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Article

Three-year Follow-up of Vaccine Response in Extremely Preterm Infants

Rubia Khalak, Michael E. Pichichero and Carl T. D'Angio
Pediatrics April 1998, 101 (4) 597-603; DOI: https://doi.org/10.1542/peds.101.4.597
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Abstract

Objective. To assess whether the adequate antibody response observed in former extremely premature infants after the primary series of immunizations is sustained after the first booster vaccines.

Subjects and Methods. Sixteen former extremely premature (<29 weeks, <1000 g at birth) and 17 former full-term (>37 weeks) infants had sera obtained for antibody titer measurement at 3 to 4 years of age. All had received the primary series and first booster vaccines for diphtheria, pertussis, tetanus, polio, andHaemophilus influenzae type b. Twelve preterm and 14 full-term children had completed the hepatitis B vaccine series.

Results. At 3 to 4 years of age, former preterm and full-term children had similar geometric mean titer (GMT) values of antibodies to tetanus, diphtheria, and pertussis. Preterm children had a lower GMT value of Haemophilus polyribosylribitol phosphate (PRP) antibody than did full-term children (0.99 vs 3.06 μg/mL). Fifty percent of preterm and 88% of full-term children had PRP antibody >1.0 μg/mL; 100% of preterm and 94% of full-term children had anti-PRP titers >0.15 μg/mL. GMT values of neutralizing antibodies to polio serotypes 1 and 2 were similar, with 94% to 100% of both groups above protective levels (≥1:8). The difference in GMT values of polio serotype 3 approached significance (29 vs 73); fewer preterm children had protective titer values (75% vs 100%). Among children vaccinated against hepatitis B, 75% of preterm and 71% of full-term children were protected (10 mIU/mL).

Conclusions. Preterm children immunized at the recommended chronological ages displayed antibody responses similar to those for full-term children for most immunizing antigens. Responses to PRP and polio serotype 3 were less robust than those of full-term children.

  • Abbreviations:
    AAP =
    American Academy of Pediatrics •
    TT =
    tetanus toxoid •
    HbOC =
    Haemophilus influenzae type b oligosaccharide-CRM197-conjugate vaccine •
    Dip =
    diphtheria •
    Pert =
    pertussis •
    PRP–OMP =
    Haemophilus influenzaetype b polyribosylribitol phosphate-outer membrane protein conjugate vaccine •
    GMT =
    geometric mean titer •
    PRP =
    polyribosylribitol phosphate •
    Hep B =
    hepatitis B •
    HBsAg =
    hepatitis B surface antigen •
    DTwP =
    diphtheria–tetanus–whole cell pertussis vaccine •
    OPV =
    oral polio vaccine •
    DTP =
    diphtheria–tetanus–pertussis vaccine •
    ELISA =
    enzyme-linked immunosorbent assay •
    HBsAb =
    hepatitis B surface antibody •
    RIA =
    radioimmunoassay •
    PT =
    pertussis toxoid •
    FHA =
    pertussis filamentous hemagglutinin •
    PRN =
    pertussis pertactin •
    FIM =
    pertussis fimbriae protein •
    USFDA =
    United States Food and Drug Administration •
    EU =
    ELISA units •
    eIPV =
    enhanced potency inactivated polio vaccine •
    DTaP =
    diphtheria–tetanus–acellular pertussis vaccine

    • The American Academy of Pediatrics (AAP) recommends, with some specific exceptions, that “prematurely born infants, including those of low birth weight, should be immunized at the usual chronological age … .1” In a previous study,2 we evaluated the immunologic response of extremely premature infants (<29 weeks' gestation, <1000 g at birth) to tetanus (TT), polio, and Haemophilus influenzae type b oligosaccharide-CRM197-conjugate (HbOC) vaccines. Although our findings generally supported those of others3-9 in suggesting that chronological age after birth, rather than gestational age, is a reasonable guideline for determining age for vaccinations, some concerns remained. We found that preterm infants were less likely than full-term infants to have protective levels of neutralizing antibody to polio serotype 3. Pullan and Hull5 reported nine infants of 26 to 27 weeks' gestational age had lower mean titer values to diphtheria (Dip), pertussis (Pert), and TT than did premature infants of older gestational age after the completion of the primary immunization series, although these were still above the values they considered protective. Others10 11 have raised concerns that the H influenzae type b polyribosylribitol phosphate-outer membrane protein conjugate (PRP–OMP) vaccine may be inadequately immunogenic in preterm infants.

