PEDIATRICS Vol. 109 No. 3 March 2002, pp. 498-504
Seven-Year Follow-up of Vaccine Response in Extremely Premature Infants
* Department of Pediatrics, Strong Children’s Research Center, University of Rochester School of Medicine and Dentistry, Rochester, New York
Department of Medicine, Strong Children’s Research Center, University of Rochester School of Medicine and Dentistry, Rochester, New York
Department of Microbiology and Immunology, Strong Children’s Research Center, University of Rochester School of Medicine and Dentistry, Rochester, New York
 |
ABSTRACT |
|---|
 TOP ABSTRACT INTRODUCTIONMETHODSRESULTSDISCUSSIONCONCLUSIONREFERENCES |
|---|
Objective. To assess the immune response of 7-year-old former extremely preterm (PT) infants to routine childhood immunizations.
Methods. Sixteen PT (<29 weeks and <1000 g) infants, followed since their primary immunizations at the recommended chronological ages, and 16 age-matched full-term (FT) control subjects were evaluated at 7 years of age. Antibodies to Haemophilus influenzae type b polyribosylribitol phosphate (Hib-PRP), tetanus, pertussis, diphtheria, polio, and hepatitis B (HBsAb) were measured.
Results. The FT group had higher antidiphtheria geometric mean titers (GMT) than the PT group (1.07 vs 0.36 IU/mL). All FT and 13 of 16 PT had protective diphtheria antibody titers (>0.1 IU/mL). The tetanus GMT were 4.22 IU/mL (FT) and 1.99 IU/mL (PT). All children had protective tetanus titers (>0.01 IU/mL). Pertussis titers did not differ between FT and PT. Hib-PRP GMT were higher in FT than in PT (3.21 vs 1.41 µg/mL). All children had anti-PRP 
0.15 µg/mL; 12 of 16 FT and 10 of 16 PT had levels 1.0 µg/mL. Polio serotype 1 and 2 GMT were similar between groups, and all children had protective titers (8). Polio serotype 3 GMT were 59 (FT) and 24 (PT) Karber units; all FT and 12 of 16 PT had protective titers. Among children who had received hepatitis B vaccine, GMT were similar in FT and PT children (120 vs 186 mIU/mL, and similar proportions of children (11 of 16 FT and 12 of 14 PT) had protective HBsAb titers (>10 mIU/mL).
Conclusions. At 7 years of age, PT children had lower antibody titers to many vaccine antigens than FT children. However, most PT children maintained antibody titers in the protective range.
Key Words: premature infant • vaccines • immunization • immunity • follow-up studies
Abbreviations: AAP, American Academy of Pediatrics • Hib, Haemophilus influenzae type b • PRP, polyribosylribitol phosphate • HBsAg, hepatitis B surface antigen • ELBW, extremely low birth weight • PT, preterm • DTwP, diphtheria-tetanus-whole cell pertussis vaccine • FT, full-term • GMT, geometric mean titer • HBsAb, hepatitis B surface antibody • HBV, hepatitis B vaccine • ELISA, enzyme-linked immunosorbent assay • EU, ELISA units
|
INTRODUCTION |
|---|
|
TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONCONCLUSIONREFERENCES |
|---|
The American Academy of Pediatrics (AAP) recommends that "prematurely born infants, including infants of low birth weight, should be immunized at the usual chronological age in most cases."1 However, the AAP also cautions that "some studies suggest a reduced immune response in very-low-birth weight infants (<1500 g) immunized by the usual schedule."1
Several studies have examined premature infants’ responses to routine childhood vaccinations. Decreased mean titers of antibodies to diphtheria, pertussis, tetanus toxoid, Haemophilus influenzae type b polyribosylribitol phosphate (Hib-PRP), and hepatitis B surface antigen (HBsAg) have been described in premature infants.2–8 Premature infants of lower gestational age are more likely to have lower titers.4,5 Few studies have examined extremely low birth weight (ELBW) infants’ responses to immunizations, and these have assessed reactions and titers only over the short term.2,4,5,9 The long-term results of immunizing ELBW infants based on current AAP recommendations have not previously been evaluated.
