review of 8 years of experience with infanrix hexa™ (dtpa–hbv–ipv/hib hexavalent vaccine)

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663www.expert-reviews.com ISSN 1476-0584© 2009 Expert Reviews Ltd

Vaccine Profile

10.1586/ERV.09.32

Fred Zepp†, Heinz-Josef Schmitt, Jan Cleerbout, Thomas Verstraeten, Lode Schuerman and Jeanne-Marie Jacquet †Author for correspondenceUniversity Hospital, Department of Pediatrics, Johannes Gutenberg University, Langenbeckstrasse 1, 55131 Mainz, Germany Tel.: +49 6131 177 326 Fax: +49 6131 173 [email protected]

Combination vaccines that include multiple antigens within one formulation are now widely accepted as an effective means of eliciting protection against several diseases at the same time. Owing to improvements in quality and convenient modes of administration, they have become part of routine pediatric practice. Hexavalent vaccines, including diphtheria, tetanus, pertussis, hepatitis B, polio and Haemophilus influenzae type b antigens represent the latest advance in the development of combination vaccines. Over 8 years since its first licensure, this review looks at the immunogenicity, efficacy and safety profile of the only hexavalent pediatric vaccine currently in use – Infanrix hexa™ (diphtheria, tetanus, acellular pertusis–hepatitis B virus–inactivated poliovirus vaccine/Haemophilus influenzae type b vaccine [DTPa–HBV–IPV/Hib]; GlaxoSmithKline Biologicals, Rixensart, Belgium) – through published clinical trials and postmarketing surveillance data. These data show DTPa–HBV–IPV/Hib to be highly immunogenic and well tolerated across a range of different primary and booster vaccination schedules, as well as when administered concomitantly with other licensed vaccines (e.g., pneumococcal conjugate vaccine). Additional issues surrounding the use of hexavalent vaccines are also reviewed.

Keywords: combination • Haemophilus influenzae type b • hepatitis B • hexavalent • immunogenicity • Infanrix hexa™ • pertussis • safety • vaccination

Review of 8 years of experience with Infanrix hexa™ (DTPa–HBV–IPV/Hib hexavalent vaccine)Expert Rev. Vaccines 8(6), 663–678 (2009)

Importance of combination vaccinesThe growing number of childhood diseases for which active infant vaccination is rec-ommended has led to increasingly complex and crowded vaccination schedules [1,2,101]. Combination vaccines represent an important means of simplifying vaccination strategies and improving compliance. The development of pediatric combination vaccines began with the combination of diphtheria, tetanus and per-tussis (DTP) antigens into one DTP vaccine; over the years, antigens to other diseases have been subsequently added to the DTP ‘back-bone’. Combination vaccines, particularly DTP-based vaccines, are now widely accepted as a means of eliciting protection against sev-eral diseases simultaneously, and have become part of routine pediatric practice. However, despite their success, there is always the risk of interaction between the components of indi-vidual vaccines when they are combined as one vaccine; as a result, there is a clear need to

thoroughly evaluate and monitor the efficacy and safety of combination vaccines before and after licensure.

In Europe, vaccination of infants against diph-theria, tetanus, pertussis, polio and Haemophilus influenzae type b (Hib) disease is recommended in most countries [3,101]; the hepatitis B vaccine is also commonly incorporated into infant vac-cination schedules [4,5,101]. Hexavalent vaccines combining all of these antigens in one dose were first licensed in Europe by the EMEA in 2000 and represent the latest advance in com-bination vaccine technology. At the time of writing, only one hexavalent vaccine, Infanrix hexa™ (diphtheria, tetanus, acellular pertu-sis–hepatitis B virus–inactivated poliovirus vaccine/Haemophilus influenzae type b vaccine [DTPa–HBV–IPV/Hib]; GlaxoSmithKline [GSK] Biologicals, Rixensart, Belgium), is avail-able commercially; this is composed of diphthe-ria, tetanus and Pa antigens (pertussis toxoid [PT], filamentous hemagglutinin [FHA] and

Expert Rev. Vaccines 8(6), (2009)664

Vaccine Profile

pertactin [PRN]); hepatitis B surface antigen (HBsAg, referred to as the hepatitis B virus or HBV component); IPV (serotypes 1, 2 and 3) and Hib polyribosylribitol phosphate (PRP) antigen conjugated to tetanus toxoid (Table 1) [6]. All antigenic components of this vaccine have been in widespread clinical use for more than a decade [7,8]. This review examines knowledge generated in assessing the efficacy and safety of the DTPa–HBV–IPV/Hib vaccine 8 years after the beginning of its generalized use.

Immunogenicity of DTPa–HBV–IPV/HibAlthough most countries recommend completing the primary course of DTP vaccinations within the first 6 months of life (e.g., doses given at 2–3–4 months or 2–4–6 months of age), vaccination schedules can differ markedly between countries. A number of countries employ the WHO Expanded Program on Immunization (EPI) schedule of DTP vaccinations at 6, 10 and 14 weeks of age (e.g., the Philippines and South Africa) [102]. Others may use a 3–5–11- or 3–5–12-month schedule (e.g., Italy and Sweden) [101,102]. Most countries recommend booster doses in the second year of life, the timing of which differs from country to country [9].

The capacity to induce a strong immune response and protect against disease in different vaccination scenarios worldwide is of the utmost importance. Since its licensure, the immunogenicity of DTPa–HBV–IPV/Hib has been assessed across a range of primary vaccination schedules and booster doses, and a number of studies have been published [10–29] (representative studies are detailed in Tables 2 & 3). In these studies, antibody responses above thresh-old titers generally considered to correlate with protection were seen in the large majority of subjects, irrespective of the dosing

schedule. After 1 month following completion of a three-dose pri-mary vaccination schedule in the first 6 months of life, seropro-tection rates ranged between 91.0% (57.4% if a higher anti-PRP cut-off value of >1.0 µg/ml is included [21]) and 100% [10,12,13,15–25] for diphtheria, tetanus, HBV, IPV and Hib antigens, and vac-cine response/seropositivity rates were 85.1–100% for pertussis antigens [10,13,15–25]. In the 3–5–11- or 3–5–12-month schedule, 1 month after administration of the second dose, seroprotection rates for diphtheria, tetanus, HBV, IPV and Hib antigens were 88.3–100% [11,14,29], and vaccine response rates for all pertussis antigens were 95.7–100% [11,14,29]. Similarly, 1 month after admin-istration of a booster dose in the second year of life, seroprotec-tion rates were between 96.8% and 100% for D, T, HBV, IPV and Hib antigens, and vaccine response/seropositivity rates were 86.0–100% for pertussis antigens [21,24–28].

Today, additional data are available that document the long-term persistence of antibodies in the years following booster vaccination. One study by Heininger et al. measured antibody persistence in children 4–6 years of age who had received a booster dose of DTPa–HBV–IPV/Hib at 12–18 months of age [26]. The study found that between 75.0 and 98.9% of chil-dren remained seroprotected for D, T, HBV, IPV and Hib anti-gens, while 34.5–98.9% remained seropositive for the pertussis antigens 3.5–4 years after receiving the booster dose (Table 3). The 34.5% seropositivity rate was for the PT component of the vaccine (the authors commented that this probably reflects the absence of exposure to pertussis disease in this population and may be indicative of continued protection). Further studies that investigate the ability of DTPa–HBV–IPV/Hib to maintain sero-protection or seropositivity against these diseases in the long term

are ongoing. The persistence of immunity to hepatitis B is a particular focus of these studies, as no HBV booster vaccination is currently recommended after the infant vaccination schedule. The findings from recent follow-up analyses confirm that primary and booster vaccinations with DTPa–HBV–IPV/Hib induce persistent levels of antibodies against the antigen components (including hepatitis B) for several years [30,31].

The immune response to some specific antigens across different schedules with DTPa–HBV–IPV/Hib, as well as related topics, will be discussed in the following sections in more detail.

Hepatitis B responseHepatitis B represents a serious global health burden. An estimated 2 billion people worldwide are infected with the virus and 350 million people have chronic liver infections [103]. In 2002, hepatitis B accounted for 600,000 deaths world-wide [104]. The WHO advocates universal

Table 1. Composition of the DTPa–HBV–IPV/Hib (Infanrix hexa™) vaccine.

Component Concentration (per 0.5 ml dose)

Diphtheria toxoid* Not less than 30 IU

Tetanus toxoid* Not less than 40 IU

Bordetella pertussis antigens • Pertussis toxoid* • Filamentous hemagglutinin*

• Pertactin*

25 µg25 µg8 µg

Hepatitis B surface antigen‡§ 10 µg

Poliovirus (inactivated) • Type 1 (Mahoney strain)¶

• Type 2 (MEF-1 strain)¶

• Type 3 (Saukett strain)¶

40 D-antigen unit8 D-antigen unit32 D-antigen unit

Haemophilus influenzae type b polysaccharide (polyribosylribitol phosphate)§

Conjugated to tetanus toxoid as carrier protein

10 µg 20–40 µg

*Adsorbed on aluminum hydroxide, hydrated (Al[OH]3).

‡Produced in yeast cells (Saccharomyces cerevisiae) by recombinant DNA technology.§Adsorbed on aluminum phosphate (AlPO

4).

¶Propagated in Vero cells. DTPa–HBV–IPV/Hib: Diphtheria, tetanus, acellular pertussis–hepatitis B virus–inactivated poliovirus vaccine/Haemophilus influenzae type b vaccine.Data taken from [6].

Zepp, Schmitt, Cleerbout, Verstraeten, Schuerman & Jacquet

www.expert-reviews.com 665

Vaccine ProfileTa

ble

2. R

epre

sen

tati

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win

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fere

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sch

edu

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(mo

nth

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ts a

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g s

ero

pro

tect

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nth

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ple

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n o

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e p

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ary

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inat

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sch

edu

le (

%)

Ref

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ti-D

>0

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/ml

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>0

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/ml

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ti-H

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g>

10 m

IU/m

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8

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0 µ

g/m

l

2–3

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ith

no b

irth

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ose

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HBV

Ger

man

y (1

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100

100

98

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9.0

100

99.

377

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9.3

99.

29

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[10]

2–4

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wit

h no

bir

th

do

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f H

BV

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n (4

0)

100

100

97.5

100

96

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3]

3–4

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ith

no b

irth

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ose

of

HBV

Ger

man

y (4

16–4

72)

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8 10

0 9

8.5

9

9.8

99.

0 10

0 9

6.0

67

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98

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98

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97.4

[1

7]

3–5

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wit

h no

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do

se o

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BV§

Ger

man

y an

d It

aly

(177

)

97.1

(10

0)

100

(10

0)

98

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8.9

)9

8.8

(10

0)

95.0

(10

0)

99.

4(1

00

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.7(1

00

)62

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9.4

)10

0(1

00

)9

8.7

(10

0)

100

(10

0)

[14]

6–1

0–1

4 w

eeks

, wit

h H

BV d

ose

at

bir

th¶

Phili

ppi

nes

(3

20);

gr

oup

1 (1

60

) als

o re

ceiv

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do

se

at b

irth

; gr

oup

2 (1

60

) di

d no

t

≥94

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96

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(98

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5]

* Th

e ta

ble

do

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ot p

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n ex

hau

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s.

‡V

acci

ne

resp

ons

e is

defi

ned

as

the

app

eara

nce

of

anti

bo

die

s ab

ove

th

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toff

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ue

>5 E

L.U

/ml)

in in

itia

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nce

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o o

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cent

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on

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itia

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ero

po

siti

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ub

ject

s [1

0,13

,14]

.§V

alu

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rote

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ter

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seco

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se o

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ont

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ccin

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n sc

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ule

. Val

ues

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aren

thes

es d

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rop

rote

ctio

n o

r va

ccin

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spo

nse

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s 1

mo

nth

afte

r th

e th

ird

do

se o

f th

e 3

–5–1

1-m

ont

h va

ccin

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n sc

hed

ule

.¶Se

rop

rote

ctio

n/v

acci

ne

resp

ons

e ra

tes

sho

wn

as >

94

.5%

ind

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e w

her

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ata

for

ind

ivid

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ntig

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are

not

sp

ecifi

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th

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ub

lish

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on

gre

ss a

bst

ract

. Val

ues

fo

r an

tip

ertu

ssis

ant

ibo

die

s (P

T, F

HA

an

d PR

N) a

re

defi

ned

in t

he

abst

ract

as

sero

conv

ersi

on

rate

s.D

: Dip

hth

eria

; DTP

a–H

BV

–IPV

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: Dip

hth

eria

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anu

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lar

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tuss

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epat

itis

B v

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acti

vate

d p

olio

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s va

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aem

op

hilu

s in

flu

enza

e ty

pe

b va

ccin

e; E

L.U

: ELI

SA u

nit;

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A: F

ilam

ento

us

hem

agg

luti

nin

; H

BsA

g: H

epat

itis

B s

urf

ace

anti

gen

; HB

V: H

epat

itis

B v

iru

s; n

/a: N

ot a

vaila

ble

; PR

P: P

oly

rib

osy

lrib

ito

l ph

osp

hate

; PR

N: P

erta

ctin

; PT:

Per

tuss

is t

oxo

id; T

: Tet

anu

s; V

R: V

acci

ne

resp

ons

e.

8 years of experience with Infanrix hexa™ (DTPa–HBV–IPV/Hib hexavalent vaccine)


Vaccine ProfileTa

ble

3. R

epre

sen

tati

ve s

tud

ies

sho

win

g im

mu

no

gen

icit

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oo

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cin

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ith

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(In

fan

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d

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b

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(m

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(n)

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ng

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op

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ero

po

siti

vity

or

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se‡ 1

mo

nth

aft

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oo

ster

vac

cin

atio

n (

%)

Ref

.

An

ti-D

>0

.1 IU

/ml

An

ti-T

>0

.1 IU

/ml

An

ti-H

BsA

g>

10 m

IU/m

lA

nti

-p

olio

1

>1:

8

An

ti-

po

lio 2

>

1:8

An

ti-

po

lio 3

>

1:8

An

ti-P

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An

ti-P

T >

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A

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>

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l

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0 µ

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8 (D

TPa–

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ib a

lon

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man

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mon

th

po

stb

oo

st(2

71–3

07)

3.5

–4 y

ears

p

ost

bo

ost

(86

–89

)

100

n =

307

75.0

n

= 8

8

100

n =

307

76.4

n

= 8

9

98

.7n

= 3

07

91.0

n

= 8

9

100

n =

281

96

.6

n =

89

100

n =

271

92.0

n =

87

100

n =

279

98

.8

n =

86

99.

3 n

= 3

07

98

.9

n =

88

99.

0 n

= 3

07

77.5

n

= 8

8

100

n =

307

34

.5

n =

87

100

n =

30

6

98

.9

n =

88

100

n =

307

87.6

n

= 8

9

[26]

12–2

3 (D

TPa–

HBV

–IPV

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ib +

7v

PCV

)

Ger

man

y (1

28)

100

100

96

.810

010

010

010

09

6.8

100

(VR

)9

6.8

(V

R)

98

.4 (

VR

)[2

1]

12–2

3 (D

TPa–

HBV

–IPV

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ib +

M

MR

-V)

Ger

man

y (1

01–1

34

)10

0

n =

13

410

0

n =

13

49

9.2

n =

131

100

n

= 1

04

100

n

= 1

0510

0 n

= 1

0110

0 n

= 1

34

100

n =

13

410

0 n

= 1

34

100

n =

132

93.3

n

= 1

34

[28]

* Th

e ta

ble

do

es n

ot p

rese

nt a

n ex

hau

stiv

e lis

t of

stu

die

s.

‡B

oo

ster

vac

cin

e re

spo

nse

to p

ertu

ssis

ant

igen

s is

defi

ned

as

the

app

eara

nce

of

anti

bo

die

s in

init

ially

ser

on

egat

ive

sub

ject

s o

r a

twof

old

incr

ease

in p

reva

ccin

atio

n an

tib

od

y ti

ters

aft

er t

he

bo

ost

er d

ose

in in

itia

lly

sero

po

siti

ve s

ub

ject

s [2

1].

§V

alu

es in

par

enth

eses

den

ote

sero

pro

tect

ion

/ser

op

osi

tivi

ty r

ates

mea

sure

d 3.

5–

4 ye

ars

po

stb

oo

ster

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PCV

: Sev

en-v

alen

t p

neu

mo

cocc

al c

onj

ug

ate

vacc

ine;

D; D

ipht

her

ia; D

TPa–

HB

V–I

PV/H

ib: D

ipht

her

ia, t

etan

us,

ace

llula

r p

ertu

ssis

–hep

atit

is B

vir

us–

inac

tiva

ted

po

liovi

rus

vacc

ine

/Hae

mo

phi

lus

infl

uen

zae

typ

e b

vacc

ine;

EL.

U: E

LISA

uni

t; F

HA

: Fila

men

tou

s h

emag

glu

tini

n; H

BsA

g: H

epat

itis

B s

urf

ace

anti

gen

; PR

N: P

erta

ctin

; PR

P: P

oly

rib

osy

lrib

ito

l ph

osp

hate

; PT:

Per

tuss

is t

oxo

id; M

MR

–V: M

easl

es–m

um

ps–

rub

ella

–var

icel

la

vacc

ine;

T: T

etan

us;

VR

: Vac

cin

e re

spo

nse.



Vaccine Profile

infant vaccination against hepa titis B [103], and has recommended the inclusion of a hepatitis B vaccine in all national vaccin ation programs from 1997 onwards [4,32,33]. Hepatitis B is often trans-mitted from mothers to their newborns at the time of birth, this being a major route for hepatitis B transmission [34]. Furthermore, hepatitis B infection at younger ages carries a higher risk of pro-gression to a chronic carrier state, which can lead to the develop-ment of fatal complications in later life [33,34]. Hepatitis B vac-cination programs implemented via DTP-based combination vaccines provide an effective way of protecting infants against this disease [34,35].

As highlighted in Tables 2 & 3, results from several studies con-firm the immunogenicity of the hepatitis B component of the DTPa–HBV–IPV/Hib vaccine, irrespective of the vaccination schedule used. When administered on a three-dose primary vac-cination course in the first 6 months of life, seroprotection rates for hepatitis B (i.e., anti-HBsAg levels >10 mIU/ml) ranged from 93.4 to 100% 1 month after completion of the schedule [10,12,13,15–

20,22,23,25]. Seroprotection rates for hepatitis B ranged from 94.8 to 98.3% after two doses, and 98.6 to 99.1% following all three doses, when DTPa–HBV–IPV/Hib was administered using a 3–5–11- or 3–5–12-month vaccination schedule [11,14,29]. With the accelerated 6–10–14-week EPI schedule, a birth dose of HBV vaccine is necessary to achieve targeted seroprotection rates 95% or higher [6,25].

In children previously primed with three doses of DTPa–HBV–IPV/Hib in the first 6 months of life, a booster dose of the same vaccine in the second year of life is highly immunogenic, with anti-HBsAg seroprotection rates of 96.8–100% reported 1 month after boosting [21,22,24–26,28].

Long-term protection against hepatitis B offered by infant HBV vaccines in nonendemic parts of the world is a topic that is start-ing to be explored today, as those individuals vaccinated as infants reach adolescence and adulthood [36,38]. Long-term protection is of the utmost importance, as it is needed in older age groups; it is therefore the object of particular scrutiny from regulatory authori-ties. Indeed, a decrease in the immunogenicity of the hepatitis B component was the reason for suspension of one alternative infant HBV-containing combination vaccine by the EMEA in 2005, as it was found that its use could lead to diminished long-term protection against hepatitis B [105].

Vaccination with DTPa–HBV–IPV/Hib has been shown to provide sustained protection against hepatitis B into early child-hood; the follow-up study by Heininger and colleagues [26] showed that 91% of children remained seroprotected against hepatitis B at 4–6 years of age, 3.5–4 years after booster vaccination. Recent data show that 7–9-year-old children previously vaccinated with four doses of DTPa–HBV–IPV/Hib mount a response to an add-itional HBV vaccine dose: 98.4% achieve anti-HBsAg concentra-tions of 10 mIU/ml or more and 93.6% anti-HBsAg concentra-tions of 100 mIU/ml or more, with anti-HBsAg geometric mean concentrations (GMCs) increasing approximately 100-fold [30]. This strong anamnestic response is indicative of immune mem-ory to HBV persisting for up to 6.5 years after the fourth dose of DTPa–HBV–IPV/Hib.

Haemophilus influenzae type b (Hib) responseHaemophilus influenzae type b causes a number of serious dis-eases, including meningitis and pneumonia, and has been esti-mated to cause 386,000 deaths each year worldwide, most of which are in children 0–4 years of age [106]. The majority of these occur in developing countries without established vac-cination programs. Invasive Hib disease was endemic and a major cause of morbidity and mortality among children under 5 years of age in regions such as Europe and Australia before the introduction of mass vaccination programs [38–40]. Although Hib disease can be treated with antibiotics, the most effective means of controlling it is by vaccination; this generally takes place in young children, who are in the highest risk group for Hib infection [41,106].

When first introduced, DTPa–Hib combination vaccines were shown to be associated with an immune interference, leading to decreased antibody concentrations against the Hib component of the vaccine [42–44]. This phenomenon was also observed with DTPa–HBV–IPV/Hib [10]. The precise mecha-nism underlying this interference still remains poorly under-stood, but it may be related to the absence of an adjuvant effect of the whole-cell pertussis (Pw) component, as this interference has generally not been observed with DTPw combination vac-cines to the same extent [44–46]. However, a group of experts in the field of Hib vaccination who reviewed all existing data concluded that the interference did not impair the protective capacity of the combination vaccines and therefore did not have major clinical implications. The expert group recommended that DTPa–Hib combination vaccines should be adopted into routine vaccin ation schedules ‘with the proviso that careful clinical surveillance of Hib disease is maintained’ [44]. Of note, the interference does not appear to impair antibody function or the induction of immunologic memory to Hib. In a clini-cal study, induction of immunologic memory was observed in infants who received a three-dose primary course of DTPa–HBV/Hib, using a 3–4–5-month vaccination schedule [47]. Subsequent administration of unconjugated PRP at 1 year of age (alongside a DTPa–HBV booster) elicited protective anti-PRP antibody levels (>0.15 µg/ml) in all but three out of the 369 vaccinees, indicating successful induction of immunologic memory. Protective anti-PRP antibody levels were also observed in 13 infants who failed to demonstrate a measurable immune response after the primary vaccination course [47].

Following DTPa–HBV–IPV/Hib vaccination accord-ing to a three-dose primary vaccination schedule in the first 6 months of life, seroprotection against Hib is between 91.0 and 100% [10,13,15–23,25]. When administering DTPa–HBV–IPV/Hib using the 3–5–11- or 3–5–12-month vaccination schedule, sero-protection rates for Hib were 88.3–93.5% after the first two doses and between 99.1 and 100% following all three doses [11,14,29]. Induction of immune memory to the Hib component by the hexavalent vaccine was demonstrated [15]. After 1 month fol-lowing a booster dose in the second year of life, seroprotection rates were between 99 and 100% [21,22,24–27]. Heininger and col-leagues found that 98.9% of individuals retained seroprotection



Vaccine Profile

against Hib 3.5–4 years after a booster dose of DTPa–HBV–IPV/Hib [26]. More recently, Zinke et al. showed that over 99% of 7–9-year-old children retained anti-PRP concentrations of at least 0.15 µg/ml after four doses of DTPa–HBV–IPV/Hib [31].

Since their licensure, there have been reports relating to the effectiveness of hexavalent vaccines in the field. In Germany, the Hib vaccine was introduced as part of a DTPa combin ation vaccine in 1990. Follow-up studies of the effectiveness of Hib-containing combination vaccines in practice, including hexavalent vaccines, have shown that they are highly effective in reducing the incidence of invasive Hib disease [48–50]. The effectiveness of hexavalent vaccines against invasive Hib disease in Germany has been reported to be 90.4% after completion of the full primary vaccination course, and 100% after booster vaccination [50].

The value of a booster dose of Hib vaccine in the second year of life was recently highlighted in the UK [51] and the Republic of Ireland [52]. Hib vaccination without booster was introduced in the UK and Ireland during 1992 according to a 2–3–4-month or 2–4–6-month primary vaccination schedule, respectively. In the UK, a catch-up schedule was also introduced for those under 4 years of age. Although disease rates initially fell rapidly, an increase in Hib disease incidence was first observed in the UK in 1999 and continued into 2002 [51]. This small rise following an initial fall was also observed in Ireland [52], and booster doses were subsequently recommended. There are several possible contribu-tory factors for the increased incidence, which include decreas-ing herd immunity; the short, early 2–3–4-month UK schedule possibly leading to earlier waning of immunity, coupled with the absence of a Hib booster dose in the second year of life; and the DTPa–Hib combination vaccine used during 2000–2001 being less immunogenic than the DTPw/Hib combination vaccine used up to that point [53]. The quality, maturation and protective capac-ity of specific Hib antibodies were shown to be equivalent in subjects who received primary and booster vaccination with Hib vaccine, administered either alone, as DTPa–HBV–IPV/Hib, or as other DTPa–Hib combinations [54].

Safety & tolerability of DTPa–HBV–IPV/HibAlong with its immunogenicity, the safety of DTPa–HBV–IPV/Hib has also been assessed across a wide range of primary vaccin-ation schedules and following booster doses in the second year of life [10–26,28,29,55,56]. In the following section, a summary of safety data for DTPa–HBV–IPV/Hib accumulated since licensure (from clinical trials and from safety monitoring) is given.

Safety & tolerability across different vaccination schedules: clinical trialsIn studies comparing DTPa–HBV–IPV/Hib with lower-valent DTPa or DTPw combination vaccines, or when coadministered with other vaccines, according to typical primary vaccination schedules (6–10–14 weeks, 2–3–4 months, 2–4–6 months, 3–4–5 months, 3–5–11 or 3–5–12 months), a low incidence of solicited, clinically significant (grade 3; i.e., preventing normal daily activities) adverse events (AEs) was reported in the first 4 (or 8) days postvaccination (Figure 1) [10,11,13,14,16,17,19–23,25,29,55].

Across the primary vaccination schedule, the incidence ranged between 0 and 10% of doses administered. Serious adverse events (SAEs) were rare (e.g., 2.6% in more than 2000 infants admin-istered DTPa–HBV–IPV/Hib according to a three-dose primary vaccination schedule, most of which were common childhood disorders considered unrelated to vaccination, such as respiratory and urinary tract infections, and gastrointestinal disorders) [17].

Across the studies, tolerability was generally similar or super ior to that of the control vaccine. Indeed, a significantly higher inci-dence of localized redness and swelling occurred in subjects receiv-ing a DTPw–IPV/Hib vaccine compared with subjects receiving DTPa–HBV–IPV/Hib or separate doses of DTPa–HBV–IPV and Hib in primary vaccination [55]. With all DTPa vaccines, the frequency and severity of swelling increases with age and additional doses of vaccine, as seen following the fourth or fifth dose [57]. Higher incidences of local symptoms were observed after the administration of the DTPa–HBV–IPV/Hib booster dose in the second year of life than were seen after the administration of primary doses [21].

Overall, the most commonly reported local reactions in all stud-ies of DTPa–HBV–IPV/Hib published since its launch have been injection-site reactions of pain, redness and swelling, with systemic effects of irritability, drowsiness and fever. Most AEs were mild and transient, with SAEs reported rarely and at rates similar to those experienced with pentavalent vaccines. As with other DTPa vaccines [57,58], cases of extensive limb swelling have been reported after administration of a booster dose of DTPa–HBV–IPV/Hib. In a study by Saenger and colleagues [56], 103 out of 4032 sub-jects (2.6%) reported large swelling reactions (>50 mm and/or noticeable diffuse swelling or increased limb circumference) after receiving a booster dose of DTPa–HBV–IPV/Hib in the second year of life. Of these, two subjects (0.05% of the study cohort) reported swelling involving at least one adjacent joint.

Safety in the field: monitoring dataMore than 28 million doses of DTPa–HBV–IPV/Hib have been distributed to date since first approval on 23 October 2000. Table 4 summarizes the ten most frequent spontaneously reported AEs for DTPa–HBV–IPV/Hib according to the GSK worldwide safety database, referred to as the Operating Companies Event Accession and Notification System, where all spontaneously reported AEs received by GSK are stored [GSK, Data on file]. The main strengths of such databases are related to the size and diversity of the expo-sure they represent, whereas the main weaknesses of databases consisting of spontaneous safety reports are related to the qual-ity of the reports, the under-reporting of most minor AEs unless solicited and the lack of denominators.

Adverse events were reported with a frequency of between 0.7 and 5.9 per 100,000 doses distributed. The incidences of local and systemic AEs following administration of DTPa–HBV–IPV/Hib are comparable to those seen with other licensed DTPa-based vaccines. The vaccine (administered in a primary vaccination course or as a booster dose) is well tolerated, with local adverse reactions, including redness, pain, and swelling, and systemic fever being the most commonly reported events. As with other



Vaccine Profile

DTPa vaccines, extensive swelling reactions, including swelling of the entire injected limb, have been reported very rarely in a postmarketing setting. Although swelling may interfere with walking, most children have no limitation of activity, with reac-tions resolving without sequelae. Convulsions (with or without fever) are the most frequently spontaneously reported nervous system disorders. More severe nervous system disorders, such as encephalitis/encephalomyelitis or Guillain–Barré syndrome, have been sporadically reported after administration of DTPa–HBV–IPV/Hib (frequencies of 0.02 and 0.01 per 100,000 dis-tributed doses, respectively, as at October 2008), without an established causal relationship with the vaccine [GSK, Data on file]. Recently, European Union (EU) regulators asked manufactur-ers to add a warning/precaution to the EU product information for all vaccines likely to be administered to children regarding the potential risk of apnea and the need for subsequent respira-tory monitoring when the primary vaccination course is admin-istered to high-risk premature infants [107]. The potential risk of apnea for the complete Infanrix™-based vaccine range was assessed by reviewing spontaneous reports of events suggestive of breathing abnormal ities and the literature data, and by tak-ing into account official recommendations from external bodies, such as the American Academy of Pediatrics [59] and the Advisory Committee on Immunization Practices [60]. From this review, it was concluded that the potential risk of apnea and the need for re spira tory monitoring for 48–72 h should be considered when administering the primary vaccination course to very premature infants (born <28 weeks of gestation), and particularly for those with a previous history of respiratory immaturity. However, as the benefit of vaccination is high in this group of infants, vaccination should not be withheld or delayed [6,107]. In support of this, studies with DTPa–HBV–IPV/Hib have shown it to be well tolerated in premature infants, with a generally good immune response to all antigens reported [19,27].

Sudden unexpected death in infantsIn the past, there had been suggestions of a temporal associ-ation between DTPw vaccines and sudden unexpected death (SUD), owing to the observed ‘clustering’ of SUD cases occur-ring within a few days of the administration of a DTPw vac-cine [9,61,62]. However, subsequent studies found no causal rela-tionship between DTPw vaccines and SUD [9,62–64]. Based on the available clinical evidence, and given that SUD is most common in infants less than 6 months of age, cases of SUD a few days after DTPw vaccination were considered chance occurrences [9].

With regard to hexavalent DTPa combination vaccines, in the first 2.5 years following their introduction, postmarketing safety monitoring (pharmacovigilance) reported five cases of SUD in the first and second year of life in Austria and Germany that were temporally associated with vaccination [65].

The scientific committee of the EMEA, now known as the Committee for Medicinal Products for Human Use (CHMP), met in April 2003 to review the available data and assess the safety of hexavalent vaccines [108,109]. Based on the data available, the

CHMP concluded that it was not possible to establish a ‘cause and effect’ association between hexavalent vaccine use and SUD, as there were a number of other possible risk factors considered (including a family history of epilepsy and convulsions in three of the five cases). They concluded that there was no change in the risk–benefit profile of these vaccines, and did not recommend any changes to the present conditions of use [108].

In response to these reports, a large systematic study was under-taken in Germany to investigate possible links between the two approved hexavalent vaccines licensed in Germany (Infanrix hexa and Hexavac™ [Sanofi Pasteur]) and cases of SUD in the first and second years of life from November 2000 to June 2003 [66,67]. The study found no evidence of an association between the use of either hexavalent vaccine and SUD in the first year of life. A possible signal for increased risk of SUD in the second year of life was reported with one of the vaccines (revealed to be Hexavac by the author in a subsequent publication [67]), although the author stated that this did not prove an association between hexavalent vaccine use and SUD [66].

An observed/expected ana lysis of cases of SUD following vac-cination with DTPa–HBV–IPV/Hib was conducted by GSK as part of the Infanrix hexa Periodic Safety Update Report ([PSUR] No. 12, 14 December 2007). The estimates were calculated based on national birth cohort (Germany), the incidence of the disease in the first or second year of life, the proportion of SUD occurring in a given month and the proportion of children receiving a dose of vaccine during that month. To obtain worldwide estimates, the value for Germany was multiplied by a factor of 2.44 (the ratio of total doses of hexavalent vaccine distributed worldwide compared with the distribution in Germany). This ana lysis shows that the number of SUD cases reported within 14 days of vaccination with

Table 4. Most frequent adverse events for DTPa–HBV–IPV/Hib (Infanrix hexa™) from launch up to the present, spontaneously reported to the GlaxoSmithKline worldwide safety database (OCEANS).

AE Number of AEs Frequency per 100,000 doses

Pyrexia 1572 5.9

Injection-site erythema 570 2.1

Injection-site swelling 488 1.8

Crying 465 1.7

Injection-site reaction 294 1.1

Injection-site induration 256 1.0

Hypotonia 218 0.8

Urticaria 210 0.8

Pallor 200 0.8

Erythema 196 0.7

AE: Adverse event; DTPa–HBV–IPV/Hib: Diphtheria, tetanus, acellular pertussis–hepatitis B virus–inactivated poliovirus vaccine/Haemophilus influenzae type b vaccine; OCEANS: Operating Companies Event Accession and Notification System.



