Published online December 1, 2005
PEDIATRICS Vol. 116 No. 6 December 2005, pp. 1292-1298 (doi:10.1542/peds.2004-2336)
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow P3Rs: Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when P3Rs are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow E-mail this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My File Cabinet
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via CrossRef
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Omeñaca, F.
Right arrow Articles by Dal-Ré, R.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Omeñaca, F.
Right arrow Articles by Dal-Ré, R.
Related Collections
Right arrow Infectious Disease & Immunity
Right arrowRelated AAP Red Book topics:
Pertussis (Whooping Cough)
Hepatitis B
Haemophilus influenzae Infections
Diphtheria
Tetanus (Lockjaw)
Poliovirus Infections

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

Felix Omeñaca, MD, PhD*, José Garcia-Sicilia, MD, PhD{ddagger}, Pilar García-Corbeira, MD§, Reyes Boceta, BPh§, Alejandro Romero, MD{ddagger}, Gloria Lopez, MD{ddagger} and Rafael Dal-Ré, MD, PhD§

* Departments of Neonatology
{ddagger} Paediatrics, La Paz Hospital, Madrid, Spain
§ Medical Department, GlaxoSmithKline, Tres Cantos, Madrid, Spain


   ABSTRACT
TOP
 ABSTRACT
METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Objective. Preterm infants are at increased risk from infections and should be vaccinated at the usual chronological age. The aim of the study was to evaluate the immunogenicity and reactogenicity of a hexavalent diphtheria–tetanus–acellular pertussis–hepatitis B virus–inactivated polio and Haemophilus influenzae type b (DTPa-HBV-IPV/Hib) vaccine in preterm infants.

Methods. In a comparative trial, 94 preterm infants between 24 and 36 weeks (mean ± SD gestational age: 31.05 ± 3.45 weeks; mean birth weight: 1420 ± 600 g) and a control group of 92 full-term infants were enrolled to receive 3 doses of a DTPa-HBV-IPV/Hib vaccine at 2, 4, and 6 months. Immunogenicity was assessed in serum samples that were taken before and 4 weeks after primary vaccination. Evaluation of reactogenicity was based on diary cards.

Results. All preterm (n = 93) and full-term (n = 89) infants who were included in the immunogenicity analysis had seroprotective titers to diphtheria; tetanus; and polio virus types 1, 2, and 3. The immune response to the Hib and hepatitis B components was lower in preterm than in full-term infants: 92.5% versus 97.8% and 93.4% versus 95.2%, respectively. Vaccine response rates for pertussis antigens were >98.9% in both study groups. Although most geometric mean titers were lower in preterm infants, titers were similar for pertussis, a major threat for premature infants. The vaccine was well tolerated, and there were no differences in reactogenicity between groups. Some extremely immature infants experienced transient cardiorespiratory events within the 72 hours after the first vaccination with no clinical repercussion.

Conclusions. Preterm infants who were immunized with the hexavalent DTPa-HBV-IPV/Hib vaccine at 2, 4, and 6 months displayed good immune response to all antigens. The availability of this vaccine greatly facilitates the vaccination of premature infants.

Key Words: preterm infants immunization • combined vaccines • DTPa-HBV-IPV/Hib vaccine

Abbreviations: DTPa-HBV-IPV/Hib, diphtheria–tetanus–acellular pertussis–hepatitis B virus–inactivated polio and Haemophilus influenzae type b • GA, gestational age • HBsAg, hepatitis B surface antigen • IU, international unit • PT, pertussis toxin • FHA, filamentous hemagglutinin • PRN, pertactin • PRP, Haemophilus influenzae type b polysaccharide • NU, neonatology unit • GMT, geometric mean titer • GMC, geometric mean concentrations • wP, whole-cell pertussis

In developed countries, there is a 7% to 9% premature birth rate in all deliveries with increasing survival rates. However, therapy and prevention in this population is often based on scant evidence. Thus, the recommendation to immunize preterm infants at their chronological age with the same vaccines scheduled for full-term children is based on studies that are often outdated and/or involve a small number of subjects.1, 2

Preterm infants have a higher risk for infection such as pertussis3 as a result of their immature immune system, the pulmonary sequelae of mechanical ventilation, and a deficit of maternal antibodies such as immunoglobulin G crossing the placenta mainly in the last 4 to 6 weeks of gestation.4 Immunizations are often delayed, exposing these infants to a serious risk for diseases, when they are most vulnerable.

