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
The specific scientific and technological objectives are:
1. What immunisation schedule is optimal to achieve humoral, CTL and mucosal
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
- Stockholm Söder Hospital - Gay Men’s Health Clinic (Venhalsan) Söder Hospital SE-Stockholm, Sweden
- Muhimbili University, College of Health Sciences - Department of Microbiology and Immunology Muchs Dar Es Salaam, Tanzania
- University of Cape Town - Department of Medical Virology Cape Town, South Africa
- Ludwigs-Maximilians University Munich - Department of Infectious Diseases and Tropical Medicine DE-Munich, Germany