Periodic Reporting for period 4 - HIVACAR (Evaluating a Combination of Immune-based Therapies to Achieve a Functional Cure of HIV Infection) Reporting period: 2021-01-01 to 2022-06-30 Summary of the context and overall objectives of the project The HIVACAR project led by IDIBAPS is part of Horizon 2020. It has been awarded with a budget of 6.7 million € and comprises 14 institutions from 7 countries. It is aimed at looking into therapeutic strategies that could lead to change the current paradigm of HIV treatment by obtaining a functional cure for HIV (control of viral load to levels below the threshold of 50 copies/ml and maintenance of high CD4+ T-cell count after discontinuation of antiretroviral therapy) by effectively targeting residual virus replication and viral reservoirs. The ultimate goal is to understand how to control HIV replication over long periods of time or life without antiretroviral treatment. The associated proof-of-concept phase I/IIa clinical trial will be carried in 5 centres of 4 European countries. Dr. Felipe Garcia, senior consultant of the Infectious Diseases Department at Hospital Clínic and researcher of the IDIBAPS team on Infectious Diseases and AIDS, coordinates this study. HIVACAR started in Jan2017 and runs for 5 years.According to WHO, 37 million people in the world live with HIV and there are more than 2 million of new infections each year. Several prevention strategies are effective, but they are difficult to maintain. New cost-effective and viable therapeutic strategies are needed. Combined antiretroviral therapy is highly effective, but on its own is unable to eradicate HIV infection. Its significant cost is an important limitation for widespread use. Achieving a functional cure would allow people to live with the virus at undetectable levels without needing to take therapy continuously, and the risk of transmission would be minimised.HIVACAR proposes the administration of a combination of immunotherapy with therapeutic vaccines (one of them customised for each person), a potent antibody with the capacity to neutralise the site of binding of the virus, and a latency reversing agent: a molecule to make the virus vulnerable to immune system and therapeutic interventions. It will be determined whether this combination can activate the immune system mechanisms necessary to remove infected cells from the latent viral reservoir. If the interventions are successful, their future implementation is expected to lead to a reduction of 15-30% of the actual costs related to HIV. The project is also expected to improve the quality of life of people living with HIV. HIVACAR has been conceived under the framework of responsible research and innovation; representatives of people with HIV and other stakeholders have a key role from the inception of the project until obtaining results. Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far HIVACAR has completed 50 of the 66 months programme,during the third reporting period, the advance in the WP: WP1 SCIENTIFIC COORDINATION AND PROJECT MANAGEMENT: The project management structures have continued functioning in the phase of the project. Ample opportunities for interaction between project partners have been provided in the shape of virtual General Assembly Meetings and Steering Committee Meetings. Moreover, an extension of 6 months has been requested and approved by the EC to mitigate the impact that COVID-19 and lockdown had on the project. WP2 DESIGN AND MANUFACTURING OF A PERSONALISED mRNA VACCINE: During the third reporting period, WP2 has been focused on the manufacturing and characterization of 4 virtual batches of plasmid DNA and mRNA encoding HIVACAR T cell immunogen sequences. One of these four sequences has been selected to produce the technical batch for the GMP-like production to test the vaccine toxicity in vivo. WP3 CLINICAL TRIAL PREPARATION AND MONITORING: All the work of this WP was performed mainly in the first period. As we commented in the first report, we submitted the documents after advisory meetings with EMA and AEMPS (regulatory authority that is the coordinator of the VHP). Although the submission was rejected the AEMPS suggested to present again the documents with the changes implemented. Due to the delay in finding a new company, and having the new preclinical data, this submission has not been done yet and it is expected to be done early Q2 after the results of immunogenicity and toxicity are ready. A new protocol, PIS and Pharmacy manual has been prepared. In addition, a lab analytical, statistical analytical plan had been prepared.WP5 IMMUNE MONITORING AND CLINICAL DATA ANALYSIS: The work in WP5 during this reporting have focused on the organization of the bioanalysis plan for the clinical trial and second to initiate authority approval of clinical study procedures involving genetical modified products (i.e. the MVA vaccine).WP6 SOCIO ECONOMIC AND PSYCHO-SOCIAL IMPACT AND PATIENT ENGAGEMENT: As reported previously 2 surveys have been prepared and will be conducted in two segments.However due to the COVID-19 emergency, which significantly reduced the response of the local communities, those activities (in line with the rest of the project) have been postponed to 2021.WP7 DISSEMINATION AND EXPLOITATION: no specific event or press release has been launched due to the nature of the work done in these 18 months, the activities have been also limited due to the COVID-19 situation. Nevertheless, different oral presentations have been performed to disseminate the project results. Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far) There is an intense interest in developing strategies to target HIV-1 reservoirs that constitute barriers to an HIV cure. Different strategies to obtain an HIV cure are currently being assessed, such as intensification of cART, stem cell therapy or gene therapy. Some of these strategies pose different drawbacks: they are not effective, have potential safety problems, are technically very complicated and/or are in a very preliminary stage of development. Among current strategies, some are safe, scalable, cost-effective, viable and have yielded promising results. These are: 1) therapeutic vaccines to induce robust and broad T-cell responses able to suppress HIV replication, 2) passive immunisations with broadly neutralising antibodies (bNAbs) to suppress active virus spreading and replication and 3) latency reversing agents (LRA) to induce virus expression in latently infected cells.In HIVACAR, a first-in-man approach will be performed with a combination of a mRNA personalised therapeutic vaccine, a bNAB and a latency reversing agent. The personalised vaccine will be guided by the integration of host genetics and autologous viral sequence data that aims to maximise coverage of T cell targets harboured in the viral reservoir. This type of strategy has rendered good results in cancer but has never been used in HIV. Thus, a combination of immune-based therapies with latency reversing agents will be investigated to understand if it helps eliminate viral reservoirs and induce new and effective HIV immune responses that can contain viral rebound after cART cessation. To do this, an innovative phase I/IIa, multinational, multi-centre, randomised, open-label, controlled clinical trial will be conducted. Results are expected in late 2021.Any innovative therapeutic approach in HIV infection has ethical, economic, and psychosocial consequences. A detailed study about these aspects is conducted, involving both participants in the HIVACAR clinical trial and the greater community of people living with HIV. Results will be disseminated to people living with HIV, policy makers and the general public in Europe to better inform their future decisions. science.jpg
