Comparison of Three Licensed Influenza Vaccines
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|ClinicalTrials.gov Identifier: NCT03068949|
Recruitment Status : Active, not recruiting
First Posted : March 3, 2017
Last Update Posted : December 9, 2020
|Condition or disease||Intervention/treatment||Phase|
|Influenza||Biological: FluBlok Biological: Fluzone Biological: FluCelVax Biological: Fluzone HD||Phase 4|
Previous observations to date lead to the following model: Traditional egg-derived TIV have contaminating internal virion proteins that preferentially elicit memory CD4 T cells specific for these proteins. These CD4 T cells will have limited efficacy as helpers for the neutralizing Ab response and will suppress the CD4 T cell response to new HA epitopes in the vaccine. The current study will test this hypothesis by comparing CD4 cell responses to specific epitopes, and the subsequent B cell and antibody response, in subjects receiving a vaccine containing only HA protein to vaccines with more complex antigenic characteristics. The CD4 T cell reactivity to pools of unique, conserved, and total pH1 HA peptides as well as H3, influenza B HA, NP, and M1 peptides will be quantified using cytokine Elispot assays and flow cytometry, and then compared to the subsequent antibody and B cell response.
Investigators will also use this study as an opportunity to evaluate the effects of prior vaccination. Recent studies have emphasized the potential negative effect of vaccination in prior years on both the immune response as well as the protective effectiveness of current vaccine. In order to evaluate this phenomenon in the context of multiple vaccine formulations, prior vaccination history of the subjects will be reviewed and subjects stratify vaccination based on vaccine history.
In addition, subjects who participated in this study in a previous year are eligible to re-enroll, and will receive the same vaccine that they were randomized to previously. This will allow an evaluation of differences between vaccine formulations in the responsiveness to multiple vaccinations.
Furthermore, recent studies indicate reports that the glycosylation pattern of viral hemagglutinins produced in cell culture can vary depending on the host cell used, and that this can affect CD4 T cell immunogenicity and antibody recognition. As a cell culture-based influenza vaccine production platform offers many advantages and may eventually supplant the traditional egg-based approach, it is of great value to understand the CD4 T cell response induced by this vaccine and how this affects neutralizing Ab production.
Recent data have also suggested that the failure of seasonal influenza infection to induce substantial levels of stalk specific antibody may be due to the relatively inaccessible nature of this epitope. As part of this study, investigators will also compare the specificity of the human antibody response between the vaccine groups, with the hypothesis that the rHA vaccine will more readily allow targeting of these important, broadly conserved epitopes. There is compelling preliminary data demonstrating that multiple antibodies that we have isolated have a particularly slow on rate when they bind to the HA-stalk versus the HA-globular head epitopes on whole virions, but not on recombinant HA trimmers expressed in baculovirus. The hypothesis is that a free, recombinant HA vaccine will allow more efficient targeting of the HA-Stalk epitopes.
|Study Type :||Interventional (Clinical Trial)|
|Actual Enrollment :||494 participants|
|Intervention Model:||Parallel Assignment|
|Masking:||Double (Participant, Outcomes Assessor)|
|Primary Purpose:||Basic Science|
|Official Title:||A Comparison of CD4 T Cell Induction and Antibody Responses Between a Pure Hemagglutinin Influenza Vaccine and Licensed Subvirion Influenza Vaccine Made in Eggs or Cell Culture in Healthy Adults.|
|Actual Study Start Date :||October 28, 2015|
|Actual Primary Completion Date :||June 30, 2020|
|Estimated Study Completion Date :||June 30, 2021|
Active Comparator: FluBlok
FluBlok 0.5 mL given IM X1
FluBlok trivalent Influenza Vaccine .5 mL given Intramuscularly
Active Comparator: Fluzone
Fluzone 0.5 mL given IM X1
Fluzone Quadrivalent Influenza Vaccine .5 mL given intramuscularly
Active Comparator: FluCelVax
FluCelVax 0.5 mL given IM X 1
FluCelVax Quadrivalent Influenza Vaccine .5 mL given intramuscularly
Active Comparator: Fluzone HD
Fluzone HD 0.5 mL given IM X1
Biological: Fluzone HD
Fluzone HD Trivalent High Dose Influenza Vaccine .5 mL given intramuscularly
- The percent increase of CD4 cells per mL of blood. [ Time Frame: Baseline to Day 7 ]CD4 T cell reactivity to pools of unique, conserved, and total pHA peptides derived from the pH1N1 HA (hemagglutinin) , as well as H3, influenza B HA, NP (neuraminidase), and M1 peptides will be quantified using cytokine Elispot. The number of CD4 cells will be correlated with the antibody titer as measured by HAI.
- The percent increase of CD4 cells per mL of Blood. [ Time Frame: Baseline to Day 7 ]CD4 T cell reactivity to pools of unique, conserved, and total pHA peptides derived from the pH1N1 HA, as well as H3, influenza B HA, NP, and M1 peptides will be quantified using flow cytometry assays.
- Change in Serum HAI antibody defined as the highest dilution resulting in complete inhibition of hemagglutination [ Time Frame: Baseline to Day 7 ]This is an exploratory objective: Serum hemagglutination-inhibition (HAI). HAI will be performed in microtiter format using turkey RBCs (red blood cells) and egg-grown, betapropriolactone-inactivated A/California/07/09 virus as antigen. The titer of antibody will be defined as the highest dilution resulting in complete inhibition of hemagglutination. Sera will be treated with receptor-destroying enzyme and heat inactivated prior to testing at an initial starting dilution of 1:4. Sera with no detectable HAI titer will be assigned a titer of 1:2 for calculation purposes. Serum antibody titers will be correlated with CD4 cells measured by ELISPOT.
- Number of participants with increased antibody specificity of cloned plasmablasts [ Time Frame: Day 7 to Day 28 ]This is an exploratory objective: Peripheral Blood Mononuclear Cells (PBMC) will be obtained before and on day 7 and 28 after vaccine and evaluated for B-cell responses. B cell responses will be evaluated by memory cell assay.
- Ratio of B cells reactive with the HA stalk versus the globular head. [ Time Frame: Day 7 to Day 28 ]This is an exploratory objective: Peripheral Blood Mononuclear Cells (PBMC) will be obtained before and on day 7 and 28 after vaccine and evaluated for B-cell responses. B cell responses will be evaluated by antibody secreting cell assay.
- Number of participants with increased RNA transcripts [ Time Frame: Baseline to Day 3 ]This is an exploratory objective: Whole blood will be collected in PaxGene tubes and the early innate response will be assessed by RNASeq analysis of the transcriptome.
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03068949
|United States, New York|
|University of Rochester Medical Center, Vaccine Research Unit Room 3-5000|
|Rochester, New York, United States, 14642|
|Principal Investigator:||Angela Branche, MD||University of Rochester|