We intend to carry out a demonstration project with three genetic vaccines that will induce a cellular immune response towards HIV-l regulatory proteins. The prototype vaccines, tested earlier for safety and immunogenicity in small animals and in non-human primates, will be given firstly to HIV-l infected individuals known to lack pre-immunization responses to HIV-l Nef, Tat and Rev and secondly to noninfected individuals at risk for HIV infection. The objective of this project is to show, that the prototype vaccines can be economically produced under GMP conditions and that the vaccines are safe, immunogenic and have a beneficial therapeutic effect in the HIV infected individuals.
Preparation of the prototype vaccines. Three eukaryotic DNA vectors, a non-replicating (pHCMV), another one with limited self-replicative capacity (pBamNeo) and a non-replicating vaccinia virus (MVA) have been developed to express single HIV genes (nef. tat or rev). The capacity of these delivery systems has been evaluated for protein expression in-vitro and for immunogenicity and safety in-vivo in experimental animals and for one of the vectors, in human volunteers. The plasmid DNAs will be prepared under GMP conditions by one of the SME partners, SBL vaccine and tested for CQ.
Human studies: The demonstration study (a pilot type investigation) will be performed in voluntary HIV-infected asymptomatic individuals. For each of the three immunogenic gene constructs (HIV nef, tat or rev), 20 patients/center will be immunized in Munich, Stockholm and Tampere, using one of the three expression systems. Furthermore, 29 high-risk but non-infected sexual partners to HIV-1 infected patients will be vaccinated with a combination of vectors expressing all three proteins. Thus, altogether 60 immunized HIV-1 infected patients and 27 immunized non-infected individuals will be monitored for safety and immunogenicity. This includes the studies of T cell subset profiles, Th1 and Th2 type responses towards recombinant Nef, Tat and Rev proteins and cytotoxic T lymphocyte responses towards target cells infected with vaccinia recombinants or sensitised with Nef, Tat and/or Rev specific peptides. In addition the extent, class and subclass of the HIV-1 specific antibody response, and changes in virological (e.g. virus load) and clinical parameters will be studied.
Vaccination of humans with genetic vaccines should confer a considerable impact for vaccinology in two aspects: exploring the usefulness of genetic vaccines in vaccination strategies and the immunization of individuals with an already ongoing chronic viral disease.
Funding SchemeCSC - Cost-sharing contracts
105 21 Stockholm
105 21 Solna