With annual HIV infection rates still exceeding two million people a year, development of an HIV vaccine remains a world-wide urgency. The HIV vaccine research group is therefore exploring novel vaccination strategies and aims at a better understanding of immune responses that are induced by HIV or are required for protection. Currently, the following projects are pursued:
Antigen-specific T 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 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 the antibody response to heterologous viral antigens.
As a proof-of-concept, we introduced T helper cell epitopes of tetanus toxoid (TT) into HIV VLPs and immunized naïve mice or mice that had been immunized by Tetanol, a commercially available Tetanus vaccine, with HIV VLPs. Much higher HIV Env IgG1 antibody responses were observed in Tetanol-immunized mice that received VLPs containing the TT T helper cell epitopes than in naïve mice receiving the same TT-VLPs or Tetanol-primed mice receiving VLPs lacking the TT epitopes. Since the IgG1 subtype response induced in Tetanol-primed mice has less efficient Fc-effector functions we also identified T helper cell epitopes induced by HBVAXPRO, a licensed hepatitis B vaccine, and incorporated them into HIV VLPs. We currently exploring intrastructural help effects induced by different hepatitis B vaccines. To prepare for clinical studies, we have also identified HB-virus S-antigen-specific T helper cell epitopes recognized by most human vaccines.
In addition to VLP vaccines, liposomes may also be an attractive vaccine platform to harness T helper cells induced by licensed vaccine. In collaboration with Polymun Scientific Immunbiologische Forschung GmbH the incorporation of T helper cell epitopes into liposomes was optimized and we are currently exploring the coupling of HIV Env trimers to the surface of liposomes.
This project follows the innovative strategy to improve the efficacy of HIV vaccines by induction of affinity-matured HIV Env antibodies in the absence of HIV-specific T helper cells. The rational behind this strategy is based on observations that passive immunization with neutralizing antibodies can prevent infection and evidence that HIV-specific cellular immune responses may increase the susceptibility of acquisition of HIV infection. Since induction of the neutralizing antibodies is expected to depend on T-cell help, the project explores in relevant animal models the possibility to substitute HIV-specific T-cell help by T helper cells with other specificities.
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 viral portal of 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 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 >50-fold reduction of HIV-1 Env-mediated infection events. Inhibition of infection was also detected under non-neutralizing conditions. Based on the Env switching challenge virus a simultaneous challenge model is currently developed to address the breadth of protection in a non-human primate model.
HIV infection causes profound and often irreversible changes to the innate and adaptive immune system. For example, a permanent state of immune activation as well as depletion and dysfunction of CD4+ T-cells that are important regulators of humoral and cellular responses, all contribute to an overall impaired immunity even in ART-treated HIV infection. The main aim of this project is to study the effect of ART-treated HIV infection on the immunity gained from vaccines administered prior to HIV infection. For this purpose, an initial focus is set on immune responses of adults to the measles virus and tetanus toxin (both primed in childhood). The various objectives currently being evaluated include measurements of (i) cellular and soluble markers of inflammation, (ii) antigen-specific T-cell responses, (iii) antigen-specific antibody levels and (iv) transcriptome analysis of sorted antigen-specific T-cells. Gaining a deeper understanding of how HIV infection alters antigen-specific responses may provide clues for how these responses could be improved to the benefit of an enhanced vaccine-induced protective immunity. Samples from HIV-infected subjects are obtained in collaboration with Prof. Dr. med. Thomas Harrer (Medizinische Klinik 3 – UK Erlangen).