We followed a group of extremely premature infants (<1000 g and <29 weeks’ gestation) since their primary immunizations. At 7 months of age, 16 preterm (PT) infants were assessed after they had received diphtheria-tetanus-whole cell pertussis (DTwP), polio, and Hib immunizations at the chronological ages of 2, 4, and 6 months.10 These infants generated titers of anti-tetanus, anti-PRP, and neutralizing antibodies to polio serotypes 1 and 2 similar to those seen in full-term (FT) infants. PT infants less often had protective levels of neutralizing antibody to polio serotype 3 than FT infants. The children were again evaluated between 3 and 4 years of age after their first booster vaccinations. At that time, the PT children had lower titers of Hib-PRP, and fewer PT children had protective levels of polio serotype 3 antibody than FT children.11
The aim of this study was to assess the immune response in former ELBW infants after all boosters through school entry. We hypothesized that the geometric mean titers (GMT) of antibodies to diphtheria, tetanus toxoid, pertussis, Haemophilus PRP, polio, and HBsAg in fully immunized formerly premature children would be similar to those of their FT counterparts.
|
METHODS |
|---|
|
TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONCONCLUSIONREFERENCES |
|---|
Children
Sixteen former ELBW infants from our neonatal intensive care unit, whom we have followed since birth for their immune responses to routine vaccinations, were eligible for this study.10,11 This is the same group that was evaluated in 1992–1993 for their immune response at 6 to 7 months of age and again in 1996, when they were 3 to 4 years of age. The children were born between January 1, 1992, and December 1, 1992. The initial enrollment criteria included gestational age at birth <29 weeks and birth weight <1000 g. Infants with the following conditions were excluded from the initial enrollment: those who had received intravenous immunoglobulin or exchange transfusion within 2 weeks of immunization; had received fresh-frozen plasma, white blood cell transfusion, or systemic corticosteroids within 1 week of immunization; had culture-proven sepsis <1 week from immunization; or were positive for human immunodeficiency virus or cytomegalovirus or had other known defects of the immune system.
The control group comprised 16 ex-FT infants. Nine of these were part of a control group enrolled from the pediatric clinic at Strong Children’s Hospital for our analysis at 3 to 4 years of age. These control subjects were age matched and had received appropriate vaccinations for their age administered through the clinic. Seven of the previous control subjects refused participation in this round and were replaced by ex-FT, 6- to 7-year-old children who had up-to-date vaccine status. These new control subjects were enrolled consecutively when they presented to have blood drawn for an unrelated clinical study that did not involve vaccine administration.
Extremely low hepatitis B surface antibody (HBsAb) titers were discovered in the FT control children who had received hepatitis B vaccine (HBV) in the pediatric clinic. The reason for these low titers remains unclear. As a result, a separate group of comparison sera from 16 children aged 4 to 7 years who had received HBV beginning at 1 week after birth in an office setting were used for HBsAb comparisons only. These samples were randomly selected from serum from age-appropriate children banked during an unrelated study of acellular pertussis vaccine.12
Protocol
The premature group had received their primary series of vaccines at 2, 4, and 6 months’ corrected age from specified lot numbers provided by Lederle-Praxis Biologicals Division of American Cyanamid Company (now Wyeth Lederle Vaccines & Pediatrics, Rochester, NY).10 After 6 months of age in the PT group and for all vaccinations for the FT group, children were given commercially available vaccines procured, stored, and administered by the primary care provider. The recommended vaccines during the period in which the children were immunized included a primary series given at 2, 4, and 6 months of 3 doses of DTwP vaccine, 3 doses of Hib conjugate vaccine (if given as the Hib-PRP-CRM197 conjugate), and 2 doses of polio vaccine.13 Recommended toddler boosters at 12 to 18 months included DTwP, polio, and Hib vaccines.13 Recommended preschool boosters at 4 to 5 years of age included the DTwP vaccine and the polio vaccine.14 HBV began to be used routinely in our area in the middle of the initial enrollment period in 1992. Thus, there was no standardized regimen of HBV administration in the study groups.
Beginning in January 1999, when all of the children were at least 6 years of age, they had 1 mL of serum (2 mL of whole blood) drawn during visits to the General Clinical Research Center at the University of Rochester. Some PT children had moved out of the Rochester area. In those instances, sample collection was coordinated through individual pediatricians, and serum was shipped to us on dry ice. All samples were stored at -20°C and then were analyzed as a single group.
The Research Subjects Review Board of the University of Rochester approved this study. Informed consent was obtained from the parents for the study at time of blood draw. A questionnaire about the children’s interim health and immunization status was administered to the parents at the time of blood draw. Proof of immunization status and history of any adverse reactions to vaccinations since the last phase of our study 3 to 4 years previously were taken from records provided by the parents and the pediatricians.
