Published online March 20, 2006
PEDIATRICS Vol. 117 No. 4 April 2006, pp. e717-e724 (doi:10.1542/peds.2005-0348)
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Haemophilus influenzae Type b Immunization in Infants in the United Kingdom: Effects of Diphtheria/Tetanus/Acellular Pertussis/Hib Combination Vaccine, Significant Prematurity, and a Fourth Dose

Janet E. Berrington, MDa, Andrew J. Cant, MDb, John N.S. Matthews, PhDc, Marilyn O'Keeffe, PhDc, Gavin P. Spickett, DPhil, FRCPd and Alan C. Fenton, MDa

a Department of Neonatology, Royal Victoria Infirmary, Newcastle Upon Tyne, England
b Department of Paediatric Immunology and Infectious Diseases, Newcastle General Hospital, Newcastle Upon Tyne, England
c School of Mathematics and Statistics, University of Newcastle Upon Tyne, Newcastle Upon Tyne, England
d Department of Immunology, Royal Victoria Infirmary, Newcastle upon Tyne, England


   ABSTRACT
TOP
 ABSTRACT
METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
OBJECTIVE. To measure anti-polyribosylribitolphosphate (PRP) antibody and anti–tetanus toxoid (TT) antibody responses in UK infants to explore the effects of (1) immunization with an acellular diphtheria/tetanus/pertussis/Haemophilus influenzae type b (DTPHib) combination vaccine, (2) significant preterm delivery, and (3) a fourth dose of conjugated Hib vaccine (PRP-T) in those with a low anti-PRP antibody (<1.0 µg/mL) after primary immunization.

METHODS. A prospective study was conducted in 4 tertiary neonatal units at a time when 2 types of DTPHib vaccines were used interchangeably in the United Kingdom for primary immunization: acellular (DTPaHib) and whole cell. Timing and type of all vaccine doses were as per standard UK practice. Blood was taken before and after immunization. A total of 166 preterm and 45 term infants completed the study; 97 (15 term) infants who had anti-PRP antibody <1.0 µg/mL were offered a fourth dose of PRP-T; 61 (55 preterm) then had repeat antibody measurements. Anti-PRP and anti-TT antibody after primary immunization relative to gestation and number of whole cell vaccine doses received was measured, as well as anti-PRP antibody after a fourth dose of PRP-T.

RESULTS. A total of 49% of preterm and 33% of term infants had anti-PRP antibody <1.0 µg/mL after full primary immunization. Receipt of 1 or more acellular vaccine doses was associated with lower anti-PRP antibody, a dose response effect being observed. Preterm infants were less likely to have anti-PRP antibody >1.0 µg/mL compared with term infants. A total of 93% of infants who were given a fourth dose had anti-PRP antibody >1.0 µg/mL. Anti-TT antibody responses were satisfactory for all infants but also reduced by each DTPaHib dose received.

CONCLUSION. Infants who receive DTPaHib, are significantly preterm, or who do not receive a fourth dose of conjugated Hib vaccine may be at increased risk for Hib disease.

Key Words: Haemophilus influenzae type b • immunization • preterm • acellular • booster

Abbreviations: Hib—Haemophilus influenzae type b • PRP-T—polyribosylribitolphosphate-tetanus conjugate • DTPw—diphtheria/tetanus/whole-cell pertussis • DTPwHib—diphtheria/tetanus/whole-cell pertussis/Haemophilus influenzae type b • Men C—Neisseria meningitidis serotype C • DTPaHib—diphtheria/tetanus/acellular pertussis/Haemophilus influenzae type b • GMT—geometric mean titer • EIA—enzyme immunoassay • TT—tetanus toxoid • DTPHib—diphtheria/tetanus/pertussis/Haemophilus influenzae type b • GSK—GlaxoSmithKline • CI—confidence interval • RIA—radioimmunoassay

The introduction of the Haemophilus influenzae type b (Hib) polyribosylribitolphosphate-tetanus conjugate vaccine (PRP-T) in the United Kingdom in 1992 reduced invasive Hib disease from 22.9 per 100000 infants who were younger than 5 years to a nadir of 0.65 per 100000 in 1998. Subsequently, a year-by-year increase in the incidence of invasive Hib disease reached 4.6 per 100000 in 2002.1 These findings question the effectiveness of the United Kingdom's "accelerated" Hib immunization schedule at 2, 3, and 4 months of postnatal age with no fourth dose in the second year of life.2 This "no boost" policy was based on reassuring antibody levels and surveillance data from term infants who were immunized with diphtheria/tetanus/whole-cell pertussis (DTPw) in 1 limb and PRP-T in another.3,4 Changes in the immunization schedule—combining DTP and PRP-T into a single injection (DTPwHib), the addition of a vaccine against Neisseria meningitidis serotype C (Men C), and the change from a whole-cell (DTPwHib) to a 3-component acellular (DTPaHib) combination vaccine—may have altered Hib immunogenicity and might explain the rise in Hib disease, as may the waning impact of the initial catch-up campaign on Hib carriage or a combination of these events in association with the lack of boosting.5

