Published online December 4, 2006
PEDIATRICS Vol. 119 No. 1 January 2007, pp. e179-e185 (doi:10.1542/peds.2005-2907)
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ARTICLE

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

Felix Omeñaca, MD, PhDa, José Garcia-Sicilia, MD, PhDb, Pilar García-Corbeira, MDc, Reyes Boceta, BPhc and Victorio Torres, MDb

a Departments of Neonatology
b Paediatrics, La Paz Hospital, Madrid, Spain
c Medical Department, GlaxoSmithKline, Tres Cantos, Madrid, Spain


   ABSTRACT
TOP
 ABSTRACT
METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
 REFERENCES
 
BACKGROUND. Prematurity may be a risk factor for Haemophilus influenzae type b vaccine failure. This article evaluates the Haemophilus influenzae type b immunogenicity of a hexavalent diphtheria-tetanus-acellular pertussis-hepatitis B-inactivated poliovirus/Haemophilus influenzae type b vaccine in preterm infants (<37 weeks' gestation).

METHODS. This was an open-label, parallel group study. Preterm (N = 94) and term infants (N = 92) received 3 doses of a diphtheria-tetanus-acellular pertussis-hepatitis B-inactivated poliovirus/Haemophilus influenzae type b vaccine at 2, 4, and 6 months with a booster dose at 18 to 20 months. Antipolyribosyl ribitol phosphate antibody concentrations were determined in serum samples taken before and 1 month after primary and booster vaccination.

RESULTS. Postprimary seroprotection rates (antipolyribosyl ribitol phosphate ≥0.15 µg/mL) were lower in preterm than in term infants (92.5% vs 97.8%), with antipolyribosyl ribitol phosphate geometric mean concentrations of 2.241 vs 4.247 µg/mL. A progressive reduction in immune response to the Haemophilus influenzae type b antigen was observed with decreasing length of gestation and decreasing birth weight when cutoff ≥1 µg/mL was considered. Prebooster seroprotection rates and antipolyribosyl ribitol phosphate geometric mean concentrations were low in both groups (antipolyribosyl ribitol phosphate ≥1.0 µg/mL in 10.7% of preterm and 28.4% of term infants). A vigorous response to booster vaccination was seen in both groups, with no differences in postbooster seroprotection rates or antipolyribosyl ribitol phosphate geometric mean concentrations between the 2 groups (antipolyribosyl ribitol phosphate ≥1.0 µg/mL in 100% of preterm and 98.5% of term infants).

CONCLUSIONS. Primary vaccination with a hexavalent diphtheria-tetanus-acellular pertussis-hepatitis B-inactivated poliovirus/Haemophilus influenzae type b vaccine at 2, 4, and 6 months with a booster dose at 18 to 20 months elicits a satisfactory antipolyribosyl ribitol phosphate response in preterm infants compared with term controls. Immunologic response decreased with decreased gestational age and birth weight.

Key Words: Hib vaccines • PRP response • preterm infants • immunization • combined vaccines • DTaP-HBV-IPV/Hib vaccine

Abbreviations: Hib—Haemophilus influenzae type b • DTaP—diphtheria-tetanus-acellular pertussis • HBV—hepatitis B virus • IPV—inactivated poliovirus • PRP—polyribosyl ribitol phosphate • ATP—according-to-protocol • GMC—geometric mean concentration • CI—confidence interval

The number of infants born prematurely has risen considerably in recent years as a result of both an increase in the actual number of preterm births (<37 weeks' gestation) and improved survival rates in extremely premature infants (<28 weeks' gestation).1 Current guidelines recommend that preterm infants receive routine childhood vaccinations at the same chronological age and using the same vaccine doses as those born at term, regardless of their actual length of gestation or birth weight.2 However, data to support this approach are recognized to be scarce.3,4 Despite these recommendations, available data suggest that routine pediatric vaccinations are often delayed in preterm infants.5,6 This problem may be exacerbated by growing concerns among parents and pediatricians about the number of injections required to comply with current vaccination schedules.7 This is cause for some concern, because preterm infants are known to be particularly vulnerable to vaccine-preventable diseases, such as pertussis,8 pneumococcal infections,9 and invasive Haemophilus influenzae type b (Hib) infection.10

