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

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

Subject Demographics.

<p>Subject Demographics.</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

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

Hotspot analysis of the microarray data of V2 Abs in the plasma from vaccinees in the case-control study.

<p>The upper panel shows an aggregate response across all sub-types averaged across vaccinees as a function of the V2 sequence in subtype B strain HxB2. An individual aggregate response is computed using a sliding window mean statistic of 9 AAs, i.e., peptides with HxB2 positions of 9 contiguous AAs averaged together. In the lower portion of the figure, the actual sequence of each of the overlapping 15-mers spanning V2 positions 160–183 is shown. The seven sets of peptides represent the consensus V2 regions of HIV-1 Group M and of subtypes A, B, C, D, CRF01_AE and CRF02_AG. Peptides are colored according to their average response across all vaccinees, with a scale of 0 (white) to 1.76 (red). All responses are calculated using normalized intensities and by subtracting the intensities of baseline pre-bleeds.</p

ELISA reactivity of human anti-V2 mAbs 697-D and 2158 with AIDSVAX subtype E (A244, green square) and AIDSVAX subtype B (MN, O) gp120 immunogens.

<p>The pink dashed line represents twice background levels.</p

Estimated odds ratios (OR) and 95% confidence intervals for each of the V2 assays.

<p>Data are derived from the categorical analyses shown in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0053629#pone-0053629-t001" target="_blank"><b>Table 1</b></a>. Estimated ORs compare subgroups defined by High vs. Low responses except for comparisons for analyses of IgA V2 A244 K178 and V2 MN which compare Positive vs. Negative responses. For evaluation of biotinylated V2 Peptide 6, comparison is between High and Negative responses.</p