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Shaping CTL Immunodominance With Conserved HIV Vaccines After Early Treatment (BCN01)
Beatriz Mothe1; Christian Manzardo2; Pep Coll1; Sara Moron-Lopez1; Lucy Dorrell3; Bonaventura Clotet4; Javier Martinez-Picado1; Christian Brander1; Tomás Hanke5; for the BCN01 Study Group
1IrsiCaixa Inst for AIDS Rsr, Badalona, Spain;2Hosp Clinic-IDIBAPS, Univ de Barcelona, Barcelona, Spain;3Univ of Oxford, Oxford, UK;4Lluita Contra la SIDA Fndn, Germans Trias i Pujol Univ Hosp, Barcelona, Spain;5The Jenner Inst, Oxford, UK
Therapeutic T-cell vaccines targeting the most conserved regions of the HIV-1 proteome have the potential to enhance host immune control and facilitate clearance of the latent reservoir.
BCN01 (NCT01712425) is a phase I, multicenter trial to evaluate the safety, immunogenicity and impact on the latent reservoir of a combined ChAdV63-MVA.HIVconsv vaccine in early-treated individuals (<6m from HIV-1 infection, n=24) who initiated TDF/FTC/RAL 1 wk after diagnosis. Individuals received ChAdV63.HIVconsv (5x1010vp, im) and MVA.HIVconsv (2x108pfu, im) 8 or 24 wk after (Short vs Long regimen) and were followed for 6 months. Immunogenicity to the HIVconsv vaccine insert and the rest of the HIV-1 proteome was assessed by IFNg ELISPOT in cryopreserved PBMC. 24 unvaccinated controls were included to compare viral reservoir decay during 1st year of early-treatment initiation. Proviral DNA was quantified in purified CD4+ T-cells by droplet digital PCR. Single-copy assay was performed to investigate potential viral reactivation during vaccinations.
22 individuals (92%) induced HIVconsv de-novo Tcell responses during vaccination schedule (not detectable before cART initiation). Responses were increased in 50% participants after ChAdV63 prime and in 100% of participants after MVA booster vaccination (median of 938 SFC/106 PBMC, range 73-6,805 at peak, p=0.0001, Wilcoxon t-test compared to pre-vaccination). No significant expansion of T-cells targeting HIV-1 regions outside the vaccine insert was noted, reflective of an effective shift of CTL immunity towards conserved regions (48% of total HIV-1 T-cells being HIVconsv-specific). No significant differences in peak or longevity of induced T-cells were observed between Short and Long vaccination regimens. Levels and decay of proviral DNA after cART were not associated with vaccine-induced immunogenicity nor differed from non-vaccinated individuals. Viral reactivation was not observed during vaccinations.
Heterologous vaccination with ChAdV63 and MVA.HIVconsv was a safe strategy to induce new and shift pre-existing immune response towards conserved regions of HIV-1 in a cohort of early-treated individuals. Reservoir decay during first year of early-treatment was not further impacted by vaccinations. This is the first therapeutic vaccine trial able to demonstrate a refocusing of the CTL immunodominance pattern towards conserved regions of HIV-1 and may provide the base for effective kick and kill strategies.