Influenza
Conditions
Keywords
influenza, premature infant, very low birth weight infant, immunization, vaccine
Brief summary
Severe influenza respiratory disease is increasingly recognized in children. Influenza hospitalization rates in high-risk infants, such as premature infants, are increased some five-fold over rates in other children. The recently-licensed live attenuated influenza vaccine (LAIV) promotes better immune responses than the trivalent inactivated vaccine, but can cause wheezing. The balance of risks and benefits for LAIV in extremely premature infants, who may be at increased risk for both influenza disease and vaccine side effects, is unknown. The specific aim of this project is to compare the immune response and reactions of trivalent, inactivated influenza vaccine (TIV) and live, attenuated, intranasal influenza vaccine (LAIV) in groups of former premature (PT), very (V) LBW and former full-term (FT) infants aged 24-35 months. The investigators hypothesize that the immune response in FT infants will be greater with LAIV than TIV, and that wheezing episodes will be no more than twice as frequent in LAIV as in TIV recipients. The study will enroll 14 former premature, VLBW infants and 14 former full-term infants. Children will be randomized to receive one dose either TIV or LAIV. Vaccine reactions will be measured. One to two teaspoons mL of blood will be drawn at 0 and 7-14 days from immunization, and less than one teaspoon of blood will be drawn at 28-42 days.
Detailed description
Background. Influenza infection causes an estimated 1 million deaths worldwide yearly. Severe influenza respiratory disease is increasingly recognized in children. Influenza hospitalization rates in high-risk infants, such as premature infants, are increased some five-fold over rates in other children. Influenza vaccine immunogenicity is generally modest even in healthy children, and influenza vaccines have been incompletely studied in premature infants. The recently-licensed live attenuated influenza vaccine (LAIV) is more immunogenic than the trivalent inactivated vaccine, but its use in infants and high risk children is limited by side effects. The risk/benefit ratio of LAIV in extremely premature infants, who may be at increased risk for both influenza disease and vaccine side effects, is unknown. Aim. The specific aim of this project is to compare the immunogenicity and reactogenicity of trivalent, inactivated influenza vaccine (TIV) and live, attenuated, intranasal influenza vaccine (LAIV) in groups of former premature (PT), very low birth weight (VLBW) and former full-term (FT) infants aged 24-35 months. Hypotheses. 1. The humoral immunogenicity of LAIV, as measured by hemagglutination inhibition (HI), will be greater than that of TIV. This will be the co-primary outcome for this study. 2. Vaccine reactogenicity, as measured by medically-attended wheezing episodes, will be no more than twice as frequent in LAIV as in TIV recipients. This will be the co-primary outcome for this study. 3. Functional B-cell responses, as measured by antibody secreting cell (ASC) enzyme linked immunospot (ELISPOT), will be greater in LAIV-immunized infants than TIV-immunized infants. 4. Peak T-cell cytokine responses, as measured by interferon gamma (IFNγ), interleukin (IL)-2 and IL-4 ELISPOT, will be greater in LAIV-immunized infants than TIV-immunized infants. 5. Hemagglutinin-specific nasal immunoglobulin A (IgA) will be measureable following LAIV immunization. 6. Former premature infants will have similar adaptive immune responses, but elevated reactogenicity to both vaccines, when compared to former full-term infants. Design. The study will enroll 14 former premature, VLBW infants and 14 former full-term infants. Subjects, who will be eligible to receive either TIV or LAIV as part of routine care, will be randomized to receive one dose either TIV or LAIV, according to prevailing recommendations for influenza immunization. Randomization will be stratified by prematurity status. Vaccine reactogenicity will be measured by using parent diaries following immunization and questionnaires at each visit. Five to 10 mL of blood will be drawn at 0 and 7-14 days from immunization for isolation of peripheral blood mononuclear cells (PBMC), and 1 mL of blood will be drawn for serum separation for antibody determination at 0 and 28-42 days. Antibody levels and T- and B-cell responses to vaccine will be measured. Potential Impact. This study is designed to assess the immunogenicity and reactogenicity of two current influenza vaccines in premature infants. The data will be used to estimate the sample size for a definitive trial in younger premature infants.