    Previously published studies of vaccine immunogenicity in preterm infants have provided primarily short-term data.3-11Experience with the PRP–OMP vaccine12 13 suggests that the magnitude of initial antibody response is related to persistence of protective titers. Because there is evidence that preterm infants may have decreased titers of antibody in response to some vaccines, the persistence of antibody after vaccination in preterm infants may differ from that in full-term infants.

    The aim of this study was to assess the persistence of antibody levels at 3 to 4 years of age in preterm children immunized according to the AAP-recommended schedule for preterm infants. We hypothesized that the geometric mean titer (GMT) values of antibodies to Dip, TT, Pert, polio, Haemophilus polyribosylribitol phosphate (PRP), and hepatitis B (Hep B) surface antigen (HBsAg) in fully immunized preterm children would not be distinguishable from those of fully immunized full-term children.

    METHODS

    Subjects

    Sixteen former extremely premature children studied previously in infancy2 were evaluated at 3 to 4 years of age. The children were born between January 1, 1992, and December 1, 1992. Half of subjects were female and 44% were nonwhite, accurately reflecting the population of our neonatal intensive care unit.14Initial enrollment criteria included weight <1000 g and estimated gestational age <29 weeks at birth. Children who did not complete the primary series of vaccines at the recommended times were excluded at the time of the initial study. A total of 23 subjects were enrolled in the first phase of the study at 8 weeks of age. Seven did not complete the first phase; 1 of these died, 1 withdrew from the study, 1 was dropped because a serum sample was not obtained, and 4 did not receive study immunizations within the time window allowed (study vaccine was not available in 2 cases: 1 subject had the 2-month immunization delayed because of severe pulmonary disease [and subsequently died] and 1 subject missed several appointments for the 6-month vaccine). Sixteen subjects (70% of enrollees) completed the first portion of the study.

    For comparison of antibody levels, 17 3- to 4-year-old former full-term children were enrolled from the outpatient pediatric continuity clinic at our hospital. These full-term children (gestational age >37 weeks at birth) were approached for inclusion in the study at a clinic visit if they required a routine blood draw (eg, for hematocrit or lead level). There was no intentional matching on characteristics other than age and immunization status. Children were excluded if the second set of booster immunizations had already been administered.

    Protocol

    All preterm children had received their primary series from specific lots of vaccine.2 Primary and booster vaccines for the full-term children and booster vaccines for the preterm children were given by the children's primary care providers, using commercial lots of vaccine and following AAP guidelines. Serum samples were obtained between March 1996 and June 1996. The dates ensured that all children had received 12 to 18-month doses of diphtheria-tetanus-whole cell pertussis (DTwP), oral polio (OPV), and HbOC vaccines, but that no child had received 4- to 6-year booster doses of DTP or OPV.

    The study was approved by the Human Subjects Review Board of the University of Rochester, and informed consent for the study was sought at the time of contact for the blood drawing appointment. A five-item questionnaire regarding general health and immunization status was administered at the time of the visit. Proof of immunization status and history of adverse reactions, if any, were obtained from parent's immunization booklet or the primary care provider's record.

    Serum Analysis

    Serum samples were identified by medical record number only and all sera tested at one time. Sera from both the preterm group and the full-term group were assayed for anti-PRP, anti-TT, anti-Pert, and anti-Dip antibodies by enzyme-linked immunosorbent assay (ELISA), polio antibodies by microneutralization assay, and Hep B surface antibody (HBsAb) by radioimmunoassay (RIA) in Dr Pichichero's laboratory in the Department of Microbiology and Immunology at the University of Rochester.

    Dip and TT ELISA

    Dip and TT ELISA studies were performed by methods similar to those of Melville-Smith and Balfour15 and Simonsen et al.16 The minimal level of detection for Dip and TT was 0.05 IU/mL.

