Fig 1.
CONSORT flow diagram of the HIV-CORE 003 trial.
All CPHPC-treated volunteers completed the study protocol. Among the 20 volunteers allocated to the placebo Group, 2 volunteers were lost to follow-up of whom 1 discontinued vaccinations.
Fig 2.
Vaccine immunogen HIVconsv and the design of the HIV-CORE 003 trial.
(A) Schematic representations of the HIVconsv immunogen and six pools P1-P6 of a total of 199 overlapping peptides used for the detection of the human vaccine-elicited T-cell responses. HIVconsv is a chimaeric protein assembled from 14 highly conserved regions of the HIV-1 proteome, the HIV-1 protein origins of which are colour-coded below. (B) Volunteers in the phase I/IIa HIV-CORE 003 trial were randomized into Group 1 for depletion of serum amyloid P component (SAP) by a 26-hour infusion of drug CPHPC, or Group 2 receiving saline infusion alone as placebo, whereby the DNA was injected after 24 hours of infusion. All volunteers were boosted with non-replicating recombinant virus vaccines expressing the same HIVconsv immunogen as indicated. cD–pSG2.HIVconsv DNA with CPHPC infusion prior to DNA administration; pD–pSG2.HIVconsv with placebo infusion prior to DNA; C–non-replicating simian (chimpanzee) adenovirus-vectored vaccine ChAdV63.HIVconsv; and M–non-replicating poxvirus-vectored vaccine MVA.HIVconsv. The number of volunteers recruited into each study group is indicated.
Table 1.
Non-serious adverse events.
Fig 3.
DNA priming of human T-cell responses with and without SAP depletion.
Volunteers received heterologous vaccine regimens, which included priming with DNA either preceded or not by depletion of SAP. The vaccines were as follows: cD–pSG2.HIVconsv DNA after a 24-hour infusion of SAP-depleting CPHPC and additional 2-hour infusion after DNA administration (pink); pD–pSG2.HIVconsv DNA with 26-hour infusion of saline as placebo (green); C–simian adenovirus ChAdV63.HIVconsv; and M–poxvirus MVA.HIVconsv. All vaccines were delivered by intramuscular needle injection. Vaccine-induced T cells were enumerated in a fresh ex vivo (A-D and F) or following a 10-day expansion (E) IFN-γ ELISPOTs assay using 6 peptide pools P1-P6 spanning the HIVconsv immunogen. (A) Total frequencies were calculated as the sum of T cells responding to 6 pools of peptides P1-P6. The times of vaccine administration are indicated below the graphs. (B) Comparison of AUC using group median T-cell frequencies for each time point in the CPHPC (n = 13) and placebo (n = 13) groups. Only volunteers with full a data set were used. (C) Peak responses to individual pools P1-P6 elicited by plasmid DNA (week 0–8) are shown. (D) Peak T-cell frequencies induced following plasmid pSG2.HIVconsv DNA (week 0–8), ChAdV63.HIVconsv (week 8–12) and MVA.HIVconsv (week 16–20). (E) The proliferative capacity determined as the frequencies of HIVconsv-specific T cells following a 10-day restimulation of samples from week 12. (F) Breadth of induced T-cell responses defined as the number of recognized peptides pools (out of 6) following the ChAdV63.HIVconsv boost, whereby breadth for all (left) and HLA-A*02:01-positive subjects receiving CPHPC (n = 11) or placebo (n = 9) (right) are shown. Data are presented as median with range. (G) Bars depict the number of responders to 0–6 peptide pools P1-P6. The median, interquartile and total range, and individual values are plotted for each visit (A, C, D, and E).
Fig 4.
Functionality of vaccine-induced human T cells primed using plasmid DNA in the presence or absence of SAP.
The functionality of T cells elicited with (pink) and without (green) CPHPC treatment prior to the DNA administration was assessed in the Luminex assay measuring the concentration of secreted signalling molecules into the culture supernatant by volunteers' PBMC following a 48-hour HIVconsv peptide restimulation. The functionality of specific T cells was determined after pSG2.HIVconsv DNA (CV1 and PV1), ChAdV63.HIVconsv (CV2 and PV2) and MVA.HIVconsv (CV3 and PV3) administration. At no point and for no measured cytokine were the values statistically separable between the CPHPC and placebo recipients (Mann-Witney test).
Fig 5.
HLA-A*02:01/YQY tetramer-aided analysis of human CD8+ T-cell memory subsets.
For six HLA-A*02:01-positive vaccine recipients, frozen and thawed PBMCs from indicated time point were analyzed for memory subsets defined as TN−naïve T cells (CD45RAhiCCR7hiCD27hi). TCM—central memory (CD45RAloCCR7hiCD27hi), TTM—transitional memory (CD45RAloCCR7loCD27hi), TEM—effector memory (CD45RAloCCR7loCD27lo), and TTD—terminally differentiated (CD45RAhiCCR7loCD27lo). See S1 Fig for the gating strategy. D–pSG2.HIVconsv DNA; C–ChAdV63.HIVconsv; M–MVA.HIVconsv. The number next to the regimen indicates weeks after administration of the last vaccine.