Parents and pediatricians are increasingly worried about the number of injections that have to be administered to children at each vaccination visit.5 Large combinations of vaccines, which have the advantage of reducing the number of injections, have recently been licensed. The immunogenicity and safety of the new hexavalent combinations have been demonstrated in full-term infants. To the best of our knowledge, there is no clinical experience with hexavalent vaccines in preterm infants.

We conducted a trial to evaluate the immunogenicity and reactogenicity of an hexavalent diphtheria–tetanus–acellular pertussis–hepatitis B virus–inactivated polio and Haemophilus influenzae type b (DTPa-HBV-IPV/Hib) vaccine that was administered at 2, 4, and 6 months of age in a group of preterm infants who were aged 24 to 36 weeks.


   METHODS
TOP
 ABSTRACT
 METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Design and Patients
A group of preterm infants and a control group of full-term infants were primed with a DTPa-HBV-IPV/Hib vaccine at 2, 4, and 6 months. Because weight is subject to multiple influences, preterm infants were stratified by gestational age (GA): 34 to 36, 31 to 33, 28 to 30, and 24 to 27 weeks. Postconceptional age was determined by known date of last menstrual period and/or early ultrasonogram and subsequently confirmed by neonatal examination. The study protocol was approved by the Research Ethics Committee of La Paz Hospital and conducted following the Good Clinical Practices guidelines. Written informed consent was obtained from the parents or guardians before enrollment.

The study was conducted between March 2000 and June 2001 in preterm infants who were aged 8 to 12 weeks and healthy full-term infants who were aged 6 to 12 weeks at the time of first vaccination. Infants were eligible when they had no history of diphtheria, tetanus, pertussis, hepatitis B, polio, and/or Hib vaccination or disease. Infants were excluded from the study when they had major congenital defects or serious chronic illnesses, severe neurologic damage or nontreatable convulsions, or known or suspected immune dysfunction; were born to a mother who was known to be HIV positive or hepatitis B surface antigen (HBsAg) positive; had acute disease or rectal temperature ≥38°C (immunization deferred), a history of allergic reaction to any of the vaccine components, or an episode of apnea (cessation of respiration ≥20 s) within the 7 days before vaccination; were receiving steroids 30 days before the first vaccine dose; had received any immunoglobulin therapy within 2 months before enrollment or during the trial; or had been administered any vaccines or experimental drug or vaccine during the 30 days after/before the administration of the study vaccine.

Study Vaccine
A 0.5-mL dose of the DTPa-HBV-IPV contained ≥30 international units (IU) of diphtheria toxoid; ≥40 IU of tetanus toxoid; 25 µg of adsorbed pertussis toxin (PT); 25 µg of adsorbed filamentous hemagglutinin (FHA); 8 µg of adsorbed pertactin (PRN); 10 µg of HBsAg; 40, 8, and 32 D-antigen units of polio virus types 1, 2, and 3, respectively; and 0.7 mg of aluminum as salts. The conjugate Hib vaccine was supplied as a lyophilized pellet that contained 10 µg of Haemophilus influenzae type b polysaccharide (PRP) conjugated to 20 to 40 µg of tetanus toxoid, 0.12 mg of aluminum phosphate, and 10 mg of lactose. The mixed administration (DTPa-HBV-IPV/Hib) was prepared by reconstituting the lyophilized Hib vaccine pellet with liquid DTPa-HBV-IPV vaccine. A needle of 25G x 5/8 in at 2 months and of 23G x 1 in at 4 and 6 months was used for vaccine administration conducted by the same 2 nurses. The vaccine was manufactured by GlaxoSmithKline Biologicals (Rixensart, Belgium). Only 1 lot of the vaccine was used.

