Research Group of K. Überla/D. Damm

Antigen-specific T follicular helper cells provide critical signals for cognate B-cells to differentiate into memory B-cells and plasma cells. In the context of particulate vaccines composed of different proteins, T helper cell epitopes and B-cell epitopes do not need to be covalently linked. HIV-Env specific B-cells for example can internalize virus-like particles (VLPs) containing HIV Env and Gag. This leads to presentation of Env- and Gag-derived peptides on their MHC-II molecules explaining our observation that Gag-specific T helper cells can provide help for Env-specific antibody responses. In mouse experiments, Gag-specific T helper cells not only enhanced anti-Env IgG levels up to 100-fold but also modulated the IgG subtype response. A major aim of our research is therefore to develop novel vaccine platforms that exploit T helper cells induced by common licensed vaccines to improve Fc-effector functions and the mucosal antibody response to heterologous viral antigens.

As a proof-of-concept, we introduced T helper cell epitopes of tetanus toxoid (TT) into HIV VLPs. Mice that had been immunized by Tetanol, a commercially available Tetanus vaccine, or naïve mice, were then injected with HIV VLPs containing the TT epitope. Much higher HIV Env-specific IgG1 antibody responses were observed in Tetanol primed mice. Since the IgG1 antibody response to HIV Env has less efficient Fc effector functions, mice were also immunized with hepatitis B vaccines or an experimental tuberculosis vaccine (H1/CAF01) and then boosted with VLPs containing matched T helper cell epitopes. Primed mice had higher HIV Env IgG2a and IgG2b antibody responses after booster immunizations with matched VLPs and the magnitude of this HIV Env antibody responses correlated with T follicular helper cell responses to the hepatitis B and H1 T helper cell epitopes.

To extend the concept of intrastructural help to non-enveloped viruses, we established an E-coli-based production system for L1 VLPs of HPV-16. Different coupling strategies were explored to coat the L1 VLPs with HIV-Env. First immunization experiments with HIV Env coated VLPs revealed strong antibody responses to Env, but also antibody responses to the HPV-VLPs. 

Antibodies targeting the HIV-1 Env protein have been shown to prevent systemic infection in non-human primate models of AIDS. To explore whether these antibodies can block infection of the “first cell” at the portal of viral entry, challenge viruses based on simian immunodeficiency virus (SIV) were developed that use HIV-1 Env for entry into target cells during the first replication cycle, but then switch to SIV Env for all subsequent rounds of the infection. Passive immunization of monkeys with a broadly neutralizing antibody binding to Env of HIV-1, but not SIV, prior to rectal exposure to the switching challenge virus led to a >100-fold reduction of HIV-1 Env-mediated infection events. Using this challenge model under non-neutralizing conditions did not reveal a major reduction of HIV-1 Env mediated first infection events. Consistently, the same broadly neutralizing antibody with mutations inactivating the interaction with Fc-receptors reduced the HIV-1 Env-mediated infection events to a similar extent, indicating that non-neutralizing effector mechanisms do not contribute notably to sterilising immunity in the strictest sense.

Borna Disease Virus (BoDV-1) is a neurotropic RNA virus that causes severe inflammation of the central nervous system (CNS) with a case fatality rate of over 95% in humans, following zoonotic spillover infections from its natural host - the white-toothed, bicolored shrew (Crocidura leucodon). No vaccines or therapeutic options are currently available against BoDV-1. Our translational research aim is to develop neutralizing antibodies directed against the viral glycoprotein and de novo entry inhibitors after identification of the yet unknown cellular receptor. Currently, we generate soluble and nanoparticulate BoDV-1 vaccine candidates and characterize immune responses in antibody-humanized mice. Furthermore, we establish tools and assays to identify the cellular receptor of the virus as prerequisite to develop molecular entry inhibitors.

Extracellular vesicles (EVs) are spontaneously budding from the surface of eukaryotic cells (ectosomes) or being secreted in late endosomes, also known as multivesicular bodies (MVBs), and released upon fusion of MVBs with the cellular plasma membrane (exosomes). Beside host factors, EVs may carry any type of antigen that was present on the endosomal or plasma membranes of producer cells. Our aim is to specifically load extracellular vesicles with antigenic and/or immunostimulatory cargo (immunomodulatory EVs; iEVs) in vivo after immunization with mRNA-LNPs coding for membrane-embedded molecules. Subsequently, we characterize adaptive immune responses modulated by these EVs.