Interventions
BIOLOGICALLive attenuated influenza vaccine
One dose of live attenuated influenza vaccine, according to routine immunization recommendations
BIOLOGICALInactivated influenza vaccine
One dose of inactivated influenza vaccine, according to routine immunization recommendations
Sponsors
University of Rochester
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
24 Months to 35 Months
Healthy volunteers
Yes
Inclusion criteria
Subjects must meet all relevant criteria (by time of influenza vaccination) to participate. 1. (a) Former premature (\<32 weeks' gestation at birth), VLBW (\<1500 grams' birth weight) infant, 24 months, 0 days - 35 months, 31 days of age, OR (b) Former full-term (37-42 weeks' gestation at birth), normal birth weight (\>2500 grams' birth weight) infant, 24 months, 0 days - 35 months, 31 days of age. 2. Influenza immunization in prior season. 3. Eligible for either influenza immunization (TIV or LAIV). 4. Parental permission. 5. Parents likely to be able to comply with study visits.
Exclusion criteria
Subjects may not participate if they meet any one of these criteria. 1. Known immunodeficiency in child or in a close household contact. 2. History of: * Recurrent episodes of wheezing, * Medically-attended wheezing illness in past year, or * Hospitalization for a wheezing illness. 3. Systemic corticosteroid administration at time of influenza vaccination. 4. Requiring supplemental oxygen at time of influenza vaccination. 5. Contraindication to either influenza immunization (e.g. egg allergy, aspirin therapy). 6. Physician-diagnosed influenza illness in the current influenza season. 7. Any condition determined by investigator as likely to interfere with evaluation of the vaccine or be a significant potential health risk to the subject.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Humoral Immunogenicity | 28-42 days | Hemagglutinin specific antibody, as measured by hemagglutination inhibition |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Medically-attended Wheezing | 42 days | Wheezing that triggers a visit for medical care |
Participant flow
Recruitment details
Subjects recruited during influenza season 2010-2011
Pre-assignment details
No significant pre-assignment details
Participants by arm
| Arm | Count |
|---|---|
| Inactivated Influenza Vaccine One dose of inactivated influenza vaccine, according to routine immunization recommendations
Inactivated influenza vaccine : One dose of inactivated influenza vaccine, according to routine immunization recommendations | 2 |
| Live Attenuated Influenza Vaccine One dose of live attenuated influenza vaccine, according to routine immunization recommendations
Live attenuated influenza vaccine : One dose of live attenuated influenza vaccine, according to routine immunization recommendations | 1 |
| Total | 3 |
Baseline characteristics
| Characteristic | Inactivated Influenza Vaccine | Live Attenuated Influenza Vaccine | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 2 Participants | 1 Participants | 3 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 0 Participants | 0 Participants | 0 Participants |
| Region of Enrollment United States | 2 participants | 1 participants | 3 participants |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 2 Participants | 1 Participants | 3 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 0 / 2 | 0 / 1 |
| serious Total, serious adverse events | 0 / 2 | 0 / 1 |
Outcome results
Primary
Humoral Immunogenicity
Hemagglutinin specific antibody, as measured by hemagglutination inhibition
Time frame: 28-42 days
Secondary
Medically-attended Wheezing
Wheezing that triggers a visit for medical care
Time frame: 42 days
Population: Total N
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Inactivated Influenza Vaccine | Medically-attended Wheezing | wheezing | 0 participants |
| Inactivated Influenza Vaccine | Medically-attended Wheezing | medical care | 0 participants |
| Live Attenuated Influenza Vaccine | Medically-attended Wheezing | wheezing | 0 participants |
| Live Attenuated Influenza Vaccine | Medically-attended Wheezing | medical care | 0 participants |