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. Further investigation is required to optimize vaccine responses in premature infants. The overall goals of this project are to generate estimates of effect size and variance of influenza vaccine immunogenicity for use in planning a larger multi-center trial, and to develop the collaborative network of centers necessary for such a trial.
Objective and Hypotheses. The primary objective of this study is to measure influenza vaccine immunogenicity in extremely-low-birth-weight (ELBW, \< 1001 grams at birth), premature (\< 30 weeks' gestation) infants receiving trivalent, inactivated, split-virion influenza vaccine (TIV). We hypothesize that the geometric mean titer (GMT) of antibody to each of the three vaccine components will be lower in ELBW infants receiving their first series of TIV than in full-term (FT, \>37 weeks' gestation), normal-birth-weight (\>2500 grams) infants.
Specific Aim. To measure the humoral and cellular immunogenicity of influenza vaccine in extremely-low-birth-weight (ELBW, greater than or equal to 1000 grams at birth), premature infants receiving trivalent, inactivated, split-virion influenza vaccine (TIV) for their first influenza vaccine series in 2007-8.
Design. This prospective, cohort, immunogenicity study will estimate the GMT to influenza in ELBW infants, with a comparison group of FT infants. Using the established vaccine study infrastructure at a consortium of five centers (the University of Rochester, the University of Texas Southwestern Medical Center, Wake Forest University, the University of Miami and the State University of New York at Buffalo), we will recruit 46 un-immunized (for influenza) ELBW infants, 6-17 months old and 46 un-immunized FT infants, 6-17 months old. Infants will receive the recommended 2 doses of TIV, 4 weeks apart, with blood drawing at the first vaccine dose and 4-6 weeks after the second. Antibody to each vaccine component will be measured by hemagglutination inhibition. The frequency of hemagglutinin-specific T cell interleukin (IL)-2, IL-4 and interferon gamma (IFNγ) responses will be measured by ELISPOT assay. The primary outcome will be influenza GMT. A sample size of 46 subjects per group provides 80% power, using a two-sided alpha = 0.05, to detect a 1.5-fold difference in GMT between groups, assuming a standard deviation (SD) spanning 0.5 to 2.0 times the value of each GMT. In addition, the five-center consortium will monitor the quality of the collaboration, strengthen its capabilities through the design and implementation of a secure, web-based information system, and expand its efforts by seeking additional, outside funding to implement a companion protocol assessing live attenuated influenza vaccine in premature infants.
Potential Impact. This study is designed to assess the immunogenicity of the current generation of influenza vaccines in premature infants. This and future trials assessing novel immunization strategies (such as an additional vaccine dose) or vaccines (for instance, the live attenuated influenza virus vaccine) in premature infants could eventually lead to the tailoring of specific vaccine strategies for this high-risk group. In addition, this proposal would bring to maturity a multi-center, collaborative mechanism for vaccine trials in premature infants.