    Pertussis Toxoid (PT), Filamentous Hemagglutinin (FHA), Pertactin (PRN), and Fimbriae (FIM) ELISA

    ELISA methods for determination of PT, FHA, PRN, and FIM were provided by the United States Food and Drug Administration (USFDA), courtesy of Dr Bruce D. Meade, Bethesda, MD.17 For each ELISA, a minimum level of detection was determined. This value was defined as the minimum amount of antibody, in units, that had to be present for the serum to have at least one point within the linear range of the reference serum dose–response curve. This was estimated to be 2 ELISA units (EU) per milliliter for PT, 3 EU/mL for FHA, 4 EU/mL for PRN, and 3 EU/mL for FIM. All values <5 EU were reported as <5 EU.

    Polio Assays

    Levels of neutralizing antibodies to polio serotypes 1, 2, and 3 were measured by the methods outlined by Woods and Heath18 and Parker and Pallansch.19 The lowest final dilution tested was 1:8. Values were expressed as the inverse of the final dilution (eg, 1:8 = 8, 1:32 = 32).

    H influenzae B ELISA

    Anti-capsular PRP antibody was quantitated by the method of Phipps,20 using PRP oligosaccharide (lower limit of detection = 0.10 μg/mL).

    Hep B RIA

    HBsAb was measured by RIA using a commercial kit (AUSUB kit, Abbott, N Chicago, IL). The lower limit of detection was 10 mIU/mL.

    Reference Sera

    Reference sera were provided by the USFDA (Dr Bruce Meade) for quantitation of antibody to PT, FHA, FIM, and PRN. Human sera, lot 3 (PT, FHA, and FIM) and lot 4 (PRN) with an assigned unitage of 200 EU/mL for PT and FHA, 100 EU/mL for FIM, and 90 EU/mL for PRN were used as references for their respective ELISA studies. Dip and TT reference sera were obtained from Wyeth-Lederle Pediatrics and Vaccines, Rochester, NY. These sera had an assigned unitage of 0.3 IU/mL and 55 IU/mL, based on the USFDA Bureau of Biologics standard reference sera. The H influenzae type b reference serum was provided by the USFDA (Dr Carl Frasch, Bethesda, MD) with assigned unitage of 70 μg/mL of anti-PRP antibody. Hep B reference serum (Statens Seruminstitute, Copenhagen, Denmark) was standardized against the World Health Organization Reference of 125 mIU/mL.

    Control Sera

    Every assay included control sera. The ELISA studies included three controls with an established high, medium, and low antibody concentration for that assay. The control sera were alternately included on each plate. For Hep B, two control sera with low and medium titers were included in each assay run.

    Calculation of Antibody Concentrations

    ELISA unitage for each sample was calculated using the reference line adaptation of the parallel line bioassay program.21

    Data Analysis

    The primary outcome variable in the study was the GMT of antibody to each antigen studied. The geometric mean is a measure of central tendency, as with the arithmetic mean, but measures the mean of the logarithms of the data. A logarithmic scale is useful for expressing data that may be skewed toward very high values, such as titers of immunoglobulins. A subsidiary outcome variable was the proportion of children with protective levels of each antibody. For the purposes of data analysis, sera with antibody concentrations below the minimum detectable level were assigned a value equal to half that level. Power analysis for the previous portion of this study had estimated that a sample of 14 subjects would detect a difference of 20% from the GMT reported for full-term children receiving the HbOC vaccine.2 22 Statistical analysis was performed using the Stata 4.0 statistical package (Stata Corporation, College Station, TX). GMT values were calculated for all antigens to achieve a normal distribution of data. Analysis of continuous variables were performed using the two-sided student's t test for paired or unpaired samples, as appropriate. Paired analysis was used only to compare 7- to 8-month with 3-year serologies in the preterm group. Unpaired analyses were used for all other comparisons. For categorical variables, Yates corrected χ2 analysis was used when all expected cell values were 5. The two-tailed Fisher exact test was used if an expected cell value was <5. The McNemar test was used for paired data.23