In population studies, administration of DTPwHib via a combined injection administered in a single limb resulted in a similar proportion of infants' achieving >1.0 µg/mL (the presumed "protective level") as when DTPw and PRP-T were administered by separate injection in separate limbs, and combined administration was approved in the United Kingdom in 1996.6–8 DTPaHib had previously been shown to reduce both anti-PRP antibody geometric mean titer (GMT) and the proportion who achieved >1.0 µg/mL in term infants in the UK accelerated schedule (using a 2-component DTPaHib vaccine),9 but the relevance of this finding initially was unclear.10 As a result of shortfalls in DTPwHib production, a 3-component DTPaHib vaccine was made available in the United Kingdom in 1999 and distributed alongside a DTPwHib vaccine from 1999 to 2002. Individual infants therefore could receive doses of either DTPwHib or DTPaHib at each of the 3 primary immunizations, resulting in 8 ways in which DTPaHib and DTPwHib vaccines were administered in the United Kingdom during this period (Table 1). Later, against a background of rising Hib disease, a retrospective review of the risk for Hib disease in relation to type of pertussis component given showed an increased risk for infants who received 3 acellular vaccines (odds ratio: 6.7), but this study obtained complete immunization data for only 64% of control subjects.11


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  		TABLE 1 Possible Immunization Options of DTPwHib and DTPaHib Vaccine Doses Received by Individual Study Infants

 
Other risk factors, including preterm delivery, have also been associated with Hib vaccine failure.12 Although a trend for increased relative risk for invasive Hib disease in preterm infants has been demonstrated, statistical significance was not shown perhaps because of the small numbers of preterm infants with Hib disease.13 In the absence of sufficient surveillance data on the effect of different immunization schedules on Hib disease in preterm infants, postimmunization levels of anti-PRP antibody may help to determine which schedules are likely to give protection. Only limited postprimary series UK data are available and pertain to small numbers of infants13–15 and/or select and unrepresentative groups.15 Compared with term control subjects, these data have shown a reduction in anti-PRP antibody response by significantly preterm infants (<32 weeks' gestation) who were immunized with separate-limb DTPw and PRP-T,13 those who were immunized with 3 doses of DTPaHib,14 and those who were treated with dexamethasone15 (Fig 1). There are no prospective immunogenicity data of the effect of the various combinations of DTPaHib/DTPwHib used in the United Kingdom (Table 1) and minimal UK data on which to base the decision regarding a fourth dose of PRP-T in preterm infants. Only 2 published studies assessed booster responses in preterm infants; the first addressed a select group of 12 infants who all were treated postnatally with steroid (who showed no improvement in GMT after a fourth dose16), and the second addressed preterm infants who all had received 3 doses of DTPaHib over their primary series (where an adequate response to a fourth dose was seen).17


Figure 1
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  		FIGURE 1 Previous UK Hib trials. GMT (95% CI) by vaccine type and whether by separate or combined injection is shown.

 
We aimed to study the effect of significant preterm delivery and DTPaHib use on Hib antibody responses (anti-PRP) and to measure the response to a booster dose of PRP-T in those who had an anti-PRP antibody level <1.0 µg/mL after primary immunization. In a UK population, we asked whether receipt of 1 or more doses of DTPaHib during the primary schedule would result in both lower anti-PRP GMT and less likelihood of an individual response >1.0 µg/mL (or >0.15 µg/mL) in comparison with those who received 3 doses of DTPwHib, whether preterm infants <32 weeks' gestation would respond less well to PRP-T than term infants (but equally well to tetanus) as measured by GMT and the proportion who achieved the predetermined protective levels, and whether a single additional dose of PRP-T would generate postbooster levels of anti-PRP antibody >1.0 µg/mL.


