Concept and results
In the Vaccine Adjuvant Research section we study innate immune activation, identify molecular patterns that activate DCs and investigate antigen delivery and uptake mechanisms with the purpose of developing novel vaccine adjuvants
In our pursuit to design the ideal adjuvant for a vaccine antigen we systematically modify the composition of the vaccine delivery system and/or the immunomodulators. We modify the composition of the delivery particles in order to change physical characteristics of the vaccine delivery system, e.g. in terms of size, fluidity or charge. Such modifications can be used to ensure optimal antigen adsorption, vaccine depot, in-vivo uptake and presentation etc. Dependent on the antigen, the liposome fluidity can e.g. have profound influence on the level of CMI response, balance between antibody isotypes and the distribution of effector vs. memory cells. In our search for the optimal immunomodulator we have found that several mycobacterial lipids have profound immunomodulatory effects which can be exploited in vaccine development. We have been involved in the discovery of TDB as an effective immunomodulator for induction of cell-mediated immune responses and the dissection of the signalling pathway involved. The immunomodulator discovery program has also identified the mycobacterial monomycoloyl glycerol (MMG) as an effective activator of human dendritic cells and as an immunomodulator giving rise to a prominent Th1 response in animal models. In this discovery program it has also been important for us to understand the innate mechanisms activated by these novel immunomodulators. Finally the route of vaccination is also under evaluation in the group and has been shown to have a major impact on the immune response induced. We are therefore working with different immunization strategies including delivery to the upper airways to improve protective immune responses at mucosal surfaces.
Our special focus is on liposome-based adjuvants and the first generation CAF-adjuvant (CAF01) developed in our lab consists of liposomes formed of N,N´-dimethyl-N,N´-dioctadecylammonium (DDA) stabilised with the synthetic mycobacterial immunomodulator α,α´-trehalose 6,6´-dibehenate (TDB) which is inserted into the lipid bilayers.
DDA acts as a delivery vehicle serving to promote uptake and presentation of the vaccine antigen in the relevant subset of antigen-presenting cells (APCs) whereas TDB is a CLEC-4 ligand which activates APCs through the Syk-Card9 signalling pathway thereby inducing a combined Th1 and Th17 responses. Together the two components, DDA and TDB, act in synergy to generate highly potent T-cell and antibody responses shown to be effective in vaccines against a range of different diseases, e.g. in animal models of melanoma, influenza, chlamydia, tuberculosis (TB), group A streptococcus and malaria.
Figure: The CAF01 adjuvant enhances antigen uptake and presentation. When a vaccine antigen is formulated with the CAF01 adjuvant, antigenpresenting cells readily acquire the antigen, leading to enhanced antigen presentation. This efficiently promote antigen-specific T lymphocytes and long-term immunological memory. In the photomicrograph is seen a dendritic cell (red) with internalized antigen (green) in distinct endosomal compartments.
CAF01 induce a robust memory T-cell responses characterised by a very large proportion of multifunctional T cells. These cells are maintained at a very high frequency more than one year after vaccination and, importantly, also confers long-lived protection against virulent Mycobacterium tuberculosis at levels which are comparable to or better than BCG. Biodistribution studies using radiolabelled vaccine components have shown that CAF01 maintain this efficient memory response through the formation of an efficient depot at the injection site.
CAF01 has been tested in two phase I clinical trials to evaluate the safety, tolerability and immunogenicity of different doses of CAF01 administered in combination with a lead TB vaccine candidate (Clinical trial no. NCT00922363) and a HIV-1 Peptide cocktail (Clinical trial no. NCT01141205) respectively. Both studies showed that CAF01 is safe and induces a strong CMI response in humans.
Building on the principles of CAF01, we can further modulate the formulation when designing tailor-made adjuvants for specific disease targets through changing the liposomes or by incorporation of different immuno-modulators or different combinations of immunomodulators (TLR and non-TLR) into the cationic liposomes.
Currently we combine mycobacterial non-TLR ligands with conventional TLR ligands in the different delivery vehicles. Our aim is to induce highly diverse and complex immune responses and by adjusting the different parameters we have demonstrated that we can influence both the antibody isotype, the duration of vaccine depot, and the CTL/Th1/Th17 balance.
Our second generation adjuvant, CAF09, which consist of DDA, MMG and polyIC have thus shown to be very effective at inducing antigen specific cytotoxic T cells against protein- and peptide based antigens. This adjuvant is thus a potential candidate for vaccines against e.g. HIV, Cancer, pandemic influenza etc. It is presently undergoing preclinical development with the purpose of entering clinical trials early 2016.
Vaccine delivery and formulation is a multidisciplinary project spanning both applied and basic research at the highest international level. This includes:
biochemical and physico-chemical characterizations of adjuvant systems
studies of the distribution and fate of vaccine formulations in vivo
basic immunological characterizations of adjuvant function in vivo and in vitro
characterizations of vaccine-induced immune responses in humans and animal models
protective immune responses in different challenge models
Currently, we have protein and peptide-based vaccine projects within the fields of TB, influenza, chlamydia, HIV and group A streptococcus as well as therapeutic melanoma and human papilloma virus vaccines under evaluation. In addition, we have extensive experience within preclinical development of adjuvanted subunit vaccines and are involved in supporting first-in-man trials of novel adjuvants.
The research is carried out in collaboration with research groups from Danish and foreign universities, biotech companies and governmental institutions.
Last revised 27 August 2015