Keywords: Mucosal vaccines; Mycobacterium tuberculosis; tuberculosis; HIV; AIDS
Human Immunodeficiency Virus and Mycobacterium tuberculosis enter the human body at mucosal sites. The aim of the present project is to develop mucosally delivered vaccines against HIV and TB, which will induce local immunity able to neutralise the pathogens at their port of entry and systemic immunity able to prevent systemic spread of the infection. The possible development of mucosal vaccines against malaria will be also investigated. The goal of the project derives from the recent proof of concept that mucosal vaccines are feasible in humans.
In this project, existing antigens, which are known to be protective in animal models against HIV and TB, will be formulated for mucosal delivery and tested in clinical trials. The antigens used for the initial clinical trials will be the latest generation of the envelope protein of HIV, which, being deleted of the loop 2, unmasks some of the conserved epitopes and induces broadly neutralising antibodies against primary isolates of HIV, the Gag and Tat proteins of HIV and the fusion protein of Ag85B and ESAT-6 of TB.
While the first trials are being performed, new systems to deliver mucosal vaccines and basic mechanisms of mucosal immune responses and memory in humans will be studied. This will allow better understanding of the clinical results and optimisation of second-generation vaccines to be tested in developing countries during the second phase of the project.
The project will be managed using the industrial knowledge of planning and management, to focus the participating laboratories in advancing the development of vaccines against HIV, TB and malaria while increasing the understanding of mucosal immunology.
HIV/AIDS and TB are causing a global health crisis unprecedented in the recent history of mankind and account for more than 4 million deaths every year, with the majority of this occurring in developing countries, particularly in sub-Saharan Africa. Since the start of the HIV epidemic, 21 million people have died and 57 million people have become infected. Mycobacterium tuberculosis affects one-third of the world population and represents the main cause of death in HIV-infected patients. Furthermore, TB represents a dramatic problem in Eastern Europe due to the extremely high prevalence of drug-resistant TB. This epidemiological situation is a major problem for all of Europe due to the impact of the migration of the spread of clinically relevant strains (World Health Organisation report 2002).
No vaccines have yet been developed for HIV and the efficacy of the currently used BCG vaccine varies in different populations and regions from 0 to 80%. Despite this, vaccination is one of the most cost-effective interventions; the economic value associated with vaccines, mainly those for developing countries, is negligible but industry finds them an unattractive area of investment.
The vast majority of existing vaccines are still administered by systemic injection. Although widely accepted, parenteral vaccination is not devoid of potential drawbacks. Most of the pathogens invade their human hosts at the level of the mucosal surfaces, which represent the very first antimicrobial barrier through non-specific (anatomical) and specific (immune) defence mechanisms. Mucosal vaccination would offer several advantages over the parenteral route of vaccination. Firstly, by inducing local microbial-specific immune responses, it would block pathogens at the port of entry, thus increasing the general efficacy of the vaccine. It is therefore likely that highly effective vaccines against mucosally transmitted diseases such as HIV/AIDS and TB, can effectively engage the mucosal immune system. Secondly, by avoiding the traumatic procedure of injection, mucosal vaccination would increase the compliance and consequently the coverage. Thirdly, it could facilitate vaccine delivery, especially in poorer countries. Last, but not least, mucosal immunisation would significantly decrease the risk of unwanted spread of infectious agents via contaminated syringes, especially in areas with a high incidence of viral hepatitis and human immunodeficiency virus infections.
It has been recently shown, both in mice and in humans, that the mucosal route is optimal for boosting immune responses primed by systemic immunisations (e.g. intramuscular). Considering that a great part of the population in developing countries is already vaccinated with BCG, it is expected that TB mucosal vaccines would be also more effective acting as a boost to systemic vaccination.
In consideration of the extremely high prevalence and incidence of HIV and TB infections, the development of effective mucosal vaccines would have a tremendous impact, forming the basis for a global use and subsequent impact on general public health, both in Europe and in developing countries.
The aim of the project is to develop vaccines that induce mucosal and systemic immunity against HIV/AIDS and TB. Existing antigens, which are known to be protective in animal models, will be formulated for mucosal delivery and tested in clinical trials. In parallel, pre-clinical studies will be performed to optimise mucosal vaccination against HIV, TB and malaria. Ultimately, the ambitious but realistic goal of the project is to provide candidate mucosal vaccines against HIV and TB that could subsequently enter the path towards licensure through phase II and III clinical trials in developing countries.