Reactogenicity Analysis
Diary cards were used by parents or by the research staff, in the case of infants who were vaccinated in the neonatology unit (NU), to record solicited local reactions (pain, redness, and swelling at the injection site) and general symptoms (fever, irritability, loss of appetite, drowsiness, or sleeping more than usual) on the day of vaccination and on the 3 subsequent days. Intensity of symptoms was graded from 1 to 3; total incidence and grade 3 are reported here. Definitions were as follows: fever, rectal temperature ≥38.0°C (grade 3 fever = >39.5°C); grade 3 pain, child cried when limb was moved; grade 3 redness or swelling, diameter ≥20 mm; grade 3 irritability, inconsolable and persistent crying. For all other symptoms, grade 3 was defined as preventing normal daily activities. Unsolicited symptoms during a 30-day follow-up period after each vaccination and serious adverse events during the entire period were also recorded. The occurrence of cardiorespiratory events (apnea, bradycardia, O2 desaturation) of preterm infants who were vaccinated in the NU were witnessed and recorded by the nurses who cared for the infants as part of clinical practice. Bradycardic episodes and/or desaturations were recorded as unsolicited symptoms only when there was a resurgence or an increase of the same 72 hours after immunization.

Immunogenicity Analysis
Blood samples were drawn before the first dose and 30 to 35 days after the third dose. Serum samples were stored at –20°C until serologic analyses were performed at GlaxoSmithKline Biologicals in a blinded manner. Antibodies against D and T toxoids, PT, FHA, PRN, PRP, and HBV were determined with enzyme-linked immunosorbent assay. The assay cutoff values were 0.1 IU/mL for the D and T toxoid antibodies. To ensure a good correlation with titers that were obtained by the neutralization tests,6, 7 5 enzyme-linked immunosorbent assay units/mL for the 3 pertussis antibodies, 0.15 µg/mL for anti-PRP, 10 mIU/mL for anti-HBs,8 and antibodies against the 3 types of polioviruses were assessed by a neutralization assay with a cutoff of 1:8.9 Antibody levels that were more than or equal to the assay cutoff were considered to be protective, with the exception of antibodies against pertussis, for which no serologic correlate of protection has been established. For anti-pertussis antibodies, a vaccine response was defined as the appearance of antibodies more than or equal to the assay cutoff in patients who were seronegative before vaccination or at least maintenance of the prevaccination antibody levels in previously seropositive patients, thereby taking into account the decay of maternal antibodies.10

Statistical Analysis
The primary objective of this study was to show that the immune response to Hib in preterm infants was not inferior to that of full-term infants with respect to anti-PRP antibody 1 month after the full vaccination course. The clinical limit of noninferiority was set at a 10% difference (preterm vs full-term infants) for seroprotection rates (anti-PRP ≥0.15 µg/mL). The 90% confidence interval for differences in seroprotection rates was calculated using a 1-way analysis of variance model on the log-transformed antibody titers. The preterm group was considered not to be inferior when the upper limit of the 90% confidence interval was below the limit defining clinical inferiority.


   RESULTS
TOP
 ABSTRACT
 METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
A total of 186 infants were enrolled in the study, and 185 completed it (93 preterm and 92 full-term infants). Parent's consent withdrawal was the reason for dropout in 1 preterm infant. Ninety-three preterm and 89 full-term infants complied with the criteria for the immunogenicity analysis. Three full-term infants were excluded from this analysis for unknown postvaccination serologic status (n = 1), deviation from vaccination schedule (n = 1), and noncompliance with blood sampling (n = 1). The numbers of preterm infants (62 singletons, 13 twins, and 2 triplets) included in each age stratum were as follows: 34 to 36 (n = 29), 31 to 33 (n = 24), 28 to 30 (n = 21), and 24 to 27 weeks (n = 20). Demographics and clinical conditions of preterm infants are presented in Table 1. The mean age of preterm and full-term infants at first immunization was 8.6 ± 0.63 weeks (range: 8–11 weeks) and 8.2 ± 0.81 (range: 6–11 weeks), respectively.


View this table:
[in this window]
[in a new window]
  		TABLE 1. Demographics and clinical conditions of preterm infants (n = 94)

 
Immunogenicity Analysis
Postprimary anti-PRP titers ≥0.15 µg/mL and ≥1.0 µg/mL were observed in 92.5% and 76.3% of preterm infants and 97.8% and 86.5% of full-term infants (Table 2). Noninferiority of the anti-PRP seroprotection rate in preterm versus full-term infants could not be concluded 1 month after the third dose. Postprimary geometric mean titers (GMTs) were higher in full-term infants.


