Phase 1 Study of Pandemic H1 DNA Vaccine in Healthy Adults

<div><p>Background</p><p>A novel, swine-origin influenza A (H1N1) virus was detected worldwide in April 2009, and the World Health Organization (WHO) declared a global pandemic that June. DNA vaccine priming improves responses to inactivated influenza vaccines. We describe the rapid production and clinical evaluation of a DNA vaccine encoding the hemagglutinin protein of the 2009 pandemic A/California/04/2009(H1N1) influenza virus, accomplished nearly two months faster than production of A/California/07/2009(H1N1) licensed monovalent inactivated vaccine (MIV).</p><p>Methods</p><p>20 subjects received three H1 DNA vaccinations (4 mg intramuscularly with Biojector) at 4-week intervals. Eighteen subjects received an optional boost when the licensed H1N1 MIV became available. The interval between the third H1 DNA injection and MIV boost was 3–17 weeks. Vaccine safety was assessed by clinical observation, laboratory parameters, and 7-day solicited reactogenicity. Antibody responses were assessed by ELISA, HAI and neutralization assays, and T cell responses by ELISpot and flow cytometry.</p><p>Results</p><p>Vaccinations were safe and well-tolerated. As evaluated by HAI, 6/20 developed positive responses at 4 weeks after third DNA injection and 13/18 at 4 weeks after MIV boost. Similar results were detected in neutralization assays. T cell responses were detected after DNA and MIV. The antibody responses were significantly amplified by the MIV boost, however, the boost did not increased T cell responses induced by DNA vaccine.</p><p>Conclusions</p><p>H1 DNA vaccine was produced quickly, was well-tolerated, and had modest immunogenicity as a single agent. Other HA DNA prime-MIV boost regimens utilizing one DNA prime vaccination and longer boost intervals have shown significant immunogenicity. Rapid and large-scale production of HA DNA vaccines has the potential to contribute to an efficient response against future influenza pandemics.</p><p>Trial Registration</p><p>Clinicaltrials.gov <a href="https://clinicaltrials.gov/ct2/show/NCT00973895" target="_blank">NCT00973895</a></p></div

Immunogenicity.

<p>(A) Hemagglutination Inhibition (HAI) assay with A/Mexico/4482/2009 H1N1 virus (B) Neutralizing antibodies were evaluated by the capacity of sera to prevent infection of 293A cells by replication-incompetent H1-pseudotyped virus. The 80% inhibition serum titers are shown. (C) End-point ELISA titers of H1 A/California/04/2009(H1N1) specific antibodies are shown. Pre-vaccination titers have been subtracted from each plotted value. (D) H1-specific T cell responses are shown as a number of spot forming cells (SFC) per 10⁶ PBMC as measured by ELISpot assay. Geometric means and 95% CI are shown for the study groups.</p

Rapid DNA Vaccine Manufacturing in Response to Influenza Pandemic.

<p>Rapid DNA Vaccine Manufacturing in Response to Influenza Pandemic.</p

Consort Flow Diagram.

<p>Number of individuals assessed for eligibility, enrolled and followed up.</p

Frequency of Adverse Events.

<p>Solicited reactogenicity was collected for 7 days after each vaccination for 21 days total after H1 DNA administered 3 times, and for 7 days after MIV administration. Each vaccine recipient is counted once at worst severity for any local and systemic parameter.</p><p>Frequency of Adverse Events.</p

Baseline Characteristics of Participants.

<p>Baseline Characteristics of Participants.</p

Safety and pharmacokinetics of the Fc-modified HIV-1 human monoclonal antibody VRC01LS: A Phase 1 open-label clinical trial in healthy adults

