Oral Abstract Session 01 - Global HIV Vaccine Enterprise

Topic 2: Animal Models and Preclinical Trials
P02.01
Macaques Primed with Self-Amplifying RNA
Vaccines Expressing HIV-1 Envelope and Boosted
with Recombinant Protein Show Potent T- and
B-Cell Responses
W.M. Bogers 1 , H. Oostermeijer 1 , P. Mooij 1 , G. Koopman 1 ,
E. Verschoor 1 , D. Davis 1 , J.L. Heeney 2 , Y. Cu 3 , K. Banerjee 3 ,
B. Burke 3 , A. Dey 3 , A. Geall 3 , S.W. Barnett 3
1 Biomedical Primate Research Centre, Rijswijk, Netherlands;
2 University of Cambridge, Cambridge, United Kingdom
(Great Britain); 3 Novartis Vacccines and Diagnostics, Inc.,
Cambridge, USA
Background: Self-amplifying RNAs (replicons) of positive-strand
viruses are useful vectors for delivering vaccine antigens. Novartis
has developed a self-amplifying mRNA (SAM) vaccine platform
to take advantage of cell-free RNA production and synthetic nonviral
delivery systems. In this study, the safety, immunogenicity,
and efficacy of HIV-SAM vaccines encoding HIV-1 clade C TV1
gp140 envelope glycoprotein were evaluated in rhesus macaques
using two non-viral delivery systems: lipid nanoparticle (LNP) and
a Novartis proprietary 2nd generation delivery technology (CNE).
Methods: Five groups of six macaques were primed at weeks
0, 4 and 12 with HIV-SAM vaccine formulated with LNP or
CNE, alphavirus replicon particles (VRP), recombinant TV1
gp140 glycoprotein in MF59 adjuvant, or with vector controls
encoding an irrelevant Ag. All treatment groups were boosted
intra-muscularly at weeks 24 and 36 with TV1 gp140 in MF59,
and controls with irrelevant protein in the same adjuvant.
Systemic and mucosal responses were measured throughout
the study. All macaques will be given a repeated low dose
intra-rectal challenge with the heterologous clade C SHIV-
1157ipd3N4 challenge.
Results: After priming immunizations, both IFNγ and IL2 T-cell
responses and B-cell ELISpots were higher in HIV-SAM-CNE
macaques than those in HIV-SAM-LNP, VRP and glycoprotein
alone groups. Systemic Env-specific antibody responses were also
detected by ELISA at week 6 in the RNA-immunized groups and
increased after subsequent immunizations. Neutralization, ADCC,
epitope mapping, and antibody isotyping assays are underway
to further evaluate the antibody responses in these animals. No
adverse responses to RNA immunizations were observed.
Conclusion: These studies provide the first evidence in nonhuman
primates that vaccination with formulated self-amplifying RNA
is safe and immunogenic, eliciting both humoral and cellular
immune responses.
This study was supported by NIH grant 5 PO1 AI066287-02.
P02.02
AIDS Vaccine 2012
Posters
GM-CSF Co-expressing DNA/MVA Vaccine,
Prevention of Acquisition by Two Series of SIVE660
Challenges Followed by a Series of SIV251 Challenges
H. Robinson 1 , S. Kannanganat 2 , S. Gangadhara 2 , L. Lai 2 , T. Yu 2 ,
P. Kozlowski 3 , P. Earl 4 , B. Moss 4 , R.R. Amara 2
1 GeoVax Inc., Smyrna, GA, USA; 2 Emory University, Atlanta, GA,
USA; 3 Louisiana State University Health Sciences Center, New
Orleans, LA, USA; 4 National Institute of Allergy and Infectious
Diseases, Bethesda, MD, USA
Background: In 2010 we reported prevention of acquisition of a
repeated SIVE660 challenge in rhesus macaques vaccinated with
a SIV239 DNA/MVA vaccine that co-expressed GM-CSF and VLP
in the DNA prime. The reduced risk of infection correlated with
the avidity of Env-specific IgG. Here we report studies on the
longevity and breadth of this protective response.
Methods: Following the initial 12 challenges, 5 uninfected rhesus
were monitored for one year, boosted with 1x108 pfu of MVA/
SIV239, and re-challenged 6 months later with 12 weekly rectal
doses of SIVE660. The resulting four uninfected macaques were
held an additional 6 months and challenged with 12 weekly rectal
doses of SIV251. Avidity of Env-specific IgG was determined using
a NaSCN elution ELISA. Per exposure efficacy was estimated using
a leaky effects model.
Results: Per exposure efficacies were 90% and 94% for the 1st and
2nd SIVE660 series, respectively, and 72% for the SIV251 series
of challenges. For the SIVE660 series, 50% infection was reached
by the 3rd challenge for controls, but never reached in vaccinated
animals. For the SIV251 series, 50% infection was reached by
the 2nd challenge for controls but not until 10 challenges for
vaccinated animals. Both SIVE660 and SIV251 series showed
transient low “blips” of virus. None of five E660 “blips” resulted
in anamnestic systemic Ab, whereas two of three SIV251 blips
resulted in such. Correlates also differed for the two infections
with the avidity of Env-specific IgG correlating with prevention of
acquisition for SIVE660 but not SIV251.
Conclusion: A DNA/MVA vaccine in which GM-CSF is coexpressed
in the DNA prime can provide substantial prevention
of acquisition against serial challenges over a three year period of
time. Our results also reveal SIVE660 and SIV251 rectal challenges
differing in their ability to initiate systemic Ab responses and in
their correlate for prevention of acquisition.
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POSTERS