Oral Abstract Session 01 - Global HIV Vaccine Enterprise

Oral Abstract Session 02: Vaccine Concepts – Protein Immunogens
OA02.03
Minimally Invasive and Surface Electroporation
Delivery of DNA Vaccines for the Induction of Robust
Humoral Immune Responses Against HIV Antigens
N.Y. Sardesai 1 , A.S. Khan 1 , J. Mc Coy 1 , F. Lin 1 , J.M. Mendoza 1 ,
M. Yang 1 , J. Yan 1 , N. Hutnick 2 , K. Muthumani 2 , D.B. Weiner 2 ,
K.E. Broderick 1
1 Inovio Pharmaceuticals, Blue Bell, PA, USA; 2 University of
Pennsylvania School of Medicine, Philadelphia, PA, USA
Background: Clinical data from the HVTN-080 study demonstrated
that intramuscular electroporation (EP) delivery of PENNVAX®-B
DNA vaccine and the plasmid adjuvant IL-12 generated strong
antigen specific cellular immune responses in humans with
nearly 90% response rate. We have now developed minimally
invasive EP delivery technologies (MID-EP) to target dermal
tissue and demonstrate their ability to generate strong antibody
(Ab) responses in animal models with DNA antigens – including
small pox, influenza, dengue – and have shown protection from
viremia and lethality following challenge.
Methods: We demonstrate MID-EP delivery of consensus
HIV gp140 antigens and show the generation of cross-clade
neutralizing responses in guinea pigs and rabbits. These EP
enhanced humoral responses were significantly broader and
higher than naked DNA delivery alone or with a protein antigen.
We demonstrated NAb titers against a broad panel of 15 Tier-1
HIV viruses from Clades A-D in the range of 20 -200 measured
in the Tzm-Bl neutralization assay. The magnitude but not the
breadth of the responses was boosted to 20-1000 range using a
MID-EP DNA prime-protein boost regimen.
Results: We further developed a surface EP device (SEP) for
the simultaneous, but spatially segregated, delivery of multicomponent
HIV vaccines. The SEP device operates under
substantially lower voltage parameters than conventional EP
devices resulting in significant improvements in tolerability. The
separation of multi-component HIV vaccines avoids potential
issues with plasmid interference at the transcriptional or
translational levels. SEP produces Ab responses comparable to the
penetrating DNAEP devices.
Conclusion: Our results suggest that MID/SEP electroporation
devices offer safe, tolerable and potent methods to administer
HIV DNA vaccinations in a prophylactic clinical setting. Combined
with the design of novel HIV consensus based Env antigens these
DNA-EP combination vaccines are suitable for further HIV vaccine
product development.
Oral Abstract Sessions
OA02.04
Design of Lipid Nanoparticle Delivery Agents for
Multivalent Display of Recombinant Env Trimers in
HIV Vaccination
S. Pejawar-Gaddy 1 , J. Kovacs 2 , D. Barouch 2 , B. Chen 2 , D. Irvine 1
1 Massachusetts Institute of Technology, Boston, MA, USA;
2 Harvard University School of Medicine, Boston, USA
Background: Immunization strategies that elicit antibodies
capable of neutralizing diverse strains of the virus will likely
be an important part of a successful vaccine against HIV. The
envelope trimer is the only neutralizing target on the virus, and
strategies to promote durable, high avidity antibody responses
against the native intact trimer structure are lacking. We recently
developed chemically-crosslinked lipid nanocapsules as carriers
of molecular adjuvants and encapsulated or surface-displayed
antigens, which promote follicular helper T-cell responses and
elicited high-avidity, durable antibody responses to a candidate
malaria antigen (Moon et al. Nat. Mater. 10 243 (2011); Moon et
al. PNAS 109 1080 (2012)).
Methods: To apply this system to the delivery of HIV antigens, we
developed a strategy to anchor recombinant envelope trimers to
the surfaces of these particles under conditions preserving the
antigenic integrity of the trimers, allowing multivalent display
of these immunogens for immunization. To anchor trimers in
their native orientation, gp140 trimers with terminal his-tags
were anchored to the surface of lipid nanocapsules via Ni-NTAfunctionalized
lipids.
Results: Owing to their significant size (409 kDa) and heavy
glycosylation, we found that liquid-ordered and/or gel-phase
lipid compositions were required to stably anchor trimers to
particle membranes. Trimer-loaded nanocapsules carrying
monophosphoryl lipid A elicited durable antibody responses
with titers comparable to a Complete Freund’s Adjuvant (CFA)like
emulsion in mice, without the toxic inflammation associated
with the latter adjuvant. Further, nanocapsules elicited strong
helper T-cell responses associated with a steadily increasing
avidity of trimer-binding antibody over 90 days, which was not
replicated by other adjuvants.
Conclusion: These results suggest that nanoparticles displaying
HIV trimers in an oriented, multivalent presentation can promote
key aspects of the humoral response against Env immunogens.
This work was funded by the NIH (AI095109) and the Ragon
Institute of MGH, MIT, and Harvard.
AIDS Vaccine 2012
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ORAL ABSTRACT SESSIONS