<div><p>Background</p><p>VRC01 is a human broadly neutralizing monoclonal antibody (bnMAb) against the CD4-binding site of the HIV-1 envelope glycoprotein (Env) that is currently being evaluated in a Phase IIb adult HIV-1 prevention efficacy trial. VRC01LS is a modified version of VRC01, designed for extended serum half-life by increased binding affinity to the neonatal Fc receptor.</p><p>Methods and findings</p><p>This Phase I dose-escalation study of VRC01LS in HIV-negative healthy adults was conducted by the Vaccine Research Center (VRC) at the National Institutes of Health (NIH) Clinical Center (Bethesda, MD). The age range of the study volunteers was 21–50 years; 51% of study volunteers were male and 49% were female. Primary objectives were safety and tolerability of VRC01LS intravenous (IV) infusions at 5, 20, and 40 mg/kg infused once, 20 mg/kg given three times at 12-week intervals, and subcutaneous (SC) delivery at 5 mg/kg delivered once, or three times at 12-week intervals. Secondary objectives were pharmacokinetics (PK), serum neutralization activity, and development of antidrug antibodies. Enrollment began on November 16, 2015, and concluded on August 23, 2017. This report describes the safety data for the first 37 volunteers who received administrations of VRC01LS. There were no serious adverse events (SAEs) or dose-limiting toxicities. Mild malaise and myalgia were the most common adverse events (AEs). There were six AEs assessed as possibly related to VRC01LS administration, and all were mild in severity and resolved during the study. PK data were modeled based on the first dose of VRC01LS in the first 25 volunteers to complete their schedule of evaluations. The mean (±SD) serum concentration 12 weeks after one IV administration of 20 mg/kg or 40 mg/kg were 180 ± 43 μg/mL (<i>n</i> = 7) and 326 ± 35 μg/mL (<i>n</i> = 5), respectively. The mean (±SD) serum concentration 12 weeks after one IV and SC administration of 5 mg/kg were 40 ± 3 μg/mL (<i>n</i> = 2) and 25 ± 5 μg/mL (<i>n</i> = 9), respectively. Over the 5–40 mg/kg IV dose range (<i>n</i> = 16), the clearance was 36 ± 8 mL/d with an elimination half-life of 71 ± 18 days. VRC01LS retained its expected neutralizing activity in serum, and anti-VRC01 antibody responses were not detected. Potential limitations of this study include the small sample size typical of Phase I trials and the need to further describe the PK properties of VRC01LS administered on multiple occasions.</p><p>Conclusions</p><p>The human bnMAb VRC01LS was safe and well tolerated when delivered intravenously or subcutaneously. The half-life was more than 4-fold greater when compared to wild-type VRC01 historical data. The reduced clearance and extended half-life may make it possible to achieve therapeutic levels with less frequent and lower-dose administrations. This would potentially lower the costs of manufacturing and improve the practicality of using passively administered monoclonal antibodies (mAbs) for the prevention of HIV-1 infection.</p><p>Trial registration</p><p>ClinicalTrials.gov <a target="_blank">NCT02599896</a></p></div

Maximum local reactogenicity up to day 7 after VRC01LS administration^*.

<p>Maximum local reactogenicity up to day 7 after VRC01LS administration^{<a href="http://www.plosmedicine.org/article/info:doi/10.1371/journal.pmed.1002493#t002fn001" target="_blank">*</a>}.</p

CONSORT flow diagram of the VRC 606 trial.

<p>Thirty-seven volunteers were allocated to 6 groups. All volunteers who received at least one VRC01LS administration were analyzed for safety and reactogenicity. All volunteers who completed the per-protocol dosing schedule by the time of manuscript submission (<i>n</i> = 25) were additionally analyzed for pharmacokinetic parameters, serum neutralization activity, anti-drug antibodies, and IgG1 GM allotype. These 25 volunteers were all the volunteers in groups 1–4, the first six volunteers in group 5, and the first five volunteers in group 6. GM, genetic marker; IgG1, immunoglobulin G subclass 1; IV, intravenous; SC, subcutaneous; VRC, Vaccine Research Center.</p

Measurement of antibody serum concentration (μg/mL).

<p>(A) Serum VRC01LS concentrations (colored plots) are shown from first measurement through week 24 after a single administration. The infusion dose and route are as specified in the legend. All values are the mean of duplicate samples run in different wells within the same plate. Previously published VRC01 concentrations based on historical data (black plots) after administration at weeks 0 and 4 are shown for comparison. (B) Geometric mean serum VRC01LS concentrations per group over time. The dotted line at 10 μg/mL on each graph is shown as a reference value. IV, intravenous; SC, subcutaneous.</p