There is currently renewed interest in pediatric Hib infections.11 The incidence of invasive Hib disease in early childhood has fallen dramatically since the introduction of Hib conjugate vaccines.11,12 In recent years, some European countries13–16 have seen a notable increase in cases of invasive disease in vaccinated infants, whereas in Alaska, a reemergence of Hib invasive disease because of strains indistinguishable from those isolated from vaccinated children has been described.17 This has led to reconsideration of current vaccination strategies.15,18 There is some evidence to suggest that premature infants may be at particular risk of Hib vaccine failure.13,19 We have previously shown preterm infants (<37 weeks' gestation) to display a satisfactory immune response to all of the component antigens of a hexavalent diphtheria-tetanus-acellular pertussis (DTPa)-hepatitis B (HBV)-inactivated poliovirus (IPV)/adsorbed conjugated Hib vaccine, with seroprotection/vaccine response rates generally similar to those seen in term infants after primary vaccination at 2, 4, and 6 months and a booster dose at 18 to 20 months.20,21 This article presents the results of a more detailed analysis of the immune response of this preterm cohort to the Hib component of this hexavalent vaccine.


   METHODS
TOP
 ABSTRACT
 METHODS
RESULTS
 DISCUSSION
 CONCLUSIONS
 REFERENCES
 
Subjects
This was an open-label study with 2 parallel groups: preterm subjects (<37 weeks' gestation) and a control group of term infants. Preterm subjects were stratified into subgroups based on clinical characteristics, including length of gestation, birth weight, prenatal and postnatal steroid use, need for red blood cell transfusion, and weight at 6 months. Length of gestation was determined by date of the last menstrual period and/or early ultrasound scan and subsequently confirmed by neonatal examination. Exclusion criteria were as described previously.21

Study Design
All of the subjects were primed with a DTPa-HBV-IPV/Hib vaccine (Infanrix hexa, GlaxoSmithKline Biologicals, Rixensart, Belgium) at 2, 4, and 6 months and received a booster dose of this same vaccine at 18 to 20 months of age. Vaccine composition has been described previously.21 The vaccine was administered as a 0.5-mL intramuscular injection into the right anterolateral thigh. A 25-gauge x 5/8-in needle was used for vaccine administration at 2 months and a 23-guage x 1-in needle at 4, 6, and 18 months.

The study protocol was approved by the Research Ethics Committee of La Paz Hospital and conducted in accordance with Good Clinical Practice guidelines. Written informed consent was obtained from the parents or guardians of all of the subjects before enrollment.

Immunogenicity Analysis
Immunogenicity was assessed by evaluation of anti-polyribosyl ribitol phosphate (PRP) antibody responses in blood samples obtained before and 1 month after the primary vaccination and before and 1 month after the booster dose. Serum samples were stored at –20°C until blinded serologic analysis at the GlaxoSmithKline Biologicals laboratory. Antibody concentrations were determined by a standard enzyme-linked immunosorbent assay. Seroprotection rate was defined as percentage of subjects with antibody concentrations ≥0.15 and ≥1 µg/mL for short- and long-term protection, respectively.22

Statistical Analysis
The primary objective of this study was to assess the immune response of preterm infants to the Hib component of the hexavalent vaccine compared with that of term infants after primary and booster vaccination. Exploratory analysis was performed on the according-to-protocol (ATP) cohort. Seroprotection rates and antibody geometric mean concentrations (GMCs) were calculated with exact 95% confidence intervals (CIs) at each time point. Asymptotic standardized 90% CIs were calculated for the group difference (term – preterm) in seroprotection rates at each time point. A clinical difference between vaccine groups was considered to be unlikely if the upper limit of the 90% CI for the difference between the 2 groups was <10%. Postprimary anti-PRP seroprotection rates and GMCs with exact 95% CIs were also calculated in the group of preterm infants according to gestational age and birth weight.