Serum Analysis
All of the samples were given a numerical identification so that the laboratory personnel could not identify the children. Serum analysis was done for antibodies against H influenzae PRP (lower detection limit 0.1 µg/mL), diphtheria (lower detection limit 0.05 IU/mL), tetanus toxoid (lower detection limit 0.05 IU/mL), and pertussis antigens including pertussis toxoid (lower detection limit 2 enzyme-linked immunosorbent assay [ELISA] units [EU]/ml), filamentous hemagglutinin (lower detection limit 3 EU/mL), and pertactin (lower detection limit 4 EU/mL) using ELISA as previously described.11 SmithKline Beecham (Rixensart, Belgium) generously donated the antigens. HBsAb was analyzed by radioimmunoassay (lower detection limit 10 mIU/mL). Neutralizing antibody to polio serotypes 1, 2, and 3 was assessed by microneutralization assay (lower detection limit 1:8) and converted to Karber units (the inverse of the highest dilution of serum bearing neutralizing activity).11
Avidity Assays
The strength of antibody-antigen interactions was measured using an ELISA-based avidity assay. Ammonium thiocyanate was used as the chaotropic agent.15
Hib-PRP IgG Avidity Assay
Anti-Hib-PRP IgG avidity was assayed by the method of Goldblatt,16 with modifications. Tyraminated PRP antigen was bound overnight at 37°C to flat-bottom microtiter plates (NUNC Polysorb, Rochester, NY). Each serum was diluted in phosphate-buffered saline/1% bovine serum albumin to a concentration of 0.25 µg/mL, then further diluted 1:10 in phosphate-buffered saline/0.05% Tween on addition to antigen-coated plates. After a 1-hour incubation at room temperature, plates were washed and ammonium thiocyanate added in concentrations ranging from 0.05 M to 1.6 M in an increasing 2-fold manner. After a 15-minute incubation at room temperature, the plates were washed and goat anti-human IgG alkaline phosphatase conjugate antibody added for 1 hour. The plates were then washed and developed using p-nitrophenyl phosphate (1 mg/mL; Sigma Chemical, St Louis, MO) for 1 hour. Calculation of anti-Hib-PRP avidity was determined by comparing detected anti-PRP antibody levels with and without chaotropic exposure. An avidity index was assigned to each serum sample that corresponded to the molar concentration of ammonium thiocyanate required to reduce the bound PRP antibody absorbance reading by 50%.
Diphtheria IgG Avidity Assay
Anti-diphtheria IgG avidity was assayed by thiocyanate elution ELISA as described above for anti-PRP avidity, except that diphtheria toxoid was the bound antigen, sera were prediluted to a concentration of 0.1 IU/mL, and ammonium thiocyanate was added in concentrations ranging from 0.2 M to 6.4 M.
Data Analysis
The primary outcome variable was the GMT of antibody to the vaccine antigens. The GMT, like the arithmetic mean, is a measure of central tendency and measures the average of the logarithms of the data. Secondary outcome variables included the proportion of children who achieved protective antibody levels, and diphtheria and Hib-PRP antibody avidity.
For data analysis, sera with antibody concentrations below the minimum level of detection for a particular assay were assigned a value equal to half that level. The original power analysis performed for the 7-month antibody titers estimated that a sample of 14 children would be adequate to detect a 20% difference from the GMT reported for FT children who received the Hib oligosaccharide-CRM197-conjugate vaccine, with a power of 0.80 and 
= 0.05. A sample size of 16 children per group would also be sufficient to detect any 1.5-fold difference in GMT where the standard deviation was 
0.5 times the smaller of the 2 GMT, using the same and power. Statistical analysis was performed using the Stata 6.0 statistical package (Stata Corporation, College Station, TX). Continuous variables were analyzed using the 2-sided Student t test for paired or unpaired samples, as appropriate. Dichotomous variables were assessed using the 
2 (or Fisher exact test, as appropriate) or McNemar tests for unpaired and paired data, respectively. P < .05 was considered statistically significant.
|
RESULTS |
|---|
|
TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONCONCLUSIONREFERENCES |
|---|
The children’s clinical features and demographics are presented in Table 1. The mean ages at the time of this study were similar between the PT and original FT groups. As expected, the PT children had been younger and smaller at birth than their FT counterparts. All children had received the recommended series of DTwP, polio, and Hib-PRP-CRM197 conjugate vaccines. Three children, 2 PT children and 1 FT child, had not received HBV. One additional child in each group had not completed the full series of HBV. Although the PT children had had more frequent pneumonias, ear infections, and hospitalizations during their lifetimes, they did not have a higher incidence of respiratory problems (as measured by need for asthma medications) at the time of the 7-year evaluation (Table 1). No child had experienced a disease consistent with clinical pertussis.
|
At the 6- to 7-year follow-up, the GMT for antidiphtheria antibodies were lower in the PT group than in FT infants (P = .009; Fig 1, Table 2). With a minimum protective cutoff value of 0.10 IU/mL, all FT children and 13 of 16 PT children were protected (P = .23; Table 2). The FT group had higher antitetanus GMT values than did PT children (Fig 2, Table 2). All children in both groups had tetanus titers above the minimum protective level (>0.01 IU/mL; Table 2). Antibody levels to pertussis toxin (P = .56), pertussis filamentous hemagglutinin (P = .20), and pertactin (P = .17) did not differ between PT and FT children (Fig 3). There are no well-defined minimum protective levels for pertussis antibodies.
