Community Research and Development Information Service - CORDIS


IHIVARNA Report Summary

Project ID: 602570
Funded under: FP7-HEALTH
Country: Spain

Periodic Report Summary 2 - IHIVARNA (Therapeutic TriMix / mRNA based Vaccine in Chronic HIV-1 Infected Patients Receiving Antiretroviral Therapy)

Project Context and Objectives:
Currently, 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, thus necessitating therapy throughout life. Therefore, for an effective control of the HIV epidemic new cost-effective and viable therapeutic strategies need to be evaluated.
A small proportion of HIV infected patients show a lack of clinical progression associated with strict control of viral replication in the absence of any treatment (they have referred as elite controllers). This so-called “functional cure” has been linked with potent HIV-specific immune responses observed in these patients.
Therapeutic vaccinations have emerged as one of the most promising strategies that could restore HIV-specific T-cell responses in HIV infected patients and help them control viral replication without cART. IDIBAPS has reported the most striking results in this field to date, demonstrating that a DC-based vaccine (European patent application number EP12382078.9) was able to significantly control viral load in vaccinated subjects (mean peak reduction of viral load of 94%).
Partner #1 in a double-blind placebo controlled study reported some of the best, most solid data showing that HIV-1 specific immune responses elicited by therapeutic dendritic cell (DC) vaccines pulsed ex vivo with inactivated autologous whole virus could significantly change pVL set-point (mean peak drop of -1.2 log10 copies/ml). Similar efficacy has been found in a preliminary non controlled clinical trial using DC electroporated with mRNA encoding autologous HIV-1 antigens. However, the logistics of developing a specific vaccine by ex vivo manipulating autologous DC for each patient may be prohibitive. Therefore, iHIVARNA consortium propose that in vivo targeting of DC by direct administration of a rational designed HIV mRNA encoding immunomodulating proteins might be an attractive alternative to target DCs in situ. Our candidate is highly innovative: 1. It is a mRNA based immunogen: it is expected to have a good safety profile, it is classified as nongene therapy by the American and German authorities, is easier to produce and to store regardless of the encoded antigen and is not restricted to a defined HLA type of individuals. 2. The HIV antigen encoded by mRNA has been selected with a rational design: based on our previous works selecting viral targets of protective HIV-1 specific T cell responses in 3 large cohorts of HIV infected individuals. 3. The candidate includes TriMix to target DC in vivo: our data suggest that mRNA encoding a mixture of antigen presenting cells activation molecules (CD40L, a constitutive active variant of TLR4 and CD70) significantly enhanced the induction of antigen-specific T cells. If this candidate would be able to obtain the functional cure in at least a proportion of patients it could be applicable to developing countries and would improve the care and cost of HIV infection.
The principal 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 objective of achieving a functional cure of HIV infection (i.e., 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). In order to fulfil this aim, the planned steps are:
- To manufacture HIV-TriMix-mRNA in GMP conditions.
- To perform a phase I dose escalation clinical trial and a phase IIa-proof-of-concept clinical trial to test safety, efficacy and immunogenicity.
- To ascertain immune and viral predictors and correlates of protection.

