Oral Abstract Session 01 - Global HIV Vaccine Enterprise

POSTERS
Posters
Topic 12: Vaccine Concepts and Design
P12.11
Targeting HIV-1 Envelope Glycoprotein Trimers to B
Cells Using APRIL Improves Antibody Responses
M. Melchers 1 , I. Bontjer 1 , T. Tong 1 , N. Chung 1 , P. Klasse 1 ,
D. Eggink 1 , M. Gentile 1 , A. Cerutti 1 , D. Montefiori 1 , W. Olson 1 ,
B. Berkhout 1 , J. Binley 1 , J. Moore 1 , R. Sanders 1
1 Weill Medical College of Cornell University, New York, NY, USA
Background: An HIV-1 vaccine remains elusive, in part because
various factors limit the quantity and quality of the antibodies
raised against the viral envelope glycoprotein complex (Env).
We hypothesized that targeting Env vaccines directly to B cells,
by fusing them to molecules that bind and activate these cells,
would improve Env-specific antibody responses.
Methods: We fused trimeric Env gp140 to A PRoliferation-
Inducing Ligand (APRIL), B-cell Activating Factor (BAFF), and
CD40 Ligand (CD40L).
Results: The Env-APRIL, Env-BAFF and Env-CD40L gp140 trimers
all enhanced the expression of activation-induced cytidine
deaminase (AID) expression, the enzyme responsible for
inducing somatic hypermutation, antibody affinity maturation
and antibody class-switching. They also triggered IgM, IgG and
IgA secretion from human B cells in vitro. The Env-APRIL trimers
induced higher anti-Env antibody responses in rabbits, including
neutralizing antibodies against Tier 1 viruses. The enhanced Envspecific
responses were not associated with a general increase in
total plasma antibody concentrations, indicating that the effect
of APRIL was Env-specific. All the rabbit sera raised against gp140
trimers, irrespective of the presence of CD40L, BAFF or APRIL,
recognized trimeric Env efficiently, while sera raised against
gp120 monomers did not. The levels of trimer-binding and virusneutralizing
antibodies were strongly correlated, suggesting that
gp140 trimers are superior immunogens to gp120 monomers.
Conclusion: Targeting and activating B cells with a trimeric HIV-1
Env-APRIL fusion protein may improve the induction of humoral
immunity against HIV-1. Targeting B cells directly may also be
useful for other vaccines.
246
AIDS Vaccine 2012
P12.12
The Viral Vector Vaccine VSV-GP Boosts Immune
Response upon Repeated Applications
R. Tober 2 , Z. Banki 2 , A. Ejaz 2 , A. Muik 1 , L. Egerer 2 , D. von Laer 2 ,
J. Kimpel 2
1 Applied Virology and Gene Therapy Unit, Georg-Speyer-Haus,
Frankfurt, Germany; 2 Innsbruck Medical University, Innsbruck,
Austria
Background: Vesicular stomatitis virus (VSV) is a potent candidate
vaccine vector for various viral diseases (e.g. HIV, HCV, RSV). The
biggest limitation of VSV, however, is its neurotoxicity, which
limits application in humans. The second drawback is that VSV
induces neutralizing antibodies rapidly and is thus ineffective
as a vaccine vector upon repeated applications. Our group has
recently shown that VSV pseudotyped with the glycoprotein (GP)
of the lymphocytic choriomeningitis virus (LCMV), VSV-GP, is not
neurotoxic. The aim of this project was to evaluate the potential
of VSV-GP as a vaccine vector.
Methods: For this purpose, we used Ovalbumin (OVA) as a
model antigen and analyzed immunogenicity of GP-pseudotyped
and wildtype VSV containing OVA (VSV-GP-OVA and VSV-OVA) in
vitro and in vivo in mouse models.
Results: We showed that both vectors infected murine bone
marrow-derived dendritic cells (bmDCs) in vitro. These bmDCs
were able to activate OVA specific CD8+ and CD4+ T cells.
Immunization experiments in mice revealed that both VSV-OVA
and VSV-GP-OVA induced functional OVA-specific cytotoxic T
cells (CTLs) after a single immunization. In addition, with both
viruses, mice generated antibodies against OVA. However,
boosting with the same virus was only possible for the GPpseudotyped
virus but not for wild type VSV. The efficacy of
repeated immunization with VSV-OVA was most likely limited by
high levels of neutralizing antibodies, which we detected after
the first immunization. In contrast, no neutralizing antibodies
against VSV-GP were induced even after boosting.
Conclusion: Taken together, we showed that the non-neurotoxic
VSV-GP is able to induce specific T cell and B cell responses
against the model antigen OVA to the same level as the wild
type VSV vector. However, in contrast to wild type VSV, VSV-GP-
OVA boosted the immune response upon repeated applications.
Thus, VSV-GP is a promising novel vaccine vector.