|
|
|
|
Hib-PRP antibody levels were higher in the FT group than in the PT group (P = .03; Fig 4, Table 2). All of the children in both groups achieved antibody levels
0.15 µg/mL. An antibody level of 1.0 µg/mL is often used as the immediate postvaccine peak titer associated with protection. Ten of 16 PT children and 12 of 16 FT children had titers 1.0 µg/mL (P = .45; Table 2).
|
The polio serotype 1 antibody GMT were similar in the PT and FT groups (P = .54; Fig 5, Table 2). All children’s titers exceeded the minimum protective levels of polio serotype 1 antibody, defined as
8 Karber units (Table 2). For polio serotype 2, the GMT for the PT and FT groups did not differ statistically (P = .09). Again, all children had titers 8 Karber units. The GMT of polio serotype 3 antibodies seemed somewhat lower in the PT group than in the FT group but did not differ statistically (P = .06). All FT children had protective antibody levels to serotype 3, but only 12 of 16 PT children had antibody levels in the protective range (P = .10).
|
Among children who had received HBV, children in the original FT group were found to have extremely low HBsAb titers (GMT 11 mIU/mL). As a result, a separate group of 16 comparison sera obtained from children immunized in a pediatric office setting were used for the HBsAb comparisons only. These children had a mean age of 5.5 years (Table 1). There were 7 girls in this FT group. The GMT were comparable in the FT and PT groups (P = .62; Fig 6, Table 2). With a protective level of >10 mIU/mL, 11 of 16 FT children and 12 of 14 PT children achieved minimum protective antibody levels (P = .27; Table 2).
|
To assess the effect of the newly enrolled FT controls on the data, we compared GMT for all vaccine antigens at 7 years between newly enrolled (n = 7) and previously enrolled (n = 9) FT children. There were no differences in GMT for any vaccine antigen between these subgroups (data not shown). Although racial and ethnic differences in vaccine immunogenicity have been reported,12 there were no consistent differences in vaccine titers by race in our children (data not shown).
We also compared the avidity of the Hib-PRP antibody between the sera with the 8 lowest PRP antibody levels in each of the PT and FT groups. The avidity index in the FT group was 0.34 ± 0.12 (mean ± standard deviation) and that for the PT group was 0.39 ± 0.14 (P = .5). With a cutoff value of >0.1 as a marker for moderate to high avidity, all samples achieved this level. Mean diphtheria antibody avidity between children with the lowest 8 titers in each group did not differ between PT (2.37 ± 0.43) and FT (2.39 ± 0.44) children (P = .90). All diphtheria samples had moderate to high avidity.
We also examined changes between the titers obtained at 7 years of age and those measured at 3 to 4 years of age. For this analysis, we included only the children who were represented at both times. This left 25 children, including all 16 PT children and 9 of 16 FT children. The number of children who remained provided lower power for comparisons, but several interesting trends remained.
The antidiphtheria titers trended downward between 3 and 7 years in PT children (0.68 IU/mL to 0.37 IU/mL; P = .07), whereas those of FT children remained unchanged (Table 2). The antitetanus titers remained unchanged between 3 and 7 years in the PT group (P = .39). For the FT group, they were higher at 7 years (1.46 IU/mL to 4.73 IU/mL; P = .007). All children in both groups achieved protective antitetanus titers at both times (Table 2). Pertussis titers did not change over time in either group. The Hib-PRP antibody levels in both groups tended to be higher at 7 years compared with the 3-year titers (P = .07 for the PT children, P = .26 for the FT children). The proportions of children who achieved anti-PRP titers above the protective levels did not vary with time (P = 1.0). None of the polio titers differed in the PT and FT groups between the 3- and 7-year time periods. HBsAb titers were 92 mIU/mL at 3 years and 186 mIU/mL at 7 years in the PT children (P = .42). There was no statistical difference between 3 years and 7 years in the numbers of children with minimal protective titers of HBsAb in the PT group (P = .37).
