Development of HIV-vaccines: Mastering constraints from molecular pathogenesis and financing systems

Hans Wolf; Ralf Wagner; Jens Wild; Ludwig Deml; Kurt Bieler: Regensburg

Christiane Stahl-Hennig: Göttingen; Jonathan Heeney: Rijswijk

Shao Yiming: Beijing

e-mail: hans.wolf@klinik.uni-regensburg.de

So far there has been no HIV vaccine candidate in human trials where one could reasonably expect even partial protection in field trials.

More than 10 years ago when our group in Munich and later in Regensburg started to rethink the prerequisites and corner points for HIV vaccines it became evident that conventional humoral response alone would most likely not be sufficient to control HIV induced pathogenicity. Variability of suggested key target epitopes and clade as well as isolate or even passage specific antibody species raised problems which clearly needed more work. CTL as an only means of controlling a virus was not established. Clinical studies by Koup and others were however supportive of such strategies and we took this lead to reconsider the overall concept. The working hypothesis was a more holistic approach taking into account the various routes of infection and the genetic heterogeneity of the immune system.

The consequence was a vaccine design which, from the beginning, addressed humoral and cellular responses and included major parts of the viral antigenic repertoire to minimize the development of escape mutants.

Further progress has been achieved using optimised genes and vector systems with enhanced immunogenicity compared to conventional adjuvants. Virus like particles, various live recombinant vectors including NYVAC, MVA, TienTan and Semliki Forest Virus, novel formulations for protein antigens and nucleic acid vectors with modified contents of CpG motifs were developed and has so far led to a panel of 12 components for HIV, preventive and therapeutic vaccines.

Furthermore our strategy involved early on the search for sites where clinical evaluations could be performed. China has been selected as a country with an usually good medical infrastructure and an in parts unique homogeneous pattern of HIV clades.

The framework for preclinical work required extensive collaborations which was possible through a series of interactive grants of the EC, first involving European and Chinese partners, and later for product development and enhanced analysis of clinical data as well as for first clinical trials a network of 24 groups was formed. each of the partners contributes special complementary skills.

Preclinical data in collaboration with Ch. Stahl-Hennig and G. Hunsmann from the German Primate Center in Göttingen and J. Heeney from the Dutch Primate Center in Rijswijk included primate experiments with constructs similar to the final products. These data show a rapid clearance of a challenge virus under the set point within 8 weeks past challenge judged by virus load and cellular markers.

Next goals will be human trials in Europe and China later this year. First data on efficacy could only come from planned trials in Sinkiang/China which will need considerable financial resources which could only come from larger international programmes.