Clinical trial NCT00943202: Sanofi Pasteur, TIV + H1N1, Pediatric Population
Official title: Effect of Administration of Licensed TIV Vaccine on the Safety and Immunogenicity of an Unadjuvanted Sanofi Pasteur H1N1 Influenza Vaccine in Previously Primed Infants and Toddlers (Greater Than or Equal to 6 - <36 Months), Children (Greater Than or Equal to 36 Months - 9 Years), and Adolescents (10 - 17 Years)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Influenza
Keywords: H1N1, influenza A viruses, TIV, vaccine, infants, children
Lead sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
Sponsor class: NIH
First posted: 2009-07-22
Enrollment: 531
Sex: ALL
Minimum age (years): 6
Maximum age (years): 17
Standard ages: CHILD
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

Brief summary: The purpose of this study is to assess the safety and immune response (body's defense against disease) to an experimental H1N1 influenza vaccine against the 2009 H1N1 virus. This study will help determine how and when the H1N1 flu shot should be given with the seasonal flu shot to make it most effective. The 650 participants will be divided into the following age groups: infants from 6 months-36 months old, children 36 months-9 years old, and adolescents 10-17 years old. Each age group will have 200 children. There are 4 treatment groups in each age level. Study procedures include: medical history, targeted physical exam based on history, maintaining a memory aid, and blood sample collection. Participants will be involved in the study for about 8 months.

Detailed description: Recently, a novel swine-origin influenza A/H1N1 virus was identified as a significant cause of febrile respiratory illnesses in Mexico and the United States. It rapidly spread to many countries around the world, prompting the World Health Organization (WHO) to declare a pandemic on June 11, 2009. Data from several cohorts in different age groups that received licensed trivalent seasonal influenza vaccines suggest that these vaccines are unlikely to provide protection against the new virus. In addition, adults are more likely to have measurable levels of serum hemagglutination inhibition assay (HAI) or neutralizing antibody than are children. These data indicate the need to develop vaccines against the new H1N1 strain and suggest that different vaccine strategies (e.g., number of doses, need for adjuvant) may be appropriate for persons in different age groups. If the novel influenza H1N1 2009 virus continues to circulate, it is possible that it will co-circulate with the non-pandemic seasonal influenza strains. In this situation, it might be beneficial to co-administer an H1N1 vaccine concurrent with the seasonal inactivated influenza vaccine. This protocol will explore if vaccination with the 2009-2010 licensed seasonal trivalent influenza vaccine (TIV) has an effect on antibody response to the novel influenza H1N1 2009 virus. This protocol will also examine if receiving the H1N1 vaccine either concurrent with, prior to, or following the seasonal influenza vaccine affects the antibody response to the seasonal influenza vaccine. A randomized Phase II study in infants, toddlers, children and adolescents. This study is designed to investigate the safety, reactogenicity, and immunogenicity of an inactivated influenza H1N1 virus vaccine when given concurrent with seasonal TIV, or sequentially with (before or after) seasonal influenza vaccine. Primary objectives are: safety, to assess the safety of the unadjuvanted, inactivated H1N1 vaccine when administered either concurrent with, prior to, or following licensed seasonal influenza vaccination; and immunogenicity, to assess the effect of TIV administration on antibody response to unadjuvanted, inactivated H1N1 vaccine as assessed by HAI, stratified by age of recipient. The secondary objective is: immunogenicity, to assess the effect of H1N1 vaccine administration on antibody response to TIV as assessed by HAI, stratified by age of recipient. Subjects will be randomized into 4 groups, stratified by age (150 subjects per group with 50 subjects per age stratum: greater than or equal to 6-\<36 months, greater than or equal to 36 months-9 years, and 10-17 years), to receive two 15 mcg doses of inactivated influenza H1N1 vaccine at Days 0 and 21 followed by TIV on Day 42 (Group 1), two 15 mcg doses of H1N1 vaccine of which the first dose is administered concurrently with TIV (Group 2), two 15 mcg doses of H1N1 vaccine of which the second dose is administered concurrently with TIV (Group 3), or TIV administered on Day 0 followed by two 15 mcg doses of H1N1 vaccine on Days 21 and 42 (Group 4). Following immunization, safety will be measured by assessment of adverse events for 21 days following the last vaccination (Day 42 for those who do not receive the second dose), serious adverse events and new-onset chronic medical conditions for 8 months post first vaccination (Day 201 for Groups 2 and 3 or Day 222 for Groups 1 and 4), and reactogenicity to the vaccines for 8 days following each vaccination (Day 0-7). Immunogenicity testing will include HAI and neutralizing antibody testing prior to vaccination, on the day of each vaccination (Days 0, 21 and 42) and 21 days following the third vaccine.

