Preclinical evaluation of an mRNA HIV vaccine combining rationally selected antigenic sequences and adjuvant signals (HTI-TriMix)

Guardo, Alberto C.; Joe, Patrick Tjok; Miralles, Laia; Bargalló, Manel E.; Mothe, Beatriz; Krasniqi, Ahmet; Heirman, Carlo; García, Felipe; Thielemans, Kris; Berthou, Christian; Aerts, Joeri L.; Plana, Montserrat

doi:10.1097/qad.0000000000001276

Cited by 39 publications

(41 citation statements)

References 45 publications

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“…Time until viral rebound, evolution of pVL, and viral reservoir were analyzed using a linear mixed effects model to compare the evolution over the study period. The moderate increase in T cell responses to peptides spanning the HTI sequence at week 8 of the phase I clinical trial [11,12] led to extra vigilance. A protocol amendment in order to perform a futility analysis during the phase IIa trial was implemented.…”

Section: Statistical Analysis and Interim Analysismentioning

confidence: 99%

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Therapeutic Vaccine in Chronically HIV-1-Infected Patients: A Randomized, Double-Blind, Placebo-Controlled Phase IIa Trial with HTI-TriMix

et al. 2019

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Therapeutic vaccinations aim to re-educate human immunodeficiency virus (HIV)-1-specific immune responses to achieve durable control of HIV-1 replication in virally suppressed infected individuals after antiretroviral therapy (ART) is interrupted. In a double blinded, placebo-controlled phase IIa multicenter study, we investigated the safety and immunogenicity of intranodal administration of the HIVACAT T cell Immunogen (HTI)-TriMix vaccine. It consists of naked mRNA based on cytotoxic T lymphocyte (CTL) targets of subdominant and conserved HIV-1 regions (HTI), in combination with mRNAs encoding constitutively active TLR4, the ligand for CD40 and CD70 as adjuvants (TriMix). We recruited HIV-1-infected individuals under stable ART. Study-arms HTI-TriMix, TriMix or Water for Injection were assigned in an 8:3:3 ratio. Participants received three vaccinations at weeks 0, 2, and 4 in an inguinal lymph node. Two weeks after the last vaccination, immunogenicity was evaluated using ELISpot assay. ART was interrupted at week 6 to study the effect of the vaccine on viral rebound. The vaccine was considered safe and well tolerated. Eighteen percent (n = 37) of the AEs were considered definitely related to the study product (grade 1 or 2). Three SAEs occurred: two were unrelated to the study product, and one was possibly related to ART interruption (ATI). ELISpot assays to detect T cell responses using peptides covering the HTI sequence showed no significant differences in immunogenicity between groups. There were no significant differences in viral load rebound dynamics after ATI between groups. The vaccine was safe and well tolerated. We were not able to demonstrate immunogenic effects of the vaccine.

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Section: Statistical Analysis and Interim Analysismentioning

confidence: 99%

“…In preclinical mouse experiments, HTI-TriMix was found to be immunogenic [10,11]. Next, HTI-TriMix was proved to be safe in a dose-escalating phase I clinical trial in 21 chronic HIV-1-infected patients under stable ART [10,12].…”

Section: Introductionmentioning

confidence: 99%

Therapeutic Vaccine in Chronically HIV-1-Infected Patients: A Randomized, Double-Blind, Placebo-Controlled Phase IIa Trial with HTI-TriMix

et al. 2019

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“…A novel therapy proposed by Guardo et al combined TRIMIX adjuvant and an HIV T cell immunogen (HTI) for in vivo targeting of DCs by intranodal injections [205]. The previously described TRIMIX adjuvant consists of three mRNAs encoding CD40L, the costimulatory molecule CD70, and constitutively activated TLR4 [206].…”

Section: Dcs As a Therapeutic Tool To Drive Hiv-1-specific Killer T Cmentioning

confidence: 99%

“…The HTI vaccine component consists of an mRNA expressing epitopes of Gag, Pol, Vif, and Nef proteins, chosen on the basis of antigen-specific CD4 + and CD8 + T cell reactivity [207]. Monocyte-derived DCs electroporated with this preparation were shown to induce T cell proliferation and IFN-γ responses in vitro, and intranodal injection of TRIMIX/HTI induced antigen-specific CTL responses in mice [205]. In addition, human lymph node explants treated with TRIMIX/HTI activated DCs and induced proinflammatory mediator production.…”