   METHODS
TOP
 ABSTRACT
 METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Patients
Term infants (>37 completed weeks of gestation) were recruited in the first week of life from the postnatal wards of a single site in Northern England between March and May 2002. Infants of <32 completed weeks of gestation (<32) were recruited from the 4 tertiary neonatal units in the former Northern Health Region of England between February 2001 and July 2002. Recruitment was before 6 weeks of life while infants were still hospitalized. Ethical approval was obtained from each Local Research Ethics Committee, and written consent was obtained from all parents. The design of the study with inherent lack of control over vaccine types administered and the limited preexisting information on antibody responses in such populations meant that power calculations were not performed. A total of 193 preterm infants who were recruited into the study period were compared with 50 term infants. Major congenital abnormality was the only exclusion criterion. Demographic details and other variables that might affect vaccine response were obtained from patient records. Duration of ventilation, total days in oxygen, oxygen requirement at 36 weeks' postmenstrual age, oxygen at discharge home, postnatal steroid use, blood product use, z scores for weight at immunization, type of Men C vaccine administered, and receipt of heptavalent pneumococcal vaccine (Prevenar [Prevnar in United States]; Wyeth, Collegeville, PA) were recorded. Progress of the study infants is given in Fig 2, and demographic variables are shown in Table 2.


Figure 2
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  		FIGURE 2 Flowchart of progress of infants through the study. L indicates lost contact; S, lost sample; I, incomplete immunization; D, died; C, consent withdrawn; GMT, geometric mean titer in µg/mL.

 

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  		TABLE 2 Demographic Data and Timing of Study Interventions

 
Laboratory Methods
Blood was taken just before and 6 to 8 weeks after completion of primary series immunization and 6 to 8 weeks after a fourth dose of PRP-T if given. Topical anesthetic cream (Ametop; Smith and Nephew, London, United Kingdom) was applied. Sera were separated and stored at –80°C, and pre- and postimmunization samples were analyzed together. Anti-PRP antibody (class immunoglobulin G) and anti–tetanus toxoid (anti-TT) antibody (class immunoglobulin G) were measured by commercially available enzyme immunoassay (EIA; the Binding Site, Birmingham, United Kingdom) by 1 investigator (J.E.B.). Limits of detection for the assays were 0.11 to 9.0 µg/mL (anti-PRP) and 0.01 to 9 IU/mL (anti-tetanus). The Hib assay was calibrated against reference serum from the US Food and Drug Administration (Lot 1983), and the tetanus assay was calibrated against serum from the National Institute of Biological Standards and Control (ref 76/589).

Immunizations
Details of timing of administration and specific vaccines used for individual infants were obtained from patient records (Tables 2 and 3). All study infants received DTP, Hib, polio, and Men C immunization according to routine local use during the study period, with DTP and Hib always being administered by a single combined injection regardless of the products used. The vaccines used were the whole-cell combination diphtheria/tetanus/pertussis/Haemophilus influenzae type b (DTPHib) vaccine ACT-HIBDTP (Aventis Pasteur, Lyon, France) and the acellular DTPHib combination vaccine Infanrix-Hib (GlaxoSmithKline [GSK], Middlesex, United Kingdom); the separate DTP vaccines DTPw (Aventis Pasteur) and Infanrix (DTPa; GSK); the separate PRP-T vaccines Hiberix (GSK) and ACT-HIB (Aventis Pasteur); and Men C conjugate vaccines Meningitec (Wyeth), Menjugate (Chiron, Emeryville, CA), and Neis-Vac-C (Baxter, Deerfield, IL). In addition, certain at-risk preterm infants received Prevenar (Wyeth; Table 1) at the discretion of their consultant. Infants with anti-PRP antibody <1.0 µg/mL after primary immunization were offered a booster dose of PRP-T.


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  		TABLE 3 Anti-PRP Levels Before Immunization, After Primary Immunization, and After Fourth Immunization

 
Statistical Analysis
Demographic data were not normally distributed and are presented as medians with interquartile ranges. Similarly, antibody data were skewed and therefore presented as GMTs with 95% confidence intervals (CIs). The probability of achieving an anti-PRP antibody level >1.0 µg/mL (or >0.15 µg/mL) after 3 immunizations was modeled using logistic regression and presented as odds ratios. The simultaneous effects of prematurity and of the different sequences of whole-cell and acellular immunization were assessed, with particular attention to the effect of the total number of whole-cell pertussis immunizations administered. The effects of these factors on GMTs were analyzed using censored linear regression with normally distributed residuals and presented as GMT ratios: values recorded at the limits of detection of the assay were regarded as censored. Normality was assessed using residuals plots. The design of the study did not allow strict control over the timing of the immunizations, so allowance was made by including the time between first and third immunizations and between third immunization and blood sampling in all regression analyses. Analyses were performed in Stata (version 7).18