Low titers against polio serotype 3 at 3 years were predictive of low titers at 7 years (with 3 of 4 titers <8 Karber units at 3 years remaining the same at 7 years). The same was true for Hib-PRP, with 7 of 9 titers <1.0 µg/mL at 3 years remaining <1.0 µg/mL at 7 years. Among PT infants, HBsAb titers followed a similar pattern, with most changes between 3 and 7 years related to children’s receiving or completing the HBV series in the interim. The children with diphtheria titers below the minimum protective level at 7 years were not clearly predicted by levels at 3 years.
|
DISCUSSION |
|---|
|
TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONCONCLUSIONREFERENCES |
|---|
This study analyzed the antibody response to routine childhood vaccinations in ELBW infants who were at least 6 years of age and had received their 5-year booster vaccines. PT children immunized at the recommended chronological ages displayed lower levels of antibody to several antigens than did FT children, although similar numbers of children in each group achieved minimum protective titers. This study was not designed to address the additional dimensions of immunologic memory or vaccine efficacy that may affect our understanding of the antibody titers achieved.
We previously analyzed this same group of PT infants for their vaccine response at 7 months and 3 years of age. At the 7-month analysis, we found that PT infants had decreased antibody titers against polio serotype 3 vaccine.10 At that time, there were no differences between the 2 groups in the titers against tetanus toxoid, polio serotypes 1 and 2, or H influenzae PRP. Antibodies to pertussis, diphtheria, and HBsAg were not measured. At the 3-year follow-up of the vaccine responsiveness in the same PT group, we found lower antibody responses to polio serotype 3 and PRP than in former FT children.11 There were no differences in antibody levels against diphtheria, pertussis, tetanus, polio serotypes 1 and 2, or hepatitis B.
There are few long-term follow-up studies of vaccine immunogenicity in PT infants. Conway et al17 evaluated a cohort of 30 PT children (with gestational age <35 weeks at birth) at 4 to 5 years of age around their preschool immunization boosters. Fifteen children had serum analyzed before they had received the preschool booster vaccines, and the remaining 15 children had their blood drawn after their preschool boosters. Of the children evaluated before booster administration, all had antibody titers to tetanus above the minimum protective level. Four of the 15 had diphtheria titers below the minimum protective level, and 4 had a similar paucity of antibody to at least 1 polio serotype. Antibodies to pertussis were undetectable in 2 of the 15 children. Of the 15 children evaluated after they had received boosters, all had titers well above the minimum protective levels against tetanus and diphtheria. Two children had titers below the minimum protective level for all 3 polio serotypes. Despite that no pertussis booster had been given, all but 1 child had easily detectable antibodies against pertussis. Although the data of Conway et al before and after preschool boosters were cross-sectional rather than sequential, it seems from their data that preschool boosting might bolster antibody responses to some antigens, such as diphtheria, while providing less vigorous responses to others, such as polio. Although there are differences in detail, both our data and those of Conway et al support the contention that after preschool booster immunization, most PT infants continue to have protective levels of antibody to most vaccine antigens.
In this 7-year follow-up, we found that the antibody titers to diphtheria vaccine were significantly lower in the PT group. These findings were different from our 3-year follow-up, indicating that during the last 3 to 4 years the vaccine titers of the PT group had fallen in relation to FT control subjects. Unlike the boosted PT infants reported by Conway et al,17 a small number of our PT infants had diphtheria titers below those considered protective. Similarly, our PT children had lower levels of antitetanus antibodies compared with their FT counterparts at 7 years, although all children achieved minimum protective levels. The difference between PT and FT children had not been significant at 3 years. After the preschool boosters, the FT group mounted a much stronger response than did the PT children. The only other study to measure tetanus antibody in PT children at school age reported adequate tetanus antibody levels at 4 to 5 years of age before and after preschool boosters in formerly PT children but did not compare these levels with those of FT children.17
There are no agreed-on, clinically useful protective levels for pertussis antibody. In our current analysis at 7 years of age, there continue to be no differences in antibody levels to a number of pertussis antigens between PT and FT infants. These results support similar findings by Conway et al17 in premature infants.
Anti-Hib-PRP titers were higher in our FT group than the PT group, but all children had titers above the reported long-term protective range (0.15 µg/mL). Claesson et al18 reported a 6-year follow-up of FT children who had received routine Hib-PRP-tetanus toxoid conjugate vaccination in infancy. At 6 years, 97% of FT children had titers 0.15 µg/mL. When paired with our findings in PT infants, these data suggest that, regardless of gestational age, infants who are vaccinated against Hib continue to have titers in the protective range through early childhood.
Polio-neutralizing antibody is detectable for up to 8 to 12 years after administration of live or inactivated polio booster vaccine at 6 to 10 years of age,19–21 although antibodies to serotypes 1 and 3 tend to decline more rapidly than those to serotype 2.20 At 7 years of age, approximately 2 years after the 5-year polio booster, our PT and FT groups displayed titers very similar to those seen at 3 years. Although the difference lacked statistical significance, PT infants tended to have lower polio serotype 3 titers than did FT infants, with some PT infants lacking detectable titers to this antigen. These findings are in keeping with those of Conway et al,17 who found that some PT infants lacked detectable antibody to any polio serotype even after preschool booster immunizations.