Section: Dcs As a Therapeutic Tool To Drive Hiv-1-specific Killer T Cmentioning

confidence: 99%

Role of Dendritic Cells in Exposing Latent HIV-1 for the Kill

Kristoff

Rinaldo

Mailliard

2019

Viruses

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The development of effective yet nontoxic strategies to target the latent human immunodeficiency virus-1 (HIV-1) reservoir in antiretroviral therapy (ART)-suppressed individuals poses a critical barrier to a functional cure. The 'kick and kill' approach to HIV eradication entails proviral reactivation during ART, coupled with generation of cytotoxic T lymphocytes (CTLs) or other immune effectors equipped to eliminate exposed infected cells. Pharmacological latency reversal agents (LRAs) that have produced modest reductions in the latent reservoir ex vivo have not impacted levels of proviral DNA in HIV-infected individuals. An optimal cure strategy incorporates methods that facilitate sufficient antigen exposure on reactivated cells following the induction of proviral gene expression, as well as the elimination of infected targets by either polyfunctional HIV-specific CTLs or other immune-based strategies. Although conventional dendritic cells (DCs) have been used extensively for the purpose of inducing antigen-specific CTL responses in HIV-1 clinical trials, their immunotherapeutic potential as cellular LRAs has been largely ignored. In this review, we discuss the challenges associated with current HIV-1 eradication strategies, as well as the unharnessed potential of ex vivo-programmed DCs for both the 'kick and kill' of latent HIV-1.

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“…A difficulty with these vaccines, however, involves development of methods to easily deliver them to DCs. For example, an mRNA vaccine encoding HIV T cell immunogen sequence from Gag, Pol, Vif, and Nef together with three activation signals activated DCs, upregulated maturation markers, and elicited cytokine production and enhanced T-cell proliferation along with CTL responses [100]. Administration to DCs, however, was by ex vivo electroporation of MoDCs from HIV-infected patients or intranodal immunizations of mice.…”

Section: Roles Of Dcs In Therapeutic Hiv Vaccinesmentioning

confidence: 99%

Dendritic Cells in HIV/SIV Prophylactic and Therapeutic Vaccination

Robert-Guroff

2019

Viruses

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Dendritic cells (DCs) are involved in human and simian immunodeficiency virus (HIV and SIV) pathogenesis but also play a critical role in orchestrating innate and adaptive vaccine-specific immune responses. Effective HIV/SIV vaccines require strong antigen-specific CD4 T cell responses, cytotoxic activity of CD8 T cells, and neutralizing/non-neutralizing antibody production at mucosal and systemic sites. To develop a protective HIV/SIV vaccine, vaccine regimens including DCs themselves, protein, DNA, mRNA, virus vectors, and various combinations have been evaluated in different animal and human models. Recent studies have shown that DCs enhanced prophylactic HIV/SIV vaccine efficacy by producing pro-inflammatory cytokines, improving T cell responses, and recruiting effector cells to target tissues. DCs are also targets for therapeutic HIV/SIV vaccines due to their ability to reverse latency, present antigen, and augment T and B cell immunity. Here, we review the complex interactions of DCs over the course of HIV/SIV prophylactic and therapeutic immunizations, providing new insights into development of advanced DC-targeted HIV/SIV vaccines.

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Preclinical evaluation of an mRNA HIV vaccine combining rationally selected antigenic sequences and adjuvant signals (HTI-TriMix)

Cited by 39 publications

References 45 publications

Therapeutic Vaccine in Chronically HIV-1-Infected Patients: A Randomized, Double-Blind, Placebo-Controlled Phase IIa Trial with HTI-TriMix

Therapeutic Vaccine in Chronically HIV-1-Infected Patients: A Randomized, Double-Blind, Placebo-Controlled Phase IIa Trial with HTI-TriMix

Role of Dendritic Cells in Exposing Latent HIV-1 for the Kill

Dendritic Cells in HIV/SIV Prophylactic and Therapeutic Vaccination

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