Important legal notice
Contact   |   Search on Europa   

Infectious Diseases Graphic element print icon Graphic element
Graphic element General information
  RTD Infectious Diseases Unit
  Developing countries
Graphic element Projects
  About FP6 Funding
  FP6 projects
  About FP5 Funding
  FP5 projects
Graphic element Addressed Diseases
- News
Graphic element Calls for proposals
  FP7 Calls
Graphic element Contact corner
  Scientific officers
  Subscribe to our mailing list
Framework programme: 6
Call: 3
Project number:
EC contribution: € 5 500 000
Duration: 49 months
Type: IP
Starting date: January 2006
Graphic element Recombinant Measles Virus as a Vector for HIV Vaccines
Keywords: HIV; AIDS; vaccine; recombinant measles virus


This proposal aims at demonstrating the safety and immunogenicity in humans of a novel recombinant measles virus (MV) vector for use as an AIDS vaccine. The vector is replication competent in vivo and is derived from a widely used measles vaccine strain (Schwarz), which is known to induce very long lasting immunity. Therefore, this novel vector potentially offers a unique combination of safety and potency. The recombinant HIV MV vectors will express three relatively conserved HIV proteins (Gag, Pol, Nef) from HIV clade B and A strains. A good manufacturing practices (GMP) compatible production process for the recombinant MV vector will be developed and a GMP lot will be produced for two clinical studies. The first study will evaluate the safety profile of the MV vector, while the second study will also assess the immunogenicity in MV-immune volunteers. With these two clinical studies, the project will specifically address potential shedding of the recombinant vector into the environment and the potential negative impact of pre-existing MV immunity. It is expected that at the end of the project sufficient clinical data on the safety and immunogenicity will have been generated to decide on subsequent advanced technical and clinical development of this novel vaccine approach.


In this project, the consortium partners are proposing the development of recombinant measles virus (MV) technology. The measles vaccine, a live attenuated strain of MV, is one of the most efficient and safest human vaccines available and has been given to billions of children since the Sixties. Vaccination campaigns have been very efficient to control MV outbreaks in developed countries. However, because of inadequate distribution of the vaccine in developing countries, there are still 45 million cases of measles and 800 000 child deaths per year worldwide (CDC, 1999). MV vaccine induces a life-long immunity after a single or two low-dose injections and a persistence of antibodies and CD8-positive cells has been shown for as long as 25 years after vaccination. MV vaccine is easily produced on a large scale in most countries and can be distributed at low cost. The MV genome is very stable and reversion to pathogenicity has never been observed. Moreover, MV replicates exclusively in the cytoplasm, ruling out the possibility of integration in host cell DNA. All these characteristics make live attenuated MV vaccine an attractive candidate vaccine vector and to this end, a reverse genetics system for MV has been established, allowing the production of recombinant MV with additional foreign genetic material. The MV vector has been shown to express stably a variety of genes, or combinations of genes, of a large size over more than twelve passages. This stability is likely because there is little constraint on genome size for pleomorphic viruses with a helical nucleocapsid. Interestingly, because MV infects cells of the immune system, in particular macrophages and dendritic cells, MV vectors deliver their foreign genes directly to the most efficient antigen presenting cells.

Institut Pasteur (partner 2) has developed an MV vector based on the Schwarz strain, the safest and most widely used vaccine strain. The vaccine rescued from the molecular clone was as immunogenic as the parental vaccine in primates and mice susceptible to MV infection. Recently, recombinant MV expressing envelope glycoproteins from HIV-1 was generated and shown to induce strong cellular immunity and neutralising antibodies against MV and the HIV inserts. Interestingly, pre-existing immunity to the vector did not impair the immunogenicity of the recombinant MV in mice and in macaques, leading to the possibility of using this vector in adult populations with pre-existing immunity to MV.

The consortium is proposing to construct recombinant MV vectors that express the HIV-1 clade B and A Gag, Pol, and Nef proteins. These proteins possess highly conserved regions that have been shown to be the target of CD8-positive cells, and thereby constitute a promising antigenic composition for an HIV vaccine. It has been demonstrated that CD8-positive cells from individuals infected with virus strains from different clades are highly cross-reactive with respect to the Gag, Pol, and Nef protein. By assuming a similar cross-reactivity for vaccine-induced immune responses, the proposed project will be based initially on HIV clade B antigens. The choice of clade B antigens will also allow for subsequent combination vaccine regimen using GSK’s clade B adjuvanted protein vaccine. In addition, a corresponding clade A MV vector will be constructed and compared at the pre-clinical level to the clade B construct. This will enable the consortium to choose the most appropriate vector for subsequent development after the demonstration of safety and immunogenicity of the clade B construct in phase I clinical trials.