   RESULTS
TOP
 ABSTRACT
 METHODS
 RESULTS
DISCUSSION
 CONCLUSIONS
 REFERENCES
 
A total of 186 infants were enrolled in this study (94 preterm and 92 term). Demographic and neonatal characteristics have been described previously.20 A total of 93 preterm and 89 term infants complied with the criteria for inclusion in the ATP cohort for analysis of immunogenicity of the primary vaccination course. Mean age at the time of first immunization was 8.6 ± 0.63 weeks (range: 8–11 weeks) and 8.2 ± 0.80 weeks (range: 6–11 weeks) in the 2 groups, respectively. Of the 155 infants who received booster vaccination, a total of 84 preterm infants and 68 term infants were included in the ATP cohort for analysis of immunogenicity of the booster dose. Mean age at the time of booster vaccination was 18.2 ± 0.47 months (range: 18–20 months) and 18.3 ± 0.55 months (range: 18–20 months) in the 2 groups, respectively.

Postprimary, prebooster, and postbooster seroprotection rates and anti-PRP GMC ratios (term/preterm) are shown in Table 1 and Fig 1. One month after completion of the 3-dose primary course, 92.5% of preterm infants had seroprotective levels of anti-PRP antibodies (≥0.15 µg/mL) compared with 97.8% of term infants (Table 1). The upper limit of the 90% CI for the difference between the 2 groups was >10% (difference: 5.3% [90% CI: –2.3% to 14.6%]). Anti-PRP GMCs were 2.241 µg/mL in preterm infants compared with 4.247 µg/mL in term infants on completion of the primary vaccination course (ratio: 1.89 [90% CI: 1.34 to 2.67]).


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  		TABLE 1 Proportion of Subjects With Anti-PRP Antibody Concentrations ≥0.15 µg/mL and ≥1 µg/mL and GMCs for Anti-PRP Antibodies in Preterm and Term Infants 1 Month After Completion of the Primary Course (2, 4, and 6 Months; ATP Cohort for Primary Immunogenicity) and Before and 1 Month After Booster Administration at 18 to 20 Months (ATP Cohort for Booster Immunogenicity)

 

Figure 1
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  		FIGURE 1 Postprimary, prebooster, and postbooster seroprotection anti-PRP GMC ratios (term/preterm; ATP cohorts for analysis of immunogenicity).

 
Postprimary seroprotection rates and anti-PRP antibody GMCs in preterm infants stratified according to gestational age and birth weight are shown in Tables 2 and 3. A progressive reduction in immune response to the Hib antigen was observed with decreasing length of gestation and decreasing birth weight when a cutoff of ≥1 µg/mL was considered (2-sided P value for the trend was <.05). Postprimary GMCs differed significantly between preterm infants born at 34 to 36 weeks and those born at 24 to 27 weeks and between infants weighing ≥2.0 kg and <1.0 kg at birth (3.891 vs 0.995 µg/mL and 4.155 vs 1.265 µg/mL, respectively).


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  		TABLE 2 Postprimary Anti-PRP Seroprotection Rates and GMCs in Preterm Infants Stratified According to Length of Gestation (ATP Cohort for Primary Immunogenicity)

 

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  		TABLE 3 Postprimary Anti-PRP Seroprotection Rates and GMCs in Preterm Infants Stratified According to Birth Weight (ATP Cohort for Primary Immunogenicity)

