Study of the Safety and Immunogenicity of an Influenza Vaccine Administered to Healthy Adults

A Phase 2, Observer-Blinded, Randomized, Multicenter Study in Healthy Adults to Evaluate Safety and Tolerability and to Compare Immunogenicity of a Single Dose of Either an Investigational Trivalent Inactivated Influenza Vaccine Produced in Mammalian Cell Culture or a US-licensed Trivalent Inactivated Influenza Vaccine (Fluvirin®) Produced in Embryonated Hen Eggs

The purpose of this study is to evaluate the safety and immunogenicity of cell culture-derived, inactivated, subunit influenza vaccine in comparison to licensed Fluvirin vaccine administered to healthy adults ages 18 < 50 years.

Study Overview

• Status: Completed
• Conditions: Influenza Disease; Flu
• Intervention / Treatment: Biological: Influenza Virus Vaccine

• Study Type: Interventional
• Enrollment (Actual): 613
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Kentucky
    • Bardstown, Kentucky, United States, 40004
  • Pennsylvania
    • Pittsburgh, Pennsylvania, United States, 15241
  • Utah
    • Salt Lake City, Utah, United States, 84121
    • Salt Lake City, Utah, United States, 84109

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 49 years (Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

Inclusion Criteria:

18 to <50 years of age;

1. able to comprehend and follow all required study procedures;
2. able and willing to provide written informed consent prior to study entry;
3. available for all the visits scheduled in the study;

4. in general good health as determined by:

   1. subject-reported medical history,
   2. physical examination by a qualified study nurse, a physician's assistant, or a physician,
   3. clinical judgment of the investigator; among all female volunteers, evidence of a negative pregnancy test conducted on the same day as and prior to study vaccination, and agreement to practice adequate contraception for at least 6 weeks after vaccination as further described in the protocol.

Exclusion Criteria:

1. received influenza vaccine within the past 6 months;
2. laboratory-confirmed influenza disease in the past 6 months;
3. any acute respiratory disease or infection requiring systemic antibiotic or antiviral therapy (chronic antibiotic therapy for urinary tract prophylaxis was acceptable) or fever ≥38°C (100.4°F) within the past 3 days;
4. receipt of another investigational agent within 90 days or before completion of the safety follow-up period in another study, whichever was longer, prior to enrollment, and unwilling to refuse participation in another investigational study through the end of the study;
5. any history of or current serious disease, such as: d) cancer (except for benign or localized skin cancer), e) autoimmune disease (including rheumatoid arthritis), f) advanced arteriosclerotic disease or diabetes mellitus, g) chronic obstructive pulmonary disease (COPD), h) acute, chronic, or progressive hepatic disease, i) acute, chronic, or progressive renal disease, j) congestive heart failure, k) bleeding diathesis, l) an inherited genetic anomaly (known cytogenic disorders, e.g., Down's Syndrome), m) any other serious, acute, or chronic disease including progressive neurological disease or seizure disorder unrelated to fever;
6. surgery or hospitalization planned during the study period;
7. history of any anaphylaxis, serious vaccine reactions, vaccine-associated oculorespiratory syndrome, or allergy to eggs, egg products, mercury-containing compounds (such as sodium-ethyl-mercuro-thio-salicylate), or any other vaccine component or component of the potential packaging materials (latex);
8. known or suspected disease of the immune system, or receiving immunosuppressive therapy, including use of: n) systemic corticosteroids, known to be associated with suppression of the hypothalamic-pituitary-adrenal (HPA) axis (i.e., systemic corticosteroids [15 mg/day of prednisone or its equivalent] or chronic use of inhaled high potency corticosteroids [budesonide 800 μg/day or fluticasone 750 μg/day]), both within the previous 60 days, o) receipt of immunostimulants within 60 days, p) receipt of parenteral immunoglobulin preparation, blood products, and/or plasma derivatives within the 3 months prior to study entry or anticipated during the full length of the study;
9. at high risk for developing an immunocompromising disease;
10. history of (or current) drug or alcohol abuse that in the investigator's opinion would interfere with safety of the subject or the evaluation of study objectives;
11. pregnant or breastfeeding;
12. if female of childbearing potential, refusal to use a reliable contraceptive method, as described further in the protocol, during the first 6 weeks after vaccination;

13. if female of childbearing potential and sexually active, has not used any of the following birth control methods for the specified time period prior to study entry:

    1. hormonal (e.g., oral, injection, transdermal patch, implant, cervical ring), barrier (e.g., condom with spermicide or diaphragm with spermicide), or intrauterine device (e.g., IUD) for 2 months or more prior to study entry,
    2. monogamous relationship with vasectomized partner: partner has been vasectomized for 6 months or more prior to the subject's study entry;
14. obese (e.g., with a body mass index [BMI] ≥35, where BMI reflects obesity and not high muscle mass);
15. any condition which, in the opinion of the investigator, might interfere with the evaluation of the study objectives or might interfere with the safety of the study subject.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: cTIV; Received one dose of cell-culture derived trivalent influenza vaccine (cTIV).	Biological: Influenza Virus Vaccine
Active Comparator: TIV; Received one dose of egg-derived trivalent vaccine (TIV).	Biological: Influenza Virus Vaccine