View this table:
[in this window]
[in a new window]
  		TABLE 2. Seroprotective Rates and GMTs for Anti-diphtheria; Anti-tetanus; Anti-HBsAg; Anti-polio Virus Types 1, 2, and 3; and anti-PRP Antibodies After Primary Vaccination Course

 
One month after the third vaccine dose, all preterm and full-term infants had seroprotective anti-diphtheria; anti-tetanus; and anti-polio types 1, 2, and 3 antibody levels (Table 2). Anti-polio serotype 3 GMTs were higher in full-term than in preterm infants.

All but 6 infants in the preterm group (93.4%) and all but 4 in the full-term group (95.2%) had seroprotective titers of anti-HBsAg antibodies (Table 2). The 6 nonresponders to HBV within the preterm group were 2 infants from the group aged 34 to 36 weeks and 4 infants from the group of 31 to 33 weeks. All infants <31 weeks reached titers ≥10 mIU/mL.

Seropositivity and vaccine response rates to the 3 pertussis antigens are shown in Table 3. Vaccine response rates were at least 98.9% in both study groups. GMTs were similar in preterm and full-term infants. Figure 1 shows the comparison of the anti-pertussis reverse cumulative distribution curves.


View this table:
[in this window]
[in a new window]
  		TABLE 3. Spo and VR Rates to PT, FHA, and PRN and GMTs After Primary Vaccination Course

 

Figure 1
View larger version (12K):
[in this window]
[in a new window]
  		Fig 1. Reverse cumulative distribution curves (RCC) for anti-pertussis antibodies for preterm and full-term infants. A, Anti-pertussis toxin. B, Anti-filamentous hemagglutinin. C, Anti-pertactin. Group 1, preterm infants; group 2, full-term infants.

 
Reactogenicity and Safety Analysis
The numbers of diary cards that were included in the reactogenicity analysis according to protocol were 281 and 276 for groups 1 and 2, respectively. Table 4 shows the overall incidence of total and grade 3 solicited local and general symptoms, according to the per-dose analysis, reported during the 4-day follow-up period. A total of 14.2% and 12.0% of doses were followed by fever in the preterm and full-term groups, respectively. None of the infants had fever >39.5°C. Irritability was more frequently reported in preterm infants and drowsiness in full-term infants.


View this table:
[in this window]
[in a new window]
  		TABLE 4. Overall Incidence of Total and Grade 3 Local and General Solicited Symptoms According to Per-Dose Analysis During a 4-Day Follow-up Period After Vaccination

 
Seventeen unsolicited symptoms (3 local and 14 general) that were causally related to the vaccination were recorded in 17 infants. Local unsolicited symptoms reported were induration (1 term infant and 1 preterm infant) and local heat on touch at the injection site in 1 term infant. Two premature infants who were <28 weeks had 2 and 1 episodes of apnea starting within 24 hours postimmunization, which resolved after stimulation. In 13 (42%) of the 31 infants who were hospitalized at the time of first immunization, there was a resurgence or an increase of bradycardia and desaturation episodes (n = 11) or isolated desaturation episodes (n = 2) in the 72 hours after vaccination. These 13 infants were <28 weeks of GA and had a birth weight of ≤1000 g. In 12 (92%) of 13, infants cardiorespiratory events occurred concurrently with a temperature increase of 37.1°C to 37.5°C in the 3 days after immunization.

In 17 of the 186 infants included in the study (16 in the group of preterm infants and 1 in the group of full-term infants), serious adverse experiences, mainly intercurrent infections (mainly bronchiolitis and otitis), were reported. None of them was considered to have a causal relationship with vaccination.


   DISCUSSION
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
The first studies on the vaccination of premature infants date back to the 1980s and include a small number of infants between 33 and 36 weeks.11–13 Results from subsequent studies with smaller numbers of infants are difficult to compare, as different vaccines and schedules have been used2, 14–16 in infants with diverse clinical conditions.2, 16–19

Several controlled studies with different types of monovalent or combined Hib conjugate vaccines have been conducted in preterm children.16, 17, 19, 20 The highest responses were observed with a tetanus toxoid conjugate vaccine (PRP-TT) on a 2-, 4-, 12-month schedule, with 100% seroprotection rates and highest GMTs.15 This schedule may not be adequate, as protection against invasive Hib disease must be obtained rapidly in view of the vulnerability of preterm children to infections.

