Influenza
Conditions
Keywords
Influenza, A/California/7/2009-like (2009 H1N1), A/Perth/16/2009-like (H3N2), B/Brisbane/60/2008-like (B/Victoria lineage)
Brief summary
A total of 88 children between 2 and 9 years of age will be randomized to receive a two dose schedule of either licensed live attenuated trivalent seasonal influenza vaccine (LAIV) or licensed inactivated seasonal influenza vaccine (TIV)or TIV followed by LAIV or LAIV followed by TIV separated by 28 days. Children with a laboratory documented history of prior H1N1 infection will be excluded.
Detailed description
The study will be conducted as a randomized, prospective, open-label evaluation of the clinical tolerability, vaccine virus shedding, and serum and mucosal antibody response to vaccination with either live trivalent influenza vaccine (LAIV) or trivalent influenza vaccine (TIV) in healthy children between the ages of 2 and 9 years. Children will be screened for antibody to A/Brisbane/57/07 (H1N1) and A/California/07/09 (H1N1), A/Perth/16/2009 (H3N2) and B/Brisbane/60/2008 before and at indicated times after the start of the study. They will not be randomized based on antibody levels. Children with prior documented infection with the 2009 pandemic H1N1 virus will be excluded. Vaccine will be administered on days 0 and 28. Safety of vaccination will be assessed using symptoms collected by parents for 7 days after each dose of vaccine. Serum will be obtained prior to and on day 28 following each dose of vaccine and assessed for antibody by HAI, ELISA, and neutralization techniques. Nasal secretions will be obtained by nasal wick prior to and on day 28 after each dose and assessed for HA-specific IgA (immune globulin A) and IgG (immune globulin G)antibody by ELISA. Nasal swabs will be obtained on days 2, 4, and 7 after each dose of live vaccine and assessed for the presence and magnitude of vaccine virus shedding of the live attenuated vaccine by rtRT-PCR (real-time reverse transcriptase polymerase chain reaction)and TCID50 (50% tissue culture infectious doses)on MDCK(Madin Darby Canine Kidney) cells.
Interventions
BIOLOGICALLive attenuated Influenza vaccine
0.2 mL dose delivered through nasal spray, 0.1 ml in each nostril, 2 doses separated by 28 days
BIOLOGICALTrivalent Influenza Vaccine
.25 mL given intramuscularly to children 24 to 36 months of age, 2 doses given 28 days apart, .5 mL given intramuscularly to children 37 months to 9 years of age, 2 doses given 28 day s apart.
BIOLOGICALTIV followed by LAIV
TIV .25 mL given intramuscularly to children 24 to 36 months of age or .5 mL given intramuscularly to children 37 months to 9 years of age, followed by FluMist 0.2 mL delivered by nasal spray (.1 mL in each nostril)28 days later
BIOLOGICALLAIV followed by TIV
LAIV .2 mL given through nasal spray (.1 mL in each nostril) Followed by TIV .25 mL given intramuscularly to children 24 to 25 months of age or .5 mL given intramuscularly to children 36 months to 9 years of age 28 days later
Sponsors
National Institutes of Health (NIH)
Dartmouth-Hitchcock Medical Center
University of Rochester
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
2 Years to 9 Years
Healthy volunteers
Yes
Inclusion criteria
* Aged between 2 and 9 years, inclusive. * No prior history of laboratory documented infection with novel H1N1 virus * The subject must be in good health, as determined by: vital signs (heart rate \<140 bpm; blood pressure: systolic ≥ 90 mm Hg and ≤140 mm Hg; diastolic ≤ 90 mm Hg; oral temperature \<100.0ºF (fahrenheit); medical history; and targeted physical examination, when necessary, based on medical history. Stable medical condition is defined as: no recent increase in prescription medication, dose, or frequency of medication in the last 3 months and health outcomes of the specific disease are considered to be within acceptable limits in the last 6 months. * The subject/parents are able to understand and comply with the planned study procedures, including being available for all study visits. * The subject/parents have provided informed consent prior to any study procedures. (An assent will be obtained for all children as required by the institutional IRB (Institutional Review Board.)
