title: Antibody-mediated protection against mucosal simian-human immunodeficiency virus challenge of macaques immunized with alphavirus replicon particles and boosted with trimeric envelope glycoprotein in MF59 adjuvant.
abstract: We have previously shown that rhesus macaques were partially protected against high-dose intravenous challenge with simian-human immunodeficiency virus SHIV(SF162P4) following sequential immunization with alphavirus replicon particles (VRP) of a chimeric recombinant VEE/SIN alphavirus (derived from Venezuelan equine encephalitis virus [VEE] and the Sindbis virus [SIN]) encoding human immunodeficiency virus type 1 HIV-1(SF162) gp140DeltaV2 envelope (Env) and trimeric Env protein in MF59 adjuvant (R. Xu, I. K. Srivastava, C. E. Greer, I. Zarkikh, Z. Kraft, L. Kuller, J. M. Polo, S. W. Barnett, and L. Stamatatos, AIDS Res. Hum. Retroviruses 22:1022-1030, 2006). The protection did not require T-cell immune responses directed toward simian immunodeficiency virus (SIV) Gag. We extend those findings here to demonstrate antibody-mediated protection against mucosal challenge in macaques using prime-boost regimens incorporating both intramuscular and mucosal routes of delivery. The macaques in the vaccination groups were primed with VRP and then boosted with Env protein in MF59 adjuvant, or they were given VRP intramuscular immunizations alone and then challenged with SHIV(SF162P4) (intrarectal challenge). The results demonstrated that these vaccines were able to effectively protect the macaques to different degrees against subsequent mucosal SHIV challenge, but most noteworthy, all macaques that received the intramuscular VRP prime plus Env protein boost were completely protected. A statistically significant association was observed between the titer of virus neutralizing and binding antibodies as well as the avidity of anti-Env antibodies measured prechallenge and protection from infection. These results highlight the merit of the alphavirus replicon vector prime plus Env protein boost vaccine approach for the induction of protective antibody responses and are of particular relevance to advancing our understanding of the potential correlates of immune protection against HIV infection at a relevant mucosal portal of entry.
authors.affiliation: Novartis Vaccines and Diagnostics, 350 Massachusetts Avenue, Cambridge, MA 02139, USA. susan.barnett@novartis.com
authors.forename: Susan W
authors.initials: SW
authors.lastname: Barnett
authors.forename: Brian
authors.initials: B
authors.lastname: Burke
authors.forename: Yide
authors.initials: Y
authors.lastname: Sun
authors.forename: Elaine
authors.initials: E
authors.lastname: Kan
authors.forename: Harold
authors.initials: H
authors.lastname: Legg
authors.forename: Ying
authors.initials: Y
authors.lastname: Lian
authors.forename: Kristen
authors.initials: K
authors.lastname: Bost
authors.forename: Fengmin
authors.initials: F
authors.lastname: Zhou
authors.forename: Amanda
authors.initials: A
authors.lastname: Goodsell
authors.forename: Jan
authors.initials: J
authors.lastname: Zur Megede
authors.forename: John
authors.initials: J
authors.lastname: Polo
authors.forename: John
authors.initials: J
authors.lastname: Donnelly
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Ulmer
authors.forename: Gillis R
authors.initials: GR
authors.lastname: Otten
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Miller
authors.forename: Michael
authors.initials: M
authors.lastname: Vajdy
authors.forename: Indresh K
authors.initials: IK
authors.lastname: Srivastava
mesh_terms: D016915:AIDS Vaccines / Q000008:administration & dosage / Q000276:immunology; D000276:Adjuvants, Immunologic / Q000008:administration & dosage; D000524:Alphavirus / Q000235:genetics / Q000276:immunology*; D000818:Animals; D000914:Antibodies, Viral / Q000097:blood / Q000276:immunology*; D002460:Cell Line; D004195:Disease Models, Animal; D015658:HIV Infections / Q000276:immunology / Q000517:prevention & control* / Q000821:virology; D015497:HIV-1 / Q000235:genetics / Q000276:immunology; D006801:Humans; D007114:Immunization; D008251:Macaca; D008297:Male; D011136:Polysorbates / Q000008:administration & dosage; D012093:Replicon; D015302:Simian Immunodeficiency Virus / Q000235:genetics / Q000276:immunology*; D013185:Squalene / Q000008:administration & dosage / Q000276:immunology; D054299:env Gene Products, Human Immunodeficiency Virus / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology*
chemical_list: D016915:AIDS Vaccines; D000276:Adjuvants, Immunologic; D000914:Antibodies, Viral; C089950:MF59 oil emulsion; D011136:Polysorbates; D054299:env Gene Products, Human Immunodeficiency Virus; D013185:Squalene
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