THE PROJECT

OBJECTIVES


OBJECTIVES

The primary aim of iHIVARNA is to successfully immunize antiretroviral-treated HIV-infected patients with 3 injections of the candidate universal HIV-TriMix-mRNA as an mRNA-based therapeutic vaccine with the final aim of improving the efficacy of therapeutic vaccination against HIV infection. In order to attain this general objective iHIVARNA will conduct the following studies:

  • The manufacturing of the HIV-TriMix-mRNA in GMP conditions to be used in clinical trials.
  • A phase I dose escalation clinical trial and a phase IIa-proof-of-concept clinical trial to test safety, efficacy and immunogenicity of the vaccine candidate.
  • Ascertaining immune and viral predictors and correlates of protection.

BACKGROUND


BACKGROUND

Nowadays, over 30 million people worldwide are infected with HIV, most of them living in developing countries. Although combined antiretroviral therapy (cART) has proven to be highly effective to prevent clinical progression and death, by itself it is unable to eradicate the infection and other alternative approaches are urgently needed. Therapeutic vaccinations – vaccines targeting HIV-infected patients with the ultimate aim of achieving a functional cure – have emerged as one of the most promising strategies that could restore HIV-specific T-cell responses in HIVñinfected patients and help them control viral replication without cART. iHIVARNA therapeutic vaccine candidate is going to be tested for the first time in two phase I and phase IIa clinical trials to assess if it is a valid alternative to lifelong cART treatment. The final objective is to study the potential role of this vaccine to reach the functional cure at least in a proportion of patients.

THE VACCINE CANDIDATE


THE VACCINE CANDIDATE

The iHIVARNA vaccine candidate HIV-TriMix-mRNA is the result of a long lasting scientific track record of the Consortium. It is based on an innovative approach that uses naked mRNA, so far recently applied in the cancer research field. The candidate has two parts: HIV that has been rationally designed based on data from large international cohorts; and TriMix to activate and target dendritic cells to improve HIV antigen presentation.

Vaccine Candidate

The combination of mRNA, rationally designed HIV antigen and TriMix is a very innovative approach for a therapeutic vaccine due to:

  • It is a mRNA based immunogen.
  • The HIV antigen encoded by mRNA has been selected with rational design based on previous works.
  • The candidate includes TriMix to target the dendritics cells in vivo.

The candidate HIV-TriMix-mRNA is expected to improve the results of other more traditional strategies already tested.

CLINICAL TRIALS


CLINICAL TRIALS

PHASE I

The primary end point is to check the safety and the secondary end point is to prove the effect of vaccination and preliminary immunogenicity. Phase I comprises patient recruitment, visits and follow up; sample collection and storage; and analysis of toxicity and preliminary immunogenicity data.

Clinical Trials 1

PHASE II

The primary end point is to prove safety and immunogenicity and the secondary end point is the change of viral reservoir and/or the dynamics of viral load rebound. Phase II comprises patient recruitment; visits and follow up; and sample collection and storage.

Clinical Trials 2


PROJECT STRUCTURE


PROJECT STRUCTURE

The work plan structure in iHIVARNA has been carefully designed to cover all aspects requiring specific effort towards a successful project completion, and divides activities into seven work packages:

Project Structure

WP 1 Scientific Coordination

Work Package objectives:

  • To provide an overall scientific direction and to drive the process of the project, steering efforts of partners for the achievement of milestones and ensuring that the work is undertaken with appropriate quality levels.
  • To provide a unified scientific, technological and strategic view throughout the project implementation.
  • To continuously assess the degree of fulfillment of the projects objectives.
  • To ensure that the project is not hampered by ethical problems and respects all relevant international and national regulation in this regard.
WP 2 Clinical Trials Management & Development

Work Package objectives:

  • To undertake the non-clinical studies.
  • The manufacturing of GMP-grade messenger RNA for the phase I and phase IIa clinical trials.
  • To seek scientific advice for the iHIVARNA clinical trial with European regulatory authorities and to prepare all the required documentation.
  • To effectively support and coordinate the clinical trials implementation.
WP 3 Clinical Trial phase I Implementation

Work Package objectives:

  • To perform a phase I, open label dose escalation.
  • To evaluate the safety of intranodal (IN) injection of HIV-TriMix-mRNA in order to select the optimal dose for the phase IIa clinical trial.
  • To assess preliminary data of immunogenicity in humans.
WP 4 Clinical Trial phase IIa Implementation

Work Package objectives:

  • To execute a randomized, parallel, double-blinded, controlled clinical phase IIa study of 70 antiretroviral treated chronic HIV-1 infected volunteers:
  • To assess the safety and toxicity of immunotherapy using iHIVARNA and TriMix mRNA for 70 patients (40 HIV/TriMix, 15 control/TriMix, and 15 control/saline).
  • To determine the immunogenicity of the vaccine preparation.
  • To determine the effects of treatment interruption after immunotherapy on blood values, plasma viral load and patients’ clinical well-being.
WP 5 Data Analysis

Work Package objectives:

To study the effect of HIV-TriMix-mRNA as compared to control vaccination on:

  • CD8/CD4+ T-cell cytokine responses (ELISPOT and ICS)
  • CD8+ T-cell HIV suppressive capacity
  • Proviral DNA reservoir and intracellular unspliced and multiple spliced HIV RNA
  • Cultivability and fitness of HIV
  • Emergence of viral escape mutations in sieve effect analyses
WP 6 Dissemination and exploitation

Work Package objectives:

  • To design a plan that allows for optimal communication within the project and the dissemination of information and knowledge generated by the project to relevant stakeholders.
  • To design and deploy the tools that will be needed to implement the plan.
  • To undertake extensive dissemination activities according to the communication plan.
  • To facilitate the take-up and use of results, in particular by promoting the definition of exploitation strategies, IPRs management policies and knowledge management activities and addressed to:
    1. Support participating partners -and specially the SMEs- in the use and protection of the project results in order to maximize their potential for market uptake.
    2. Conclude and follow-up on suitable arrangements with respect to results ownership and access rights so as to maximize their use without hampering its exploitation prospective.
    3. Devise specific exploitation/business plans for the resulting foreground with special emphasis on increasing the competitiveness of the participant SMEs.
WP 7 Project Management

Work Package objectives:

  • To set-up a project management structure that ensures an efficient operational management, including administrative, financial and legal issues, and appropriate liaison with the European Commission.
  • To ensure that the project is appropriately managed according to the work plan, supporting the Scientific Coordination in organizing and supervising the work.
  • To comprise resources, procedures and tools for ensuring that all results are delivered on time, with an adequate quality level and within cost, including quality control procedures on deliverables and interim and final review of the project achievements from a management perspective.
  • To enable the appropriate communication and work dynamics to help drive the whole Consortium as a team towards successful completion.

GENERAL INFORMATION


GENERAL INFORMATION

  • Project name: Therapeutic TriMix / mRNA based Vaccine in Chronic HIV-1 Infected Patients on Antiretroviral Therapy
  • Acronym: iHIVARNA
  • Funding scheme: Collaborative Project (Small or medium-scale focused research project)
  • Grant Agreement Number: HEALTH-602570
  • Topic: HEALTH-2013-INNOVATION-1 Safety and efficacy of therapeutic vaccines
  • Project coordinator: Dr. Felipe Garcia, IDIBAPS (Institut d’Investigacions Biomèdiques August Pi i Sunyer)
  • Duration: 48 months
  • Project start date: 1st December 2013
  • Project end date: 30th November 2017
  • Number of partners: 8
  • Project cost: 7,826,907.20 €
  • Funding: 5,984,720.00 €
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