Exclusion criteria
* Subjects with a laboratory documented history of previous novel H1N1 infection. * History of egg allergy or allergy to other components of vaccine. * History of wheezing. * The subject is immunosuppressed as a result of an underlying illness or treatment with immunosuppressive or cytotoxic drugs, or use of anticancer chemotherapy or radiation therapy. * The subject has an active neoplastic disease. * The subject has long-term (greater than 2 weeks) use of oral or parenteral steroids, or high-dose inhaled steroids (\>800 mg/day of beclomethasone dipropionate or equivalent) within the preceding 6 months (nasal and topical steroids are allowed). * The subject received immunoglobulin or another blood product within the 3 months prior to enrollment in this study. * The subject has received an inactivated vaccine within the 2 weeks or a live vaccine within the 4 weeks prior to enrollment in this study or plans to receive another vaccine within the next 28 days (or 56 days for vaccine naïve recipients). * The subject has 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. These conditions include chronic conditions recognized as risk factors for influenza complications or as contraindications for live vaccination, including chronic cardiac (exclusive of hypertension) or pulmonary conditions (including asthma), diabetes mellitus, or renal impairment. * The subject has an acute illness or an oral temperature greater than 99.9 degreesF (37.7 degrees C) within 3 days prior to enrollment or vaccination. Subjects who had an acute illness that was treated symptoms resolved are eligible to enroll as long as treatment is completed and symptoms resolve \> 3 days prior to enrollment. * The subject is currently participating or plans to participate in a study that involves an experimental agent (vaccine, drug, biologic, device, blood product, or medication) or has received an experimental agent within 1 month prior to enrollment in this study, or expects to receive another experimental agent during participation in this study, or intends to donate blood during the study period. * The subject has any condition that would, in the opinion of the site investigator, place the subject at an unacceptable risk of injury or render the subject unable to meet the requirements of the protocol. * The subject has a known human immunodeficiency virus, hepatitis B, or hepatitis C infection. * The subject has a previous history of Guillain-Barré syndrome within 6 weeks of receipt of influenza vaccination. * The subject has any condition that the principal investigator (PI) believes may interfere with successful completion of the study.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Subjects Shedding Vaccine Virus of Each Subtype by PCR | baseline to day 7 | Nasal washes were collected on days 2, 4 and 7 after vaccination. Nasal swab specimens were tested for the presence of vaccine viruses by quantitative viral culture in MDCK cells at 33º C and by real-time quantitative reverse-transcriptase polymerase chain reaction (qRT-PCR) amplification. The limit of detection of vaccine viruses was 10\^0.6 tissue culture infectious doses (50%)/ml for virus culture and 10\^0.4 tissue culture infectious doses (50%)/ml for qRT-PCR. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Mean Peak H1N1 Virus Titer, Dose 1 | days 2, 4 and 7 | After the first dose of vaccine, the virus titer from nasal secretions was measured in tissue culture on days 2, 4 and 7 and the highest titer from one of those three time points was reported. |
| Mean Peak H3N2 Virus Titer, Dose 1 | days 2, 4 and 7 | After the first dose of vaccine, the virus titer from nasal secretions was measured in tissue culture on days 2, 4 and 7 and the highest titer from one of those three time points was reported. |
| Mean Peak Influenza B Virus Titer, Dose 1 | days 2, 4 and 7 | After the first dose of vaccine, the virus titer from nasal secretions was measured in tissue culture on days 2, 4 and 7 and the highest titer from one of those three time points was reported. |
| Mean Peak H1N1 Virus Titer, Dose 2 | days 2, 4 and 7 | After the second dose of vaccine, the virus titer from nasal secretions was measured in tissue culture on days 2, 4 and 7 and the highest titer from one of those three time points was reported. |
| Mean Peak H3N2 Virus Titer, Dose 2 | days 2, 4 and 7 | After the second dose of vaccine, the virus titer from nasal secretions was measured in tissue culture on days 2, 4 and 7 and the highest titer from one of those three time points was reported. |
| Mean Peak Influenza B Virus Titer, Dose 2 | days 2, 4 and 7 | After the second dose of vaccine, the virus titer from nasal secretions was measured in tissue culture on days 2, 4 and 7 and the highest titer from one of those three time points was reported. |
Countries
United States
Participant flow
Recruitment details
In the first year participants were randomly assigned to receive LAIV twice, TIV twice, LAIV followed by TIV or TIV followed by LAIV. In the second year, randomization was confined to 2 groups: LAIV twice or TIV followed by LAIV. 8/34 participants were in the two arms not included in the analysis.