   RESULTS
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 ABSTRACT
 METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Anti-PRP Antibody
On completion of primary immunization, the GMT for anti-PRP antibody (preterm [term]) rose from 0.16 (0.21) µg/mL to 0.9 (1.45) µg/mL; 49% of preterm infants and 33% of term infants had anti-PRP antibody <1.0 µg/mL (Table 3). The GMT for anti-PRP antibody increased as the number of whole-cell vaccine doses increased (P < .0005) and was lower in preterm infants than in term infants (P < .0005). The ratios of GMTs are given in Table 4: preterm relative to term and whole-cell relative to acellular.


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  		TABLE 4 Effect of Preterm Delivery and Number of DTPwHib on Hib and Tetanus Responses After Primary Series Immunization

 
The probability of achieving anti-PRP antibody >1.0 µg/mL (or >0.15 µg/mL) also increased with the total number of whole-cell pertussis immunizations received (P < .0005 for 1.0 µg/mL, P = .003 for 0.15 µg/mL). The anti-PRP response did not vary according to the order in which whole-cell or acellular vaccines were given (P = .8), only with the total number of whole-cell immunizations. Preterm infants were less likely to have anti-PRP antibody >1.0 µg/mL (or >0.15 µg/mL) than term infants (P < .0005 for 1.0 µg/mL and P = .001 for 0.15 µg/mL). The magnitudes of these effects are shown in Table 4. No other study variable significantly affected the postprimary series anti-PRP antibody response.

A total of 93% (57 of 61) infants who received a booster and whose parents allowed retesting had anti-PRP antibody >1.0 µg/mL after boosting. The postprimary anti-PRP GMT for these infants was very low (0.24 µg/mL) and increased to 4.66 µg/mL after a fourth dose (Table 3). There was no demonstrable association between the response to the fourth dose and number of whole-cell vaccines administered over the primary series.

Anti-TT Antibody
All infants mounted satisfactory postimmunization anti-TT antibody responses (>0.01 IU/mL; term GMT 0.48 µg/mL [95% CI: 0.37–0.63] and preterm GMT 0.59 µg/mL [95% CI: 0.48–0.71]). The TT antibody response was unaffected by gestational age, but a dose-response effect increasing anti-TT antibody GMT was seen with each dose of whole-cell DTPHib vaccine received (Table 4).


   DISCUSSION
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
Infants who receive DTPaHib, are significantly preterm, or do not receive a fourth dose of conjugated Hib vaccine may be at increased risk for Hib disease. Overall, nearly half (46%) of all study infants had postprimary immunization anti-PRP antibody <1.0 µg/mL, and in the term group, the GMT for anti-PRP antibody was well below that found in the original UK studies that informed the decision not to include a booster dose of Hib vaccine.3 Many earlier studies measured antibody responses by radioimmunoassay (RIA) alone or RIA and EIA. Our study used EIA alone, but as this correlates well with RIA,19 the comparison with historical data should be valid. The use of DTPaHib was statistically associated with a reduced anti-PRP antibody response; increments in anti-PRP were produced by each dose of whole-cell vaccine received (term infants required at least 1 whole-cell vaccine to have a >50% chance of achieving a GMT >1.0 µg/mL).

This study examined Hib responses in the largest number of preterm infants who were <32 weeks yet studied, with minimal postnatal steroid use. Preterm responses to PRP-T were poor: 49% had anti-PRP antibody <1.0 µg/mL after primary immunization; antibody responses were significantly worse than for equivalently vaccinated term infants. It was reassuring to find that all infants made good responses to tetanus (a protein antigen), even infants who were particularly small and sick.

This study shows that a fourth dose of PRP-T would ensure that most infants with low levels after completing their primary series would achieve anti-PRP antibody levels >1.0 µg/mL, regardless of whether they received DTPaHib or DTPwHib immunizations. The GMT achieved after the fourth dose is consistent with the previous UK study of preterm infants who received a booster and had received 3 DTPaHib17 and in keeping with Danish data from infants <30 weeks' gestation, in whom anti-PRP GMT increased from 0.1 µg/mL to 14.7 µg/mL after boosting at 12 months of age20 and priming at 4 and 6 months. The preterm infants whom we studied represent those found in most UK tertiary neonatal units, with only 9% postnatal steroid use, and the timing of the fourth dose in this study (median 9 months) is similar to that likely to be used if a fourth dose were introduced in the United Kingdom, when boosting at the beginning of the second year of life is likely. If reversion to an acellular DTPaHib vaccine is required in the future, then these data suggest both an adequate response to this fourth dose and a response independent of the nature of the pertussis component of the priming DTPHib.

