Safety and immunogenicity of a replication-defective adenovirus type 5 HIV vaccine in Ad5-seronegative persons: a randomized clinical trial (HVTN 054)

Abstract

Background: Individuals without prior immunity to a vaccine vector may be more sensitive to reactions following injection, but may also show optimal immune responses to vaccine antigens. To assess safety and maximal tolerated dose of an adenoviral vaccine vector in volunteers without prior immunity, we evaluated a recombinant replication-defective adenovirus type 5 (rAd5) vaccine expressing HIV-1 Gag, Pol, and multiclade Env proteins, VRC-HIVADV014-00-VP, in a randomized, double-blind, dose-escalation, multicenter trial (HVTN study 054) in HIV-1-seronegative participants without detectable neutralizing antibodies (nAb) to the vector. As secondary outcomes, we also assessed T-cell and antibody responses.

Methodology/principal findings: Volunteers received one dose of vaccine at either 10(10) or 10(11) adenovector particle units, or placebo. T-cell responses were measured against pools of global potential T-cell epitope peptides. HIV-1 binding and neutralizing antibodies were assessed. Systemic reactogenicity was greater at the higher dose, but the vaccine was well tolerated at both doses. Although no HIV infections occurred, commercial diagnostic assays were positive in 87% of vaccinees one year after vaccination. More than 85% of vaccinees developed HIV-1-specific T-cell responses detected by IFN-γ ELISpot and ICS assays at day 28. T-cell responses were: CD8-biased; evenly distributed across the three HIV-1 antigens; not substantially increased at the higher dose; and detected at similar frequencies one year following injection. The vaccine induced binding antibodies against at least one HIV-1 Env antigen in all recipients.

Conclusions/significance: This vaccine appeared safe and was highly immunogenic following a single dose in human volunteers without prior nAb against the vector.

Trial registration: ClinicalTrials.gov NCT00119873.

Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Figure 1. CONSORT statement 2010 flow diagram.

Precise enrollment screening numbers are not available due to the candidate pool being screened for eligibility in multiple HVTN trials. Group 2 intervention proceeded only after a safety review of Group 1 interventions. For all analyses, both placebo groups were combined into one pool. Numbers shown in the analysis row are maximum available, with some specific assays using smaller numbers due to assay-specific losses, as detailed in the results.

Figure 2. Duration and intensity of systemic reactogenicity.

Number of vaccine recipients experiencing each level of severity in one or more systemic symptoms (malaise and/or fatigue, myalgia, headache, nausea, vomiting, chills, or arthralgia) is shown at baseline and for each day of the reactogenicity period. Panel A: 1010 PU dose; Panel B: 1011 PU dose. Only the most severe symptom level for each individual on each day is included.

Figure 3. T-cell responses to HIV antigens by IFN-γ ELISpot.

Points indicate percentage of participants with positive responses; n denotes the number in each group with ELISpot data. Lines indicate 95% confidence intervals.

Figure 4. Staining profiles for ICS analysis for two trial participants.

The expression of IFN-γ and IL-2 are shown for CD4+ and CD8+ T cells in response to stimulation with the first pools for Env, Gag, and Pol and for the negative control (peptide diluent, 1% DMSO) at day 28. Numbers on the plots are the percentages of CD4+ or CD8+ T cells producing the cytokine or combination of cytokines. Participant 1 represents an example of a high CD8+ T-cell response and Participant 2 represents low CD4+ and CD8+ T-cell responses. All responses are positive as tested for cells producing IFN-γ and/or IL-2 except for Env and Pol for participant 2. Both participants were in the 1011 PU dose group.

Figure 5. T-cell responses to HIV antigens by ICS.

Points indicate percentage of participants with positive responses (for CD4+ or CD8+ T cell subsets, and for IFN-γ or IL-2 detection); n denotes the number in each group with ICS data. Lines indicate 95% confidence intervals.

Figure 6. Magnitudes of T-cell responses to pool 1 global PTE peptides, measured by IFN-γ ELISpot assay.

Day 0 (left column) is a combined analysis including responses from PBMC from placebo recipients; day 28 (remaining columns) is sorted by HIV-1 gene product. The box plots are based only on the positive responses. The box indicates the median and interquartile range (IQR); whiskers extend to the furthest point within 1.5 times the IQR from the upper or lower quartile. The number of vaccinees with a positive response out of the total number of vaccinees tested is indicated above the bars.

Figure 7. Magnitudes of responses by ICS to pool 1 peptides at day 28 following study injection.

A) CD4+ T cell responses. B) CD8+ T cell responses. The box plots are based only on the positive responses. The box indicates the median and interquartile range (IQR); whiskers extend to the furthest point within 1.5 times the IQR from the upper or lower quartile. The number of vaccinees with a positive response out of the total number of vaccinees tested is indicated above the bars.