title: Recombinant soluble, multimeric HA and NA exhibit distinctive types of protection against pandemic swine-origin 2009 A(H1N1) influenza virus infection in ferrets.
abstract: The emergence and subsequent swift and global spread of the swine-origin influenza virus A(H1N1) in 2009 once again emphasizes the strong need for effective vaccines that can be developed rapidly and applied safely. With this aim, we produced soluble, multimeric forms of the 2009 A(H1N1) HA (sHA(3)) and NA (sNA(4)) surface glycoproteins using a virus-free mammalian expression system and evaluated their efficacy as vaccines in ferrets. Immunization twice with 3.75-microg doses of these antigens elicited strong antibody responses, which were adjuvant dependent. Interestingly, coadministration of both antigens strongly enhanced the HA-specific but not the NA-specific responses. Distinct patterns of protection were observed upon challenge inoculation with the homologous H1N1 virus. Whereas vaccination with sHA(3) dramatically reduced virus replication (e.g., by lowering pulmonary titers by about 5 log(10) units), immunization with sNA(4) markedly decreased the clinical effects of infection, such as body weight loss and lung pathology. Clearly, optimal protection was achieved by the combination of the two antigens. Our observations demonstrate the great vaccine potential of multimeric HA and NA ectodomains, as these can be easily, rapidly, flexibly, and safely produced in high quantities. In particular, our study underscores the underrated importance of NA in influenza vaccination, which we found to profoundly and specifically contribute to protection by HA. Its inclusion in a vaccine is likely to reduce the HA dose required and to broaden the protective immunity.
authors.affiliation: Virology Division, Department of Infectious Diseases & Immunology, Faculty of Veterinary Medicine, Utrecht University, Yalelaan 1, 3584 CL, Utrecht, The Netherlands.
authors.forename: Berend Jan
authors.initials: BJ
authors.lastname: Bosch
authors.forename: Rogier
authors.initials: R
authors.lastname: Bodewes
authors.forename: Robert P
authors.initials: RP
authors.lastname: de Vries
authors.forename: Joost H C M
authors.initials: JH
authors.lastname: Kreijtz
authors.forename: Willem
authors.initials: W
authors.lastname: Bartelink
authors.forename: Geert
authors.initials: G
authors.lastname: van Amerongen
authors.forename: Guus F
authors.initials: GF
authors.lastname: Rimmelzwaan
authors.forename: Cornelis A M
authors.initials: CA
authors.lastname: de Haan
authors.forename: Albert D M E
authors.initials: AD
authors.lastname: Osterhaus
authors.forename: Peter J M
authors.initials: PJ
authors.lastname: Rottier
mesh_terms: D000818:Animals; D000914:Antibodies, Viral / Q000096:biosynthesis; D003429:Cross Reactions; D004196:Disease Outbreaks / Q000517:prevention & control; D005260:Female; D005289:Ferrets / Q000276:immunology*; D019267:Hemagglutinin Glycoproteins, Influenza Virus / Q000737:chemistry / Q000276:immunology; D006801:Humans; D053118:Influenza A Virus, H1N1 Subtype / Q000276:immunology* / Q000502:physiology; D007252:Influenza Vaccines / Q000276:immunology* / Q000494:pharmacology*; D007251:Influenza, Human / Q000453:epidemiology / Q000276:immunology / Q000517:prevention & control; D008168:Lung / Q000473:pathology; D023421:Models, Animal; D009439:Neuraminidase / Q000737:chemistry / Q000276:immunology; D009976:Orthomyxoviridae Infections / Q000276:immunology* / Q000473:pathology / Q000517:prevention & control*; D055503:Protein Multimerization; D012995:Solubility; D013552:Swine / Q000821:virology; D014614:Vaccines, Synthetic / Q000276:immunology / Q000494:pharmacology; D014779:Virus Replication
chemical_list: D000914:Antibodies, Viral; D019267:Hemagglutinin Glycoproteins, Influenza Virus; D007252:Influenza Vaccines; D014614:Vaccines, Synthetic; D009439:Neuraminidase