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Hiv nucleic acid vaccination - targeting of antigen presenting cells and induction of specific musocal and systemic immune responses

Objective

The broad aims of this proposal are to develop an HIV nucleic acid-based mucosal vaccination strategy to facilitate the efficient development of a vaccine for AIDS. We propose to develop a well-characterised nonhuman primate model for mucosal HIV vaccine strategies. A principal goal will be to study antigen presenting cells (APC) involved in generating specific types of mucosal and systemic immune responses. This proposal aims to deliver nucleic acids (NA) via cutaneous and/or mucosal surfaces. This technology, combined with rodent and primates immunologic expertise coupled to the primate AIDS models, provides a critical competitive research resource for the development and evaluation of mucosal HIV-1 vaccines.
It is the aim to accelerate the preclinical understanding or development of:
1) processes involved in inducing mucosal immunity to HIV, including the understanding of APC-vaccine interactions.
2) new HIV-vaccine delivery systems for inducing mucosal immunity.
3) to develop a primate model system for the evaluation of mucosal DNA immunisation.
4) immune mechanisms of protection against mucosal exposure.

This knowledge will have spin offs and may enhance the development of European HIV-1 vaccine candidates as effective products to the clinic. This proposal combines a vaccine manufacturer, and adds complementary immunological knowledge from three different Universities with the pre-clinical AIDS vaccine development expertise of the Biomedical Primate Research Centre (BPRC). The primate facility and its experienced staff will utilise their unique primate resources in concert with these experts to facilitate vaccine development and immunological understanding of mechanisms of protective mucosal immunity. This is a new vaccine initiative which allows a methodical approach that will provide a better understanding of mucosal immunity in primates. This is of great importance for a systematic approach toward HIV vaccines designed to induce 'effective' mucosal immunity. In view of the predominantly mucosal route of entry of HIV and the distinct lymphocyte recirculation pattern for the mucosa, a basic understanding of this system and how it can be primed most efficiently is a pivotal point in the improvement of HIV vaccine strategies. APC will be targeted and their migration to draining lymph nodes, where they interact with specific B and T cells, will be studied in situ . Once targeting of specific APC is studied and migration of specific APC has been defined then HIV-1 immunogenicity studies will be performed in mice, and progress to monkeys. The immune responses which correlate with different APC targeting protocols will be assessed. Two well characterised model antigens which are in clinical trials (HIV-1 gp120 and HSV-2 gD ) will be used, in some cases together with SIV gag (for cases in which SHIV challenges will take place). Genetic constructs encoding the model antigens will be evaluated and compared for the humoral and cellular immune responses they induce mucosally as well as systemically. The accumulated knowledge will be applied to the last phase of the study which will involve a vaccine efficacy study in the rhesus monkey model, using HIV/SIV (SHIV) chimeras as challenge viruses. The last phase of the project will be undertaken to determine if the immune responses which correlate with the ability to protect from establishment of infection and/or disease.

Coordinator

FOUNDATION BIOMEDICAL PRIMATE RESEARCH CENTRE
Address
157,Lange Kleiweg 139
2288 GJ Rijswijk Zh
Netherlands

Participants (4)

NATIONAL UNIVERSITY OF IRELAND - MAYNOOTH
Ireland
Address

47 Maynooth - Co. Kildare
Smithkline Beecham Biologicals S.A
Belgium
Address
89,Rue De L'institut 89
1330 Rixensart
United Medical and Dental Schools of Guy's and St Thomas's Hospitals
United Kingdom
Address
London Bridge
SE1 7EH London
Vrije Universiteit Amsterdam
Netherlands
Address
7,Van Der Boechorststraat 7
1007 MC Amsterdam