In studies that followed subjects from 5 to 10 years after HBV during infancy, 57% to 98% of children have been reported to have persistent antibody 10 mIU/mL at follow-up.22–27 GMT range from 22 to 331 mIU/mL, although many studies report GMT only for subjects with detectable HBsAb (10 mIU/mL).22,24,26,27 Several factors have been correlated with long-term persistence of antibody, with recombinant vaccines being superior to plasma-derived vaccines, 4-dose regimens being superior to 3-dose ones, and vaccine initiation outside the newborn period and high initial titers begetting high antibody at follow-up.22–25 Children with low titers at follow-up display immunologic memory after a booster dose of vaccine.23,28
Recombinant HBV immunogenicity at 3 years after immunization beginning before neonatal hospital discharge has been compared between PT (<37 weeks’ gestation) and FT infants in a group of Alaska Natives.29 The PT infants had very low titers (HBsAb GMT 0.7 mIU/mL, 8% 10 mIU/mL). However, the FT infants in that study also had titers well below those reported in other studies (HBsAb GMT 1.3 mIU/mL, 15% 10 mIU/mL). Our group of PT children, 86% of whom had HBsAb titers 10 mIU/mL, had a seropositivity rate at 7 years of age similar to many groups of FT children described in the literature. The rate may be somewhat lower, however, than for some FT cohorts that began immunization after the immediate neonatal period, in whom seropositivity rates as high as 98% have been reported at 5 years of age.24
Avidity of an antibody refers to its functional affinity as defined by the interaction between a complex antigen and a bivalent antibody.16 We analyzed the avidity of antidiphtheria and anti-Hib-PRP in our 2 groups to assess the functional quality of these antibodies in PT children. All samples in both the PT and FT groups had moderate to high avidity. The results suggest that although the PT children had lower titers against diphtheria and PRP, functionally the antibodies were similar to those produced in FT children.
This study has several limitations. First among these is the relatively small sample size. Small sample sizes particularly predispose to type II error (ie, not finding a difference that truly exists in the population) in studies. Additional studies of larger size are warranted to confirm the findings in these children. Conversely, the multiple serologic endpoints compared between groups raise the possibility of type I error (ie, finding differences where none exist in the population). Although the high level of statistical significance of some of the differences suggests that type I error is unlikely for those comparisons, a larger sample size would be useful in clarifying some of the smaller differences between groups. In addition, changes in the FT group between 3 and 7 years limited the power of comparisons over time in the FT group. The PT group, with complete follow-up during the 7-year period, suffered less from this limitation. Finally, this long-term observational study was not designed to elucidate the biological reasons behind the decrement in titers seen in the PT infant group. Although several of the PT infants were still small (<1500 g) and ill (requiring mechanical ventilation or supplemental oxygen) at the time of initial vaccination, the group is too small for any meaningful subgroup analyses.10 Valuable information about possible causes could be garnered by long-term follow-up of other groups of PT infants in which gestational age-, weight-, or illness-related differences in primary vaccine responses have been detected.
|
CONCLUSION |
|---|
|
TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONCONCLUSIONREFERENCES |
|---|
Former extremely PT infants who were immunized on the basis of prevailing AAP recommendations mounted lower antibody responses to most vaccines, and these differences became more pronounced over time. Despite these lower titers, most extremely PT children had antibody titers above the minimum protective level for most vaccines. When measured, antibody avidity in PT children was also comparable with that in their FT counterparts. On the basis of these findings, the AAP guidelines for vaccination of PT infants seem to ensure adequate antibody levels against vaccine-preventable diseases through school age. However, the continued and widening gap between FT and PT children’s antibody levels suggests that the differing vaccine responses of extremely PT infants may have lifelong consequences.
|
ACKNOWLEDGMENTS |
|---|
This study was supported, in part, by General Clinical Research Center grant (GCRC) 5 M01 RR00044 from the National Center for Research Resources, National Institutes of Health, and by the University of Rochester Vaccine Treatment Evaluation Unit, National Institute of Allergy and Infectious Diseases (N01-AI-45248).
We thank the staff at the GCRC for cooperation and Joan Merzbach for help in facilitating visits. We also thank our subjects and their parents and pediatricians, without whom this study would not have been possible.
|
FOOTNOTES |
|---|
Received for publication Jul 5, 2001; Accepted Nov 19, 2001.
