Oral Abstract Session 01 - Global HIV Vaccine Enterprise

ORAL ABSTRACT SESSIONS
80
Oral Abstract Sessions
Oral Abstract Session 09: Clinical Trials
OA09.03
First-in-Human Phase 1 Trial of the Safety and
Immunogenicity of a Recombinant Adenovirus
Serotype 5 HVR48 (rAd5HVR48) HIV-1 Vaccine
S.R. Walsh 1 , M.S. Seaman 1 , J.A. Johnson 2 , R.P. Tucker 2 ,
K.H. Krause 2 , M. Weijtens 3 , M.G. Pau 3 , J. Goudsmit 3 , R. Dolin 1 ,
D.H. Barouch 4 , L.R. Baden 2
1 Beth Israel Deaconess Medical Center, Boston, MA, USA;
2 Brigham & Women’s Hospital, Boston, MA, USA; 3 Crucell,
Leiden, Netherlands; 4 Ragon Institute of MGH, MIT and
Harvard, Boston, MA, USA
Background: Adenovirus serotype 5 (Ad5) is a potent vector,
but widespread seroprevalence may limit its potential use.
Replacement of the hexon variable regions (HVR) of Ad5 with
the HVR of the less prevalent Ad48 may result in a potent vector
which bypasses pre-existing vector immunity.
Methods: Recombinant Ad5 with seven HVRs derived from
Ad48 and expressing the VRC EnvA test antigen (rAd5HVR48.
ENVA) was made. 48 healthy volunteers who were seronegative
to Ad5, Ad48, HIV-1, and HIV-2 were enrolled in a randomized,
double-blind, placebo-controlled, dose-escalation phase 1 study.
The first three groups of 12 subjects received doses of 109 , 10 10 ,
or 1011 vp of rAd5HVR48.ENVA vector (n=10/group) or placebo
(n=2/group) at weeks 0, 4, and 24 and the fourth group received
a single injection of 10 10 vp or placebo. We performed prespecified
blinded immunogenicity analyses at day 56 and day
196 after the first immunization.
Results: 31/48 (65%) of subjects were female; median age at
enrollment was 24 (range: 18-50). Vaccination was generally well
tolerated: mild to moderate local and systemic reactogenicity
was observed after the initial immunization, more commonly
in the highest dose group, but typically resolved within 24h.
No vaccine-associated SAEs occurred. In all four dose groups,
10 subjects per group developed positive EnvA-specific ELISA
titers and EnvA-specific interferon-gamma ELISPOT responses
following vaccination. Immune responses were seen two weeks
following inoculation in the majority of subjects. Two subjects per
group exhibited no vector- or insert-specific immune responses
at any timepoint and are presumed placebo recipients.
Conclusion: The rAd5HVR48 vector is generally safe and
immunogenic in humans at all three doses. Immune responses
against EnvA could be detected two weeks following the first
inoculation. Ad5HVR48 is a promising new chimeric vector to
evaluate novel inserts in further clinical trials.
AIDS Vaccine 2012
OA09.04
Antibody-Mediated Inhibition of HIV-1 Elicited by
HIV-I DNA Priming and Boosting with Heterologous
HIV-1 Recombinant MVA in Healthy Tanzanian Adults
A. Joachim 1 , C. Nilsson 2 , S. Aboud 1 , E.F. Lyamuya 1 , M. Robb 3 ,
M. Marovich 4 , C. Ochsenbauer 5 , B. Wahren 2 , E. Sandström 6 ,
G. Biberfeld 2 , G. Ferrari 7 , V.R. Polonis 5
1 Muhimbili University of Health and Allied Sciences (MUHAS),
Dar es Salaam, United Republic of Tanzania; 2 Karolinska
Institutet / Institute for Infectious Disease Control (SMI),
Stockholm, Sweden; 3 The Henry M. Jackson Foundation,
Rockville, MD, USA; 4 Walter Reed Army Institute of Research
(WRAIR), Rockville, MD, USA; 5 Department of Medicine,
University of Alabama at Birmingham, Birmingham, AL, USA;
6 Venhälsan, Karolinska Institutet (KI) at Södersjukhuset,
Stockholm, Sweden; 7 Department of Surgery, Duke University
Medical Center, Durham, NC, USA
Background: We evaluated HIV antibody (Ab) responses
elicited by immunization, in a phase I/II placebo-controlled
double blind trial using multiclade, multigene HIV-1-DNA prime
boosted with HIV-MVA conducted among healthy volunteers in
Tanzania (HIVIS03).
Methods: Sixty HIV-uninfected volunteers, randomized into
groups of 20 received placebo or 1 mg HIV-DNA intradermally
(id) or 3.8 mg intramuscularly (im). DNA plasmids containing HIV-
1 gp160 subtypes A, B, C; rev B; p17/p24 gag A, B and RTmut B
were given at months 0, 1 and 3 using a needle-free Biojector
device. HIV-MVA expressing CRF01_AE HIV-1 env, gag, pol was
administered im by needle at months 9 and 21. Sera were
tested at baseline, two months post-first and four weeks postsecond
HIV-MVA boosting. HIV Ab responses were tested using
pseudoviruses and TZM-bl cells as well as luciferase-expressing
infectious molecular clones (IMC-LucR) in PBMC-based
assays. ADCC responses were tested using the flow cytometry
GranToxiLux-based assay.
Results: Neutralizing Ab activity was demonstrated only in the
PBMC assay, and after the second MVA boost in 24 (83%) of 29
vaccinees against the clade CRF01_AE CM235 IMC and in 21 (72%)
of 29 vaccinees against clade B SF162-IMC. NK cell depletion
from PBMC targets resulted in a significant loss of HIV inhibition
by vaccinee sera, indicating a role of Ab-mediated Fcγ-receptor
function. Vaccine-induced ADCC responses were detected in 21
(75%) of 28 vaccinees after the second HIV-MVA boost. ADCC
Ab titers did not differ significantly between id- (median 840,
range 300-5400) and im-primed (median 880, range 400-3600)
vaccinees (p=0.45).
Conclusion: HIV-DNA priming followed by two HIV-MVA boosts
elicited HIV-specific inhibitory and/or ADCC-mediating antibody
responses in a high proportion of Tanzanian adults.