Clinical trial NCT03603509: Gene Signatures of Influenza Vaccine Responses in Older Adults
Official title: Transcriptomic Signatures of Influenza Vaccine Responses
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Influenza
Keywords: Fluad, MF59, Fluzone, HDFlu, Influenza, Vaccine
Lead sponsor: Mayo Clinic
Sponsor class: OTHER
Collaborators: name: National Institute of Allergy and Infectious Diseases (NIAID)
First posted: 2018-07-27
Enrollment: 241
Sex: ALL
Minimum age (years): 65
Standard ages: OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Eligible subjects who consent and enroll will be randomly assigned to receive either the Fluad Vaccine or Fluzone High-Dose vaccine.
Primary purpose: BASIC_SCIENCE

Brief summary: The purpose of this research study is to better understand the immune response to the Adjuvanted Subunit flu vaccine (MF59) and the High Dose flu vaccine (HDFlu) in people 65 years of age and older. The research team will be studying why immune response diminishes as people get older in both men and women. The ultimate goal is to understand how flu immunity develops after vaccination. This information may lead to the development of more effective flu vaccines in the future.

Detailed description: The overall goal of this proposal is to determine how vaccine type, sex, and gene expression influence both innate and T helper cell immune responses using systems biology and bioinformatics as tools to comprehensively assess the human transcriptome. We will evaluate sex-dependent immune responses to two unique influenza vaccines in a population of older adults; the recently FDA-licensed MF59-adjuvanted influenza subunit vaccine and the high-dose split virion influenza virus vaccine. The influence of sex on immune response to vaccination has been observed across multiple vaccines (including standard dose influenza vaccines, but the mechanisms are unknown, it affects all age groups regardless of hormonal status, and existing studies focus almost exclusively on humoral immune responses. Relatively little is known about the effect of sex on innate and T helper responses following vaccination and we are unaware of any studies evaluating the effect of sex on immune responses to adjuvanted influenza vaccine. The presence of adjuvant (MF59Flu) or higher antigen (Ag) dose leads to greater immunogenicity through mechanisms that have not been fully deciphered and are likely to be different. Further, a direct comparison of innate and T helper immune responses between adjuvanted and high dose influenza vaccines has not been reported.

The study design will include 200 generally healthy individuals (ages ≥65) who meet all inclusion criteria. 100 subjects will receive each vaccine with equal sex representation in each subgroup (a factorial design for sex by vaccine type). Subjects will undergo venipuncture for blood samples (\~100 mL each, sufficient for the proposed assays) before vaccination and at three timepoints after vaccination (Day 1, Day 8, Day 28).

The clinical characterization of our study subjects will include demographic information, height, weight, BMI, waist circumference, medications, and medical conditions that do not meet exclusion criteria (see Protection of Human Subjects). We will also quantify blood leukocyte populations (CBC, WBC differential).

Immunosenescence and cytomegalovirus (CMV) infection can affect influenza vaccine-induced immune responses. We will evaluate whether CMV seropositivity or other measures of immunosenescence are associated with immune response and whether they interact with vaccine type/sex.

We will monitor/characterize transcriptional changes (mRNA and miRNA) as well as measures of immune function (cytokine secretion, leukocyte surface phenotype, hemagglutination inhibiting antibody titer, and memory B cell ELISPOT) at each time point.

Eligibility criteria: Inclusion Criteria:

* Male or female adults ages 18-40 or of 65 and or older at the time of enrollment
* Eligible to receive Fluad® (MF59Flu) or Fluzone® (HDFlu) if age 65 or older
* No history of anaphylactic reaction to gelatin, neomycin, or other vaccine component
* Not pregnant
* No immunosuppression or immunodeficiency
* No acute illness at time of vaccination
* Determined by medical history and clinical judgment to be eligible for the study, by being generally healthy, with no autoimmune or immunosuppressive conditions and having stable current medical conditions (subjects with preexisting stable disease, defined as disease not requiring significant change in therapy or hospitalization for worsening disease 12 weeks before receipt of study vaccine, will be eligible. A change in dose or therapy within a category (e.g., change from one nonsteroidal anti-inflammatory drug to another) is allowed. A change to a new therapy category (e.g., surgery or addition of a new pharmacological class) is only allowed if it is not caused by worsening disease. A change to a new therapy category caused by worsening disease is considered significant and therefore ineligible for enrollment.
* Patients with diabetes mellitus are eligible for inclusion if they have had a hemoglobin A1c measurement of \<8.0 within the past 6 months prior to enrollment. These hemoglobin A1c measurements are recommended at least twice yearly by the American Diabetes Association (ADA), and the target levels here are representative of the goals of the ADA. These hemoglobin A1c levels will ensure that these participants have good glycemic control. (American Diabetes Association. American Diabetes Association Position Statement: Standards of Medical Care in Diabetes- 2015. Diabetes Care 2015;38(Suppl. 1): S1-S94)
* Able to follow study procedures in the opinion of the investigator
* Expected to be available for the duration of the study
* Weighs \>110 lbs

Exclusion Criteria:

* Known or suspected immunodeficiency or receiving treatment with immunosuppressive therapy including cytotoxic agents or systemic corticosteroids (e.g., for cancer, HIV, or autoimmune disease). If systemic corticosteroids have been administered short term for treatment of an acute illness, subjects will be included if corticosteroid therapy (inhaled, intranasal, and intra-articular corticosteroid therapy is permitted) has been discontinued for at least 30 days.
* Serious chronic medical conditions including metastatic malignancy, severe chronic obstructive pulmonary disease requiring supplemental oxygen, end-stage renal disease with or without dialysis, clinically unstable cardiac disease, or any other disorder that, in the investigator's opinion, precludes the subject from participating in the study. Diabetic patients will be excluded if they do not have a hemoglobin A1c measurement within the past 6 months or if they had a hemoglobin A1c measurement of an A1c \>8.0
* Receipt of any blood products, including immunoglobulin, within 6 months of study enrollment.
* Current anticoagulant therapy or a history of bleeding diathesis that would contraindicate intramuscular (IM) injection. (Note: antiplatelet drugs such as aspirin and clopidogrel are permitted.)
* Receipt of any vaccines within the past 30 days prior to enrollment
* Receipt of the current seasonal influenza vaccine other than in this study
* Acute illness within the last 30 days
* Blood donation within the last 58 days prior to study enrollment
* Any medical condition that would, in the opinion of the investigator, interfere with the evaluation of the study objectives
* Pregnant patients will be excluded
* Any condition (e.g. allergic reaction, Guillain-Barre Syndrome) that precludes their receipt of the influenza vaccine

Primary outcomes:
measure: Innate Cell IFNa2a Production
timeFrame: Baseline, Day 1
measure: Hemagglutination Inhibition Ab Titer
timeFrame: Baseline and Day 28
measure: T Cell Gene Expression
timeFrame: Baseline, Day 28
measure: T Cell miRNA Expression
timeFrame: Baseline, Day 8, Day 28
measure: Innate IFNAR1 Cell Gene Expression
timeFrame: Baseline, Day 8
measure: Innate Cell miRNA Expression
timeFrame: Baseline, Day 1, Day 8
measure: Memory B Cell ELISPOT
timeFrame: Day 28
Secondary outcomes:
measure: T Cell ELISPOT Response
timeFrame: Day 28
measure: T Cell Phenotype
timeFrame: Day 28
measure: Innate Cell Phenotype
timeFrame: Day 1 (stim)
measure: CMV Serostatus
timeFrame: Baseline
measure: CD4/CD8 Ratio
timeFrame: Day 28
Other outcomes:
Locations:
city: Rochester
country: United States
facility: Mayo Clinic in Rochester
state: Minnesota
Study officials:
affiliation: Mayo Clinic
name: Richard B Kennedy
role: PRINCIPAL_INVESTIGATOR
References: