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, Andrew J. Cant, John N.S. Matthews, Marilyn O'Keeffe, Gavin P.
Spickett and Alan C. Fenton
Pediatrics 2006;117;717-724; originally published online Mar 20, 2006;
DOI: 10.1542/peds.2005-0348

This information is current as of June 14, 2006

The online version of this article, along with updated information and services, is
located on the World Wide Web at:
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ARTICLE

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 OKeeffe, PhDc, Gavin P. Spickett, DPhil, FRCPd,
Alan C. Fenton, MDa
Departments of aNeonatology and dImmunology, Royal Victoria Inrmary, Newcastle Upon Tyne, England; bDepartment of Paediatric Immunology and Infectious
Diseases, Newcastle General Hospital, Newcastle Upon Tyne, England; cSchool of Mathematics and Statistics, University of Newcastle Upon Tyne, Newcastle Upon Tyne,
England
The authors have indicated they have no nancial relationships relevant to this article to disclose.

ABSTRACT
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 g/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 g/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 g/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
g/mL compared with term infants. A total of 93% of infants who were given a
fourth dose had anti-PRP antibody 1.0 g/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.

www.pediatrics.org/cgi/doi/10.1542/
peds.2005-0348
doi:10.1542/peds.2005-0348
Key Words
Haemophilus inuenzae type b,
immunization, preterm, acellular, booster
Abbreviations
HibHaemophilus inuenzae type b
PRP-Tpolyribosylribitolphosphatetetanus conjugate
DTPw diphtheria/tetanus/whole-cell
pertussis
DTPwHib diphtheria/tetanus/whole-cell
pertussis/Haemophilus inuenzae type b
Men CNeisseria meningitidis serotype C
DTPaHib diphtheria/tetanus/acellular
pertussis/Haemophilus inuenzae type b
GMT geometric mean titer
EIA enzyme immunoassay
TTtetanus toxoid
DTPHib diphtheria/tetanus/pertussis/
Haemophilus inuenzae type b
GSKGlaxoSmithKline
CI condence interval
RIAradioimmunoassay
Accepted for publication Sep 13, 2005
Address correspondence to Alan C. Fenton,
MD, Neonatal Unit, Ward 35, Royal Victoria
Inrmary, Newcastle Upon Tyne NE1 4LP,
United Kingdom. E-mail: a.c.fenton@ncl.ac.uk
PEDIATRICS (ISSN Numbers: Print, 0031-4005;
Online, 1098-4275). Copyright 2006 by the
American Academy of Pediatrics

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e717

HE 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 100 000 infants who were younger than 5 years to a nadir of 0.65
per 100 000 in 1998. Subsequently, a year-by-year increase in the incidence of invasive Hib disease reached
4.6 per 100 000 in 2002.1 These findings question the
effectiveness of the United Kingdoms 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 vaccinemay 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
g/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 1996.68 DTPaHib had
previously been shown to reduce both anti-PRP antibody geometric mean titer (GMT) and the proportion
who achieved 1.0 g/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 King-

dom 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
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 infants1315 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
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 g/mL after primary immunization. In a UK
population, we asked whether receipt of 1 or more doses

TABLE 1 Possible Immunization Options of DTPwHib and DTPaHib Vaccine Doses Received by
Individual Study Infants
Total No. of DTPwHib Doses Over Primary Series

Option
First immunization
Second immunization
Third immunization

1
A
A
A

2
W
A
A

3
A
W
A

4
A
A
W

5
W
W
A

6
W
A
W

7
A
W
W

8
W
W
W

A indicates DTPaHib; W, DTPwHib.

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BERRINGTON, et al

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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.

of DTPaHib during the primary schedule would result in

both lower anti-PRP GMT and less likelihood of an individual response 1.0 g/mL (or 0.15 g/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 g/mL.
METHODS
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.
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 80C, and pre- and postimmunization samples were analyzed together. Anti-PRP antibody (class
immunoglobulin G) and antitetanus 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 g/mL (anti-PRP) and 0.01 to 9 IU/mL (antitetanus). 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
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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 g/mL.

TABLE 2 Demographic Data and Timing of Study Interventions

n

Birth Weight,
g

Term
After primary 45 3450 (31433852)
After booster
6 3587 (30654026)
Preterm
After primary 166 1035 (8401372)
After booster 55 1002 (8001360)

Gestation, Received Received

wk
Prevenar, Postnatal
n (%)
Steroid,
n (%)
39 (3940)
40 (3940)
28 (2630)
28 (2629)

Age at Immunization
Days

Months

1st

2nd

3rd

60 (5763)

88 (8593)

119 (114126)

Booster

Interval, d
1st
68 (6276)

6.9 (6.78.1)
14 (8)
7 (12)

15 (9)
5 (9)

2nd

63 (5780) 105 (90121) 143 (124165)

64 (6371)
67 (5982)

9.2 (8.212.8)

64 (5772)

Data are median (interquartile range). Interval time from completion of primary series immunization to blood sampling (1st) or booster immunization to blood sampling (2nd).

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 (Glaxo
SmithKline [GSK], Middlesex, United Kingdom); the sepe720

BERRINGTON, et al

arate 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. In-

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TABLE 3 Anti-PRP Levels Before Immunization, After Primary Immunization, and After Fourth Immunization
After Primary, by No. of Whole-Cell DTPHib Dosesa

Before Primary

Preterm, n
GMT
% (n) 1.0
% (n) 0.15
Term, n
GMT
% (n) 1.0
% (n) 0.15

166
0.16 (0.130.19)
8 (13)
50 (83)
45
0.21 (0.140.32)
14 (6)
51 (23)

After Booster

Unknown

Total

53
0.3 (0.210.43)
20 (11)
72 (38)
18
0.8 (0.411.52)
45 (8)
94 (17)

32
0.8 (0.461.46)
44 (14)
84 (27)
12
1.7 (1.092.69)
84 (10)
100 (12)

47
1.6 (1.052.51)
66 (31)
98 (46)
12
2.85 (1.018.00)
84 (10)
92 (11)

22
2.6 (1.275.52)
86 (19)
91 (20)
3
1.8 (0.0659)
67 (2)
100 (3)

12
2.0 (1.074.63)
75 (9)
100 (12)
0

166
0.9 (0.701.16)
51 (84)
86 (143)
45
1.45 (0.972.18)
67 (30)
95 (43)

55
4.66 (3.126.42)
93 (51)
98 (54)
6
7.0 (2.321)
100 (6)
100 (6)

Data are presented as GMT (95% CI) in g/mL and the proportion who achieved 1.0 g/mL and 0.15 g/mL.
a The anti-PRP response did not vary according to the order in which whole-cell or acellular vaccines were given (P .8).

fants with anti-PRP antibody 1.0 g/mL after primary

immunization were offered a booster dose of PRP-T.

RESULTS
Anti-PRP Antibody
On completion of primary immunization, the GMT for
anti-PRP antibody (preterm [term]) rose from 0.16
(0.21) g/mL to 0.9 (1.45) g/mL; 49% of preterm
infants and 33% of term infants had anti-PRP antibody
1.0 g/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.
The probability of achieving anti-PRP antibody 1.0
g/mL (or 0.15 g/mL) also increased with the total
number of whole-cell pertussis immunizations received
(P .0005 for 1.0 g/mL, P .003 for 0.15 g/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 g/mL (or 0.15 g/mL) than term infants (P .0005 for 1.0 g/mL and P .001 for 0.15
g/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

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 g/mL (or 0.15 g/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

TABLE 4 Effect of Preterm Delivery and Number of DTPwHib on Hib and Tetanus Responses After Primary Series
Immunization
Hib
OR (95% CI)

Preterm (32 wk)

No. of DTPwHib/DTPwHibDTPaHib
0/3
1/3
2/3
3/3

GMT Ratio
(95% CI)

Tetanus, GMT Ratio

(95% CI)

1.0 g/mL

0.15 g/mL

0.18 (0.080.45)

0.12 (0.020.58)

0.40 (0.250.65)

0.96 (0.661.39)

1
2.4 (0.87.7)
6.8 (1.825.9)
3.6 (0.921.7)

1
2.5 (1.54.3)
4.6 (2.87.5)
7.5 (3.914.3)

1
1.8 (1.22.7)
2.5 (1.73.6)
3.7 (2.36.0)

1
3.6 (1.58.8)
8.3 (3.519.8)
25.7 (6.795.0)

OR indicates odds ratio.

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booster and whose parents allowed retesting had antiPRP antibody 1.0 g/mL after boosting. The postprimary anti-PRP GMT for these infants was very low (0.24
g/mL) and increased to 4.66 g/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
g/mL [95% CI: 0.37 0.63] and preterm GMT 0.59
g/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
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 g/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 wholecell vaccine to have a 50% chance of achieving a GMT
1.0 g/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 g/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 g/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
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BERRINGTON, et al

whom anti-PRP GMT increased from 0.1 g/mL to 14.7

g/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 antiPRP 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 studies3,710,13,14 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 g/mL, the GMT remains extremely low in
relation to previous UK studies even if this correction is
applied (0.23 g/mL, doubled 0.46 g/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 g/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 antiPRP 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 g/mL gives short-term protection and 1.0
g/mL gives long-term protection.26,27 In the United
Kingdom, the observed fall in the term populations
GMT for anti-PRP antibody between 1992 (5.01 g/mL)
and the current study (1.45 g/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 for-

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mulation 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.

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19.

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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, Andrew J. Cant, John N.S. Matthews, Marilyn O'Keeffe, Gavin P.
Spickett and Alan C. Fenton
Pediatrics 2006;117;717-724; originally published online Mar 20, 2006;
DOI: 10.1542/peds.2005-0348
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