HIV/AIDS

HIV Vaccine Design and Development Teams (HVDDT) Abstracts 

Paul Maddon

Trimeric Envelope Protein – SOSIP
Progenics

Appropriate cleavage and stabilization of the HIV envelope appears to be critical for the generation of neutralizing antibodies. The goal of this contract is to generate proteolytically mature, disulfide-stabilized HIV-1 gp140 envelope trimers (SOSIP gp140 trimers) that elicit broadly neutralizing antibodies. The contract represents collaboration between Progenics Pharmaceuticals and the Weill Medical College of Cornell University.

In rabbit immunogenicity studies, SOSIP gp140 trimers were superior to gp120 monomers in eliciting antibodies that neutralize homologous virus and a limited number of heterologous viruses (1, 2). Neutralization was not directed to the V3 envelope region.

The project identified a subtype A virus, KNH1144, whose envelope forms unusually stable SOSIP gp140 trimers (3). These trimers closely resembled virus-associated Env in size and topology when examined by electron microscopy (4). The sequences responsible for trimer stability were mapped to the amino-terminal region of gp41 and when transferred to gp140 glycoproteins from other HIV-1 isolates provided increased stability (5).

The project has also been evaluating the molecular basis for the inherently poor immunogenicity of HIV-1 Env. Mannose residues on gp120 were observed to induce immunosuppressive responses from human dendritic cells in vitro suggesting that demannosylation may be a way to improve the immunogenicity of gp120 or gp140 proteins (6).

References:

1. S. Beddows et al., The Journal of Virology 79, 8812 (2005).
2. S. Beddows et al., Virology. 360, 329 (2007).
3. S. Beddows et al., AIDS Res Hum Retroviruses. 22, 569 (2006).
4. S. P. Iyer et al., AIDS Res Hum Retroviruses. 23, 817 (2007).
5. A. K. Dey, K. B. David, P. J. Klasse, J. P. Moore, Virology 360, 199 (2007).
6. M. Shan et al., PLoS Pathogens 3, e169 (2007).

Mark Newman

Multiepitope DNA and MVA vectors
Pharmexa-Epimmune

The work scope of this contract is organized to support the preclinical design, development and testing of HIV vaccine candidates encoding multiple HIV-derived and highly conserved cytotoxic (CTL) and helper T lymphocyte (HTL) epitopes restricted to the most common HLA types. Prototype vaccines are designed using plasmid DNA and modified Vaccinia Virus Ankara (MVA) as the delivery formats for use individually or sequentially in prime/boost combinations. Research on the design and preclinical development efforts completed to date were used to support a DAIDS Investigational New Drug (IND) application and a Phase I clinical trial conducted by the HIV Vaccine trials Network (Protocol HVTN 067).

The epitopes selected for the first generation products were predicted to be suitable for use in slightly less than 90% of the global population based on HLA analyses and thus the initial efforts were considered as proof-of-concept. Pharmexa is therefore producing second generation vaccines encoding CTL epitopes restricted to additional HLA types. Methods for increasing the potency of the vaccines without impacting safety are also being evaluated for use with second generation products.

Susan Barnett

Alphavirus Vectors
Novartis

Through this contract, Novartis seeks to design and produce an HIV vaccine based on chimeric recombinant VEE/SIN (V/S) alphavirus replicons expressing HIV clade C genes (GagPol and Env). The contract will support the development and preclinical testing and GMP manufacture of the vaccine.

At this stage, a major goal is to develop a stable cell line which will be used to scale up production of replicon particles. Alphavirus replicons are presently produced by transient triple RNA electroporation to generate material for testing. In parallel to the development of a stable cells line, two separate recombinant alphavirus replicons expressing HIV-1 subtype C Gag, Pol and Env antigens have already been engineered. Ultimate the alphavirus-based vectors will be tested in prime / boost approaches, using Chiron Env proteins (formulated in an optimal adjuvant). Vaccine development and evaluation will be monitored by milestones, deliverables, and go/no-go decision points.

Hussein Naim

E-Z Measles Vector
Berna Biotech, a Crucell Company

An attenuated replicating vector delivered by mucosal routes offers several theoretical advantages towards the success of an HIV vaccine. Berna Biotech aspires to develop and evaluate a prophylactic HIV vaccine candidate based on the use of the Edmonston Zagreb measles (MV-EZ) as a vector. An aerosolized formulation of this live replicating measles vector–based aerosol vaccine will be subject to preclinical studies and clinical trials.

To achieve this goal, the team has generated recombinant MV-vectors expressing single and multiple genes from HIV Clade B (env, gag-pol). The immunogenicity of these constructs has been tested in mice. The product will also be tested in non-human primates NHP for its ability to generate robust, long-lasting, efficacious systemic and mucosal immune responses. Vaccine development and evaluation will be monitored by milestones, deliverables, and go/no-go decision points.

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