Participants by arm
| Arm | Count |
|---|---|
| LAIV - LAIV LAIV 0.2 ml will be given intranasally followed by LAIV 0.2 mg given intranasally 28 days later
Trivalent Seasonal Live attenuated Influenza vaccine: 0.2 mL dose delivered through nasal spray, 0.1 ml in each nostril, 2 doses separated by 28 days | 11 |
| TIV - LAIV TIV will be given in a dose of .25mg 2 years to 36 months of age or .5 ml ages 37 months to 9 years intramuscularly followed by LAIV given in a dose of .2 ml intranasally 28 days later
Seasonal Influenza Vaccine TIV/LAIV: TIV .25 mL given intramuscularly to children 24 to 36 months of age or .5 mL given intramuscularly to children 37 months to 9 years of age, followed by FluMist 0.2 mL delivered by nasal spray (.1 mL in each nostril)28 days later | 4 |
| TIV - TIV TIV will be given followed by TIV 28 days later | 17 |
| LAIV - TIV LAIV will be given followed by TIV 28 days later | 2 |
| Total | 34 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Lost to Follow-up | 0 | 1 | 0 | 0 |
| Overall Study | Withdrawal by Subject | 0 | 0 | 0 | 2 |
Baseline characteristics
| Characteristic | LAIV - LAIV | TIV - LAIV | TIV - TIV | LAIV - TIV | Total |
|---|---|---|---|---|---|
| Age, Categorical <=18 years | 11 Participants | 4 Participants | 17 Participants | 2 Participants | 34 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Gender Female | 5 Participants | 1 Participants | 10 Participants | 0 Participants | 16 Participants |
| Gender Male | 6 Participants | 3 Participants | 7 Participants | 2 Participants | 18 Participants |
| Region of Enrollment United States | 11 participants | 4 participants | 17 participants | 2 participants | 34 participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 8 / 11 | 3 / 15 | 1 / 2 | 12 / 17 |
| serious Total, serious adverse events | 0 / 11 | 0 / 15 | 0 / 2 | 0 / 17 |
Outcome results
Primary
Number of Subjects Shedding Vaccine Virus of Each Subtype by PCR
Nasal washes were collected on days 2, 4 and 7 after vaccination. Nasal swab specimens were tested for the presence of vaccine viruses by quantitative viral culture in MDCK cells at 33º C and by real-time quantitative reverse-transcriptase polymerase chain reaction (qRT-PCR) amplification. The limit of detection of vaccine viruses was 10\^0.6 tissue culture infectious doses (50%)/ml for virus culture and 10\^0.4 tissue culture infectious doses (50%)/ml for qRT-PCR.
