title: Broad and potent immune responses to a low dose intradermal HIV-1 DNA boosted with HIV-1 recombinant MVA among healthy adults in Tanzania.
abstract: BACKGROUND
  We conducted a phase I/II randomized placebo-controlled trial with the aim of exploring whether priming with a low intradermal dose of a multiclade, multigene HIV-1 DNA vaccine could improve the immunogenicity of the same vaccine given intramuscularly prior to boosting with a heterologous HIV-1 MVA among healthy adults in Dar es Salaam, Tanzania.
  
  
  METHODS
  Sixty HIV-uninfected volunteers were randomized to receive DNA plasmid vaccine 1mg intradermally (id), n=20, or 3.8mg intramuscularly (im), n=20, or placebo, n=20, using a needle-free injection device. DNA plasmids encoding HIV-1 genes gp160 subtype A, B, C; rev B; p17/p24 gag A, B and Rtmut B were given at weeks 0, 4 and 12. Recombinant MVA (10(8)pfu) expressing HIV-1 Env, Gag, Pol of CRF01_AE or placebo was administered im at month 9 and 21.
  
  
  RESULTS
  The vaccines were well tolerated. Two weeks after the third HIV-DNA injection, 22/38 (58%) vaccinees had IFN-γ ELISpot responses to Gag. Two weeks after the first HIV-MVA boost all 35 (100%) vaccinees responded to Gag and 31 (89%) to Env. Two to four weeks after the second HIV-MVA boost, 28/29 (97%) vaccinees had IFN-γ ELISpot responses, 27 (93%) to Gag and 23 (79%) to Env. The id-primed recipients had significantly higher responses to Env than im recipients. Intracellular cytokine staining for Gag-specific IFN-γ/IL-2 production showed both CD8(+) and CD4(+) T cell responses. All vaccinees had HIV-specific lymphoproliferative responses. All vaccinees reacted in diagnostic HIV serological tests and 26/29 (90%) had antibodies against gp160 after the second HIV-MVA boost. Furthermore, while all of 29 vaccinee sera were negative for neutralizing antibodies against clade B, C and CRF01_AE pseudoviruses in the TZM-bl neutralization assay, in a PBMC assay, the response rate ranged from 31% to 83% positives, depending upon the clade B or CRF01_AE virus tested.
  
  
  CONCLUSIONS
  This vaccine approach is safe and highly immunogenic. Low dose, id HIV-DNA priming elicited higher and broader cell-mediated immune responses to Env after HIV-MVA boost compared to a higher HIV-DNA priming dose given im. Three HIV-DNA priming immunizations followed by two HIV-MVA boosts efficiently induced Env-antibody responses.
authors.affiliation: Department of Internal Medicine, Muhimbili University of Health and Allied Sciences, Dar es Salaam, Tanzania. drbakari@yahoo.com
authors.forename: Muhammad
authors.initials: M
authors.lastname: Bakari
authors.forename: Said
authors.initials: S
authors.lastname: Aboud
authors.forename: Charlotta
authors.initials: C
authors.lastname: Nilsson
authors.forename: Joel
authors.initials: J
authors.lastname: Francis
authors.forename: Deus
authors.initials: D
authors.lastname: Buma
authors.forename: Candida
authors.initials: C
authors.lastname: Moshiro
authors.forename: Eric A
authors.initials: EA
authors.lastname: Aris
authors.forename: Eligius F
authors.initials: EF
authors.lastname: Lyamuya
authors.forename: Mohamed
authors.initials: M
authors.lastname: Janabi
authors.forename: Karina
authors.initials: K
authors.lastname: Godoy-Ramirez
authors.forename: Agricola
authors.initials: A
authors.lastname: Joachim
authors.forename: Victoria R
authors.initials: VR
authors.lastname: Polonis
authors.forename: Andreas
authors.initials: A
authors.lastname: Bråve
authors.forename: Patricia
authors.initials: P
authors.lastname: Earl
authors.forename: Merlin
authors.initials: M
authors.lastname: Robb
authors.forename: Mary
authors.initials: M
authors.lastname: Marovich
authors.forename: Britta
authors.initials: B
authors.lastname: Wahren
authors.forename: Kisali
authors.initials: K
authors.lastname: Pallangyo
authors.forename: Gunnel
authors.initials: G
authors.lastname: Biberfeld
authors.forename: Fred
authors.initials: F
authors.lastname: Mhalu
authors.forename: Eric
authors.initials: E
authors.lastname: Sandström
mesh_terms: D016915:AIDS Vaccines / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology*; D000163:Acquired Immunodeficiency Syndrome / Q000276:immunology / Q000517:prevention & control / Q000821:virology; D000293:Adolescent; D000328:Adult; D049109:Cell Proliferation; D004337:Drug Carriers; D058501:Enzyme-Linked Immunospot Assay; D005260:Female; D005822:Genetic Vectors; D015497:HIV-1 / Q000235:genetics / Q000276:immunology*; D006805:Human Experimentation; D006801:Humans; D007117:Immunization, Secondary / Q000379:methods*; D007271:Injections, Intradermal; D007371:Interferon-gamma / Q000096:biosynthesis / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000276:immunology; D008297:Male; D009500:Neutralization Tests; D010919:Placebos / Q000008:administration & dosage; D010957:Plasmids; D013636:Tanzania; D014611:Vaccination / Q000379:methods*; D019444:Vaccines, DNA / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology*; D014614:Vaccines, Synthetic / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology; D014616:Vaccinia virus / Q000235:genetics*; D014764:Viral Proteins / Q000235:genetics; D014765:Viral Vaccines / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology*; D055815:Young Adult
chemical_list: D016915:AIDS Vaccines; D004337:Drug Carriers; D010919:Placebos; D019444:Vaccines, DNA; D014614:Vaccines, Synthetic; D014764:Viral Proteins; D014765:Viral Vaccines; D007371:Interferon-gamma