    RESULTS

    Demographic and clinical features of the study children are shown in Table 1. There were differences in the percentage of nonwhite children (44% preterm vs 88% full-term;P = .02), children on Medicaid (31% vs 100%;P = .0001), children who had had more than four ear infections or pneumonia (75% vs 6%; P = .0002), and children requiring pulmonary medications (25% vs 0%;P = .04). All preterm and full-term children enrolled in the study had completed their primary series of vaccinations for DTwP, polio (the AAP recommendations in 1992 for the polio vaccine primary series were for administration at 2, 4, and 12 to 18 months), and HbOC, along with the 12- to 18-month boosters for DTwP and HbOC. No child had yet received the 4- to 6-year booster vaccines. The primary series of immunizations of DTwP and HbOC for preterm children were given at specified intervals between 2 and 3 months, 3.5 and 5 months, and 6 and 7 months. The primary series of vaccines of DTwP and HbOC for full-term children were given at 2 to 3 months, 4 to 7 months, and 6 to 15 months. Preterm children received boosters of DTwP at 15 to 20 months and HbOC at 12 to 19 months. Full-term children received boosters of DTwP at 14 to 25 months and HbOC at 14 to 31 months. Two of the former extremely premature children and seven of the former full-term children had received a combination DTwP–HbOC vaccine (Tetramune, Wyeth-Lederle) for their first booster.

    View this table:
    Table 1.

    Demographic and Clinical Features of Children Enrolled in the Study of Immunologic Response to Routine Vaccine Schedule

    All of the former extremely premature infants had received enhanced potency inactivated polio vaccine (eIPV) at 2 months. Fifteen premature children had received OPV at 4 and 15 to 20 months, whereas 1 child completed the primary series with eIPV. All the former full-term infants had received OPV at 2 to 3 months, 4 to 7 months, and 12 to 19 months (except 1 child with delayed third dose at 31 months). Two children in the preterm group and 5 in the full-term group had received an additional dose of OPV at 6 months of age, for a total of four doses of polio vaccine. Twelve of the former extremely premature children and 14 of the former full-term children had received the Hep B vaccine series. None of the immunized preterm children, but 71% of the immunized full-term children, had begun the Hep B series before 8 weeks of age. The average age at administration of the first Hep B vaccine to the preterm infants was 7.5 months (range, 2 to 20 months). The average age for full-term infants was 2.3 months (range, 2 weeks to 13 months). All full-term children received Engerix Hep B vaccine (SmithKline Beecham Biologicals, West Point, PA). Preterm children received either Engerix or Recombivax HB (Merck Vaccine Division, Philadelphia, PA) vaccine, according to the practice of their primary care providers.

    The preterm infants' reactions to the primary series of immunizations have been reported previously.2 There were neither adverse reactions to booster immunizations by preterm children nor adverse reactions to primary or booster immunizations by full-term children noted in the pediatrician's record or parental questionnaire. No subject had clinical disease with any of the organisms against which they were immunized.

    At 3 to 4 years of age, the former preterm children and full-term children had similar anti-TT GMT values (1.58 vs 1.64 IU/mL;P = .95) (Fig 1). All of the children (Table 2) had titers above the protective level (>0.01 IU/mL).24 In Figure2, anti-Dip antibody levels are plotted. The GMT values of the two groups were similar (preterm 0.68 vs full-term 0.89 IU/mL; P = .14). With a protective level of anti-Dip antibody defined as >0.1 IU/mL,25 100% of both preterm and full-term children were protected (Table 2). The GMT values for Pert PT (10 vs 13 EU/mL), PRN (14 vs 15 EU/mL), FIM (15 vs 47 EU/mL), and FHA (14 vs 25 EU/mL) all were similar between the preterm and full-term children (P = not significant for all comparisons). Figure3 shows the values of Pert FHA, which are representative of the other Pert values. Currently, there is no defined protective level for any of the Pert antibodies.

    Fig. 1.
    Fig. 1.

    Anti-TT antibody levels. Preterm (⋄) and full-term (♦) children had equivalent GMT values at 3 to 4 years of age. Individual values (▪) for each child are shown. The antibody level considered protective (0. 01 IU/mL) is indicated by the dashed line. PT indicates preterm; FT, full-term.

    View this table:
    Table 2.

    Protective Antibody Titers At 3 to 4 Years of Age in Children Enrolled in the Study of Immunologic Response to Routine Vaccine Schedule

    Fig. 2.
    Fig. 2.

    Anti-Dip antibody levels. Preterm (⋄) and full-term (♦) children had equivalent GMT values at 3 to 4 years of age. The antibody level considered protective (0.1 IU/mL) is indicated by the dashed line.

    Fig. 3.
    Fig. 3.

    Anti-Pert FHA antibody levels. Preterm (⋄) and full-term (♦) children had equivalent GMT values at 3 to 4 years of age.