Address correspondence to Carl T. D’Angio, MD, Neonatology, Box 651, Strong Children’s Hospital, University of Rochester, 601 Elmwood Ave, Rochester, NY 14642. E-mail: carl_dangio{at}urmc.rochester.edu
|
REFERENCES |
|---|
|
TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONCONCLUSIONREFERENCES |
|---|
- American Academy of Pediatrics. Immunization in Special Clinical Circumstances. In. Pickering LK, ed. 2000 Red Book: Report of the Committee on Infectious Diseases. 25th ed. Elk Grove Village, IL: American Academy of Pediatrics;2000 :54
- Pullan CR, Hull D. Routine immunisation of preterm infants. Arch Dis Child.1989; 64 :1438 –1441[Abstract]
- Washburn LK, TM OS, Gillis DC, Block SM, Abramson JS. Response to Haemophilus influenzae type b conjugate vaccine in chronically ill premature infants. J Pediatr.1993; 123 :791 –794[Medline]
- Munoz A, Salvador A, Brodsky NL, Arbeter AM, Porat R. Antibody response of low birth weight infants to Haemophilus influenzae type b polyribosylribitol phosphate-outer membrane protein conjugate vaccine. Pediatrics.1995; 96 :216 –219[Abstract]
- Kristensen K, Gyhrs A, Lausen B, Barington T, Heilmann C. Antibody response to Haemophilus influenzae type b capsular polysaccharide conjugated to tetanus toxoid in preterm infants. Pediatr Infect Dis J.1996; 15 :525 –529[Medline]
- Kim SC, Chung EK, Hodinka RL, et al. Immunogenicity of hepatitis B vaccine in preterm infants. Pediatrics.1997; 99 :534 –536[Abstract/Full Text]
- Lau YL, Tam AY, Ng KW, et al. Response of preterm infants to hepatitis B vaccine. J Pediatr.1992; 121 :962 –965[Medline]
- Faldella G, Alessandroni R, Magini GM, et al. The preterm infant’s antibody response to a combined diphtheria, tetanus, acellular pertussis and hepatitis B vaccine. Vaccine.1998; 16 :1646 –1649[Medline]
- Losonsky GA, Wasserman SS, Stephens I, et al. Hepatitis B vaccination of premature infants: a reassessment of current recommendations for delayed immunization. Pediatrics.1999; 103(2) . Available at: http://www.pediatrics.org/cgi/content/full/103/2/e14
- D’Angio CT, Maniscalco WM, Pichichero ME. Immunologic response of extremely premature infants to tetanus, Haemophilus influenzae, and polio immunizations. Pediatrics.1995; 96 :18 –22[Abstract]
- Khalak R, Pichichero ME, D’Angio CT. Three-year follow-up of vaccine response in extremely preterm infants. Pediatrics.1998; 101 :597 –603[Abstract/Full Text]
- Christy C, Pichichero ME, Reed GF, et al. Effect of gender, race, and parental education on immunogenicity and reported reactogenicity of acellular and whole-cell pertussis vaccines. Pediatrics.1995; 96 :584 –587[Abstract]
- Peter G, ed. Red Book: Report of the Committee on Infectious Diseases. 22nd ed. Elk Grove Village, IL: American Academy of Pediatrics;1991
- Peter G, ed. Red Book: Report of the Committee on Infectious Diseases. 23rd ed. Elk Grove Village, IL: American Academy of Pediatrics;1994
- De Saussure VA, Dandliker WB. Ultracentrifuge studies on the effects of thiocyanate ion on antigen–antibody systems. Immunochemistry.1969; 6 :77 –83[Medline]
- Goldblatt D. Simple solid phase assays of avidity. In: Turner MW, Johnstone AP, eds. Immunochemistry 2: A Practical Approach. Oxford, England: IRL Press at Oxford University Press;1997 :31 –51
- Conway S, James J, Balfour A, Smithells R. Immunisation of the preterm baby. J Infect.1993; 27 :143 –150[Medline]
- Claesson BA, Trollfors B, Anderson PW, et al. Serum antibodies in six-year-old children vaccinated in infancy with a Haemophilus influenzae type b-tetanus toxoid conjugate vaccine. Pediatr Infect Dis J.1996; 15 :170 –172[Medline]
- Bottiger M. Long-term immunity following vaccination with killed poliovirus vaccine in Sweden, a country with no circulating poliovirus. Rev Infect Dis.1984; 6 :S548 –S551[Medline]
- Bottiger M. Polio immunity to killed vaccine: an 18-year follow-up. Vaccine.1990; 8 :443 –445[Medline]
- Farisano G, Trivello R, Moschen ME, et al. Poliovirus neutralizing antibody persistence after vaccination with the Sabin vaccine: a follow-up study. Ann Clin Lab Sci.1995; 25 :200 –206[Medline]