Project Results:
The first 36 months our efforts have been centered on:
1. Scientific coordination. Laboratory assessments, toxicology and regulatory issues, clinical trials intellectual property assessment, and amendments have been developed. All these issues have been discussed in the periodic Steering Committee (SC) teleconferences (held approximately every month) and agreements have been reached at the General Assembly meetings held every 6 months.
2. Clinical trials management and development. The preparatory stage towards the phase I and phase IIa clinical trial has been made as follow:
a. We have organized and performed pre-clinical studies in order to prepare regulatory documentation for the Scientific advice meeting with the national competence authority (AEMPS) in support of the Clinical Trial Application of the Phase I study. Final results have recently been published: Preclinical evaluation of an mRNA HIV vaccine combining rationally selected antigenic sequences and adjuvant signals (HTI-TriMix). Guardo AC, Joe PT, Miralles L, Bargalló ME, Mothe B, Krasniqi A, Heirman C, García F, Thielemans K, Brander C, Aerts JL, Plana M; iHIVARNA consortium.. AIDS. 2016 Sep 24. [Epub ahead of print] (see Appendix 9).
b. We have started coformulations of iHIVARNA.01 with 4 nanoparticles to perform in vitro and in vivo (animal) models (gold particles, dendrimers, PLA and polymers) to facilitate the use as a preventive vaccine against HIV infection. Preliminary results are available.
c. We have held a second Scientific advice meeting with AEMPS for the iHIVARNA clinical trial and have prepared all the required documentation for the application of the international multicentre iHIVARNA phase IIa clinical trial. An investigational medicinal dossier (IMPD), Investigational Brochure (IB) and a clinical trial protocol (CTP) were prepared and submitted in September 2016 together with other documents requested by IRBs and National Regulatory Authorities. National approvals for the phase IIa clinical trial are expected for December 2016-early 2017.
a. The manufacturing of GMP-grade messenger RNA for phase IIa clinical trials. iHIVARNA-01.3 (900 microgram HTI and 300 microg TriMix) is ready to be delivered in December 2016 (due to some issues, final delivery will be performed on February 2017).
3. Phase I clinical trial
The clinical trial has ended with the following schedule: The first group received the first dose on June 30th 2015. Last visit of the last patient was in October 2016. Final file with definitive results of short-term safety of the trial was available in July 21st 2016 and included in the documentation for phase IIa submission to regulatory authorities. Final long-term safety results, immunogenicity and transcriptome analysis will be available on December 2016. Viral reservoir changes will be available in January 2017.
4. Dissemination and exploitation During the second period of the project, the dissemination focus has been to communicate the project progress being consistent with the communication plan developed on the first period, and using the main dissemination tools (website, internal updates, etc.).
We can conclude that the project has achieved most of its objectives and technical goals for the period with minor deviations, due to delays in the clinical trials: a/ Phase I clinical trial, which started later than expected due to a late approval by AEMPS; and b/ Phase IIa clinical trial will also start with some delay mainly for two reasons 1) phase IIa clinical trial protocol and regulatory documents needed final phase I trial results and 2) planned VHP process to obtain regulatory approvals failed when AEMPS rejected being the coordinating Regulatory Authority (REF-NCA) for the process.

Potential Impact:
There is a growing interest in developing curative strategies to tackle HIV infection. A safe, affordable and scalable cure could address both the individual and public health limitations that are associated with lifelong antiretroviral therapy, as recognized by the European Parliament on the EU response to HIV/AIDS in the EU and neighbouring countries, mid-term review of Commission Communication COM(2009)569:
“...having regard to the Rome Statement adopted at the International Aids Society Conference 2011, which calls for more funding for the development of a functional cure for HIV ... Calls on the Commission and Council to provide the resources needed to guarantee equitable access to HIV prevention, testing, treatment, care and support, to address stigma and other barriers to timely access to counselling, testing and early care, to increase investment in research to achieve an effective cure and to improve instruments and actions to address co-infections such as tuberculosis or hepatitis B and C, among others, through improved access to screening and effective access to treatment ...”
iHIVARNA directly addresses this question as it is aimed at developing an innovative therapeutic vaccine against HIV infection with the final objective of inducing HIV specific immune responses to achieve a long-term control of viral replication without antiretroviral therapy (functional cure).
The iHIVARNA new immunogen has characteristics that are aimed at overcoming some of the problems of other therapeutic vaccines against HIV and to be potentially applicable to other diseases:
1. It is an mRNA-based immunogen. Compared with other gene-based approaches such as recombinant viruses or plasmids, mRNA is expected to have a better safety profile because it is a molecule that is only transiently present within the cell and is naturally and quickly degraded. Thus, it was classified as non-gene therapeutic by the American (Food and Drug Administration) and German (Paul Ehrlich Institute) authorities. Compared with proteins, mRNAs are easier to produce and to store regardless of the encoded antigen. In contrast to peptide-based vaccination, mRNA-based vaccination offers the advantage of not being restricted to a defined human leukocyte antigen type of individuals and is thus readily applicable to patients with any human leukocyte antigen haplotype.
2. The HIV antigen selection was based on a rational design and the same approach could be used for other pathogens.
3. The vaccine candidate also includes TriMix to activate DC in vivo. The use of mRNA encoding immunomodulating proteins might be an attractive alternative to potentiate DCs in vivo in other vaccines.
Therefore, we expect that the optimized strategy offered by iHIVARNA consisting of in vivo targeting of rationally designed mRNA towards DCs will induce functional cure in at least a proportion of the patients. If successful, this would entail a substantial improvement in the care of HIV infection at a significantly reduced cost. Moreover, it could also be applicable to developing countries and extend the proportion of patients with long-term control of their infection. The ideal scenario would be to treat HIV infected patients with antiretroviral therapy so that they reach an undetectable level of viral load and a normal level of CD4+ T-cell counts, and subsequently immunize these patients with the therapeutic vaccine. If a proportion of patients reaches life-long functional cure, it would simplify and improve the care of these patients and change the course of the epidemic. The cost of a therapeutic vaccine will be much lower than life-long antiretroviral therapy.
In summary, all efforts in iHIVARNA are devoted to obtain results relevant for the advancement of an HIV functional cure.

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