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MUVADEN
HIV/AIDS
Framework programme: 5
Project number:
QLK2-CT-2002-00882
EC contribution: € 2 110 000
Duration: 36 months
Type: RS
Starting date: 1 September 2002
Graphic element Mucosal Vaccines Against Human and Simian Immunodeficiency Viruses Based on Dendritic Cells
Keywords: Mucosal immunity; dendritic cell-based vaccine; immunopathology; viral load; complement; cytokine; lymph node; thymus; central nervous system

Summary:

Successful containment of the worldwide spread of HIV-1 requires vaccines with a  high protective efficacy, low cost and simple immunisation schedules. The aim of this project is to assess the efficacy of new vaccine candidates (cationic lipid-DNA and single cycle lentiviral vector, recombinant S. gordonii), developed by this consortium, in inducing mucosal and systemic immunity and protection against mucosal challenge with pathogenic SIV in rhesus macaques. Questions will also be addressed on vaccine biology. Knowledge gained here can direct the project towards the design of mucosal vaccine delivery and could provide concepts useful for other human pathogenic viruses and tumours.

Problem:

The development of an HIV vaccine poses an unprecedented challenge to the scientific community. The inexorable spread of HIV worldwide, especially in developing countries, and the devastating clinical consequences of AIDS can only be contained by a vaccine with high protective efficacy, low cost, and simple immunisation schedules. Yet, almost two decades after the first demonstration of HIV and its etiologic role in AIDS, this vaccine still is a goal, not a reality. An HIV vaccine is most desperately needed in regions of the world in which HIV infections are endemic. Live recombinant bacterial and viral vectors are being explored as tools for eliciting immune responses against HIV. However, these vectors hold the potential to revert to more virulent strains capable of causing disease, especially in immunocompromised hosts. Caution is necessary since significant numbers of individuals are already infected with HIV, and therefore immunosuppressed. Of the many novel vaccine strategies currently being explored as potential HIV vaccines, plasmid DNA immunogens is one of the more intriguing but vaccine performance has to be improved by adjuvants and/or by the prime-boost vaccination strategy.

Aim:

Safe, effective, and affordable vaccines are needed that elicit the broadest and most robust immune responses against HIV, particularly at mucosal sites where the virus gains entry into the body.  In the present project, new innovative vaccine candidates will be designed and used that offer the potential for oral administration, will show ease of manufacturing and have safety advantages. The lipid-DNA vaccines provide immunological advantages in their presentation of multiple epitopes of SIV to the immune system for extended periods. Virus-like particles (incomplete viruses) will also be used, which can only undergo a single cycle of replication and initiate the synthesis of viral proteins during that process. They are therefore safe. SIV genetic material will be engineered into Streptococcus gordonii. This approach provides a safety advantage, since the bacterium is a commensal of the human oral cavity, and also has the potential to be effective and affordable. Under close and complex virologic, immunologic and molecular pathologic monitoring, immune responses, protection and also vaccine biology will be addressed. The project will evaluate and compare in depth the effects of different prime-boost vaccination strategies (oral versus parenteral) for their capacity to access and mobilise dendritic cells, the professional antigen presenting cells, and to induce immunity and protection to a mucosal challenge with SIV. A greater understanding of the mechanisms whereby vaccines generate HIV/SIV-specific immune responses and protection at the sites of infection is imperative to guide vaccine development.

Expected Results:

It is assumed that

  1. oral application of the new vaccine candidates can be used to induce mucosal immunity and study protection against mucosal transmission of SIV
  2. evidence will be provided to show that the oral route can elicit strong immunity, including mucosal antibodies
  3. co-administration of adjuvants through the mucous membrane is efficient to mobilise and mature dendritic cells thereby assisting the immune system in the generation of SIV-specific protective immune responses that are beneficial for the course of the disease
  4. new information will be delivered on the potency of oral vaccination, relative to standard modes of vaccine delivery
  5. the complex investigative methods including analyses of lymphoid and non-lymphoid tissues offer a chance to detect SIV and  host responses at important levels that are overlooked if blood is the only tissue being characterised.