Time frame: baseline to day 7
Population: Outcome for shedding of live vaccine in all participants who received a live vaccine
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Trivalent Seasonal Live Attenuated Influenza Vaccine | Number of Subjects Shedding Vaccine Virus of Each Subtype by PCR | shedding B | 1 participants |
| Trivalent Seasonal Live Attenuated Influenza Vaccine | Number of Subjects Shedding Vaccine Virus of Each Subtype by PCR | shedding H3N2 | 1 participants |
| Trivalent Seasonal Live Attenuated Influenza Vaccine | Number of Subjects Shedding Vaccine Virus of Each Subtype by PCR | shedding H1N1 | 1 participants |
| Seasonal Influenza Vaccine (TIV-LAIV) | Number of Subjects Shedding Vaccine Virus of Each Subtype by PCR | shedding B | 10 participants |
| Seasonal Influenza Vaccine (TIV-LAIV) | Number of Subjects Shedding Vaccine Virus of Each Subtype by PCR | shedding H3N2 | 5 participants |
| Seasonal Influenza Vaccine (TIV-LAIV) | Number of Subjects Shedding Vaccine Virus of Each Subtype by PCR | shedding H1N1 | 6 participants |
| All First Dose Live Vaccine | Number of Subjects Shedding Vaccine Virus of Each Subtype by PCR | shedding H3N2 | 9 participants |
| All First Dose Live Vaccine | Number of Subjects Shedding Vaccine Virus of Each Subtype by PCR | shedding H1N1 | 9 participants |
| All First Dose Live Vaccine | Number of Subjects Shedding Vaccine Virus of Each Subtype by PCR | shedding B | 10 participants |
Secondary
Mean Peak H1N1 Virus Titer, Dose 1
After the first dose of vaccine, the virus titer from nasal secretions was measured in tissue culture on days 2, 4 and 7 and the highest titer from one of those three time points was reported.
Time frame: days 2, 4 and 7
| Arm | Measure | Value (LOG_MEAN) | Dispersion |
|---|---|---|---|
| Trivalent Seasonal Live Attenuated Influenza Vaccine | Mean Peak H1N1 Virus Titer, Dose 1 | 1.8 log10 TCID(50)/ml | Standard Deviation 1.7 |
| Seasonal Influenza Vaccine (TIV-LAIV) | Mean Peak H1N1 Virus Titer, Dose 1 | 0.0 log10 TCID(50)/ml | Standard Deviation 0 |
| All First Dose Live Vaccine | Mean Peak H1N1 Virus Titer, Dose 1 | 1.4 log10 TCID(50)/ml | Standard Deviation 1.9 |
| TIV - TIV | Mean Peak H1N1 Virus Titer, Dose 1 | 0.0 log10 TCID(50)/ml | Standard Deviation 0 |
Secondary
Mean Peak H1N1 Virus Titer, Dose 2
After the second dose of vaccine, the virus titer from nasal secretions was measured in tissue culture on days 2, 4 and 7 and the highest titer from one of those three time points was reported.
Time frame: days 2, 4 and 7
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Trivalent Seasonal Live Attenuated Influenza Vaccine | Mean Peak H1N1 Virus Titer, Dose 2 | 0.3 log10 TCID(50)/ml | Standard Deviation 0.99 |
| Seasonal Influenza Vaccine (TIV-LAIV) | Mean Peak H1N1 Virus Titer, Dose 2 | 0 log10 TCID(50)/ml | Standard Deviation 0 |
| All First Dose Live Vaccine | Mean Peak H1N1 Virus Titer, Dose 2 | 0 log10 TCID(50)/ml | Standard Deviation 0 |
| TIV - TIV | Mean Peak H1N1 Virus Titer, Dose 2 | 1 log10 TCID(50)/ml | Standard Deviation 1.8 |
Secondary
Mean Peak H3N2 Virus Titer, Dose 1
After the first dose of vaccine, the virus titer from nasal secretions was measured in tissue culture on days 2, 4 and 7 and the highest titer from one of those three time points was reported.