 
Use of prenatal steroids was not found to impact significantly on the postprimary immune response to Hib. Seroprotection rates (anti-PRP ≥0.15 µg/mL) were 94.1% (95% CI: 85.6% to 98.4%) in infants who had received prenatal steroids compared with 88.0% (95% CI: 68.8% to 97.5%) in those who had not. Respective anti-PRP GMCs were 2.109 µg/mL (95% CI: 1.491 to 2.983 µg/mL) and 2.644 µg/mL (95% CI: 1.368 to 5.108 µg/mL). Postprimary anti-PRP GMCs were lower in subjects who had received postnatal steroids than in those who had not, but this difference was not statistically significant: 1.711 µg/mL (95% CI: 0.893 to 3.645 µg/mL) vs 2.307 µg/mL (95% CI: 1.660 to 3.206 µg/mL), respectively.

Postprimary seroprotection rates and anti-PRP antibody GMCs in preterm infants stratified according to other clinical characteristics are summarized in Table 4. Postprimary immune response to PRP was found to be significantly lower in preterm infants who received red blood cell transfusions than in those who had not been transfused, with respective anti-PRP GMCs of 1.309 vs 3.305 µg/mL. Immune response to primary vaccination was also found to be related to weight at 6 months. Anti-PRP GMCs were significantly lower in infants under the 10th percentile than in those above the 50th percentile for weight at this time (88.9% vs 100.0% and 1.326 vs 4.574 µg/mL, respectively). Gestational age, weight at 6 months, prenatal steroids, and red blood cell transfusion were significantly related to anti-PRP antibody GMCs in an univariate analysis, whereas in multivariate analysis only weight at 6 months was significant.


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  		TABLE 4 Postprimary Anti-PRP Seroprotection Rates and GMCs in Preterm Infants Stratified According to Other Clinical Characteristics (ATP Cohort for Primary Immunogenicity)

 
Prebooster and postbooster seroprotection rates and anti-PRP GMCs are shown in Table 1. Seroprotection rates were found to be low in both preterm and term infants before booster administration at 18 to 20 months. All of the preterm infants and 98.5% of term infants had anti-PRP antibody concentrations ≥1.0 µg/mL after booster administration at 18 to 20 months. The upper limit of the 90% CI for the difference between the 2 groups was <10% (difference: –1.5% [90% CI: –6.3% to 1.7%]). Anti-PRP GMCs were 70.896 µg/mL in preterm infants compared with 63.345 µg/mL in term infants after booster vaccination.

Unlike response to primary vaccination, the immune response to the booster dose was not found to vary significantly with length of gestation with postbooster anti-PRP levels ≥1 µg/mL achieved in 100% of subjects in each of the 4 subgroups. Postbooster anti-PRP GMCs were 68.975 µg/mL in infants born at 34 to 36 weeks, 79.701 µg/mL in those born at 31 to 33 weeks, 97.039 µg/mL in those born at 28 to 30 weeks, and 45.462 µg/mL in those born at 24 to 27 weeks.


   DISCUSSION
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
CONCLUSIONS
 REFERENCES
 
Despite current recommendations that routine childhood immunizations should not be delayed in preterm infants,3 comparatively few studies have been undertaken to assess the safety and immunogenicity of pediatric vaccines in this population to date.3,4 In particular, very few other studies have evaluated the immunogenicity of Hib vaccines in premature infants.10,23–28 Results of the present study are generally in keeping with those of these other studies, although comparison with earlier findings is complicated by the differences in population characteristics and study design between trials, including the type of Hib vaccine and vaccination schedule used.

The present study is one of the largest and most detailed analyses of Hib vaccine immunogenicity undertaken in preterm infants to date. Immune response to PRP after primary vaccination was found to be lower in preterm infants than in term control subjects. Almost all of the previous studies support these findings, irrespective of the type of vaccine or primary vaccination schedule used. Only a single study undertaken to date has failed to reveal any significant differences in postprimary anti-PRP response between preterm and term infants.25 Data are available for 16 preterm infants aged <29 weeks' gestation primed with a PRP-mutant diphtheria toxoid (CRM197) conjugate vaccine at 2, 4, and 6 months. Anti-PRP antibody levels were ≥0.15 µg/mL in all of the subjects after administration of the third vaccine dose, with postprimary anti-PRP GMC 5.75 µg/mL in preterm subjects compared with 6.74 µg/mL in term control subjects. This is higher than the corresponding values in the present study (2.241 and 4.247 µg/mL, respectively).

