Phase 1 study of pandemic H1 DNA vaccine in healthy adults

Abstract

Background: 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).

Methods: 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.

Results: 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.

Conclusions: 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.

Trial registration: Clinicaltrials.gov NCT00973895.

Conflict of interest statement

Competing Interests: The authors would like to clarify the affiliation and address competing interests and financial disclosure of one of the authors, Dr. Gary Nabel. Dr. Gary Nabel is currently employed by Sanofi, USA, however his involvement in the planning of the clinical trial and any significant input on the manuscript were completed while he was employed at the Vaccine Research Center, NIAID, NIH. Dr. Nabel is named on patent applications for the CMV-R promotor used in the vaccine in the manuscript. The identification number for the patent is as follows: US 7,094,598. There are no further patents, products in development or marketed products to declare. This does not alter the authors’ adherence to all the PLOS ONE policies on sharing data and materials.

Figures

Fig 1. Rapid DNA Vaccine Manufacturing in Response to Influenza Pandemic.

Fig 2. Consort Flow Diagram.

Number of individuals assessed for eligibility, enrolled and followed up.

Fig 3. Immunogenicity.

(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.