Description

Despite the clinical efficacy of combined anti-retroviral therapy (cART), this treatment by itself is unable to eradicate HIV infection and to restore an effectively virus-suppressive immune response against HIV. Therefore, cART has to be taken life-long. Treatment resistance, adverse effects in the medium-long term and the significant cost of cART are important limitations for lifelong adherence to this therapy.
It has been extensively shown that the immune system plays a crucial role in the control of HIV infection. Thus, individuals exist that spontaneously control their infection without additional cART, the so-called long-term non-suppressors. However, cART does not fully restore a normal immune status in HIV-infected individuals, and patients still experience co-morbidities, such as increased cardiovascular disease, bone disorders and cognitive impairment. In addition, interruption of antiretroviral therapy almost invariably leads to the re-emergence of detectable viral replication and the progression of AIDS. These concerns highlight the urgency by which new therapeutic strategies must be developed and tested. Therefore, for an effective control of the HIV epidemic new cost-effective and viable therapeutic strategies need to be evaluated. Given the fact that the immune system plays such a crucial role both in the pathogenesis and in the control of HIV infection, several interventions to boost the immune system have been explored. Therapeutic vaccination, which is aimed at enhancing HIV-specific immune responses is a promising new approach. Especially vaccination with autologous dendritic cells has shown both immunological and clinical benefit, measured as the time off cART, in a number of clinical studies. One of the main bottlenecks which severely limits the potential for widespread use of DC vaccination is that each vaccine has to be prepared individually for each patient. Therefore, we want to explore the possibility of using direct intranodal administration of mRNA for immunization. One of the problems for HIV vaccination research is that the host range of HIV limits its infection to humans and human primates. Moreover, HIV infection of chimpanzees does not reflect the disease course observed in humans. Ethical constraints and significant cost also put severe limitations on the use of these models. The model that most closely replicates the course of HIV infection in humans is a SIV infection in non-human primates. Therefore, many preclinical vaccination studies have been performed in this model, mostly using macaques. Nevertheless, also for this model questions have been raised as to its validity for the human situation and more and more limitations are also put on this kind of research, which can only be performed in specialized facilities under very stringent conditions, again resulting in a prohibitive cost for large-scale preclinical vaccination studies. For these reasons, over the last few years, a lot of research has been performed to develop small animal models (mostly mice) that closely mimic the course of a human HIV infection.
In this project, we want to perform a thorough preclinical evaluation of a new type of therapeutic vaccine using different mouse models. The vaccine involves a direct intranodal injection of mRNA encoding on the one hand an antigen and on the other hand activating signals. First, we will evaluate the immunogenicity of our vaccination approach in naïve wild-type mice. This will give us important information as to which vaccine formulation will be most suited for therapeutic vaccination. Second, we will use well-established naturally infectious models such as influenza and LCMV to study the efficacy of our vaccination approach. Finally, we will evaluate our vaccine in a humanized mouse model consisting of a HLA-A2 transgenic NSG mouse in which cord blood-derived CD34+ human hematopoietic stem cells are injected. This will allow the analysis of HIV-specific immune responses in the context of an HLA-A2 restricted human immune system.
This project is part of a larger multicentric project which involves the evaluation of an intranodally administered mRNA based therapeutic vaccine consisting of activation signals (constitutively active TLR4, CD40L and CD70) and a rationally designed HIV-antigen sequence for the treatment of HIV infected patients. For this purpose, both a phase I (dose limitation) and a phase IIa trial are planned. The partners involved are the Institute for Tropical Medicine Antwerp (G. Vanham), the Erasmus University Rotterdam (R. Gruters), IRSICAIXA Barcelona (C. Brander) and Hospital Clinical Barcelona (F. Garcia, coördinator). For the study with influenza, a collaboration with X. Saelens of the University of Ghent has been set up. For the study with LCMV, a collaboration with Karl Sebastian Lang of the
University of Essen has been established. Michel Moutschen of the University of Liege will provide the necessary expertise for the development of humanized mouse models.
AcronymIWT712
StatusFinished
Effective start/end date1/01/1531/12/18

    Research areas

  • mRNA, HIV, vaccination, Immunity

    Flemish discipline codes

  • Vaccines

ID: 4967134