Study of Live, Attenuated Influenza Vaccination in Preterm and Full-Term Infants

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 (V) LBW and former full-term (FT)
infants aged 24-35 months.

Hypotheses.

1. The humoral immunogenicity of LAIV, as measured by 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) ELISPOT, will
be greater in LAIV-immunized infants than TIV-immunized infants.

4. Peak T-cell cytokine responses, as measured by IFNγ, IL-2 and IL-4 ELISPOT, will be
greater in LAIV-immunized infants than TIV-immunized infants.

5. Hemagglutinin-specific nasal 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.

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.