- Gonzalez ML, Gonzalez JB, Salva F, Lardinois R. A 7-year follow-up of newborns vaccinated against hepatitis B. Vaccine.1993; 11 :1033 –1036[Medline]
- Shih HH, Chang MH, Hsu HY, Lee PI, Ni YH, Chen DS. Long term immune response of universal hepatitis B vaccination in infancy: a community-based study in Taiwan. Pediatr Infect Dis J.1999; 18 :427 –432[Medline]
- del Canho R, Grosheide PM, Mazel JA, et al. Ten-year neonatal hepatitis B vaccination program, The Netherlands, 1982–1992: protective efficacy and long-term immunogenicity. Vaccine.1997; 15 :1624 –1630[Medline]
- Da Villa G, Peluso F, Picciotto L, Bencivenga M, Elia S, Pelliccia MG. Persistence of anti-HBs in children vaccinated against viral hepatitis B in the first year of life: follow-up at 5 and 10 years. Vaccine.1996; 14 :1503 –1505[Medline]
- Resti M, Azzari C, Mannelli F, Rossi ME, Lionetti P, Vierucci A. Ten-year follow-up study of neonatal hepatitis B immunization: are booster injections indicated? Vaccine.1997; 15 :1338 –1340[Medline]
- Marion SA, Tomm Pastore M, Pi DW, Mathias RG. Long-term follow-up of hepatitis B vaccine in infants of carrier mothers. Am J Epidemiol.1994; 140 :734 –746[Abstract]
- Resti M, Di Francesco G, Azzari C, Rossi ME, Vierucci A. Anti-HBs and immunological memory to HBV vaccine: implication for booster timing [letter]. Vaccine.1993; 11 :1079[Medline]
- Kesler K, Nasenbeny J, Wainwright R, McMahon B, Bulkow L. Immune responses of prematurely born infants to hepatitis B vaccination: results through three years of age. Pediatr Infect Dis J.1998; 17 :116 –119[Medline]
PEDIATRICS (ISSN 1098-4275). ©2002 by the American Academy of Pediatrics
CiteULike 
Connotea 
Del.icio.us 
Digg 
Facebook 
Reddit 
Technorati 
Twitter What's this?
This article has been cited by other articles:
|
|
 |
|
  C. T. D'Angio, P. A. Boohene, A. Mowrer, S. Audet, M. A. Menegus, D. S. Schmid, and J. A. Beeler Measles-Mumps-Rubella and Varicella Vaccine Responses in Extremely Preterm Infants Pediatrics, March 1, 2007; 119(3): e574 - e579. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. Omenaca, J. Garcia-Sicilia, P. Garcia-Corbeira, R. Boceta, and V. Torres Antipolyribosyl Ribitol Phosphate Response of Premature Infants to Primary and Booster Vaccination With a Combined Diphtheria-Tetanus-Acellular Pertussis-Hepatitis B-Inactivated Polio Virus/Haemophilus influenzae Type b Vaccine Pediatrics, January 1, 2007; 119(1): e179 - e185. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J Bonhoeffer, C-A Siegrist, and P T Heath Immunisation of premature infants Arch. Dis. Child., November 1, 2006; 91(11): 929 - 935. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. Omenaca, J. Garcia-Sicilia, P. Garcia-Corbeira, R. Boceta, A. Romero, G. Lopez, and R. Dal-Re Response of Preterm Newborns to Immunization With a Hexavalent Diphtheria-Tetanus-Acellular Pertussis-Hepatitis B Virus-Inactivated Polio and Haemophilus influenzae Type b Vaccine: First Experiences and Solutions to a Serious and Sensitive Issue Pediatrics, December 1, 2005; 116(6): 1292 - 1298. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. E. Baley and E. G. Leonard The Immunologic Basis for Neonatal Immunizations NeoReviews, October 1, 2005; 6(10): e463 - e470. [Full Text] [PDF]
|
|
|
|
|
|
M. J Robinson, C. Heal, E. Gardener, P. Powell, and D. G. Sims Antibody Response to Diphtheria-Tetanus-Pertussis Immunization in Preterm Infants Who Receive Dexamethasone for Chronic Lung Disease Pediatrics, April 1, 2004; 113(4): 733 - 737. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. N. Saari and and Committee on Infectious Diseases Immunization of Preterm and Low Birth Weight Infants Pediatrics, July 1, 2003; 112(1): 193 - 198. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P T Heath, R Booy, J McVernon, J Bowen-Morris, H Griffiths, M P E Slack, A C Moloney, M E Ramsay, and E R Moxon Hib vaccination in infants born prematurely Arch. Dis. Child., March 1, 2003; 88(3): 206 - 210. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Are Preemies Protected? So Far, So Good Journal Watch Pediatrics and Adolescent Medicine, April 1, 2002; 2002(401): 2 - 2. [Full Text]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