    Figure 4 illustrates the anti-PRP antibody levels. The preterm children had a lower GMT than the full-term children (0.99 vs 3.06 μg/mL; P = .02). If the protective range is defined as 0.15 μg/mL10 11 22 26-29, 100% of the preterm children and 94% of the full-term children were protected (Table 2). Only 50% of the preterm children, compared with 88% of the full-term children, had anti-PRP antibody titers >1.0 μg/mL (P = .03), which has been suggested as the immediate postvaccine peak titer associated with protection.10 11 22 26-29

    Fig. 4.
    Fig. 4.

    Anti-PRP antibody levels. Preterm children (⋄) had a lower GMT than full-term children (♦) at 3 to 4 years of age. Antibody levels of 0.15 μg/mL (dotted line) and 1.0 μg/mL (dashed line) are both indicated (see text).

    Preterm and term children were evaluated with regard to whether they had received combined DTwP/HbOC (Tetramune) or separate DTwP and HbOC vaccines. Among children who received the separate vaccine preparations, the GMT for Dip, TT, and Pert was equivalent between preterm and term children, and the percentage of children with protective antibodies to Dip and TT remained unchanged. The GMT of PRP children who received separate vaccines was 1.16 for preterm children and 2.45 for full-term children (P = .22). The percentage of children with a titer of PRP >.15 μg/mL was unchanged. The groups of children who received Tetramune were not compared because of the small numbers in the groups.

    Any detectable level of polio neutralizing antibody (≥1:8) is considered protective.30 For polio serotype 1, 100% of the preterm children and 94% of the full-term children had adequate protection (Table 2). The GMT values for the two groups were 153 and 128 (P = .74) (Fig5), respectively. Of both preterm (GMT of 134) and full-term children (GMT of 222), 100% showed protection against polio serotype 2 (P = .17 for difference in GMT values). The GMT values for serotype 3 were 29 in the preterm children and 73 in the full-term children (P = .07). Seventy-five percent of the preterm children and 100% of the full-term children showed a protective level of neutralizing antibody to polio serotype 3 (P = .04) after the 12- to 18-month vaccine (Table 2).

    Fig. 5.
    Fig. 5.

    Polio neutralizing antibody titers. Preterm (⋄) and full-term (♦) children had equivalent GMT values for all three serotypes at 3 to 4 years of age. The detectable level of neutralizing antibody is indicated by the dashed line. Fewer preterm children had detectable levels of antibody to serotype 3 (see also Table 2).

    The GMT values were reevaluated for the subgroup of children who had received only three polio vaccines. The GMT for polio serotypes 1 and 2 were equivalent between groups, and the numbers of children with protective titers did not change. The GMT for polio serotype 3 was statistically different between preterm and full-term children (23 vs 88; P = .006); however, the percentage of preterm vs full-term children protected was not different (71% vs 100%;P = .10). The analysis of GMT of preterm vs full-term children receiving four polio vaccines would be unreliable because of the extremely small number of patients in each group.

    Among the subset of children who had received the complete Hep B vaccine series, the GMT of HBsAb in the preterm children was 149 mIU/mL, whereas that in the full-term group was 23 mIU/mL (P = .03) (Fig 6). Using a cutoff of >10 mIU/mL,31 75% of the preterm and 71% of the full-term children (P = 1.0) had protective titers (Table 2).

    Fig. 6.
    Fig. 6.

    Hep B surface antibody titers. Preterm children (⋄) had a higher GMT than full-term children (♦) at 3 to 4 years of age. The antibody level considered protective (10 mIU/mL) is indicated by the dashed line.

    Data of the preterm children's titers of TT, PRP, and polio antibodies at 7 to 8 months of age (before booster vaccines) collected from our previous study are shown in Table 3 to allow for comparison with preterm children's titers of these antibodies after booster vaccines (Table 2). Dip and Pert had not been evaluated at 7 to 8 months of age. All children had protective levels of TT antibody in both 7- to 8-month and 3- to 4-year sera. GMT values of PRP antibody fell from 5.75 to 0.99 μg/mL between the 7- to 8-month and 3- to 4-year samples (P < .0001). The percentage of children with anti-PRP >1.0 μg/mL fell from 82% to 50% (P = .03). However, 100% of children at both times had anti-PRP >.15 μg/mL. GMT values of neutralizing antibody to polio serotype 3 were unchanged (18 at 7 to 8 months vs 29 at 3 to 4 years; P = .35). The percentage of children with detectable polio 3 antibody, however, rose from 31% to 75% (P = .008).