Dexamethasone, used for chronic lung disease, may significantly impair the immune response of preterm infants. Even a fourth dose of Hib vaccine administered 6 weeks after completion of primary vaccination in infants who received dexamethasone did not increase postprimary immunogenicity.21 As the use of postnatal steroids has markedly declined (only 10% of infants received dexamethasone in this study), conclusions on the impact on the Hib response cannot be drawn.

In this study, although the noninferiority of the Hib response in preterm versus full-term infants could not be demonstrated, seroprotection rates (92.5%) that were reached in preterm infants seem satisfactory after vaccination with the hexavalent combination. Only 4 premature infants who were <27 weeks of GA had titers below the cutoff. The protective level of anti-PRP antibody has been the subject of a prolonged debate. Recently, it was proposed that the immune memory and antibody production are imperfect and are acquired in an age-dependent manner.22 Although preterm infants had lower anti-Hib antibody concentrations (2.2 vs 4.4 µg/mL), it also has been described that a lower antibody response is not associated with impaired function of the antibodies induced or with the induction of immune memory against Hib.23 Moreover, geometric mean concentrations (GMCs) in the group of preterm infants seem to be similar to those found in full-term children who are immunized with the same vaccine at 2, 3, and 4 months.24 Diphtheria and tetanus toxoids were highly immunogenic, and seroprotection rates were similar in preterm and full-term infants as shown previously.19

The immune response that is elicited by 2 or 3 doses of the oral or inactivated poliovirus vaccine, given on different schedules, has in general been fairly uniform.12, 25, 26 A low rate of response to IPV in preterm infants with chronic illness27 and a low response against serotype 3 virus has been described in extremely premature infants.19 All preterm newborns in this study had seroprotective titers against the 3 poliovirus types, although GMTs for serotype 3 were much lower than in full-term infants. It is difficult to explain why this phenomenon has been observed even after the booster dose.28, 29

Studies on the hepatitis B vaccination in preterm infants are fairly heterogeneous, in terms of GA,14 weight,30, 31 design,30, 32, 33 and doses.30, 31, 33–35 In the only study published in preterm children (mean GA of 32 weeks) who were vaccinated with a combined DTPa-HBV, high levels of antibodies to all of its components were elicited.14 High GMCs for HBV (4.677 mIU/mL) were achieved after the third dose given 6 months after the second one. In this study, although GMCs were lower in preterm infants, seroprotection rates to HBV were similar between the 2 groups. Within the preterm group, only 6 infants (all >31 weeks of GA) did not respond to vaccination. Two of the nonresponders had severe intrauterine growth retardation and poor weight gain in the first 6 months of life. This observation is in line with reports that nonresponders are more likely to be preterm infants of higher GA and to have gained less weight before the initiation of vaccination.33

The response to whole-cell pertussis (wP) vaccines has been considered adequate in preterm children.11, 13 In the past decade, several studies showed the appearance of episodes of apnea and/or bradycardia (5%–30% of cases) after the administration of DTwP vaccines.36, 37 These events were more frequent in extremely immature infants with serious clinical conditions.38 It has been recommended that these infants be administered the first dose of vaccines at 2 months, with cardiorespiratory monitoring in the NU before being discharged from hospital.39

In the present study, 42% of preterm infants who were vaccinated in the NU experienced changes in their cardiorespiratory situation 72 hours after vaccination. These events were of no clinical significance and occurred in the smallest and most unstable infants. It is likely that some infants had such episodes irrespective of immunization. Slack et al40 reported that the incidence of cardiorespiratory events after immunization with DTPa-Hib given concurrently with meningococcal serogroup C vaccines (38% of premature infants experienced more cardiorespiratory events than in the preceding 24 hours) is similar to that described with DTwP-Hib alone. More recently, Pfister et al41 reported that cardiorespiratory events after DTPa-IPV-Hib immunization of premature infants were mild and without detrimental impact on their clinical course.