The objective of the project is the demonstration of safety and immunogenicity of a recombinant HIV MV vector in adult HIV-uninfected volunteers. This includes the identification of a suitable dose of recombinant MV, the demonstration of an acceptable reactogenicity profile, and the characterisation of potential virus shedding. Furthermore, the vaccine will have to induce significant levels of HIV-specific CD8-positive cells in volunteers with pre-existing immunity, and ideally also measurable CD4-positive cell and antibody responses.

Expected results:

A mostly sequential development path has been defined. The first stage is the construction and characterisation of recombinant MV expressing HIV clade B Gag, Pol, and Nef proteins. The characterisation includes the evaluation of immunogenicity in mice, established growth characteristics in a production cell line and analysis of genetic stability. Based on these results, a corresponding HIV clade A MV vector will be developed and compared to the clade B vector in a monkey immunogenicity study.

Several parameters that are relevant for the development of a production process that is compatible with GMP manufacture will be assessed. When a suitable HIV clade B MV vector is selected and a process has been established, GMP clinical lot production will be initiated and the resulting material subjected to a formal QC release. The GMP material will also serve for toxicology studies in macaques in order to assess the reactogenicity, toxicity, biodistribution and shedding of the recombinant MV. The analysis of the GMP lots, the data from the toxicology study, and other supportive data will be compiled in a dossier for submission to regulatory authorities.

The early clinical development comprised in this project will address two main issues concerning the recombinant MV vector technology. These issues are the potential in vivo shedding of a genetically modified organism (GMO), and the impact of pre-existing MV immunity. A first phase I dose-escalation study under confinement conditions to assess the safety of the recombinant MV will be initiated upon regulatory approval. In order to minimise the impact of pre-existing immunity, this study will be conducted in volunteers that have only low titer MV antibodies or are completely seronegative. Therefore, MV serological screening of a larger number of volunteers and identification of eligible study participants will be required. Both reactogenicity and virus shedding will be investigated in this first clinical trial. Depending on the results from the study, a larger clinical trial will be initiated in seropositive volunteers with varying antibody titers to expand the safety data and to evaluate the immunogenicity of the vaccine in the face of significant pre-existing immunity. It is anticipated that the results from this second study will provide the necessary safety and immunogenicity information to decide on a potential advanced development of the recombinant MV vectors as candidate HIV vaccines. The choice of the vector (HIV clade A or clade B) will be made, based on the comparative monkey study immunogenicity data and the cross-reactivity data from the second clinical trial.


Gerald Voss
GlaxoSmithKline Biologicals
Rue de l’Institut 89
1330 Rixensart

Tel: +32 2 656 8243
Fax: +32 2 656 9049


Official Address Other Information
Frédéric Tangy
Institut Pasteur
Unité des virus lents
Rue du Dr. Roux 25-28
FR-75724 Paris CEDEX 15
Tel: +33 1 45 68 87 73
Fax: +33 1 40 61 31 67
Geert Leroux-Roels
Gent Universiteit
Centre for Vaccinology
Sint Pietersnieuwstraat 25
BE-9000 Gent
Tel: +32 9 240 3422
Fax: +32 9 240 6311
Odile Launay
Centre Cochin-Pasteur d’essais vaccinaux
Hôpital Cochin
Rue du Faubourg Saint-Jacques 27
FR-75679 Paris CEDEX 14
Tel: +33 1 43 25 38 67
Fax: +33 1 40 46 93 08
David Lewis
St. George’s, University of London
Department of Infectious Diseases
Cranmer Terrace
UK-SW17 ORE London
United Kingdom
Tel: +44 20 8725 5826
Fax: +44 20 8725 3487
Neil Almond
National Biological Standards Board
Division of Retrovirology
Blanche Lane, South Mimms
UK-EN6 3QG Potters Bar
United Kingdom
Tel: +44 1707 641220
Fax: +44 1707 649865

Graphic element