Oral Abstract Session 01 - Global HIV Vaccine Enterprise

Topic 4: Clinical Vaccine Trials and Trial Site Challenges
P04.25 LB
rAd5/NYVAC-B is Superior to NYVAC-B/rAd5 and is
Dependent on rAd5 Dose for Neutralizing Antibody
Responses Against HIV-1
D.C. Montefiori 1 , Y. Huang 2 , S. Karuna 3 , M. Allen 4 , N. Kochar 2 ,
S. Chappuis 5 , J. Gaillard 5 , G. Tomaras 1 , B. Graham 6 , P. Bart 5 ,
G. Pantaleo 5
1 Duke University Medical Center, Durham, NC, USA; 2 SCHARP,
Seattle, WA, USA; 3 Fred Hutchinson Cancer Research Center/
HVTN, Seattle, WA, USA; 4 NIAID-NIH, Bethesda, MD, USA;
5 Lausanne University Hospital, Switzerland; 6 Vaccine Research
Center, NIH, Bethesda, MD, USA
Background: HVTN 078 is a phase 1b clinical trial of heterologous
vector prime/boost vaccine regimens (NYVAC-B/rAd5 vs. rAd5/
NYVAC-B) in healthy, HIV-1 uninfected, Ad5 seronegative adults.
The rAd5 expressed a clade B Gag-Pol fusion protein and secreted
gp140s of HIV-1 strains 92RW020 (clade A), HxB2/Bal-V3/_V1V2
(clade B) and 97ZA012 (clade C). The NYVAC-B expressed a clade
B Gag-Pol-Nef polyprotein and the secreted gp120 of Bx08
(clade B). A total of 80 participants were randomized into a
placebo group (P) and four treatment groups: T1, 2x NYVAC-B/1x
rAd5 (1010 ); T2, 1x rAd5 (108 )/2x NYVAC-B; T3, 1x rAd5 (109 )/2x
NYVAC-B; T4, 1x rAd5 (1010 )/2x NYVAC-B.
Methods: Binding and neutralizing antibodies were assessed at 2
weeks post-final boosting. Neutralization was assessed with tier
1 and tier 2 Env-pseudotyped viruses in TZM-bl cells, and with
tier 2 Env.IMC.LucR viruses in A3R5 cells.
Results: A dose effect for increasing anti-Env binding antibodies
was seen, with higher doses of rAd5 being optimal. For neutralizing
antibodies, positive response rates/median titers across the
treatment groups were highest against MN.3 (69.3%/116)
followed by SF162.LS (42.1%/54), BaL.26 (18.4%/15.5),
MW965.26 (14.5%/31) and Bx08.16 (11.8%/19.5). Five subjects
neutralized all 5 tier 1 viruses, 5 subjects neutralized 4 viruses, 7
subjects neutralized 3 viruses, 14 subjects neutralized 2 viruses
(MN.3 and SF162.LS) and 18 subjects neutralized 1 virus (MN.3).
Aggregate magnitude-breadth scores across the tier 1 panel
were strongest for T4 followed by T3, T1 and T2. Differences
were significant for T1 vs. T3 (p=0.048) and T1 vs. T4 (p=0.004).
Responses against tier 2 viruses were weak and sporadic in the
A3R5 assay and were nearly absent in the TZM-bl assay.
Conclusion: A 10 10 dose of rAd5 was superior to the two lower
doses of 109 and 108 for both binding and neutralizing antibodies.
At the highest rAd5 dose tested, rAd5/NYVAC-B was superior to
NYVAC-B/rAd5 for neutralizing antibodies.
P04.26 LB
AIDS Vaccine 2012
Posters
DNA Plasmid HIV Vaccine Design, Number Of Doses,
Participant Gender, And Body Mass Index Affect
T-Cell Responses Across HIV Vaccine Clinical Trials
C. Morgan 1 , X. Jin 2 , X. Yu 1 , S. De Rosa 1 , J. Kublin 1 , B. Metch 1 ,
M. Keefer 2 , The NIAID HIV Vaccine Trials Network 1
1 HIV Vaccine Trials Network / Fred Hutchinson Cancer
Research Center, Seattle, WA, USA; 2 University of Rochester
Medical Center, Rochester, NY, USA
Background: Numerous studies have evaluated individual DNA
plasmid vaccines. We evaluated data from 10 HIV vaccine clinical
trials that utilized common, validated immunogenicity assays
to objectively investigate factors that influence DNA plasmidinduced
T-cell responses.
Methods: This retrospective analysis included data from 1218
healthy, HIV-1 uninfected adults enrolled in 10 DNA HIV vaccine
clinical trials conducted within the HIV Vaccine Trials Network.
HIV-specific T-cell responses from peripheral blood mononuclear
cells were measured using validated IFN-γ ELISpot and
intracellular cytokine staining assays. The effects of DNA vaccine
HIV antigens, number of doses, gender, body mass index (BMI),
and age were evaluated.
Results: When plasmids expressing Gag, Env and Pol were coadministered,
the highest T-cell response rate was against Env
(38.1%) and much less to Gag (4.6%) or Pol (4.5%). Comparing 2,
3, and 4 DNA injections, 3 vaccinations compared to 2 improved
the magnitude of Env-specific CD8+ T-cell response (p=0.048), but
not CD4+ T-cell responses, and a 4th vaccination had no additional
effect. HIV-specific CD4+ T-cell response rates were higher in
females (50.9%) than in males (27.7%, p=0.0002). Having lower BMI
(p=0.025) was independently associated with higher HIV-specific
CD4+ T-cell response rates. There were no significant differences
in HIV-specific CD8+ T-cell response frequencies by gender or BMI.
Lower HIV-specific CD4+ T-cell responses were seen with the 18-
20 (36.4%) and 41-50 (23.3%) age groups compared to the 21-30
(44.0%) and 31-40 (41.%) groups, but these differences were not
significant (p=0.0565) and no differences were seen in HIV-specific
CD8+ T-cell responses by age.
Conclusion: Pooled data across DNA HIV vaccine clinical trials
indicate that plasmid inserts, number of doses, gender, and BMI
can affect T-cell responses. These factors should be considered in
vaccine research.
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POSTERS