Only a single other study has investigated the immunogenicity of a combined DTPa/Hib conjugate vaccine in preterm infants.28 This involved 105 infants born at <32 weeks' gestation primed with a combined DTPa/Hib conjugate vaccine coadministered with a meningococcal serogroup C conjugate vaccine at 2, 3, and 4 months. Only 55% of preterm infants were found to be seroprotected (anti-PRP ≥0.15 µg/mL) after primary vaccination compared with 80% of term control subjects, with respective postprimary anti-PRP GMCs of 0.27 and 0.81 µg/mL. These seroprotection rates and GMCs are lower than the corresponding values in this analysis. Combination of Hib conjugate vaccines with DTP vaccines containing acellular pertussis has been reported to induce lower antibody responses to the Hib PRP antigen than when these vaccines are administered separately.22,29 However, protective antibody concentrations applied for Hib polysaccharide vaccines may be inappropriate for Hib conjugates.22,29 Combined DTPa/Hib conjugate vaccines have been shown to induce immunologic memory against Hib despite apparently reduced seroprotection rates.22,30 It is possible that the lower antibody response seen with such combined vaccines may increase dependence on immunologic memory to achieve adequate protection.18 However, the relative contributions of antibody and memory in conferring protection against invasive Hib disease and the extent to which Hib conjugate vaccines establish these 2 effector mechanisms remains to be determined.31

Results of our study show a progressive reduction in anti-PRP immune response with decreasing gestational age, particularly in terms of the proportion of infants with anti-PRP antibody concentrations ≥1.0 µg/mL and anti-PRP antibody GMCs. In all, 20% of infants ≤27 weeks failed to respond to vaccination. This is cause for some concern, because such infants are particularly vulnerable to Hib infection. This is in keeping with the results of previous studies,10 although conflicting data are available.25 Immune response to PRP was also found to decrease with decreasing birth weight. Expression of IgG receptors on polymorphonuclear cells is known to be reduced in preterm infants compared with adults and seems closely related to both birth weight and gestational age.32 This may, at least in part, account for the reduced anti-PRP immune responses typically reported in very low birth weight and extremely preterm infants. However, assessment of vaccine immunogenicity in premature infants is complicated by the frequent co-occurrence of factors such as postnatal undernourishment, reduced muscular mass at the time of vaccination, and pulmonary and/or neurologic sequelae, which may also impair immune response.

Prenatal steroids were not found to have a significant impact on anti-PRP immune response in premature infants in the present study. In contrast, Hib IgG was found to be 88% higher in infants who did not receive prenatal steroids in another study.28 However, this difference fell to 51% after adjusting for age at time of administration of the third vaccine dose. Similarly, postnatal steroid use was not found to significantly influence immune response to PRP in the present study, although only 10% of study participants received postnatal dexamethasone. This is in keeping with the results of other studies,24,28 although use of dexamethasone for the treatment of chronic lung disease was reported to significantly impair antibody response of preterm infants to immunization against Hib in 1 other trial.27 We found immune response to PRP to be significantly lower in infants who required red blood cell transfusion, although results were not confirmed by multivariate analysis, taking into consideration gestational age, weight at 6 months, prenatal steroids, and red blood cell transfusions. Results of another study showed anti-PRP immune response in preterm infants to be negatively related to the volume of intravenous immunoglobulin received.24

