Keywords: HIV; vaccine; adjuvant; viral vector; innate immune responses
Most candidate vaccines specific for HIV-1 are designed to stimulate cell-mediated immune responses. These include different viral and non-viral vectors and a combination of prime/boost protocols. Preliminary data already suggest that the immune responses elicited by these vaccines are limited and likely to be insufficient for protection. In this project, the aim is to enhance both cell-mediated and neutralising antibody responses by the use of two novel adjuvants that target innate and adaptive immunity, respectively: bacterial Flagellin via Toll-like receptor 5 signaling and polymeric (Mega) CD40 ligand via stimulation of CD40 on dendritic cells and lymphocytes. In addition, a new approach for adjuvant signaling will be developed with a novel alphavirus vaccine virus replicon vector of Semliki Forest virus, a virus which recently has been shown to strongly target the innate immune pathways including Toll-like receptors. The novel adjuvant strategies will be combined to existing vaccines and analysed as to whether such treatment can shape the immune responses into effective responses. Studies will be performed in human and murine settings (based amongst others on analysis of T and B cell memory responses) to get key comparative information for the development of new formulation of HIV-specific vaccines. The effect of the adjuvants and vectors on innate immune signals will also be thoroughly characterised. Finally, vaccines and vaccine-adjuvant combinations also using alphavirus and poxvirus vectors will be evaluated in animal challenge models to obtain immune correlates of protection. This project will provide the basis for a more effective HIV vaccine.
Successful vaccination against HIV infection is a major challenge for public health. In light of recent clinical trials, it appears necessary to develop new strategies for improving the magnitude and broadening the immune response against the virus. The current HIV-specific candidate vaccines are mainly aimed at targeting cellular immunity and have a limited immunogenicity restricted to a few epitopes. Therefore, new vaccines that stimulate stronger and broader T cell responses as well as neutralising antibodies need to be developed. Recent advances emphasised the key role of innate immunity pathways in the stimulation of effective adaptive immune responses. This proposal intends to assess different approaches that activate the innate immune system in order to selectively trigger, enhance and shape cellular and humoral neutralising responses.
The specific aims are to:
VaccTIP anticipates that the development of an effective HIV vaccine will require the generation of both humoral (neutralising antibodies) and cellular immunity. VaccTIP is planning to investigate novel adjuvant molecules (Flagellin and Mega-CD40L) and viral vectors in order to elicit and potentiate both humoral and cellular immune responses. The effect of these adjuvant molecules, in combination with different virus vector-based vaccines, will be tested for the clade C virus that causes 50% of HIV infections worldwide and which prevails in developing countries.
The new concept that VaccTIP will test is the requirement for different adjuvant molecules in order to stimulate selectively the different components of the immune response. In other words, it is possible that the stimulation of a broad neutralising antibody activity will require the combination of virus vectors, based on a vaccine with specific adjuvant properties. These properties may be different from those required for developing potent cellular immune responses. Thus, VaccTIP will test the hypothesis that different vaccine strategies will have to be combined in order to be able to develop both humoral and cellular immune responses.
The accumulation of knowledge and cross-cutting scientific strategies towards developing an effective HIV vaccination will have a major impact on the AIDS vaccine research and outcome of AIDS vaccine clinical trials. VaccTIP will establish novel technologies in the field of development of adjuvants with enhanced immunogenicity.
Microbiology and Tumor Biology Center
171 77 Stockholm
Tel: +46 8 4572550
Fax: +46 8 310848
|Official Address||Other Information|
|2||Giuseppe Pantaleo||Div. of Immunology and Allergy|
Laboratory of AIDS Immunopathogenesis
University of Lausanne
|Tel: +41 21 314 1071 |
Fax: +41 21 314 1070
|3||Stéphane Demotz||Apoxis SA |
18-20 Avenue de Sevelin
|Tel: +41 21 620 6084 |
Fax: +41 21 620 6099
|4||Jean-Claude Sirard||Institut de Biologie |
FR-59021 Lille, Cedex
|Tel: +33 3 20 87 10 76 |
Fax: +33 3 20 87 11 83
|5||Mariano Esteban||Centro Nacional de Biotechnologia|
|Tel: +34 91 585 4553 |
Fax: +34 91 585 4506