    View this table:
    Table 3.

    Protective Antibody Titers at 7 to 8 Months of Age in Preterm Infants Enrolled in the Study of Immunologic Response to Routine Vaccine Schedule

    DISCUSSION

    The current study investigated the adequacy of vaccine antibody titers in extremely premature children at 3 to 4 years of age and compared them with a cohort of full-term children. We found that former extremely premature children immunized at the recommended chronological ages displayed antibody responses similar to those for full-term children for Dip, TT, Pert, polio serotypes 1 and 2, and Hep B. Responses to polio serotype 3 were lower in preterm children than in full-term children. The outcome for H influenzae PRP antibody was mixed, with preterm children having a lower GMT of antibody but similar protective levels.

    In our previous analysis of the same preterm children,2 we reported that extremely premature infants and historical full-term control infants had similar anti-TT antibody titers. In this study, we also found a similar level of protection. This high degree of protection was also seen in the anti-Dip antibody levels, with all preterm and full-term children protected. Levels of anti-Dip antibody were not evaluated as a part of our previous study. Although there is no defined protective range for Pert, GMT values for all Pert antigens measured were similar between the preterm and full-term groups. However, the GMT of Pert FIM and FHA showed greater variation between preterm and full-term children than did PT and PRN, although the differences did not reach statistical significance. This may be attributable to the variable response to the different antigens seen with whole-cell vaccines32 or differences in vaccine from lot to lot and from manufacturer to manufacturer. The source of vaccine was not controlled for booster doses in preterm infants or any doses in full-term infants. The immune system of preterm children may respond to individual pertussis antigens differently than full-term children, a notion that deserves further investigation with purified acellular component vaccines. The evidence at present suggests that the protection afforded by the DTwP vaccine appears unaffected by gestational age at administration, at least during a 3- to 4-year follow-up. A similar level of protection is likely to be offered by the diphtheria–tetanus–acellular pertussis vaccine (DTaP) now preferred by the AAP,33 because the DTaP appears to be at least as immunogenic as the DTwP.34

    We found that a similar percentage of preterm and full-term children were protected against H influenzae type b if the protective range was defined as 0.15 μg/mL of anti-PRP antibody. However, a lower percentage of preterm children maintained antibody titers >1.0 μg/mL, and GMT values of anti-PRP antibody were lower in preterm than in full-term children. Although antibody levels >1.0 μg/mL immediately after vaccination may provide a better correlation with protection, sustained levels of 0.15 μg/mL are considered adequate for immunity.10 11 22 26-29 Washburn et al11and Munoz et al10 reported the responses of premature infants given the PRP–OMP vaccine at 2 and 4 months, postnatally. After the primary series of two doses (at 2 and 4 months) of PRP–OMP vaccine, 53% to 55% of preterm infants achieved antibody titers >1.0 μg/mL at 5 months of age. The authors of those studies concluded that preterm infants do not respond as effectively as full-term infants to the PRP–OMP vaccine. In our cohort of preterm infants immunized with the HbOC vaccine (which is given on a different schedule [2, 4, and 6 months] and contains a different immunizing antigen than the PRP–OMP vaccine1), 82% of the infants had titers >1.0 μg/mL at 7 to 8 months of age.2 Our preterm cohort's titers at 3 to 4 years of age had fallen to levels lower than those of full-term children, although their titers remained within the range associated with protection against H influenzae type b disease. H influenzae conjugate vaccines stimulate T-cell memory.35 It is thus likely that an adequate anamnestic response will be triggered by reexposure to antigen even in infants with very low levels of detectable antibody. Even if an additional drop in antibody levels occurs in our preterm cohort, they are likely to remain primed to respond to challenge with H influenzae. Continued follow-up of this and similar cohorts of preterm children may help clarify their susceptibility to H influenzae disease in later childhood.