Eligibility criteria: Inclusion Criteria:

* Are males or non-pregnant females aged 6 months to 17 years, inclusive.
* All subjects 6 months to 9 years must be "primed".
* Subjects of child-bearing potential must agree to practice adequate contraception that may include, but is not limited to, abstinence, barrier methods such as condoms, diaphragms, spermicides, intrauterine devices, and licensed hormonal methods during the study for at least 30 days following the last vaccination.
* The subject must be in good health, as determined by axillary (\<10 years of age) or oral temperature (axillary temperature \<100 degrees Fahrenheit or oral temperature \<101 degrees Fahrenheit), medical history, and targeted physical examination based on medical history.
* Subject and/or parent(s)/legal guardian(s) must be willing and able to comply with planned study procedures and be available for all study visits.
* Subject and/or parent(s)/legal guardian(s) must provide written informed consent prior to initiation of any study procedures, and subject may provide written assent as appropriate.

Exclusion Criteria:

* Have a known allergy to eggs or other components of the vaccine (including gelatin, formaldehyde, octoxinol, thimerosal and chicken protein).
* Have a positive urine or serum pregnancy test within 24 hours prior to vaccination or are breastfeeding.
* Have immunosuppression as a result of an underlying illness or treatment, or use of anticancer chemotherapy or radiation therapy (cytotoxic) within the preceding 36 months.
* Have an active neoplastic disease or a history of any hematologic malignancy.
* Have long term use of glucocorticoids including oral, parenteral or high-dose inhaled steroids (\>800 mcg/day of beclomethasone dipropionate or equivalent) within the preceding 6 months. (Nasal and topical steroids are allowed.)
* Have a diagnosis of schizophrenia, bipolar disease, or other major psychiatric diagnosis or major depression.
* Have been hospitalized for psychiatric illness, history of suicide attempt, or confinement for danger to self or others.
* Are receiving any psychiatric drugs (aripiprazole, clozapine, ziprasidone, haloperidol, molindone, loxapine, thioridazine, thiothixene, pimozide, fluphenazine, risperidone, mesoridazine, quetiapine, trifluoperazine, chlorprothixene, chlorpromazine, perphenazine, trifluopromazine, olanzapine, carbamazepine, divalproex sodium, lithium carbonate or lithium citrate) or any drugs for treatment of depression.
* Have a history of receiving immunoglobulin or other blood product within the 3 months prior to vaccination in this study.
* Received an experimental agent (vaccine, drug, biologic, device, blood product, or medication) within 1 month prior to vaccination in this study or expect to receive an experimental agent during the study period (prior to Day 180 after the last vaccination).
* Have received any live licensed vaccines within 4 weeks or inactivated licensed vaccines within 2 weeks prior to vaccination in this study or plan receipt of such vaccines within 21 days following the last vaccination. This is inclusive of routine childhood immunizations provided outside the scope of this study. The initiation of this protocol does not take precedence over routine immunizations.
* Has received a licensed 2009-2010 seasonal influenza vaccine.
* Have an acute or chronic medical condition that, in the opinion of the investigator, would render vaccination unsafe, or would interfere with the evaluation of responses.
* Have a history of severe reactions following previous immunization with influenza virus vaccines.
* Have an acute illness, including an axillary temperature greater than 100 degrees Fahrenheit or an oral temperature greater than or equal to 101 degrees Fahrenheit, within 3 days prior to vaccination.
