title: Differential antigen requirements for protection against systemic and intranasal vaccinia virus challenges in mice.
abstract: The development of a subunit vaccine for smallpox represents a potential strategy to avoid the safety concerns associated with replication-competent vaccinia virus. Preclinical studies to date with subunit smallpox vaccine candidates, however, have been limited by incomplete information regarding protective antigens and the requirement for multiple boost immunizations to afford protective immunity. Here we explore the protective efficacy of replication-incompetent, recombinant adenovirus serotype 35 (rAd35) vectors expressing the vaccinia virus intracellular mature virion (IMV) antigens A27L and L1R and extracellular enveloped virion (EEV) antigens A33R and B5R in a murine vaccinia virus challenge model. A single immunization with the rAd35-L1R vector effectively protected mice against a lethal systemic vaccinia virus challenge. The rAd35-L1R vector also proved more efficacious than the combination of four rAd35 vectors expressing A27L, L1R, A33R, and B5R. Moreover, serum containing L1R-specific neutralizing antibodies afforded postexposure prophylaxis after systemic vaccinia virus infection. In contrast, the combination of rAd35-L1R and rAd35-B5R vectors was required to protect mice against a lethal intranasal vaccinia virus challenge, suggesting that both IMV- and EEV-specific immune responses are important following intranasal infection. Taken together, these data demonstrate that different protective antigens are required based on the route of vaccinia virus challenge. These studies also suggest that rAd vectors warrant further assessment as candidate subunit smallpox vaccines.
authors.affiliation: Division of Viral Pathogenesis, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
authors.forename: David R
authors.initials: DR
authors.lastname: Kaufman
authors.forename: Jaap
authors.initials: J
authors.lastname: Goudsmit
authors.forename: Lennart
authors.initials: L
authors.lastname: Holterman
authors.forename: Bonnie A
authors.initials: BA
authors.lastname: Ewald
authors.forename: Matthew
authors.initials: M
authors.lastname: Denholtz
authors.forename: Colleen
authors.initials: C
authors.lastname: Devoy
authors.forename: Ayush
authors.initials: A
authors.lastname: Giri
authors.forename: Lauren E
authors.initials: LE
authors.lastname: Grandpre
authors.forename: Jean-Michel
authors.initials: JM
authors.lastname: Heraud
authors.forename: Genoveffa
authors.initials: G
authors.lastname: Franchini
authors.forename: Michael S
authors.initials: MS
authors.lastname: Seaman
authors.forename: Menzo J E
authors.initials: MJ
authors.lastname: Havenga
authors.forename: Dan H
authors.initials: DH
authors.lastname: Barouch
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D000914:Antibodies, Viral / Q000097:blood / Q000627:therapeutic use; D001835:Body Weight; D018890:Chemoprevention / Q000379:methods; D004481:Ectromelia virus / Q000235:genetics; D004797:Enzyme-Linked Immunosorbent Assay; D005822:Genetic Vectors; D008562:Membrane Glycoproteins / Q000235:genetics / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D009500:Neutralization Tests; D012899:Smallpox / Q000276:immunology* / Q000517:prevention & control*; D012900:Smallpox Vaccine / Q000235:genetics / Q000276:immunology*; D014616:Vaccinia virus / Q000276:immunology*; D014759:Viral Envelope Proteins / Q000235:genetics / Q000276:immunology; D014764:Viral Proteins / Q000235:genetics / Q000276:immunology
chemical_list: C110360:A27L protein, Orthopoxvirus; C446940:A33R protein, Vaccinia virus; D000914:Antibodies, Viral; C087715:L1R protein, Vaccinia virus; D008562:Membrane Glycoproteins; D012900:Smallpox Vaccine; D014759:Viral Envelope Proteins; D014764:Viral Proteins; C074512:42kDa protein, Vaccinia virus