DNA Priming for Seasonal Influenza Vaccine: A Phase 1b Double-Blind Randomized Clinical Trial

<div><p>Background</p><p>The efficacy of current influenza vaccines is limited in vulnerable populations. DNA vaccines can be produced rapidly, and may offer a potential strategy to improve vaccine immunogenicity, indicated by studies with H5 influenza DNA vaccine prime followed by inactivated vaccine boost.</p><p>Methods</p><p>Four sites enrolled healthy adults, randomized to receive 2011/12 seasonal influenza DNA vaccine prime (n=65) or phosphate buffered saline (PBS) (n=66) administered intramuscularly with Biojector. All subjects received the 2012/13 seasonal inactivated influenza vaccine, trivalent (IIV3) 36 weeks after the priming injection. Vaccine safety and tolerability was the primary objective and measurement of antibody response by hemagglutination inhibition (HAI) was the secondary objective.</p><p>Results</p><p>The DNA vaccine prime-IIV3 boost regimen was safe and well tolerated. Significant differences in HAI responses between the DNA vaccine prime and the PBS prime groups were not detected in this study.</p><p>Conclusion</p><p>While DNA priming significantly improved the response to a conventional monovalent H5 vaccine in a previous study, it was not effective in adults using seasonal influenza strains, possibly due to pre-existing immunity to the prime, unmatched prime and boost antigens, or the lengthy 36 week boost interval. Careful optimization of the DNA prime-IIV3 boost regimen as related to antigen matching, interval between vaccinations, and pre-existing immune responses to influenza is likely to be needed in further evaluations of this vaccine strategy. In particular, testing this concept in younger age groups with less prior exposure to seasonal influenza strains may be informative.</p><p>Trial Registration</p><p>ClinicalTrials.gov <a href="http://clinicaltrials.gov/ct2/show/NCT01498718" target="_blank">NCT01498718</a></p></div

VRC 701 Consort diagram of subject disposition.

<p>VRC 701 Consort diagram of subject disposition.</p

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

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

Influenza strains included in DNA vaccine prime and IIV3 boost.

<p>The trial was conducted at 4 clinical sites in the United States: Center for Vaccine Development, Saint Louis University, Saint Louis, Missouri; Cincinnati Children’s Hospital Medical Center Cincinnati, Ohio; Hope Clinic of the Emory Vaccine Center, Atlanta, Georgia; and Baylor College of Medicine, Houston, Texas. The first subject was screened for recruitment on December 20, 2011, study vaccinations began on January 10, 2012 and study follow-up continued through April 17, 2013.</p><p>Influenza strains included in DNA vaccine prime and IIV3 boost.</p

GMT 4 weeks Post-Boost for Study Groups by Baseline Immune Response: GMT (95% CI).

<p>GMT 4 weeks Post-Boost for Study Groups by Baseline Immune Response: GMT (95% CI).</p

Solicited Reactogencity within 7 Days of Injection.

<p>Note: Subjects are counted once at the maximum severity reported for each symptom.</p><p>Solicited Reactogencity within 7 Days of Injection.</p

Frequency of previous seasonal influenza vaccinations.

<p>*All subjects received 2011/2012 IIV3 at least 8 weeks prior to enrollment in the trial.</p><p>Frequency of previous seasonal influenza vaccinations.</p

Subject Demographics.

<p>Subject Demographics.</p

Rapid DNA Vaccine Manufacturing in Response to Influenza Pandemic.

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