title: Low-dose penile SIVmac251 exposure of rhesus macaques infected with adenovirus type 5 (Ad5) and then immunized with a replication-defective Ad5-based SIV gag/pol/nef vaccine recapitulates the results of the phase IIb step trial of a similar HIV-1 vaccine.
abstract: The Step Trial showed that the MRKAd5 HIV-1 subtype B Gag/Pol/Nef vaccine did not protect men from HIV infection or reduce setpoint plasma viral RNA (vRNA) levels but, unexpectedly, it did modestly enhance susceptibility to HIV infection in adenovirus type 5 (Ad5)-seropositive, uncircumcised men. As part of the process to understand the results of the Step Trial, we designed a study to determine whether rhesus macaques chronically infected with a host-range mutant Ad5 (Ad5hr) and then immunized with a replication defective Ad5 SIVmac239 Gag/Pol/Nef vaccine were more resistant or susceptible to SIV infection than unimmunized rhesus macaques challenged with a series of escalating dose penile exposures to SIVmac 251. The Ad5 SIV vaccine induced CD8(+) T cell responses in 70% of the monkeys, which is similar to the proportion of humans that responded to the vaccine in the Step Trial. However, the vaccine did not protect vaccinated animals from penile SIV challenge. At the lowest SIV exposure dose (10(3) 50% tissue culture infective doses), 2 of 9 Ad5-seropositive animals immunized with the Ad5 SIV vaccine became infected compared to 0 of 34 animals infected in the other animal groups (naive animals, Ad5-seropositive animals immunized with the empty Ad5 vector, Ad5-seronegative animals immunized with the Ad5 SIV vaccine, and Ad5-seronegative animals immunized with the empty Ad5 vector). Penile exposure to more concentrated virus inocula produced similar rates of infection in all animal groups. Although setpoint viral loads were unaffected in Step vaccinees, the Ad5 SIV-immunized animals had significantly lower acute-phase plasma vRNA levels compared to unimmunized animals. Thus, the results of the nonhuman primate (NHP) study described here recapitulate the lack of protection against HIV acquisition seen in the Step Trial and suggest a greater risk of infection in the Ad5-seropositive animals immunized with the Ad5 SIV vaccine. Further studies are necessary to confirm the enhancement of virus acquisition and to discern associated mechanisms.
authors.affiliation: Center for Comparative Medicine, University of California, Davis, California, USA.
authors.forename: Huma
authors.initials: H
authors.lastname: Qureshi
authors.forename: Zhong-Min
authors.initials: ZM
authors.lastname: Ma
authors.forename: Ying
authors.initials: Y
authors.lastname: Huang
authors.forename: Gregory
authors.initials: G
authors.lastname: Hodge
authors.forename: Michael A
authors.initials: MA
authors.lastname: Thomas
authors.forename: Janet
authors.initials: J
authors.lastname: DiPasquale
authors.forename: Veronique
authors.initials: V
authors.lastname: DeSilva
authors.forename: Linda
authors.initials: L
authors.lastname: Fritts
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Bett
authors.forename: Danilo R
authors.initials: DR
authors.lastname: Casimiro
authors.forename: John W
authors.initials: JW
authors.lastname: Shiver
authors.forename: Marjorie
authors.initials: M
authors.lastname: Robert-Guroff
authors.forename: Michael N
authors.initials: MN
authors.lastname: Robertson
authors.forename: Michael B
authors.initials: MB
authors.lastname: McChesney
authors.forename: Peter B
authors.initials: PB
authors.lastname: Gilbert
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Miller
mesh_terms: D016915:AIDS Vaccines / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology*; D000260:Adenoviruses, Human / Q000235:genetics / Q000502:physiology; D000818:Animals; D000914:Antibodies, Viral / Q000276:immunology; D003673:Defective Viruses / Q000235:genetics / Q000502:physiology; D004195:Disease Models, Animal; D015686:Gene Products, env / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology*; D015683:Gene Products, gag / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology*; D015693:Gene Products, nef / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology*; D005822:Genetic Vectors / Q000235:genetics / Q000378:metabolism; D006678:HIV / Q000235:genetics / Q000276:immunology; D015658:HIV Infections / Q000276:immunology / Q000517:prevention & control* / Q000821:virology; D015497:HIV-1 / Q000235:genetics / Q000276:immunology; D006801:Humans; D007114:Immunization; D008253:Macaca mulatta; D008297:Male; D018449:SAIDS Vaccines / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology*; D016097:Simian Acquired Immunodeficiency Syndrome / Q000276:immunology / Q000517:prevention & control* / Q000821:virology; D015302:Simian Immunodeficiency Virus / Q000235:genetics / Q000276:immunology*
chemical_list: D016915:AIDS Vaccines; D000914:Antibodies, Viral; D015686:Gene Products, env; D015683:Gene Products, gag; D015693:Gene Products, nef; D018449:SAIDS Vaccines