HIV-l vaccines are urgently needed, especially in developing nations. Also, HIV vaccine study sites are needed in developing nations for more rapid development and deployment of vaccines. DNA plasmid vaccines are promising candidates but their potency needs to be improved. The programme will explore various modes of increasing the immunogenicity of priming with plasmid DNA; intradermal injections, with GM-CSF as adjuvant, intramucosal injections and boosting with a modified vaccinia Ankara vector, MVA. Vaccines produced from subtypes appropriate for Tanzania will be used and a study site will be established in Dar es Salaam. The prerequisites for approval will be addressed on all levels, paving the way for future trials. Immunogenicity studies will continue in Dar es Salaam, with a focus on mucosal immunity and durability of the immune response.
The general objectives of the research are:
1. to optimise the immunisation schedule for DNA vaccine priming and MVA
vaccine boosting in the development of HIV-1 preventive vaccines,
2. to develop the expertise and capability to study HIV-1 vaccines in Tanzania.
The specific scientific and technological objectives are:
1. What immunisation schedule is optimal to achieve humoral, CTL and mucosal immunity?
2. Can mucosal immunisation prime for im MVA boosting?
3. Is id immunisation superior to im DNA plasmid immunisation in humans?
4. Can GM-CSF improve id immunisation?
5. What is the durability of immune response after HIV-1 immunisation?
Plasmid DNA inmunogens are promising candidates for a HIV vaccine due to the profile of the induced immune response, cost and robustness. However, the immune response is weak when given alone as a standard intramuscular injection. The immune response may be increased in several ways. Intradermal immunisation has, in other systems, given stronger responses that have been further increased by concomitant GM-CSF. Intramucosal administration might accomplish the same thing and, in addition, prime for systemic as well as mucosal immunity. The response can be further boosted with later administration of the same antigen in a live, non-replicating vector, MVA. This combination has significantly reduced SIV infection in immunised macaques. All these avenues will be explored in an initial safety study in Sweden, where an indication of the most efficient routes will be identified. However, it is in developing nations that there is greatest need for HIV vaccines. The subtype of HIV used in these studies will consider this and the capacity to continue these studies will be established in Tanzania. This capacity building will be a venture in its own right since it includes extensive community interaction, study-participant preparation and logistical work. In Tanzania, this proposal covers the first of a series of immunogenicity studies where the most promising concepts that were safety tested in the first trial will be expanded upon. For these studies, a partnership has been put together with extensive experience of working with and producing HIV vaccines, and a documented capacity to evaluate systemic and mucosal humoral immunity, various aspects of both CD4 and CD8 mediated immunity as well as expertise in local HIV strain variability. The partnership will also continue to pursue phase III HIV vaccine capability in two sites in Tanzania through other grants.
1. The safety of priming with OVA plasmids given im, id +/- GM-CSF and
intramucosally, prior to boosted with MVA vectors carrying the same HIV genes
env, gag and pol of a nature appropriate to Tanzania will be explored in
2. A process that enables HIV vaccine trials to be carried out in Tanzania will be completed.
3. A clinical trials unit capable of HIV vaccine trials under GCP will be established in Tanzania.
4. DNA priming, with a MVA boost, will be optimised in a phase I/II trial in Tanzania.
Karolinska Institutet, Stockholm Söder Hospital
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