title: Influenza virus-like particles elicit broader immune responses than whole virion inactivated influenza virus or recombinant hemagglutinin.
abstract: Influenza virus is a highly infectious respiratory pathogen that results in severe morbidity and mortality. The current licensed trivalent vaccine formulations in the U.S. are made from virus grown in allantoic fluid from infected hen eggs that is then chemically inactivated and split into subunit components. These vaccines elicit antibodies, primarily to the viral hemagglutinin (HA), which are efficacious in healthy adults, but are limited in protecting high risk individuals, such as the elderly and immunocompromised. To address the need for improved influenza vaccines and the limitations of egg-based manufacturing, we have engineered an influenza virus-like particle (VLP) as a new generation of non-egg or non-mammalian cell culture-based candidate vaccine against influenza infection. VLPs, based on the A/Fujian/411/2002 (H3N2) isolate, were purified from the supernatants of Spodoptera frugiperda Sf9 insect cells following infection of baculovirus vectors encoding an expression cassette comprised of only three influenza virus structural proteins, hemagglutinin (HA), neuraminidase (NA), and matrix (M1). Mice or ferrets were vaccinated intramuscularly with VLPs in a dose sparing experiment, based on HA concentration (3 microg-24 ng), and the immune responses were compared to responses elicited in animals vaccinated with recombinant HA (rHA) or inactivated whole influenza virions (WIV). All vaccinated animals had high titer anti-HA antibodies regardless of the vaccine immunogen and animals vaccinated with the highest doses of VLPs (3 microg and 600 ng) also had antibodies against NA. Purified rHA elicited primarily IgG1 antibodies, which is indicative of a T helper (Th) type 2 response, whereas mice vaccinated with the VLPs or WIV were associated with a dominant Th1 immune response (IgG2a and IgG2b). Interestingly, VLPs elicited antibodies that recognized a broader panel of antigenically distinct H3N2 viral isolates compared to rHA or WIV in a hemagglutination-inhibition (HAI) assay.
authors.affiliation: Novavax, Inc., Rockville, MD 20850, USA. rbright@novavax.com
authors.forename: Rick A
authors.initials: RA
authors.lastname: Bright
authors.forename: Donald M
authors.initials: DM
authors.lastname: Carter
authors.forename: Shannon
authors.initials: S
authors.lastname: Daniluk
authors.forename: Franklin R
authors.initials: FR
authors.lastname: Toapanta
authors.forename: Attiya
authors.initials: A
authors.lastname: Ahmad
authors.forename: Victor
authors.initials: V
authors.lastname: Gavrilov
authors.forename: Mike
authors.initials: M
authors.lastname: Massare
authors.forename: Peter
authors.initials: P
authors.lastname: Pushko
authors.forename: Nutan
authors.initials: N
authors.lastname: Mytle
authors.forename: Thomas
authors.initials: T
authors.lastname: Rowe
authors.forename: Gale
authors.initials: G
authors.lastname: Smith
authors.forename: Ted M
authors.initials: TM
authors.lastname: Ross
mesh_terms: D000818:Animals; D000914:Antibodies, Viral / Q000097:blood*; D016367:Baculoviridae; D002478:Cells, Cultured; D005260:Female; D005289:Ferrets; D006385:Hemagglutination Inhibition Tests; D019267:Hemagglutinin Glycoproteins, Influenza Virus / Q000235:genetics / Q000276:immunology; D053118:Influenza A Virus, H1N1 Subtype / Q000276:immunology; D053122:Influenza A Virus, H3N2 Subtype / Q000276:immunology*; D007252:Influenza Vaccines / Q000008:administration & dosage* / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D009976:Orthomyxoviridae Infections / Q000276:immunology / Q000517:prevention & control* / Q000821:virology; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000276:immunology; D018411:Spodoptera; D014611:Vaccination; D015164:Vaccines, Inactivated / Q000008:administration & dosage / Q000276:immunology; D014771:Virion / Q000276:immunology*
chemical_list: D000914:Antibodies, Viral; D019267:Hemagglutinin Glycoproteins, Influenza Virus; D007252:Influenza Vaccines; D011994:Recombinant Proteins; D015164:Vaccines, Inactivated