Oral Abstract Session 01 - Global HIV Vaccine Enterprise

Oral Abstract Session 09: Clinical Trials
OA09.05
A First-in-Man, Double Blind, Placebo Controlled
Study of the Candidate Therapeutic Vaccine Opal-
HIV-Gag(c) in HIV Infected Patients Receiving HAART
A.G. Jackson 1 , H.N. Kløverpris 1 , A. Handley 1 , P. Hayes 1 ,
J. Gilmour 1 , M. Atkins 1 , B. Walker 1 , J. Ackland 1 , M. Sullivan 1 ,
P. Goulder 1
1St. Stephen’s AIDS Trust, London, United Kingdom (Great
Britain)
Background: Preclinical studies of overlapping 15mer peptides
spanning SIV, SHIV or HIV pulsed autologously ex vivo have
demonstrated high level, virus-specific T cells responses and viral
load suppression in Macaca nemestrina. The objective of this
study was to evaluate the safety and preliminary immunogenicity
of Clade C consensus peptides administered ex vivo to HIV
positive adults.
Methods: Synthetic 15mer peptides (n=123, Opal-HIV-Gag(c))
spanning Clade C, consensus Gag were manufactured to current
good manufacturing practice and evaluated in a good laboratory
practice toxicology study in Macaca mulatta. A first-in-human,
single centre, placebo-controlled, double-blind, dose escalation
study was conducted. Twenty three people with well controlled
HIV (CD4+ > 350cells/mm3 and a HIV < 400 copies/mL),
stratified by clade, were enrolled in four groups: 12mg (n=6),
24mg (n=7), 48mg (n=2) or matching placebo (n=8). Treatment
was administered intravenously bedside (closed system) by
enrichment of 120mL of whole blood for WBCs using a Sepax
S-100 device, ex vivo mixing the peptides (or diluent alone) and
incubation at 37°C for one hour prior to reinfusion. Subjects
received 4 administrations at 4 weekly intervals followed by a
12 week post-treatment follow up. Immunogencity was assessed
by ELIspot.
Results: Opal-HIV-Gag(c) was generally well tolerated at doses
of 12 and 24mg. There was an increased incidence of temporally
associated pyrexia, chills, rigor, and transient/self-limiting
lymphopenia in Opal-HIV-Gag(c) recipients compared to placebo.
Only 2 subjects were recruited to the 48mg cohort. A serious
adverse event of anuria, hypotension and tachycardia secondary
to diarrhoea occurred following a single dose of vaccine at 48mg.
No difference in ex vivo IFN-γ ELISpot response was observed at
any time.
Conclusion: An infectious cause for the event could not be
identified, leaving the possibility of immunologically-mediated
reaction to the vaccine thus leading to early termination of
the study.
Oral Abstract Sessions
OA09.06 LB
Multiple Antibody Specificities (gp41, V1V2, and V3)
Elicited in the Phase II Multiclade (A, B, C) HIV-1 DNA
Prime, rAd5 Boost Vaccine Trial
W.B. Williams 1 , K. Jones 1 , A. Krambrink 2 , D. Grove 2 , P. Liu 1 ,
N.L. Yates 1 , M.A. Moody 1 , G. Ferrari 1 , J. Pollara 1 , Z. Moodie 2 ,
C.A. Morgan 2 , H. Liao 1 , D.C. Montefiori 1 , C. Ochsenbauer 3 ,
J. Kappes 3 , S. Hammer 4 , J. Mascola 5 , R. Koup 5 , L. Corey 6 ,
G. Nabel 5 , P. Gilbert 2 , G. Churchyard 7 , M. Keefer 8 , B.S. Graham 5 ,
B.F. Haynes 1 , G.D. Tomaras 1
1 Duke Human Vaccine Institute, Duke University Medical
Center, Durham, NC, USA; 2 SCHARP, Fred Hutchinson Cancer
Research Center, Seattle, WA, USA; 3 Department of Medicine,
University of Alabama at Birmingham, Birmingham, AL, USA;
4 Columbia University Medical Center, New York, NY, USA;
5 Vaccine Research Center, National Institute of Allergy and
Infectious, Bethesda, MD, USA; 6 University of Washington,
Seattle, WA, USA; 7 The Aurum Institute, Johannesburg, South
Africa; 8 Division of Infectious Disease, University of Rochester
Medical Center, Rochester, NY, USA
Background: The phase II DNA prime, rAd5 boost vaccine (HVTN
204) exhibited sufficient safety and immunogenicity to advance
into a phase IIb efficacy trial (HVTN 505) in Ad5 seronegative
volunteers in the US. In the RV144 ALVAC prime, A/E gp120
protein boost trial, levels of V1V2 IgG antibodies significantly
correlated with decreased risk of infection.
Methods: Sera from 203 vaccinees receiving VRC-HIVDNA016-
00-VP DNA (m 0,1,2), and VRC-HIVADV014-00-VP rAd5 (m 6), at
two weeks post rAd5 boost, and 208 placebos were examined
for binding gp140 and gp120 recombinant proteins, gp41, and
an antigen panel of 16 V1V2 IgG scaffolds representing clades A,
B and C V1V2 sequences. A subset of vaccinees and placebo was
screened for binding CD4BS antigens. Monoclonal antibodies
were generated from antigen specific memory B cell sorts and
tested for binding, neutralization, ADCC and virion capture.
Results: Clade A and B V1V2 IgG antibodies were elicited in
38.4% and 19.2% of vaccinees, respectively. A clonal lineage
of 3 gp41 mAbs (CH69, CH70, CH71), and a V3-specific gp120
mAb (CH73) were generated from vaccinees. The gp41 mAbs
captured infectious HIV-1 transmitted/founder viruses, while
CH73 mediated ADCC activity against subtypes B and C infected
cells, neutralized subtypes B and C tier 1A viruses, and bound
multiple Envs of subtypes A, B and C.
Conclusion: The phase II multi-clade DNA prime, rAd5 boost
vaccine regimen elicited antibody responses to multiple epitope
specificities, including V1V2, V3, and gp41. CH69-CH71 and CH73
mAbs represent the initial human mAbs from HVTN 204 vaccine
recipients, and reflect the functional profile of vaccine-elicited
antibodies. These data suggest that the HVTN 505 Phase IIb
efficacy study using this same vaccine regimen may provide an
opportunity to examine a diversity of antibody specificities that
have been hypothesized as a correlate of HIV-1 infection risk.
AIDS Vaccine 2012
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ORAL ABSTRACT SESSIONS