Time frame: days 2, 4 and 7
| Arm | Measure | Value (LOG_MEAN) | Dispersion |
|---|---|---|---|
| Trivalent Seasonal Live Attenuated Influenza Vaccine | Mean Peak H3N2 Virus Titer, Dose 1 | 0.9 log10 TCID(50)/ml | Standard Deviation 1.6 |
| Seasonal Influenza Vaccine (TIV-LAIV) | Mean Peak H3N2 Virus Titer, Dose 1 | 0 log10 TCID(50)/ml | Standard Deviation 0 |
| All First Dose Live Vaccine | Mean Peak H3N2 Virus Titer, Dose 1 | 0 log10 TCID(50)/ml | Standard Deviation 0 |
| TIV - TIV | Mean Peak H3N2 Virus Titer, Dose 1 | 0 log10 TCID(50)/ml | Standard Deviation 0 |
Secondary
Mean Peak H3N2 Virus Titer, Dose 2
After the second dose of vaccine, the virus titer from nasal secretions was measured in tissue culture on days 2, 4 and 7 and the highest titer from one of those three time points was reported.
Time frame: days 2, 4 and 7
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Trivalent Seasonal Live Attenuated Influenza Vaccine | Mean Peak H3N2 Virus Titer, Dose 2 | 0.3 log10 TCID(50)/ml | Standard Deviation 0.9 |
| Seasonal Influenza Vaccine (TIV-LAIV) | Mean Peak H3N2 Virus Titer, Dose 2 | 0 log10 TCID(50)/ml | Standard Deviation 0 |
| All First Dose Live Vaccine | Mean Peak H3N2 Virus Titer, Dose 2 | 0 log10 TCID(50)/ml | Standard Deviation 0 |
| TIV - TIV | Mean Peak H3N2 Virus Titer, Dose 2 | 0.3 log10 TCID(50)/ml | Standard Deviation 1.2 |
Secondary
Mean Peak Influenza B Virus Titer, Dose 1
After the first dose of vaccine, the virus titer from nasal secretions was measured in tissue culture on days 2, 4 and 7 and the highest titer from one of those three time points was reported.
Time frame: days 2, 4 and 7
| Arm | Measure | Value (LOG_MEAN) | Dispersion |
|---|---|---|---|
| Trivalent Seasonal Live Attenuated Influenza Vaccine | Mean Peak Influenza B Virus Titer, Dose 1 | 1.6 log10 TCID(50)/ml | Standard Deviation 2 |
| Seasonal Influenza Vaccine (TIV-LAIV) | Mean Peak Influenza B Virus Titer, Dose 1 | 0 log10 TCID(50)/ml | Standard Deviation 0 |
| All First Dose Live Vaccine | Mean Peak Influenza B Virus Titer, Dose 1 | 2.1 log10 TCID(50)/ml | Standard Deviation 2.9 |
| TIV - TIV | Mean Peak Influenza B Virus Titer, Dose 1 | 0 log10 TCID(50)/ml | Standard Deviation 0 |
Secondary
Mean Peak Influenza B Virus Titer, Dose 2
After the second dose of vaccine, the virus titer from nasal secretions was measured in tissue culture on days 2, 4 and 7 and the highest titer from one of those three time points was reported.
Time frame: days 2, 4 and 7
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Trivalent Seasonal Live Attenuated Influenza Vaccine | Mean Peak Influenza B Virus Titer, Dose 2 | 0 log10 TCID(50)/ml | Standard Deviation 0 |
| Seasonal Influenza Vaccine (TIV-LAIV) | Mean Peak Influenza B Virus Titer, Dose 2 | 0 log10 TCID(50)/ml | Standard Deviation 0 |
| All First Dose Live Vaccine | Mean Peak Influenza B Virus Titer, Dose 2 | 0 log10 TCID(50)/ml | Standard Deviation 0 |
| TIV - TIV | Mean Peak Influenza B Virus Titer, Dose 2 | 1.3 log10 TCID(50)/ml | Standard Deviation 2 |