A Randomized Clinical Trial of an Inactivated Avian Influenza A (H7N7) Vaccine

<div><h3>Background</h3><p>Concern for a pandemic caused by a newly emerged avian influenza A virus has led to clinical trials with candidate vaccines as preparation for such an event. Most trials have involved vaccines for influenza A (H5N1), A (H7N7) or A (H9N2).</p> <h3>Objective</h3><p>To evaluate dosage-related safety and immunogenicity of an inactivated influenza A (H7N7) vaccine in humans.</p> <h3>Design</h3><p>One hundred twenty-five healthy young adults were randomized to receive two doses intramuscularly of placebo or 7.5, 15, 45 or 90 µg of HA of an inactivated subunit influenza A (H7N7) vaccine (25 per group), four weeks apart. Reactogenicity was evaluated closely for one week and for any adverse effect for six months after each dose. Serum hemagglutination-inhibiting and neutralizing antibody responses were determined four weeks after each dose and at six months.</p> <h3>Results</h3><p>Reactogenicity evaluations indicated the vaccinations were well tolerated. Only one subject developed a ≥4-fold serum hemagglutination-inhibition (HAI) antibody response and a final titer of ≥1∶40 four weeks after dose two and only five subjects developed a neutralizing antibody rise and a final titer of ≥1∶40 in tests performed at a central laboratory. Four of the five were given the 45 or 90 µg HA dosage. A more sensitive HAI assay at the study site revealed a dose-response with increasing HA dosage but only 36% in the 90 µg HA group developed a ≥4-fold rise in antibody in this test and only one of these achieved a titer of ≥1∶32.</p> <h3>Conclusion</h3><p>This inactivated subunit influenza A (H7N7) vaccine was safe but poorly immunogenic in humans.</p> <h3>Trials Registration</h3><p>ClinicalTrials.gov <a href="http://clinicaltrials.gov/ct2/show/NCT00546585">NCT00546585</a></p> </div

Solicited Adverse Events (AE) after Influenza A (H7N7) Vaccinatons.

1<p>As determined in single radial immunodiffusion assays.</p>2<p>Number subjects evaluated.</p

Demographics by Study Group.

1<p>Male vs. nonmale frequency by dosage, chi-square 1.73, p = .785.</p>2<p>White vs. nonwhite frequency by dosage, chi-square 7.04, p = .134.</p>3<p>Age vs. dosage, Anova, p>.05.</p

Serum Antibody Responses to H7N7 Vaccinations¹.

1<p>Hemagglutination-inhibition antibody assays at primary study 'site.</p>2<p>As determined in single redial immunodiffusion assays.</p>3<p>Number of subjects in evaluation.</p>4<p>Increasing dosage induced increased % increase; logistic regression, p = .001.</p

Serum Antibody Responses to Influenza A (H7N7) Vaccinations¹.

1<p>As determined at central laboratory; increase defined as ≥4-fold or <10 to 40.</p>2<p>As determined in single radial immunodiffusion assays.</p>3<p>Number of subjects in evaluation.</p>4<p>Hemagglutination-inhibition (HAI) and neutralizing (neut) antibody assays at central laboratory.</p

Flow diagram of the randomized clinical trial of an inactivated subunit influenza A (H7N7) vaccine.

<p>Flow diagram of the randomized clinical trial of an inactivated subunit influenza A (H7N7) vaccine.</p

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

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