* Have any condition that would, in the opinion of the site investigator, place them at an unacceptable risk of injury or render them unable to meet the requirements of the protocol.
* Participated in a novel influenza H1N1 2009 vaccine study in the past two years or have a history of novel influenza H1N1 2009 infection prior to enrollment.
* Have known active human immunodeficiency virus (HIV), Hepatitis B or Hepatitis C infection.
* Have a history of alcohol or drug abuse.
* Plan to travel outside of North America in the time between the first vaccination and 63 days following the first vaccination.
* Have a history of Guillain-Barré Syndrome.
* Have any condition that the investigator believes may interfere with successful completion of the study.

Primary outcomes:
measure: Number of Participants Age 6 Months to Less Than 36 Months With 4-fold or Greater Hemagglutination Inhibition Assay (HAI) Antibody Titer Increases Against the Influenza H1N1 2009 Virus 21 Days Following the First Dose of H1N1 Vaccine
timeFrame: Day 0 prior to vaccination and 21 days after the first H1N1 vaccination
measure: Number of Participants Age 36 Months to 9 Years With 4-fold or Greater Hemagglutination Inhibition Assay (HAI) Antibody Titer Increases Against the Influenza H1N1 2009 Virus 21 Days Following the First Dose of H1N1 Vaccine
timeFrame: Day 0 prior to vaccination and 21 days after the first H1N1 vaccination
measure: Number of Participants Age 10 to 17 Years With 4-fold or Greater Hemagglutination Inhibition Assay (HAI) Antibody Titer Increases Against the Influenza H1N1 2009 Virus 21 Days Following the First Dose of H1N1 Vaccine
timeFrame: Day 0 prior to vaccination and 21 days after the first H1N1 vaccination
measure: Number of Participants Age 6 to Less Than 36 Months Reporting Solicited Subjective Systemic Reactions After the First Vaccination
timeFrame: Within 8 days (Day 0-7) post first vaccination
measure: Number of Participants Age 36 Months to 9 Years Reporting Solicited Subjective Systemic Reactions After the First Vaccination
timeFrame: Within 8 days (Day 0-7) post first vaccination
measure: Number of Participants Age 10 to 17 Years Reporting Solicited Subjective Systemic Reactions After the First Vaccination
timeFrame: Within 8 days (Day 0-7) post first vaccination
measure: Number of Participants Age 6 to Less Than 36 Months Reporting Solicited Subjective Systemic Reactions After the Second Vaccination
timeFrame: Within 8 days (Day 0-7) post second vaccination
measure: Number of Participants Age 36 Months to 9 Years Reporting Solicited Subjective Systemic Reactions After the Second Vaccination
timeFrame: Within 8 days (Day 0-7) post second vaccination
measure: Number of Participants Age 10 to 17 Years Reporting Solicited Subjective Systemic Reactions After the Second Vaccination
timeFrame: Within 8 days (Day 0-7) post second vaccination
measure: Number of Participants Age 6 to Less Than 36 Months Reporting Solicited Subjective Systemic Reactions After the Third Vaccination
timeFrame: Within 8 days (Day 0-7) post third vaccination
measure: Number of Participants Age 36 Months to 9 Years Reporting Solicited Subjective Systemic Reactions After the Third Vaccination
timeFrame: Within 8 days (Day 0-7) post third vaccination
measure: Number of Participants Age 10 to 17 Years Reporting Solicited Subjective Systemic Reactions After the Third Vaccination
timeFrame: Within 8 days (Day 0-7) post third vaccination
measure: Number of Participants Age 6 to Less Than 36 Months Reporting Solicited Quantitative Systemic Reactions After the First Vaccination
timeFrame: Within 8 days (Day 0-7) post first vaccination
measure: Number of Participants Age 36 Months to 9 Years Reporting Solicited Quantitative Systemic Reactions After the First Vaccination
