Adjuvanted HLA-supertype restricted subdominant peptides induce new T-cell immunity during untreated HIV-1-infection
Highlights
► A universal therapeutic HIV-1 vaccine design ► Subdominant and HLA-supertype restricted epitope peptides in adjuvant ► Treatment-naïve HIV-1-infected individuals were immunized. ► The vaccine was safe in HIV-1 infected individuals living in Denmark. ► Vaccine specific T-cell responses were induced in 10/10 vaccinated individuals.
Introduction
The aim of therapeutic vaccination against HIV-1 is to induce and direct immune responses towards selected viral determinants with the potential to better control HIV-1 infection, sustain immunological competence and thus prevent progression to AIDS [1].
There are two major challenges when designing a vaccine broadly covering T-cell epitopes, specifically the high variation among HIV-1 proteins as well as the high degree of variation and the differences in distribution of the human leucocyte antigen (HLA) alleles. In order to overcome this we designed a vaccine based on subdominant (infrequently targeted) epitopes restricted to common HLA supertypes. HLA class I molecules can be clustered into groups, designated as supertypes, representing sets of molecules that share largely overlapping peptide binding specificities [2], [3]. Subdominant T-cell responses have been shown to have a protective role against HIV-1 [4] and other viral infections [5], [6], [7]. Infrequently targeted and immune subdominant epitopes are often conserved among HIV-1 strains independent of clade and geographic origin and may therefore be good targets for a broadly effective therapeutic vaccine [4], [8], [9], [10]. 15 HIV-1-CTL peptides targeting conserved T-cell epitopes that can theoretically bind to the five HLA supertypes predominant worldwide were included in the vaccine [11]. Three CD4 T-cell epitope peptides were co-delivered to provide help for CD8 T-cell immune induction [12].
In addition, to provide a delivery vehicle that would be feasible for widespread clinical use, and enhance the immunogenicity of these 18 peptides, we have formulated them in Cationic Adjuvant Formulation no. 1 (CAF01) [13], [14]. CAF01 is a synthetic two-component liposomic adjuvant comprising the quaternary dimethyl-dioctadecyl-ammonium ion (DDA) and the immune modulator trehalose 6,6′-dibehenate (TDB) activating through the Mincle receptor [15]. CAF01 has been shown in preclinical animal models to support T-cell immunity and to be safe for entering clinical trials [16], [17], [18], [19].
In this study, we immunized 10 treatment-naïve HIV-1-infected individuals living in Denmark four times with the 18 peptides in CAF01 i.m. in a clinical phase 1 study. Here, we show that the adjuvanted peptide vaccine is safe and induces immunity to new T-cell epitopes in 10/10 untreated HIV-1-infected vaccinated individuals in Denmark.
Section snippets
Study design and ethics
This randomized, placebo-controlled, single-blinded, phase I clinical trial was approved by the National Committee for Health Research Ethics of the Danish Ministry of Health (H-D-2008-063) and the Danish Medicines Agency (Journal no. 2612-3785) and registered in the European Clinical Trials Database (EudraCT protocol 2008-002980-15) and at ClinicalTrials.gov (NCT01009762). The study was conducted in accordance with the provisions of the Declaration of Helsinki.
HIV-1-infected individuals
Induction of T-cell immunity specific for vaccine epitopes
All 10 immunized individuals, generated a de novo T-cell response to at least one of the vaccines and/or target epitopes as measured by IFNγ ELISPOT and/or a flow cytometric staining assay for the degranulation marker CD107a and intracellular cytokine staining for IFNγ, TNFα, IL-2 and MIP1β. Cumulative responses (i.e. detected at any time point, using any of the measured cytokines) are shown in Fig. 1. No new responses were detected in the individual receiving placebo. Using IFNγ ELISPOT ten
Discussion
In this study we evaluated the immunological response of treatment naïve HIV-1-infected individuals' vaccination to therapeutic immunization with minimal T cell epitope peptides in CAF01. Immunization induced new T-cell responses in all ten individuals receiving the vaccine.
Using flow cytometry, we detected more CD8 T-cell responses compared to the IFNγ ELISPOT. One apparent explanation is that flow cytometry detected five different parameters (CD107a, IFNγ, TNFα, IL-2 and MIP1β), whereas
Conclusions
The use of subdominant minimal epitopes restricted to common HLA-supertypes is a novel concept to circumvent diversity and design a universal therapeutic HIV-1 vaccine. We demonstrate that it is possible to induce new T-cell immunity and target selected epitopes in treatment-naive HIV-1-infected individuals. T-cell responses were dominated by CD107a and MIP1β expression. The peptide/CAF01 vaccine was safe and well tolerated albeit with no effect on viral load or CD4 T-cell counts in viremic
Funding
This work was supported by grants from the Danish International Development Agency (DANIDA) and the European & Developing Countries Clinical Trials Partnership (EDCTP) and the Danish AIDS Foundation.
Conflict of interest statement
The authors have no commercial or other conflicts of interest.
Acknowledgments
We gratefully thank the patients for making this study possible. We acknowledge Birgit Knudsen, Solvej Kolbjørn Jensen, Irene Jensen, Phillippa Collins, Dorthe Petersen, Lene Pors Jensen and Bente Baadegaard for the excellent technical assistance and Professor Doherty for critical reading of the manuscript.
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Present address: Centre for Geogenetics, University of Copenhagen, 1350 Copenhagen, Denmark.