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Geometric Mean Titers (GMT) After 1 Dose of Cell-culture-derived Vaccine (cTIV) or Egg-derived Vaccine (eTIV_f), Using the ANOVA Method.	Non-inferiority was measured by the ratio of postvaccination geometric mean titers (cTIV vs. eTIV_f) against all three vaccine strains as assessed by egg-derived antigen and cell-derived antigen haemagglutination inhibition (HI) assay.	3 weeks postvaccination (Day 22)
Geometric Mean Titers (GMT) After 1 Dose of Cell-culture-derived Vaccine (cTIV) or Egg-derived Vaccine (eTIV_f), Using the ANCOVA Method.	Non-inferiority was measured by the ratio of postvaccination geometric mean titers (cTIV vs. eTIV_f) against all three vaccine strains as assessed by egg-derived antigen and cell-derived antigen haemagglutination inhibition (HI) assay.	3 weeks postvaccination (Day 22)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Geometric Mean Ratio After 1 Dose of Cell-culture-derived Vaccine (cTIV) or Egg-derived Vaccine (eTIV_f), Using the ANOVA Method.	Geometric mean ratio (GMR) of Day 22 / Day 1 geometric mean antibody titers was assessed by egg-derived antigen and cell-derived antigen haemagglutination inhibition (HI) assay. The criterion is met according to European (CHMP) guideline if the mean geometric increase GMR (Day22/Day1) in HI antibody titer is > 2.5.	3 weeks postvaccination (Day 22)
Geometric Mean Ratio After 1 Dose of Cell-culture-derived Vaccine (cTIV) or Egg-derived Vaccine (eTIV_f), Using the ANCOVA Method.	Geometric mean ratio (GMR) of Day 22 / Day 1 geometric mean antibody titers was assessed by egg-derived antigen and cell-derived antigen haemagglutination inhibition (HI) assay. The criterion is met according to European (CHMP) guideline if the mean geometric increase GMR (Day22/Day1) in HI antibody titer is > 2.5.	3 weeks postvaccination (Day 22)
Geometric Mean Titers (GMT) Before and After 1 Dose of Cell-culture-derived Vaccine (cTIV) or Egg-derived Vaccine (eTIV_f), Using the ANOVA Method	Antibody titers as assessed by egg-derived antigen and cell-derived antigen haemagglutination inhibition (HI) assay.	3 weeks postvaccination (Day 22)
Percentages of Subjects With Haemagglutination Inhibition (HI) Antibody Titer ≥ 40.	Antibody titers as assessed by egg-derived antigen and cell-derived antigen HI assay. This criterion is met according to European (CHMP) guideline if the percentages of subjects achieving HI titers ≥40 is >70%. According to the US Center for Biologics Evaluation and Research (CBER) guideline, the criterion is also met if the lower limit of the 95% CI for percentages of subjects achieving seroprotection (HI antibody titer ≥1:40) is ≥70%.	3 weeks postvaccination (Day 22)
Percentages of Subjects With Seroconversion.	As the definition for seroconversion/significant increase from CHMP guideline CPMP/BWP/214/96 corresponds to that of seroconversion from the May 2007 CBER guidance, the analysis of this immunogenicity endpoint is presented as seroconversion. Seroconversion is defined as prevaccination HI titer <10 and postvaccination HI titer ≥40, or prevaccination HI titer ≥10 and a ≥4-fold increase in postvaccination HI antibody titer, on day 22. CBER criterion is met if the lower limit of the 95% CI for percentages of subjects achieving seroconversion for HI antibody (at least a 4-fold rise in HI antibody titer) postvaccination is ≥40%. CHMP criterion is also met if the percentages of subjects achieving seroconversion is >40%.	3 weeks postvaccination (Day 22)
Number of Subjects Reporting Local and Systemic Reactions	Safety and tolerability of cTIV and eTIV_f postvaccination. Difference between demography and safety numbers was due to one misrandomization.	7 days postvaccination

Collaborators and Investigators

• Sponsor: Novartis Vaccines
• Collaborators: Novartis Vaccines and Diagnostics (formerly Chiron Vaccines)

Publications and helpful links

General Publications

• Reisinger KS, Block SL, Izu A, Groth N, Holmes SJ. Subunit influenza vaccines produced from cell culture or in embryonated chicken eggs: comparison of safety, reactogenicity, and immunogenicity. J Infect Dis. 2009 Sep 15;200(6):849-57. doi: 10.1086/605506.

Study record dates

Study Major Dates

• Study Start: October 1, 2005
• Primary Completion (Actual): December 1, 2005
• Study Completion (Actual): May 1, 2006

Study Registration Dates

• First Submitted: December 9, 2005
• First Submitted That Met QC Criteria: December 9, 2005
• First Posted (Estimate): December 13, 2005

Study Record Updates

• Last Update Posted (Actual): March 24, 2017
• Last Update Submitted That Met QC Criteria: February 21, 2017
• Last Verified: December 1, 2012

More Information

Terms related to this study

• Keywords: influenza; flu
• Additional Relevant MeSH Terms: RNA Virus Infections; Virus Diseases; Infections; Respiratory Tract Infections; Respiratory Tract Diseases; Orthomyxoviridae Infections; Influenza, Human
• Other Study ID Numbers: V58P5