Vaccine molecules that polarize the immune response towards CD8+ T-cell and IgG2a/2b antibody responses (X-VAC)

Despite the huge impact that antibiotics and vaccines have had on human health, infectious diseases are still the second leading cause of death worldwide (WHO, 2002). The continued lack of efficient vaccines against diseases such as tuberculosis, HIV and malaria remind us that continued research into vaccine development is of great importance. One promising method for enhancing the efficacy of vaccines is to target antigens (that is bacterial or viral components) directly to specific immune cells responsible for initiating the immune response (so called antigen presenting cells (APC)). In this project we wish to study the effect of targeting antigens to a specific class of APC called Xcr1+ dendritic cells (DC). Previous studies by us and others have shown that this method of vaccination is efficient for induction of CD8+ T cells, also called cytotoxic T cells capable of killing virus infected cells or even tumor cells. In addition, targeting antigen to Xcr1+ DC enhanced induction of antibodies. Through this project we aim to better describe the molecular mechanisms that determine the immune response when targeting Xcr1+ DC. We have so far shown that targeting antigen to Xcr1+ DC with vaccines that are not actively taken up by the cells improve antibody responses, and provide better protection against influenza infection. In contrast, vaccines that are actively taken up by the DCs induce stronger CD8+ T cell responses. These results can be utilized to generate vaccines that predominantly induce T cell or antibody responses, and the technology is currently being evaluated in preclinical experiments for a new SARS-CoV-2 vaccine. To target antigens to Xcr1+ DCs we fuse them to the signalling molecule Xcl1, the only know signalling molecule that bind to the Xcr1 receptor. We have observed that route of immunization differentially impacts Xcl1 targeted vaccines in comparison with vaccines fused to another signalling molecule that also target DCs (CCL3). For antigen fused to Xcl1 we observed similar immune responses after intradermal and intramuscular immunization. In contrast, vaccines containing antigen fused to CCL3 induced was much more efficient when delivered by intramuscular immunization, compared to intradermal immunization. Our results have further demonstrated that targeting antigen to Xcr1 results in a response dominated by CD4+ T cells (helper T cells) of a Th1 phenotype and antibodies of the subclass IgG2a, in addition to cytotoxic T cells (killer T cells). This type of immune response is particularly good at eliminating virus or bacteria infected cells, and can potentially be in immunotherapy to kill cancer cells. Fusing antigen to Xcl1 has been demonstrated to give stronger Th1 polarization and cytotoxic T cell responses compared to targeting receptors such as DEC-205 and Clec9A, which are also expressed on Xcr1+ DCs. Our findings demonstrate that the choice of receptor plays an important role in determining the immune responses after vaccination, contrary to previous reports that immune responses are largely determined by the targeted DC population.

Forskningsprosjektet har resultert i 4 originale forskningspublikasjoner og 1 gjennomgangspublikasjon direkte tilknyttet de beskrevne arbeidspakkene. I tillegg har teknikker eller vaksinemolekyler utviklet som en del av prosjektet bidratt til ytterligere 7 publikasjoner gjennom nasjonale og internasjonale samarbeid. Prosjektet har dermed bidratt til bedre forståelse av hvordan immunresponser kan påvirkes gjennom målstyring av antigener mot DC. En PhD som forventes å forsvare sin avhandling innen utgangen av 2020 har vært ansatt på prosjektet. Det har også blitt sendt inn en Disclosure of Invention (DOFI) til Inven2 om bruken av Xcl1Del1 som målstyringsenhet i vaksiner for å oppnå bedre antistoffresponser. For PM har resultatene og metodene som er utviklet under dette prosjektet dannet grunnlaget for å søke videre finansiering. Prosjektet har også tillatt PM å etablere en uavhengig forskningsretning, og muligheten til å forfølge en stilling som uavhengig gruppeleder.

Despite the huge impact that antibiotics and vaccines have had on human health, infectious diseases are still the second leading cause of death worldwide (WHO, 2002). The continued lack of efficient vaccines against diseases such as tuberculosis, HIV and malaria, and new emerging diseases such as the recent ebola epidemic, remind us that continued research into vaccine development is of great importance. In this research proposal project manager (PM) wishes to study a novel vaccine strategy based on targeting antigens to the Xcr1 receptor, specifically expressed on cross-presenting dendritic cell (DC). PM's recent work has demonstrated that targeting Xcr1 using the chemokine Xcl1 is an efficient method for inducing cytotoxic T-cell responses, and for selective induction of Th1 associated antibodies of IgG2a/2b subclasses. By comparing antigen targeting to different receptors on the same population of DCs (Xcl1 vs Clec9A), in combination with more functional studies using Xcr1 knockout mice and bone marrow derived DCs, PM hopes to determine the mechanism behind an Xcl1 mediated immune response. One of the main questions to be addressed is whether the observed immune response is a result of targeting a specific DC population, or if ligation of the Xcl1 chemokine to the Xcr1 receptor influences the response. Using this information PM will further develop and optimize the Xcl1-mediated targeting approach for improved induction of Th1 associated IgG2a/2b antibody responses and/or CD8+ T cell responses. A better understanding of how the immune responses can be manipulated towards a CD8+ T cell or a Th1 associated antibody response could be of great value in future vaccine development against both pathogens and cancer.