Schloesser et al42 demonstrated the safety of a 2-component DTPa vaccine in a group of preterm infants (GA: 25–35 weeks) with a low incidence of adverse reactions, comparable to that of full-term infants. Vaccine response to PT was 93.5% and to FHA was 82.6%. GMCs in the group of preterm infants were lower than in full-term infants. Faldella et al,14 using a 3-pertussis component DTPa-HBV vaccine, found 100% of seroconversion rates and a high rise in antibody titers against PT, FHA, and PRN in both preterm and full-term infants. The mean antibody concentration for PRN was significantly lower in preterm infants. In this study, preterm infants had similar anti-PT, anti-FHA, and anti-PRN titers to those observed in full-term infants.

Preterm infants who were immunized with the hexavalent DTPa-HBV-IPV/Hib vaccine at the chronological age of 2, 4, and 6 months showed a good immune response to all antigens. Although most GMTs were lower than in full-term infants, titers were similar for pertussis, a major threat for preterm children. The vaccine was well tolerated in both groups. Mild and transient bradycardic/desaturation episodes might have been triggered by vaccination in some of the more immature infants. New studies are certainly needed to evaluate DTPa-HBV-IPV/Hib immunogenicity in preterm infants using different schedules, but at least this vaccine given at 2, 4, and 6 months can greatly facilitate the compliance with vaccination programs in premature newborns.


   ACKNOWLEDGMENTS
 
This study was supported by a grant from GlaxoSmithKline SA, Tres Cantos, Madrid, Spain.

We thank the parents and infants who participated in the study and the study nurses MS Cruz Morales, Carmen Ndongo, Marisa Prieto, and María José Ramiro, without whom this study would not have been possible.


   FOOTNOTES
 
Accepted Mar 2, 2005.

Reprint requests to (P.G.-C.) Medical Department, GlaxoSmithKline, c/ Severo Ochoa, 2, 28760 Tres Cantos, Madrid, Spain. E-mail: Pilar.garcia-corbeira{at}gsk.com


