs) composed of the two surface glycoproteins G and F, and the matrix protein M. Results of in vitro testing showed that the VLPs were functionally assembled and immunoreactive, and that the recombinantly expressed F protein was cleaved intracellularly similarly to the virus-synthesized F protein to produce the F1 and F2 subunits; the presence of the F1 fragment is critical for vaccine development since all the neutralizing epitopes present in the F protein are embedded in this fragment. Additional in vitro testing in human macrophage cell line THP-1 showed that both virus and the VLPs were sensed by TLR-4 and induced a Th1-biased cytokine response. Cotton rats vaccinated with RSV VLPs adjuvanted with alum and monophosphoryl lipid A induced potent neutralizing antibody response, and conferred protection in the lower as well as the upper respiratory tract based on substantial virus clearance from these sites. To the best of our knowledge, this is the first VLP/virosome vaccine study reporting protection of the lower as well as the upper respiratory tract: Prevention from replication in the nose is an important consideration if the target population is infants < 6 months of age. This is because continued virus replication in the nose results in nasal congestion and babies at this age are obligate nose breathers. In conclusion, these results taken together suggest that our VLPs show promise to be a safe and effective vaccine for RSV.
authors.affiliation: Department of Tropical Medicine, Medical Microbiology and Pharmacology, John A. Burns School of Medicine, University of Hawaii at Manoa, Honolulu, Hawaii, United States of America.
authors.forename: Pramila
authors.initials: P
authors.lastname: Walpita
authors.affiliation: Department of Tropical Medicine, Medical Microbiology and Pharmacology, John A. Burns School of Medicine, University of Hawaii at Manoa, Honolulu, Hawaii, United States of America.
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Johns
authors.affiliation: Department of Tropical Medicine, Medical Microbiology and Pharmacology, John A. Burns School of Medicine, University of Hawaii at Manoa, Honolulu, Hawaii, United States of America.
authors.forename: Ravi
authors.initials: R
authors.lastname: Tandon
authors.affiliation: Department of Pediatrics, Emory University, Atlanta, Georgia, United States of America; Children's Healthcare of Atlanta, Atlanta, Georgia, United States of America.
authors.forename: Martin L
authors.initials: ML
authors.lastname: Moore
mesh_terms: D000818:Animals; D057134:Antibodies, Neutralizing / Q000276:immunology; D016207:Cytokines / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D056724:Immunity, Humoral; D008168:Lung / Q000276:immunology* / Q000821:virology; D009666:Nose / Q000276:immunology* / Q000821:virology; D051381:Rats; D012136:Respiratory Syncytial Viruses / Q000737:chemistry*; D018417:Th1 Cells / Q000276:immunology / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000378:metabolism; D015854:Up-Regulation / Q000276:immunology; D014611:Vaccination; D014764:Viral Proteins / Q000276:immunology
chemical_list: D057134:Antibodies, Neutralizing; D016207:Cytokines; C495347:Tlr4 protein, rat; D051197:Toll-Like Receptor 4; D014764:Viral Proteins