DNA Vaccine Delivered by a Needle-Free Injection Device Improves Potency of Priming for Antibody and CD8+ T-Cell Responses after rAd5 Boost in a Randomized Clinical Trial

<div><p>Background</p><p>DNA vaccine immunogenicity has been limited by inefficient delivery. Needle-free delivery of DNA using a CO₂-powered Biojector® device was compared to delivery by needle and syringe and evaluated for safety and immunogenicity.</p><p>Methods</p><p>Forty adults, 18–50 years, were randomly assigned to intramuscular (IM) vaccinations with DNA vaccine, VRC-HIVDNA016-00-VP, (weeks 0, 4, 8) by Biojector® 2000™ or needle and syringe (N/S) and boosted IM at week 24 with VRC-HIVADV014-00-VP (rAd5) with N/S at 10¹⁰ or 10¹¹ particle units (PU). Equal numbers per assigned schedule had low (≤500) or high (>500) reciprocal titers of preexisting Ad5 neutralizing antibody.</p><p>Results</p><p>120 DNA and 39 rAd5 injections were given; 36 subjects completed follow-up research sample collections. IFN-γ ELISpot response rates were 17/19 (89%) for Biojector® and 13/17 (76%) for N/S delivery at Week 28 (4 weeks post rAd5 boost). The magnitude of ELISpot response was about 3-fold higher in Biojector® compared to N/S groups. Similar effects on response rates and magnitude were observed for CD8+, but not CD4+ T-cell responses by ICS. Env-specific antibody responses were about 10-fold higher in Biojector-primed subjects.</p><p>Conclusions</p><p>DNA vaccination by Biojector® was well-tolerated and compared to needle injection, primed for greater IFN-γ ELISpot, CD8+ T-cell, and antibody responses after rAd5 boosting.</p><p>Trial Registration</p><p>ClinicalTrials.gov <a href="http://clinicaltrials.gov/ct2/show/NCT00109629" target="_blank">NCT00109629</a></p></div

Phase I Randomized Clinical Trial of VRC DNA and rAd5 HIV-1 Vaccine Delivery by Intramuscular (IM), Subcutaneous (SC) and Intradermal (ID) Administration (VRC 011)

<div><p>Background</p><p>Phase 1 evaluation of the VRC HIV DNA and rAd5 vaccines delivered intramuscularly (IM) supported proceeding to a Phase 2 b efficacy study. Here we report comparison of the IM, subcutaneous (SC) and intradermal (ID) routes of administration.</p><p>Methods</p><p>Sixty subjects were randomized to 6 schedules to evaluate the IM, SC or ID route for prime injections. Three schedules included DNA primes (Wks 0,4,8) and 3 schedules included rAd5 prime (Wk0); all included rAd5 IM boost (Wk24). DNA vaccine dosage was 4 mg IM or SC, but 0.4 mg ID, while all rAd5 vaccinations were 10¹⁰ PU. All injections were administered by needle and syringe.</p><p>Results</p><p>Overall, 27/30 subjects completed 3 DNA primes; 30/30 subjects completed rAd5 primes. Mild local pruritus (itchiness), superficial skin lesions and injection site nodules were associated with ID and SC, but not IM injections. All routes induced T-cell and antibody immune responses after rAd5 boosting. Overall, >95% had Env antibody and >80% had Env T-cell responses.</p><p>Conclusions</p><p>The pattern of local reactogenicity following ID and SC injections differed from IM injections but all routes were well-tolerated. There was no evidence of an immunogenicity advantage following SC or ID delivery, supporting IM delivery as the preferred route of administration.</p><p>Trial Registration</p><p><a href="http://tinyurl.com/muzmnub" target="_blank">Clinicaltrials.gov NCT00321061</a></p></div

VRC 011 Baseline Characteristics of Participants.

<p>VRC 011 Baseline Characteristics of Participants.</p

Maximum Systemic Reactogenicity Summary for All Vaccinations.

<p>Maximum Systemic Reactogenicity Summary for All Vaccinations.</p

Local reactogenicity following rAd5 vaccine.

<p>All subjects who received rAd5 vaccination by needle injection (n = 15) or by Biojector injection (n = 16) were counted once at worst severity over 5 days for solicited local parameters. The graph shows the percentage with mild or moderate reaction; there were no severe reactions. The results for local parameters of pain, swelling and redness are shown individually, while “Any Local” represents the worst severity for any of the local parameters. There were no statistically significant differences between the needle and Biojector reactogenicity except for “Any Local”.</p

Worst Severity of Systemic Reactogenicity Following DNA and rAd5 Vaccinations.

<p>Worst Severity of Systemic Reactogenicity Following DNA and rAd5 Vaccinations.</p

Frequency of Vaccine-Induced Seropositivity/Reactivity Through Study Week 42.

<p>Subjects were tested at weeks 12, 30 and 42 regardless of the number of vaccines completed. This shows frequency of a “reactive EIA” using a commercial diagnostic kit (Abbott HIV-1/HIV-2 rDNA) at any time during the study. Western blot was performed only for samples with positive EIA. HIV uninfected status was confirmed by RNA PCR tests, which were consistently negative for all subjects throughout the study.</p

VRC 011 Disposition Flow Diagram of Screening, Randomization and Vaccination Completion.

<p>VRC 011 Disposition Flow Diagram of Screening, Randomization and Vaccination Completion.</p

ICS responses among the different priming groups after boosting with rAd5 IM for CD4 T cells (A) and CD8 T cells (B).

<p>The numbers above each boxplot represent the fraction of participants in each group with available data at that time point who were judged to be responders using predefined positivitycriteria. The responders are represented on the plot with red dots, and are used to construct the boxplots; blue points represent non-responders and are not included in the boxplots.</p

ELISA responses among the different groups after priming by route and vaccine indicated on X-axis (A) and boosting with rAd5 IM (B).

<p>The numbers above each boxplot represent the fraction of participants in each group with available data at that time point who were judged to be responders using predefined criteria. The responders are represented on the plot with red dots, and are used to construct the boxplots; blue points represent non-responders and are not included in the boxplots.</p