    At 3 to 4 years of age, preterm children in our study had normal responsiveness to immunization with polio serotypes 1 and 2 and improved seroconversion for polio serotype 3, when compared with their responses at 7 to 8 months of age. However, 25% of preterm children continued to have no detectable antibody against serotype 3. Conway et al9 found that a similar proportion (4/15) of preterm children had inadequate titers to at least one of the three serotypes at 4 to 5 years of age. The improvement in titers in our group between 7 and 8 months of age and 3 and 4 years of age suggests that the booster vaccine at age 4 to 5 years may improve the seroconversion rate of preterm children to full-term levels. Our population of preterm children who had inadvertently received four rather than three doses of polio vaccine is too small to draw meaningful conclusions about the utility of an additional dose at 6 months. Because wild-type polio has been eradicated in the western hemisphere, the age by which the entire population has seroconverted may be less crucial than it once was. Our preterm children also represent a specific schedule of mixed eIPV and OPV administration. Whether the response to this sequence predicts responses to the multiple possible eIPV/OPV combinations now supported by the AAP is unclear.33

    The AAP currently recommends that the Hep B vaccine series should begin for full-term infants at birth, if possible, and for preterm infants, just before discharge (if weight is >2000 g) or at 2 months of age with other vaccinations.31 This recommendation is based on the findings that preterm infants <2000 g are less likely to seroconvert than full-term infants after vaccination.36 Our observation of equal protection of preterm and full-term children immunized on the AAP-recommended schedule support the current guidelines. Although the absolute titers of our preterm infants were relatively low, they were consistent with those reported by others. Kim et al reported a GMT of 200 mIU/mL of HBsAb at 9 months of age among premature infants who seroconverted in response to Hep B vaccine.37 Among our preterm children, those who seroconverted had a GMT of 464 mIU/mL of HBsAb. Our full-term children had unusually low levels of HBsAb. The reasons for the poor response to Hep B vaccine in this unselected group of full-term children is unclear, and the number of children is too low to draw any inferences.

    Although there is a growing body of literature evaluating the immunogenic response to childhood vaccines in premature infants,3-11 long-term follow-up studies of these infants are few. Conway et al9 followed a group of preterm children through 4 to 5 years of age. Sixty-nine premature infants were divided into two groups of <32 weeks' and 32 to 35 weeks' gestational age at birth. The youngest gestational age was 26 weeks. Each group was then divided into three subgroups based on immunization schedule (3, 4, and 5 months for group A; 3, 4, 5, and 18 months for group B; 3, 4, and 10 months for group C), with 10 to 15 children in each subgroup. There was no full-term control group. Comparisons were made between the two primary groups and within each group. The children had antibody titers to Dip, TT, Pert, and polio evaluated at 19 months of age, and 43% of the children were reevaluated before and after their preschool booster. With few exceptions, there was a persistence of protective antibody titers. Our data confirm these findings in a group of extremely premature infants of significantly younger gestational age.

    In summary, this study of vaccine immunogenicity in extremely premature infants evaluated the least immunologically mature subgroup of preterm infants. We found that even these infants displayed normal immunologic responses to most immunizing antigens that persisted until 3 to 4 years of age. However, the responses to polio serotype 3 andHaemophilus PRP were less robust than those of full-term children. Further follow-up of this cohort and similar groups of children is necessary to determine whether any changes in vaccine practice are indicated in these smallest of neonatal survivors.

    ACKNOWLEDGMENTS

    Studies were conducted at the General Clinical Research Center at the University of Rochester and funded by National Center of Research Resources, United States National Institutes of Health Grant #M01RR00044-35A1 and National Institute of Allergy and Infectious Diseases Grant N01-AI-45248.

    We thank Sherry Passador, MS, who performed the serologic assays; Ms Passador and Carolyn Hall, MD, for review of this manuscript; and Joan Merzbach for help with subject and data management. We also thank our subjects, their parents, and their primary care providers, without whom this study would have been impossible.

    Footnotes

      • Received April 17, 1997.
      • Accepted September 8, 1997.

    • Reprint requests to (R.K.) Box 651, Neonatology, Children's Hospital at Strong, 601 Elmwood Ave, Rochester, NY 14642.

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    Pediatrics
    Vol. 101, Issue 4
    1 Apr 1998
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    Three-year Follow-up of Vaccine Response in Extremely Preterm Infants
    Rubia Khalak, Michael E. Pichichero, Carl T. D'Angio
    Pediatrics Apr 1998, 101 (4) 597-603; DOI: 10.1542/peds.101.4.597
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