Oral Abstract Session 01 - Global HIV Vaccine Enterprise

ORAL ABSTRACT SESSIONS
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Oral Abstract Sessions
Oral Abstract Session 02: Vaccine Concepts – Protein Immunogens
OA02.01
Identification of a Clade A HIV Envelope Immunogen
from Protocol G That Elicits Neutralizing Antibodies
to Tier 2 Viruses
S. Hoffenberg 1 , S. Kosakovsky Pond 2 , A. Carpov 1 , D. Wagner 1 ,
A. Wilson 1 , R. Powell 1 , R. Lindsay 1 , H. Arendt 1 , J. DeStefano 1 ,
P. Poignard 1 , M. Simek 1 , S. Fling 1 , S. Phogat 1 , C. Labranche 3 ,
D. Montefiori 3 , D. Burton 4 , C. Parks 1 , C. King 1 , W. Koff 1 ,
M. Caulfield 1
1 International AIDS Vaccine Initiative, Brooklyn, NY, USA;
2 University of California San Diego, San Diego, CA, USA; 3 Duke
University, Durham, NC, USA; 4 The Scripps Research Institute,
La Jolla, CA, USA
Background: Broadly neutralizing antibodies PG9 and PG16 have
been isolated from the B cells of one clade A-infected individual
from IAVI Protocol G. PG16 is relatively trimer-specific whereas
PG9 binds trimer preferentially, but can bind monomeric gp120
from several viral isolates. Both antibodies are potent neutralizers
that recognize greater than 70% of tier 2 pseudovirues in the
TZM-bl assay. We sought to begin immunogen design efforts
based on sequences from the Protocol G donor, however all
viruses isolated from the donor were resistant to neutralization
by PG9 and PG16. We used a bioinformatics approach to infer
the most recent common ancestor (MRCA) sequence for the
viral envelope (Env) to identify closely related viruses sensitive
to PG9/16.
Methods: Alignment of the MRCA sequence with 99 subtype A
gp160 sequences from the Los Alamos HIV database identified
BG505 as the virus with the highest degree of homology (73%)
to the MRCA sequence.
Results: Pseudoviruses prepared with this Env are sensitive to
neutralization with a broad panel of bNAbs, including PG9 and
PG16, indicating that BG505 has an antigen profile desirable in a
vaccine candidate. When expressed as a soluble gp120 monomer
from 293T cells, BG505 displayed a unique antigenicity profile
– it bound well to both PG9 and PG16. We further show that a
point mutation enables production of stable gp120 monomers
that preserves the major neutralization epitopes on Env. Finally,
we show that an adjuvanted formulation of this gp120 protein
elicited neutralizing antibodies in rabbits (following a gp120
DNA vaccine prime) and that the resulting antisera compete
with the bNAbs from 3 non-overlapping epitope classes for
binding to gp120.
Conclusion: The results indicate that BG505 Env warrants further
investigation as an HIV vaccine candidate either as a protein or in
a viral vector platform.
AIDS Vaccine 2012
OA02.02
Prime-Boost Regimen Potency and Efficacy with
Alphavirus Replicons (SIV Antigen) in Non-human
Primates Challenged with Low-Dose Intra-rectal
SIVsmE660
K. Banerjee 1 , S. Balsitis 1 , T. Jamil 1 , C. Jones 1 , A. Dey 1 , J. Flandez 1 ,
L. Brito 1 , Y. Cu 1 , C. Beard 1 , S. Santra 2 , R. Pal 3 , N. Miller 4 ,
N.M. Valiante 1 , P. Mason 1 , S.W. Barnett 1 , G.R. Otten 1
1 Novartis Vaccines and Diagnostics, Cambridge, MA, USA;
2 Beth Israel Deaconess Medical Center, Boston, MA, USA;
3 Advanced Biosciences Laboratories, Kensington, MD, USA;
4 Division of AIDS, NIAID, MD, USA
Background: Self-amplifying RNAs (replicons) of positive-strand
viruses such as alphaviruses are potentially safe and useful
vectors for delivering vaccine antigens. Recombinant alphavirus
replicon particles (VRP), carrying the self-amplifying RNA,
protects rhesus macaques against SHIVSF162P4 challenge when
used in a prime-boost regimen.
Methods: Novartis VRPs are being further tested using a current
state-of-the art physiologically relevant low-dose SIV virus swarm
challenge. To meet the need for the large numbers of VRP an
alphavirus packaging cell line (PCL) was used for VRP production.
We manufactured, characterized, stability and small animal
potency tested VRPs expressing SIVmac239 envelope (env) and
gag/pol fusion proteins (VRP Env, VRP Gag/pol, respectively) for
a large macaque vaccine study. Macaques were co-immunized
with both VRPs thrice followed by two boosts with an MF59adjuvanted
CHO cell-derived SIVmac239 trimeric env protein.
Results: Here we show that three VRP priming immunizations
induce both env- and gag-specific IgG and T-cell responses,
robustly. Binding env-specific IgG titers were demonstrable in
100% of animals with titers ranging from ~10000-400000. T-cell
responses to env and gag developed in 80% of macaques (envspecific
range ~100-1200, gag-specific range ~100-700 SFC/106
PBMCs) when assayed using an IFNγ T-cell ELISpot. The MF59adjuvanted
Env protein by itself was also robustly immunogenic
with Env-specific IgG titers and T-cell responses ranging from
~100000-1700000 (100% response) and ~100-1000 SFC/106
PBMCs (90% response), respectively. No adverse events were
reported upon immunization of either the VRP or the MF59adjuvanted
env vaccines.
Conclusion: We provide further details on the currently ongoing
efficacy evaluations of these safe and immunogenic vaccines in
a prime-boost regimen using repeated low-dose heterologous
SIVsmE660 intra-rectal challenges. NIH Grant N01-AI-50007.