   REFERENCES
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

  1. Saari TN, the Committee on Infectious Diseases. American Academy of Pediatrics. Immunization of preterm and low birth weight infants. Pediatrics. 2003;1 :193 –198
  2. D'Angio CT. Immunization of the premature infant. Pediatr Infect Dis J. 1999;18 :824 –825[CrossRef][ISI][Medline]
  3. Wortis N, Strebel PM, Wharton M, Bardenheier B, Hardy IR. Pertussis deaths: report of 23 cases in United States, 1992 and 1993. Pediatrics. 1996;97 :607 –612[Abstract/Free Full Text]
  4. Siegrist CA, Cordova M, Brandt C, et al. Determinants of infant responses to vaccines in presence of maternal antibodies. Vaccine. 1998;16 :1409 –1414[CrossRef][ISI][Medline]
  5. Offit PA, Quarles J, Gerber MA, et al. Addressing parents' concerns: do multiple vaccines overwhelm or weaken the infant's immune system? Pediatrics. 2002;109 :124 –129[Abstract/Free Full Text]
  6. Melville-Smith ME, Seagroatt VA, Watkins JT. A comparison of enzyme-linked immunosorbent assay (ELISA) with the toxin neutralisation test in mice as a method for the estimation of tetanus antitoxin in human sera. J Biol Stand. 1983;11 :137 –144[CrossRef][ISI][Medline]
  7. Melville-Smith M, Balfour A. Estimation of Corynebacterium diphtheriae antitoxin in human sera: a comparison of an enzyme-linked immunosorbent assay with the toxin neutralisation test. J Med Microbiol. 1988;25 :279 –283[Abstract]
  8. Hollinger FB, Adam E, Heiberg D, Melnick JL: Response to hepatitis B vaccine in young adults population. Viral hepatitis and liver diseases. In: Szumness W, Alter HJ, Maynard JE, eds. Proceedings of the 1981 International Symposium. Philadelphia, PA: Franklin Institute Press; 1982:451 –466
  9. Standard procedure for determining immunity to poliovirus using the micro-neutralisation test (WHO/EPI/GEN 93.9). Geneva, Switzerland: World Health Organization; 1993
  10. Van Savage J, Decker MD, Edwards KM, Sell SH, Karzon DT. Natural history of pertussis antibody in the infant and the effect of vaccine response. J Infect Dis. 1990;161 :487 –492[ISI][Medline]
  11. Koblin BA, Townsend TR, Muñoz A, Onorato I, Wilson M, Polk BF. Response of preterm infants to diphtheria-tetanus-pertussis vaccine. Pediatr Infect Dis J. 1988;7 :704 –711[ISI][Medline]
  12. Smolen P, Bland R, Heiligenstein E, Lawless MR, Dillard R, Abramson J. Antibody response to oral polio vaccine in premature infants. J Pediatr. 1983;103 :917 –919[CrossRef][ISI][Medline]
  13. Pullan CR, Hull D. Routine immunization of preterm infants. Arch Dis Child. 1989;64 :1438 –1441[Abstract]
  14. 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[CrossRef][ISI][Medline]
  15. 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[CrossRef][ISI][Medline]
  16. 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/Free Full Text]
  17. Washburn LK, O'Shea TM, 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[CrossRef][ISI][Medline]
  18. Robinson MJ, Campbell F, Powell P, Sims D, Thorton C. Antibody response to accelerated Hib immunization in preterm infants receiving dexamethasone for chronic lung disease. Arch Dis Child Fetal Neonatal Ed. 1999;80 :F69 –F71[Abstract/Free Full Text]
  19. 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/Free Full Text]
  20. Slack MH, Schapira D, Thwaites RJ, et al. Immune response of premature infants to meningococcal serogroup C and combined diphtheria-tetanus toxoids-acellular pertussis-Haemophilus influenzae type b conjugate vaccines. J Infect Dis. 2001;184 :1617 –1620[CrossRef][ISI][Medline]
  21. Clarke P, Powell PJ, Goldblatt D, Robinson MJ. Effect of a fourth Haemophilus influenzae type b immunisation in preterm infants who received dexamethasone for chronic lung disease. Arch Dis Child Fetal Neonatal Ed. 2003;88 :58 –61
  22. Lucas AH, Granoff DM. Imperfect memory and the development of Haemophilus influenzae type b disease. Pediatr Infect Dis J. 2001;20 :235 –239[CrossRef][ISI][Medline]
  23. Eskola J, Ward J, Dagan R, Goldblatt D, Zepp F, Siegrist CA. Combined vaccination of Haemophilus influenzae type b conjugate and diphtheria-tetanus-pertussis containing acellular pertussis. Lancet. 1999;354 :2063 –2068[CrossRef][ISI][Medline]
  24. Schmitt HJ, Knuf M, Ortiz E, Sanger R, Uwamwezi MC, Kaufhold A. Primary vaccination of infants with diphtheria-tetanus-acellular pertussis-hepatitis B virus-inactivated polio virus and Haemophilus influenzae type b vaccines given as either separate or mixed injections. J Pediatr. 2000;137 :304 –312[CrossRef][ISI][Medline]
  25. Adenyi-Jones SC, Faden H, Ferdon MB, Kwong MS, Ogra PL. Systemic and local immune responses to enhanced-potency inactivated poliovirus vaccine in premature and term infants. J Pediatr. 1992;1 20:686–689