On the whole, the MUVAPRED integrated project is aimed at achieving, within the five-year lifetime of the project, the clinical demonstration of safety and immunogenicity in healthy volunteers of vaccine candidates against HIV and TB infections, to be administered via mucosal routes and to advance the basic knowledge on the possible development of mucosal vaccines against malaria. The achievement of these results will provide safe and powerful mucosal vaccines to be advanced in efficacy trials in developing countries.
This large consortium, including a major vaccine manufacturer and academic groups with expertise in clinical vaccine development, mucosal and systemic human immunity, animal models and vaccine delivery, will focus the skills of the individual participants towards the development of HIV, TB and malaria mucosal vaccines to be used in developing countries. The consortium will integrate different approaches and disciplines, and provide the necessary critical mass to test and compare different scientific ideas with the aim of delivering vaccines needed mainly in developing countries.
Via Fiorentina, 1
|Official Address||Other Information|
Microbial Pathogenesis (team 15)
|Wellcome Trust Sanger Institute |
Wellcome Trust Genome Campus
UK-CB10 1SA Cambridge
|3||Jan Holmgren||Göteborg University |
Department of Medical Microbiology
P.O. Box 435SE
405 30 Göteborg
|4||Nils Lycke||Department of Clinical Immunology
Guldhedsgatan 10 SE
413 46 Göteborg
|5||Brigitte Gicquel||Institut Pasteur |
Unité de Génétique Mycobacterienne
25 rue du Dr Roux
|6||Nathalie Winter||Institut Pasteur
Unité de Génétique Mycobacterienne
25 rue du Dr Roux
|Università di Siena,|
Dipartimento di Biologia Molecolare, LA.M.M.B.
Policlinico Le Scotte
V.le Bracci 16
|8||Stefan H.E. Kaufmann||Max Planck Institute for Infection Biology,|
Department of Immunology
|9||Barbara Ensoli||Director AIDS Division |
Department of Infectious,
Parasitic and Immune-Mediated Diseases
Istituto Superiore di Sanità
Viale Regina Elena 299
|10||Antonio Cassone||Director Department of Infectious, |
Parasitic and Immune-Mediated Diseases
Viale Regina Elena 299IT0
|11||Antonio Lanzavecchia||Institute for Research in Biomedicine (IRB)|
Via Vincenzo Vela, 6
|12||Paul Racz||Bernhard-Nocht-Institute for Tropical Medicine|
|13||Thomas Lehner|| Mucosal Immunology Group,|
Guy’s King’s and St Thomas’ Medical
and Dental School
UK-SE1 9RT London
|14||Kingston Mills||Immune Regulation Research Laboratory, Department of Biochemistry|
|15||Peter Andersen||Statens Serum Institute,|
Department of Infectious
DK-2300 Copenhagen S
|16||Francesco Dieli||Consiglio nazionale delle Ricerche|
Ist. Biomedicina e Immunologia Molecolare
Corso Tukory 211
|Istituto di Ricerche Farmacologiche|
Via Eritrea 62
|18||Andreas Radbruch||German Arthritis Research Center|
|19||David Lewis||St. George’s Hospital|
Department of Cellular and Molecular Medicine
UK-SW17 0RE London
|20||Peter SEBO||Academy of Sciences|
of the Czech Republic
Institute of Microbiology
CZ-142 20 Prague 4
|21||Philip Marsh||Centre for Emergency Preparedness|
and Response (CEPR),Health Protection Agency
UK-SP4 0JG Salisbury
|22||Gianfranco Del Prete||University of Florence|
Dip. Medicina Interna
Viale Morgagni 85
|23||Oumou Younoussa Sow||Service de Pneumo-Phtisiologie|
BP 634 Conakry
Republic of Guinea
|24||Giampietro Corradin||University of Lausanne|
Institute of Biochemistry
|25||Aldo Tagliabue||Alta Srl|
Via Nino Bixio 15
|26||Mahavir Singh||LIONEX Diagnostic and Therapeutics Gmbh|
Mascheroder Weg 1 b
|27||Christoph Heinzen||INOTECH AG|
|28||Howard Engers||The Armauer Hansen Research Institute
Jimma Road PO Box 1005
|Tel: + 251 11 321 1334 |
Fax: + 251 11 321 1563
|29||Gita Ramjee||South African Research Council HIV
Prevention Unit (MRCHPU)
123 Jan Hofmeyer Road, Westville
PO Box 19070
|Tel: + 031 242 3600 |
Fax: + 031 242 3806