timeFrame: Within 8 days (Day 0-7) post first vaccination
measure: Number of Participants Age 10 to 17 Years Reporting Solicited Quantitative Systemic Reactions After the First Vaccination
timeFrame: Within 8 days (Day 0-7) post first vaccination
measure: Number of Participants Age 6 to Less Than 36 Months Reporting Solicited Quantitative Systemic Reactions After the Second Vaccination
timeFrame: Within 8 days (Day 0-7) post second vaccination
measure: Number of Participants Age 36 Months to 9 Years Reporting Solicited Quantitative Systemic Reactions After the Second Vaccination
timeFrame: Within 8 days (Day 0-7) post second vaccination
measure: Number of Participants Age 10 to 17 Years Reporting Solicited Quantitative Systemic Reactions After the Second Vaccination
timeFrame: Within 8 days (Day 0-7) post second vaccination
measure: Number of Participants Age 6 to Less Than 36 Months Reporting Solicited Quantitative Systemic Reactions After the Third Vaccination
timeFrame: Within 8 days (Day 0-7) post third vaccination
measure: Number of Participants Age 36 Months to 9 Years Reporting Solicited Quantitative Systemic Reactions After the Third Vaccination
timeFrame: Within 8 days (Day 0-7) post third vaccination
measure: Number of Participants Age 10 to 17 Years Reporting Solicited Quantitative Systemic Reactions After the Third Vaccination
timeFrame: Within 8 days (Day 0-7) post third vaccination
measure: Number of Participants Age 6 to Less Than 36 Months Reporting Solicited Subjective Local Reactions After the First H1N1 Vaccination
timeFrame: Within 8 days (Day 0-7) post first H1N1 vaccination
measure: Number of Participants Age 36 Months to 9 Years Reporting Solicited Subjective Local Reactions After the First H1N1 Vaccination
timeFrame: Within 8 days (Day 0-7) post first H1N1 vaccination
measure: Number of Participants Age 10 to 17 Years Reporting Solicited Subjective Local Reactions After the First H1N1 Vaccination
timeFrame: Within 8 days (Day 0-7) post first H1N1 vaccination
measure: Number of Participants Age 6 to Less Than 36 Months Reporting Solicited Subjective Local Reactions After the Second H1N1 Vaccination
timeFrame: Within 8 days (Day 0-7) post second H1N1 vaccination
measure: Number of Participants Age 36 Months to 9 Years Reporting Solicited Subjective Local Reactions After the Second H1N1 Vaccination
timeFrame: Within 8 days (Day 0-7) post second H1N1 vaccination
measure: Number of Participants Age 10 to 17 Years Reporting Solicited Subjective Local Reactions After the Second H1N1 Vaccination
timeFrame: Within 8 days (Day 0-7) post second H1N1 vaccination
measure: Number of Participants Age 6 to Less Than 36 Months Reporting Solicited Subjective Local Reactions After the TIV Vaccination
timeFrame: Within 8 days (Day 0-7) post TIV vaccination
measure: Number of Participants Age 36 Months to 9 Years Reporting Solicited Subjective Local Reactions After the TIV Vaccination
timeFrame: Within 8 days (Day 0-7) post TIV vaccination
measure: Number of Participants Age 10 to 17 Years Reporting Solicited Subjective Local Reactions After the TIV Vaccination
timeFrame: Within 8 days (Day 0-7) post TIV vaccination
measure: Number of Participants Age 6 to Less Than 36 Months Reporting Solicited Quantitative Local Reactions After the First H1N1 Vaccination
timeFrame: Within 8 days (Day 0-7) post first H1N1 vaccination
measure: Number of Participants Age 36 Months to 9 Years Reporting Solicited Quantitative Local Reactions After the First H1N1 Vaccination
timeFrame: Within 8 days (Day 0-7) post first H1N1 vaccination
measure: Number of Participants Age 10 to 17 Years Reporting Solicited Quantitative Local Reactions After the First H1N1 Vaccination
timeFrame: Within 8 days (Day 0-7) post first H1N1 vaccination