  26. Linder N, Yaron M, Handsher R, et al. Early immunisation with inactivated poliovirus vaccine in premature infants. J Pediatr. 1995;127 :128 –130[CrossRef][ISI][Medline]
  27. O'Shea TM, Dillard RG, Gillis DC, Abramson JS. Low rate of response to enhanced inactivated polio vaccine in preterm infants with chronic illness. Clin Res Reg Aff. 1993;10 :49 –57
  28. Khalak R, Pichichero ME, D'Angio CT. Three-year follow-up of vaccine response in extremely premature infants. Pediatrics. 1998;101 :597 –603[Abstract/Free Full Text]
  29. Kirmani KI, Lofthus G, Pichichero ME, Voloshen T, D'Angio T. Seven-year follow-up of vaccine response in extremely premature infants. Pediatrics. 2002;109 :498 –504[Abstract/Free Full Text]
  30. 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: www.pediatrics.org/cgi/content/full/103/2/e14
  31. Patel DM, Butler J, Feldman S, Graves GR, Rhodes PG. Immunogenicity of hepatitis B vaccine in healthy very low birth weight infants. J Pediatr. 1997;131 :641 –643[CrossRef][ISI][Medline]
  32. Lau YL, Tam AY, Ng KW, et al. Response of preterm infants to hepatitis B vaccine. J Pediatr. 1992;121 :962 –965[CrossRef][ISI][Medline]
  33. Kim SC, Chung EK, Hodinka RL, et al. Immunogenicity of hepatitis B vaccine in preterm infants. Pediatrics. 1997;99 :534 –536[Abstract/Free Full Text]
  34. Ferreri R., Adinolfi B, Limardi C, Franco E, Matano A. Hepatitis B vaccination: evaluation of a short-interval dosing schedule in low-weight newborns. Curr Ther Res. 1992;52 :493 –497[CrossRef]
  35. Ballesteros-Trujillo A, Vargas-Origel A, Alvarez-Muñoz T, Aldana Valenzuela C. Response to hepatitis B vaccine in preterm infants: four-dose schedule. Am J Perinatol. 2001;18 :379 –385[CrossRef][ISI][Medline]
  36. Botham SJ, Isaacs D, Henderson-Smart DJ. Incidence of apnea and bradycardia in preterm infants following DTPw and Hib immunization: a prospective study. J Paediatr Child Health. 1997;33 :418 –421[ISI][Medline]
  37. Slack MH, Schapira D. Severe apnoeas following immunization in premature infants. Arch Dis Chid Fetal Neonatal Ed. 1999;81 :F67 –F68
  38. Sánchez PJ, Laptook AR, Fisher L, Sumner J, Risser RC, Perlman JM. Apnea after immunization of preterm infants. J Pediatr. 1997;130 :746 –751[ISI][Medline]
  39. Pourcyrous M, Korones SB, Crouse D, Bada HS. Interleukin-6, C-reactive protein, and abnormal cardiorespiratory responses to immunization in premature infants. Pediatrics. 1998;101 (3). Available at: www.pediatrics.org/cgi/content/full/101/3/e3
  40. Slack MH, Schapira C, Thwaites RJ, Andrews N, Schapira D. Acellular pertussis and meningococcal vaccines: cardio-respiratory events in preterm infants. Eur J Pediatr. 2003;162 :436 –437[ISI][Medline]
  41. Pfister RE, Aeschbach V, Niksic-Stuber V, Martin BC, Siegrist CA. Safety of DTaP-based combined immunization in very-low-birth-weight premature infants: frequent but mostly benign cardiorespiratory events. J Pediatr. 2004;145 :58 –66[CrossRef][ISI][Medline]
  42. Schloesser RL, Fischer D, Otto W, Rettwitz-Volk W, Herden P, Zielen S. Safety and immunogenicity of an acellular pertussis vaccine in premature infants. Pediatrics. 1999;103(5) . Available at: www.pediatrics.org/cgi/content/full/103/5/e60
PEDIATRICS (ISSN 1098-4275). ©2005 by the American Academy of Pediatrics



This article has been cited by other articles:


Home page
 PediatricsHome page
T. Carbone, B. McEntire, D. Kissin, D. Kelly, A. Steinschneider, K. Violaris, and N. Karamchandani
Absence of an Increase in Cardiorespiratory Events After Diphtheria-Tetanus-Acellular Pertussis Immunization in Preterm Infants: A Randomized, Multicenter Study
Pediatrics, May 1, 2008; 121(5): e1085 - e1090.
[Abstract] [Full Text] [PDF]

Home page
 PediatricsHome page
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]

Home page
 Arch. Dis. Child.Home page
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]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow P3Rs: Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when P3Rs are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow E-mail this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My File Cabinet
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via CrossRef
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Omeñaca, F.
Right arrow Articles by Dal-Ré, R.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Omeñaca, F.
Right arrow Articles by Dal-Ré, R.
Related Collections
Right arrow Infectious Disease & Immunity
Right arrowRelated AAP Red Book topics:
Pertussis (Whooping Cough)
Hepatitis B
Haemophilus influenzae Infections
Diphtheria
Tetanus (Lockjaw)
Poliovirus Infections