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Phase 1 study of pandemic H1 DNA vaccine in healthy adults.

Crank MC, Gordon IJ, Yamshchikov GV, Sitar S, Hu Z, Enama ME, Holman LA, Bailer RT, Pearce MB, Koup RA, Mascola JR, Nabel GJ, Tumpey TM, Schwartz RM, Graham BS, Ledgerwood JE, VRC 308 Study Te - PLoS ONE (2015)

Bottom Line: Vaccinations were safe and well-tolerated.Similar results were detected in neutralization assays.The antibody responses were significantly amplified by the MIV boost, however, the boost did not increased T cell responses induced by DNA vaccine.

View Article: PubMed Central - PubMed

Affiliation: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, United States of America.

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.

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Related in: MedlinePlus

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.
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pone.0123969.g003: 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.

Mentions: Immune responses to vaccination as measured by HAI, neutralization assay, ELISA and ELISpot assay are summarized in Fig 3. Antibody responses were modest after DNA immunization only, but in all cases, they improved after MIV boost. As evaluated by HAI, 6/20 (30%) of subjects developed positive responses at 4 weeks after last H1 DNA, but the number rose to 13/18 (72%) at 4 weeks after the MIV boost. Similar results were detected in the neutralization assay, 6/20 (30%) had positive response after H1 DNA injections, which rose to 15/18 (83%) at 4 weeks post MIV boost. As measured by ELISA, only 4/20 (20%) of subjects developed positive responses at 4 weeks post last DNA, but 14/18 (78%) were positive 4 weeks after the MIV boost.


Phase 1 study of pandemic H1 DNA vaccine in healthy adults.

Crank MC, Gordon IJ, Yamshchikov GV, Sitar S, Hu Z, Enama ME, Holman LA, Bailer RT, Pearce MB, Koup RA, Mascola JR, Nabel GJ, Tumpey TM, Schwartz RM, Graham BS, Ledgerwood JE, VRC 308 Study Te - PLoS ONE (2015)

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.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4401709&req=5

pone.0123969.g003: 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.
Mentions: Immune responses to vaccination as measured by HAI, neutralization assay, ELISA and ELISpot assay are summarized in Fig 3. Antibody responses were modest after DNA immunization only, but in all cases, they improved after MIV boost. As evaluated by HAI, 6/20 (30%) of subjects developed positive responses at 4 weeks after last H1 DNA, but the number rose to 13/18 (72%) at 4 weeks after the MIV boost. Similar results were detected in the neutralization assay, 6/20 (30%) had positive response after H1 DNA injections, which rose to 15/18 (83%) at 4 weeks post MIV boost. As measured by ELISA, only 4/20 (20%) of subjects developed positive responses at 4 weeks post last DNA, but 14/18 (78%) were positive 4 weeks after the MIV boost.

Bottom Line: Vaccinations were safe and well-tolerated.Similar results were detected in neutralization assays.The antibody responses were significantly amplified by the MIV boost, however, the boost did not increased T cell responses induced by DNA vaccine.

View Article: PubMed Central - PubMed

Affiliation: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, United States of America.

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.

Show MeSH
Related in: MedlinePlus