measure: Number of Participants Age 6 to Less Than 36 Months Reporting Solicited Quantitative Local Reactions After the Second H1N1 Vaccination
timeFrame: Within 8 days (Day 0-7) post second H1N1 vaccination
measure: Number of Participants Age 36 Months to 9 Years Reporting Solicited Quantitative Local Reactions After the Second H1N1 Vaccination
timeFrame: Within 8 days (Day 0-7) post second H1N1 vaccination
measure: Number of Participants Age 10 to 17 Years Reporting Solicited Quantitative Local Reactions After the Second H1N1 Vaccination
timeFrame: Within 8 days (Day 0-7) post second H1N1 vaccination
measure: Number of Participants Age 6 to Less Than 36 Months Reporting Solicited Quantitative Local Reactions After the TIV Vaccination
timeFrame: Within 8 days (Day 0-7) post TIV vaccination
measure: Number of Participants Age 36 Months to 9 Years Reporting Solicited Quantitative Local Reactions After the TIV Vaccination
timeFrame: Within 8 days (Day 0-7) post TIV vaccination
measure: Number of Participants Age 10 to 17 Years Reporting Solicited Quantitative Local Reactions After the TIV Vaccination
timeFrame: Within 8 days (Day 0-7) post TIV vaccination
measure: Number of Participants Reporting Vaccine-associated Serious Adverse Events (SAEs)
timeFrame: Day 0 through 180 days after the last vaccination
measure: Number of Participants Age 6 Months to Less Than 36 Months With a Serum Hemagglutination Inhibition Assay (HAI) Antibody Titer of 1:40 or Greater Against the H1N1 2009 Virus 21 Days Following the First Dose of H1N1 Vaccine
timeFrame: Day 21 after first H1N1 vaccination
measure: Number of Participants Age 36 Months to 9 Years With a Serum Hemagglutination Inhibition Assay (HAI) Antibody Titer of 1:40 or Greater Against the H1N1 2009 Virus 21 Days Following the First Dose of H1N1 Vaccine
timeFrame: Day 21 after first H1N1 vaccination
measure: Number of Participants Age 10 to 17 Years With a Serum Hemagglutination Inhibition Assay (HAI) Antibody Titer of 1:40 or Greater Against the H1N1 2009 Virus 21 Days Following the First Dose of H1N1 Vaccine
timeFrame: Day 21 after first H1N1 vaccination
Secondary outcomes:
measure: Number of Participants Age 6 to Less Than 36 Months With 4-fold or Greater Hemagglutination Inhibition Assay (HAI) Antibody Titer Increases Against the Virus Strains in the 2009-2010 Trivalent Influenza Vaccine (TIV) 21 Days Following the Last Vaccination
timeFrame: Day 0 prior to first vaccination and 21 days after last vaccination
measure: Number of Participants Age 36 Months to 9 Years With 4-fold or Greater Hemagglutination Inhibition Assay (HAI) Antibody Titer Increases Against the Virus Strains in the 2009-2010 Trivalent Influenza Vaccine (TIV) 21 Days Following the Last Vaccination
timeFrame: Day 0 prior to first vaccination and Day 21 after last vaccination
measure: Number of Participants Age 10 to 17 Years With 4-fold or Greater Hemagglutination Inhibition Assay (HAI) Antibody Titer Increases Against the Virus Strains in the 2009-2010 Trivalent Influenza Vaccine (TIV) 21 Days Following the Last Vaccination
timeFrame: Day 0 prior to first vaccination and Day 21 after last vaccination
measure: Number of Participants Age 6 to Less Than 36 Months With a Serum Hemagglutination Inhibition Assay (HAI) Antibody Titer of 1:40 or Greater Against the Virus Strains in the 2009-2010 Trivalent Influenza Vaccine (TIV) 21 Days Following the Last Vaccination
timeFrame: Day 21 after last vaccination
measure: Number of Participants Age 36 Months to 9 Years With a Serum Hemagglutination Inhibition Assay (HAI) Antibody Titer of 1:40 or Greater Against the Virus Strains in the 2009-2010 Trivalent Influenza Vaccine (TIV) 21 Days Following the Last Vaccination
timeFrame: Day 21 after last vaccination