We found anti-PRP immune response to be significantly lower in infants below the 10th percentile for weight at 6 months of age compared with those above the 50th percentile at this time, independent of gestational age. This finding was confirmed by the multivariate analysis. Similarly, Muoz et al24 found a significant relationship between weight at first immunization and Hib response. Postnatal malnutrition could probably play a role in the immune response of these infants. On the other hand, poor weight gain in the first 6 months of life has been associated with inadequate immune response to hepatitis B vaccination in preterm infants.33

Only limited data are available concerning the persistence of anti-PRP antibody responses in preterm infants after primary vaccination. Anti-PRP antibody persistence was assessed at 12 and 64 months in 1 cohort of 27 premature infants (≤32 weeks' gestation) after primary vaccination with PRP-tetanus at 2, 3, and 4 months.10 Results showed anti-PRP GMCs to be lower in prematurely born infants than in term controls at both time points. The respective proportions of preterm infants with anti-PRP antibody levels ≥0.15 and ≥1.0 µg/mL were 77% and 23% at 12 months, falling to 59% and 19% at 64 months, respectively. In another study, anti-PRP antibody persistence was evaluated at 3 and 7 years of age in 16 preterm infants who had received 4 doses of a Hib-CRM197 conjugate vaccine at 2, 4, 6, and 12 to 18 months.34,35 Anti-PRP GMCs were lower in preterm infants that in term control subjects. Nevertheless, all of the preterm subjects had anti-PRP antibody levels ≥0.15 µg/mL at both time points, with anti-PRP levels ≥1.0 µg/mL in 50% and 62.5% at 3 and 7 years, respectively.

A vigorous response to booster vaccination at 18 to 20 months was seen in the present study. Anti-PRP antibody levels were low in both preterm and term infants before administration of the booster dose (≥0.15 and ≥1.0 µg/mL in 76.2% and 10.7% of preterm subjects, respectively, compared with 83.6% and 28.4% of term control subjects). Anti-PRP levels were ≥1.0 µg/mL in all of the preterm subjects 1 month after booster administration, with postbooster anti-PRP GMCs higher than in term control subjects (70.896 and 63.345 µg/mL, respectively). Moreover, in contrast to anti-PRP responses after primary vaccination, response to the booster dose did not vary with gestational age.


   CONCLUSIONS
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
REFERENCES
 
Results of this study show anti-PRP immune responses to be generally satisfactory in preterm infants after vaccination with a hexavalent DTPa-HBV-IPV/Hib vaccine at 2, 4, 6, and 18 to 20 months of age. Future postmarketing surveillance studies including extremely preterm infants will be helpful to confirm our findings. The use of combined vaccines offers the potential to simplify pediatric vaccination strategies, potentially facilitating vaccination of preterm infants who are at particular risk of invasive Hib disease. However, alternative primary vaccination schedules may be warranted in extremely premature infants (≤27 weeks' gestation) and those with a very low birth weight (<1.0 kg). The excellent response to the booster dose in all of the preterm groups suggest that immunologic memory is elicited similarly irrespective of gestational age.


   ACKNOWLEDGMENTS
 
This study was supported by a grant from GlaxoSmithKline SA. (Madrid, Spain).

We thank Jennifer Coward and Julia Donnelly for their editorial assistance in the preparation of this article. We are also grateful to the parents and infants who participated in the study and the study nurses M. Cruz Morales, Carmen Ndongo, Marisa Prieto, and María José Ramiro, without whom this study would not have been possible.


   FOOTNOTES
 
Accepted Jul 19, 2006.

Address correspondence to Pilar García-Corbeira, MD, Medical Department, GlaxoSmithKline, c/o Severo Ochoa, 2, 28760 Tres Cantos, Madrid, Spain. E-mail: pilar.garcia-corbeira{at}gsk.com

Financial Disclosure: Dr García-Corbeira and Ms Boceta are employed by the commercial entity that sponsored the study.


   REFERENCES
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 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
 REFERENCES
 

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PEDIATRICS (ISSN 1098-4275). ©2007 by the American Academy of Pediatrics




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