Potential Application:

Deeper insight into immunity generated by vaccines, especially HIV vaccines that will block the mucosal or sexual transmission, has implications for future vaccine strategies. Given the various degree of immune responsiveness elicited by each vaccination strategy, the comparison of differently vaccinated animals will be critically important for understanding factors that are likely to be responsible for preventing infection. The knowledge gained will also have implications beyond HIV prevention. The concept of targeting antigens directly to these potent antigen presenting cells represents a new technology in HIV/SIV research, and is broadly pertinent to vaccines for other infectious agents (for example, hepatitis C virus) and tumours (melanoma).

Coordinator:

P. Racz and Klara Tenner-Racz
Bernhard-Nocht Institute for Tropical Medicine
Bernhard-Nocht-Str. 74
20359 Hamburg
Germany
Tel: +49 40 42818 499
Fax: +49 40 42818 544
E-mail: racz@bni.uni-hamburg.de

Partners:

Principal
Scientific
Participants
Official Address Other Information
2Ralph SteinmanHenry G Kunkel
The Rockefeller University
Laboratory of Cellular Physiology and Immunology
1230 York Avenue
NY 10021-6399 New York
United States of America
Tel: +1 212 327 507 8106
Fax: +1 212 327 507 8875
E-mail: steinma@rockvax.rockefeller.edu
3Klaus UeberlaDepartment of Molecular and Medical Virology
Ruhr-University Bochum
Universitaetsstr. 150
DE-44780 Bochum
Germany
Tel: +49 234 3223189
Fax: +49 234 3214352
E-mail: klaus.ueberla@ruhr-uni-bochum.de
4Gianni PozziDipartimento di Biologia Molecolare
Policlinico Le Scotte
Viale Bracci
Universita di Siena - LA.M.M.B.
IT-53100 Siena
Italy
Tel: +39 0577 233430
Fax: +39 0577 233334
E-mail: pozzi@unisi.it
5Christiane Stahl-Hennig, V.M.D.Department of Virology and Immunology
German Primate Centre
Kellnerweg 4
DE-37077 Göttingen
Germany
Tel: +49 551 3851 154
Fax: +49 551 3851 184
E-mail: stahlh@www.dpz.gwdg.de
6M. P. Dierich
Heribert Stoiber
Institute of Hygiene and Social Medicine
Fritz-Pregel-Straße 3
AT-6010 Innsbruck
Austria
Tel: +43 512 507 3400
Fax: +43 512 507 2870
E-mail: Hygiene@uibk.ac.at
Tel: +43 512 507 3405
Fax: +43 512 507 2870
E-mail: heribert.stoiber@uibk.ac.at
7Ralf IgnatiusInstitute for Medical Microbiology
Free University Berlin
Hindenburgdamm 27
DE-12203 Berlin
Germany
Tel: +49 30 8445 3620
Fax: +49 30 8445 3830
E-mail: ralf.ignatius@ukbf.fu-berlin.de
8Gudmundur GeorgssonInstitute for Experimental Pathology
University of Iceland
Keldur v/Vesturlandsveg
IS-112 Reykjavik
Iceland
Tel: +354 567 4700
Fax: +354 567 3979
E-mail: ggeorgs@hi.is
9Carlo BaroniDipartimento di Medicina Sperimentale e Patologia
Policlinico Umberto I
Universita Degli Studi Di Roma ‘La Sapienza’
II Cattedra di Anatomia ed Istologia Pathologica
Sezione di Immunopatologia
Viale Regina Elena, 324
IT-00161 Roma
Italy
Tel: +39 06 4468 606
Fax: +39 06 4940 896
E-mail: carlo.baroni@uniroma1.it
10Marco Baggiolini
Mariagrazia Uguccioni
Institute for Research in Biomedicine
Via Vicenzo Vela 6
CH-6500 Bellinzona
Switzerland
Tel: +41 91 8200 300
Fax: +41 91 8200 302
E-mail: baggiolini@unisi.ch
Tel: +41 91 8200 300
Fax: +41 91 8200 302
E-mail: mariagrazia.uguccioni@irb.unisi.ch

 
 
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