Contrary to our hypothesis, premature infants 6–17 months chronological age did not have lower humoral immune responses to two doses of TIV than those of full-term infants of similar age. Infants in both groups experienced possible vaccine-related adverse events, most commonly fever. Premature, but not full-term, infants had hospitalizations during the study period, but no hospitalization appeared related to vaccination.
Influenza vaccine’s ability to prevent infection is modest even in healthy, full-term children. The only influenza vaccines currently licensed in the U.S. for children younger than 2 years of age are trivalent, inactivated influenza vaccines (TIV), which contain 3 antigens (most commonly two influenza A antigens and one B antigen) each year. Antibody titers measured by HAI have been traditionally used to assess the immunogenicity
(ability to induce adequate titers of antibody) of TIV because of their general correlation with protection against native influenza disease or intranasal viral challenge.22, 23
Although TIV may induce adequate titers of antibody to at least one of the vaccine antigens in up to 94% of children, including those as young as 6 months, as few as 35% respond adequately to all three antigens.20, 24
Estimates of TIV efficacy
(ability to prevent disease in a controlled trial) in children range widely, from 12–100%, depending on the study, population, and match of vaccine strain to circulating strain.10, 25–28
A recent, multi-year study estimated the effectiveness
(ability to prevent disease in a clinical setting) of full vaccination against laboratory-confirmed influenza at 86% and of partial vaccination at 73% among children 6–39 months old.29
On the other hand, the effectiveness of TIV in preventing influenza-like illnesses has been estimated at about 23–25% among children who receive two doses of vaccine.13, 30, 31
In two years (2003–4, 2004–5) in which the vaccine was relatively poorly matched to the circulating strains, TIV effectiveness in preventing medical visits due to culture-confirmed influenza could not be demonstrated in children <5 years old.15, 32
Although TIV can produce adequate antibody responses in children as young as 6 weeks of age,33, 34
several studies have suggested that TIV effectiveness is low, approaching 0%, in children < 2 years of age.12–15
Previous studies of influenza vaccines in premature infants have yielded conflicting results. Groothuis and colleagues examined the response of 15 previously unimmunized, 6-to-18-month old former premature infants with continued symptoms from BPD to 2 doses of TIV.16
Although greater than 90% of children developed acceptable rises in HAI antibody titer (≥1:32), premature infants had mean antibody titers to each of the three vaccine components about one-half those of 18 previously unimmunized, 6-to-18-month-old, healthy, full-term children. The premature infants also had influenza-specific T-cell proliferative responses about one-half those of full term children. Another group of 30 previously immunized, 6-to-48-month-old former premature infants, half of whom had continued symptoms from BPD and half of whom had recovered from BPD, also had lower T-cell proliferative responses after reimmunization than healthy full term children.16
In another study of 43 former premature infants, ages 9–44 months, with BPD, 17% (influenza B antigen) to 75% (influenza A/H3N2 antigen) of children achieved a 4-fold rise in titers following administration of TIV.17
More recently, 45 previously unimmunized former premature infants, ages 6–11 months, were reported to produce antibody responses to TIV comparable to those historically reported in full-term infants, but no concurrent full-term control group was included.18
Our data confirm the more recent findings in a group with concurrent control subjects.
Several baseline differences between the premature and full-term infant groups existed in this study. Including the potentially confounding factors of gender, postnatal age at vaccination and weight at vaccination in a multivariate regression analysis removed the significant association observed in univariate analysis between prematurity and higher titers to some vaccine components. This suggests that one or more confounding factors in the premature infants may have accounted for the higher titers observed among the premature infants. That is, while the titers were higher in the premature than the full-term group, this difference was likely to be due to a factor other than prematurity itself. The number of subjects is too small to permit adequately powered stratified analyses to explore this question further.
This study has limitations. Since influenza vaccine antigens varied between 2006–7 and 2007–8, we separately evaluated each year’s antibody results. This limited the power of the comparisons, particularly for 2006–7. Nevertheless, the premature infants’ antibody responses remained at least as high as those of full-term infants in both years. Although antibody response measured by HAI titer is generally related to protection against influenza infection, elevated HAI titers alone may not offer significant protection against influenza in young infants.12–15
The results of HAI titers among our premature infants may therefore be falsely reassuring. Although no infant experienced medically-diagnosed influenza during the study period, the mild elevation of B/Yamagata titers (an antigen not contained in the vaccine) in 2007–8 suggested that some infants may have experienced sub-clinical infection with influenza A or B. Both circulated during each of the 2 seasons and may have influenced the antibody titer results.
In summary, our study findings suggest that the current TIV vaccines are immunogenic and capable of generating measurable antibody responses among very premature infants. This strongly supports immunizing premature infants as currently recommended. However, whether antibody responses alone predict protection against influenza among young formerly premature infants remains to be determined.