(2016 – 2019) – Principal Investigator for IVN Simona Ruta MD, PhD
Aim: The development and preliminary testing of a candidate vaccine based on an mRNA encoding for a rationally designed antigenic sequence (HIVACAT), which was selected based on the fact that immune responses against these regions were associated with low levels of viral load and that the epitopes were relatively conserved, associated with a combination of other mRNAs, (TriMix encoding for caTLR4, CD40 ligand and CD70), which provide a strong adjuvant activity, delivered in nanoparticles, that stabilize and protect the mRNAs.
Coordinator: Vrije Universiteit Brussel, Belgium – Joeri Aerts
- Prins Leopold Instituut voor Tropische Geneeskunde, Belgium – Guido Vanham
- Centre National de la Recherche Scientifique, Université Claude Bernard Lyon 1, France – Bernard Verrier
- Fundació Clínic per a la Recerca Biomèdica, Spain – Felipe Garcia
- Institute of Virology Stefan S. Nicolau – Simona Ruta
Working team: Simona Ruta, Carmen Diaconu, Ana Neagu, Denisa Dragu
Project financed by UEFISCDI program PN-III, ERA NET – HIVNANOVA contract 4/2016
Implementation period: 2016 – 2019
Summary: Recent data demonstrate the feasibility of dendritic cell based therapeutic vaccines to control HIV-1 infection. Nevertheless, their patient specific nature, the specialized infrastructure, the high level of expertise required for preparation and the high demands for storage and transportation preclude widespread application and commercialization. Therefore, novel vaccine candidates that retain the power of a DC-based vaccine but at the same time overcome its limitations need to be developed. mRNA-based vaccines offer significant promise in this respect. It was shown that mRNA is selectively taken up by dendritic cells upon injection in the lymph node and induces strong antigen specific immune responses. An interesting vaccine candidate could be an mRNA-based vaccine able to deliver both a rationally designed HIV antigen sequence and on the other hand potent activation signals. An important drawback of this approach is the fact that intranodal immunization is not easily applicable in clinical settings. Therefore, more standardized routes of administration need to be explored. The results obtaines in this project show that the optimal delivery system is represented by the association of mRNA with the amphipathic peptide LAH4L1, which increases the efficiency of transfection and the expression of the encoded protein, while the incorporation into PLA nanoparticles does not ensure an efficient transfection in current formulations. In vivo, biodegradable nanoparticles complexes and the association of an mRNA that encodes for activating signals (TRIMIX- TLR4 ligands, CD40 ligand and CD70) induce the synthesis of Interferon type I, a potential beneficial effect as it produce the activation of dendritic cells.
- D’haese S, Lacroix C, Garcia F, Plana M, Ruta S, Vanham G, Verrier B, Aerts JL. Off the beaten path: Novel mRNA-nanoformulations for therapeutic vaccination against HIV. J Control Release. 2021 Feb 10;330:1016-1033. doi: 10.1016/j.jconrel.2020.11.009. Epub 2020 Nov 10. PMID: 33181204.
- Dragu DL, Neagu AI, Matei L, Bleotu C, Ruta SM, Diaconu CC. Characterization of a platform based on dendritic cells for new therapeutic vaccine development. Rom Biotechnol Lett. 2020; 25(5): 1899-1907. DOI: 10.25083/rbl/25.5/1899.1907
Communications at national/international congresses
- Simona Ruta. Strategii terapeutice inovative în infecţia HIV / New therapeutic strategies for HIV infection. A XI-a Conferinţă Naţională de Microbiologie şi Epidemiologie, 08-10 noiembrie 2018, Sibiu
- Catalin Tucureanu , Iuliana Caras, Vlad Tofan, Sonia Ciulean , Mihaela-Roxana Ioghen, Octavian Ioghen , Crina Stavaru, Adrian Onu, Salageanu Aurora, Simona Ruță Influența diferitelor combinații de liganzi pentru receptori ai imunitătii innascute -adjuvanți asupra maturării și funcției celulelor dendritice/ Influence of different pattern recognition receptor agonists- adjuvant combinations on dendritic cell maturation and function Simpozionul Nicolae Cajal ediţia a XIII-a , p8, Bucuresti, Martie 22 – 24, 2018
- Simona Ruta, Aura Temereanca, Ruxandra Burlacu, Anya Umlauf, Thomas Marcotte, Luminita Ene, Cristian Achim. Ce factori influenteaza statusul neurocognitiv la pacienti cu infectie HIV de lunga durata? / what are the risk factors for neurocognitive impairments in hiv-infected patients. “Academician Nicolae Cajal” Symposium, 20 martie-1 aprilie 2017, Bucuresti.