measure: Number of Participants Age 10 to 17 Years With a Serum Hemagglutination Inhibition Assay (HAI) Antibody Titer of 1:40 or Greater Against the Virus Strains in the 2009-2010 Trivalent Influenza Vaccine (TIV) 21 Days Following the Last Vaccination
timeFrame: Day 21 after last vaccination
measure: Number of Participants Age 6 to Less Than 36 Months With a Serum Hemagglutination Inhibition Assay (HAI) Antibody Titer of 1:40 or Greater Against the H1N1 2009 Virus 21 Days Following the Second Dose of H1N1 Vaccine
timeFrame: Day 21 after the second H1N1 vaccination
measure: Number of Participants Age 36 Months to 9 Years With a Serum Hemagglutination Inhibition Assay (HAI) Antibody Titer of 1:40 or Greater Against the H1N1 2009 Virus 21 Days Following the Second Dose of H1N1 Vaccine
timeFrame: Day 21 after the second H1N1 vaccination
measure: Number of Participants Age 10 to 17 Years With a Serum Hemagglutination Inhibition Assay (HAI) Antibody Titer of 1:40 or Greater Against the H1N1 2009 Virus 21 Days Following the Second Dose of H1N1 Vaccine
timeFrame: Day 21 after the second H1N1 vaccination
measure: Number of Participants Age 6 to Less Than 36 Months With 4-fold or Greater Hemagglutination Inhibition Assay (HAI) Antibody Titer Increases Against the Influenza H1N1 2009 Virus 21 Days Following the Second Dose of H1N1 Vaccine
timeFrame: Day 0 prior to first vaccination and 21 days after the second H1N1 vaccination
measure: Number of Participants Age 36 Months to 9 Years With 4-fold or Greater Hemagglutination Inhibition Assay (HAI) Antibody Titer Increases Against the Influenza H1N1 2009 Virus 21 Days Following the Second Dose of H1N1 Vaccine
timeFrame: Day 0 prior to first vaccination and 21 days after the second H1N1 vaccination
measure: Number of Participants Age 10 to 17 Years With 4-fold or Greater Hemagglutination Inhibition Assay (HAI) Antibody Titer Increases Against the Influenza H1N1 2009 Virus 21 Days Following the Second Dose of H1N1 Vaccine
timeFrame: Day 0 prior to first vaccination and 21 days after the second H1N1 vaccination
Other outcomes:
Locations:
city: Atlanta
country: United States
facility: Emory Children's Center - Pediatric Infectious Diseases
state: Georgia
city: Atlanta
country: United States
facility: Emory University School of Medicine - Emory Children's Center - Pediatric Infectious Diseases
state: Georgia
city: Iowa City
country: United States
facility: University of Iowa
state: Iowa
city: St. Louis
country: United States
facility: Saint Louis University Hospital - Internal Medicine - Infectious Diseases, Allergy & Immunology
state: Missouri
city: Cincinnati
country: United States
facility: Cincinnati Children's Hospital Medical Center
state: Ohio
city: Nashville
country: United States
facility: Vanderbilt University - Pediatric - Vanderbilt Vaccine Research Center
state: Tennessee
city: Galveston
country: United States
facility: The University of Texas Medical Branch
state: Texas
city: Houston
country: United States
facility: Baylor College of Medicine
state: Texas
Study officials:
References:
citation: Frey SE, Bernstein DI, Gerber MA, Keyserling HL, Munoz FM, Winokur PL, Turley CB, Rupp RE, Hill H, Wolff M, Noah DL, Ross AC, Cress G, Belshe RB. Safety and immune responses in children after concurrent or sequential 2009 H1N1 and 2009-2010 seasonal trivalent influenza vaccinations. J Infect Dis. 2012 Sep 15;206(6):828-37. doi: 10.1093/infdis/jis445. Epub 2012 Jul 16.
citation: Kotloff KL, Halasa NB, Harrison CJ, Englund JA, Walter EB, King JC, Creech CB, Healy SA, Dolor RJ, Stephens I, Edwards KM, Noah DL, Hill H, Wolff M. Clinical and immune responses to inactivated influenza A(H1N1)pdm09 vaccine in children. Pediatr Infect Dis J. 2014 Aug;33(8):865-71. doi: 10.1097/INF.0000000000000329.