This study used an observational design to assess anti-PRP antibody response in relation to DTPaHib and preterm delivery, as well as measured the response to a fourth dose of PRP-T given to poor responders. These issues do not lend themselves readily to randomized, controlled trials, and studies of this nature contribute important data. There is more variation in the timing of immunizations and sampling after immunization, with a longer interval than in some studies3,7–10,13,14 but less than or equal to others6,15; and documentation of vaccine type was complete except for in 12 preterm infants, who therefore were excluded from the vaccine type analysis. The variability in vaccine timing and blood sampling between groups of infants within the current study has been accounted for in the statistical analysis, ensuring their validity. However, when comparing with historical data, differences in timing require specific consideration. Previous studies aimed to sample 4 to 6 weeks after immunization; we aimed for 6 to 8 weeks after immunization. If a full half-life of antibody had decayed as a result of later sampling in our study, then doubling the GMT would compensate; for the study population that failed to achieve a postprimary anti-PRP antibody level of >1.0 µg/mL, the GMT remains extremely low in relation to previous UK studies even if this correction is applied (0.23 µg/mL, doubled = 0.46 µg/mL). This GMT is also much lower than that seen as long as 43 months after immunization with separate limb PRP-T and DTP (1.06 µg/mL; 95% CI: 0.8–1.38).21 It therefore seems unlikely that timing of sampling accounts for the low anti-PRP antibody level.

The clinical significance of postimmunization anti-PRP antibody levels has been questioned.22,23 It is well established that anti-PRP antibody protects against Hib disease.24,25 Most studies suggest that an antibody level of >0.15 µg/mL gives "short-term protection" and >1.0 µg/mL gives "long-term protection."26,27 In the United Kingdom, the observed fall in the term population's GMT for anti-PRP antibody between 1992 (5.01 µg/mL) and the current study (1.45 µg/mL) has been mirrored by rising Hib disease. This suggests that antibody levels reflect the degree of protection against Hib disease and so are a useful tool for evaluating changes in vaccine formulation and possible reasons for increasing Hib rates, as well as allowing some comparison with previous studies.

A campaign to give a fourth dose of Hib vaccine to children who are younger than 4 years was also undertaken in the United Kingdom during 2003, so children who may have received DTPaHib between 1999 and 2002 have received a booster immunization.28 A decision on whether to give a fourth dose routinely is awaited. Other countries that use DTPaHib have not seen a rise in Hib disease, suggesting that the poor response in UK infants is either unique to this particular (3-component) acellular DTPaHib vaccine or attributable to its use at earlier ages and without a fourth dose, although other factors may also partially account for increasing incidence of Hib disease such as has been seen in the Netherlands, where separate-limb DTPw and PRP-T continue to be administered.29

This study revealed surprisingly poor anti-PRP antibody responses; the 3-component DTPaHib vaccine was associated with markedly reduced Hib immunogenicity at all gestational ages, an important consideration if this vaccine were introduced into other regimens. Infants who do not receive a fourth dose for any reason are probably at increased risk for invasive, damaging, and life-threatening Hib disease. The poor response of preterm infants to either type of DTPHib vaccine used in the UK schedule is of particular concern and strongly suggests that that they merit a fourth dose of PRP-T.


   ACKNOWLEDGMENTS
 
This study was supported by Northern and Yorkshire Research and Development Regional Research Training Fellowship (Dr Berrington), Northern and Yorkshire Research and Development Commissioned Research (Child Health Fund), The Sir Jules Thorn Charitable Trust, and The Newcastle Health Care Charity.

We acknowledge the help of the Northern Neonatal Provider Consortium staff, laboratory staff, and the parents of infants who were included in the study.


   FOOTNOTES
 
Accepted Sep 13, 2005.

Address correspondence to Alan C. Fenton, MD, Neonatal Unit, Ward 35, Royal Victoria Infirmary, Newcastle Upon Tyne NE1 4LP, United Kingdom. E-mail: a.c.fenton{at}ncl.ac.uk

The authors have indicated they have no financial relationships relevant to this article to disclose.


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 RESULTS
 DISCUSSION
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