Vaccine ProfileD

ose

s o

r su

bje

cts

(%)

20

16

12

8

4

0

1 2 3 4 5 6 7

Pain

Redness

Swelling

Incidence of grade 3 local symptoms (days 0–3 postvaccination)

Primary schedule(three doses in first 6 months)

Booster dose(in second year of life)

20

16

12

8

4

0

Do

ses

or

sub

ject

s (%

)

Incidence of grade 3 general symptoms (days 0–3 postvaccination)

1 2 3 4 5 6 7

Primary schedule(three doses in first 6 months)

Booster dose(in second year of life)

Fever (>39.5°C)

Irritability

Drowsiness

DTPa–HBV–IPV/Hib alone

*

Study

Study

A

B

Figure 1. Representative studies showing the incidence of grade 3 symptoms associated with DTPa–HBV–IPV/Hib (Infanrix hexa™). (A) Local symptoms and (B) general symptoms.1 = DTPa–HBV–IPV/Hib administered at 2–3–4 months (showing incidence as percentage of subjects) [10].2 = DTPa–HBV–IPV/Hib administered at 2–4–6 months (coadministered with tetanus toxoid-conjugated meningococcal C vaccine [MenC-TT]; showing cumulative incidence after all three primary doses) [23].3 = DTPa–HBV–IPV/Hib administered at 2–4–6 months (coadministered with CRM

197-conjugated meningococcal C vaccine [MenC-CRM];

showing cumulative incidence after all three primary doses) [16].4 = DTPa–HBV–IPV/Hib administered at 2–3–4 months (coadministered with seven-valent pneumococcal conjugate vaccine [7vPCV]; dose 3 values shown) [21].5 = DTPa–HBV–IPV/Hib (booster) administered at 12−18 months [26].6 = DTPa–HBV–IPV/Hib (booster) administered at 12−23 months (coadministered with 7vPCV) [21].7 = DTPa–HBV–IPV/Hib administered at 12−23 months (coadministered with measles–mumps–rubella–varicella vaccine [MMR-V]) [28].Grade 3 pain: child cries when limb is moved/spontaneously painful; grade 3 redness/swelling: redness/swelling >20 mm in diameter; grade 3 drowsiness: drowsiness that prevents normal activity; grade 3 irritability/fussiness: crying that cannot be comforted/prevents normal activity.*Incidence of grade 3 fever in study 7 [28] was assessed over days 0–14 postvaccination; incidence over days 0–3 postvaccination is not specified in the paper. Incidence of irritability or drowsiness is also not specified. The authors suggest that the 18% incidence rate of grade 3 fever in the DTPa–HBV–IPV/Hib–MMR-V coadministration group is largely due to the measles component (typically known to induce a peak fever rate during the second week postvaccination). In the group receiving DTPa–HBV–IPV/Hib alone, an incidence rate of 3.3% was recorded over days 0–14 postvaccination.DTPa–HBV–IPV/Hib: Diphtheria, tetanus, acellular pertussis–hepatitis B virus–inactivated poliovirus vaccine/Haemophilus influenzae type b vaccine.



Vaccine Profile

GSK’s DTPa–HBV–IPV/Hib vaccine is below the number of cases expected for this time period in the first year of life. In the second year of life, the number of SUDs reported within 1–5 days after vaccination with DTPa–HBV–IPV/Hib is comparable with the number expected. Beyond the first 5 days postvaccination, the observed number of SUDs is below the number expected. The results of this ana lysis are presented in Table 5.

Interestingly, the recent publication of a meta-ana lysis exam-ining the relationship between DTP vaccinations and sudden infant death syndrome (i.e., SUD in children <1 year of age) contradicts earlier reports, suggesting instead that DTP vaccina-tion may be associated with a significantly lower risk of sudden infant death syndrome [68]. However, there were some limita-tions to the meta-ana lysis, including the temporal proximity of these studies to ‘Back to Sleep’ campaigns, which may also have influenced the findings.

Impact of DTPa–HBV–IPV/Hib on vaccine coverage & timeliness of vaccinationSome advantages of combination vaccines include fewer injec-tions and therefore reduced trauma to the infant, as well as simplified administration. Combination vaccines may also be the most effective way of ensuring high rates of compliance with complex vaccination schedules, leading to better vaccine coverage and more timely vaccination [69–71]. For example, in a recent study conducted in Germany, the vaccination records of 2701 children born between 1996 and 2003 were gathered and assessed [70]. The percentage of children receiving their 2–3–4-month primary and 11- to 14-month booster vaccinations on time (i.e., first dose, full primary series and full vaccination by 3, 5 and 15 months of age, respectively) was calculated. This was then shown across a time period when the vaccines that were predominantly used shifted sequentially from monovalent to tetravalent, to pentavalent, and finally, to hexavalent vaccines.

The study showed that, on average, fewer children receiving monovalent vaccine were vaccinated on time compared with those receiving tetravalent, pentavalent and hexavalent vaccines (e.g., full Hib vaccination on time: 13.3 [monovalent] versus 39.1% [hexavalent DTPa–HBV–IPV/Hib]). It was also found that hexavalent vaccines decrease the median age of vaccine receipt compared with monovalent vaccines (e.g., full vaccina-tion on time: -2.2 months for Hib, -3.2 months for polio and -1.4 months for HBV). Several other possible explanations for these observations were considered by the authors, including socioeconomic factors and behavioral aspects, but when these factors were controlled for, there was no difference in the results.

Combination vaccines were also found to be associated with increased coverage. In a recent retrospective study of infants in the USA, vaccine coverage rates in those given a combination vac-cine (e.g., a pentavalent DTPa–HBV–IPV vaccine) were greater than in those who received the same antigenic components but in lower-valent vaccines [71]. Combination vaccines also offer further benefits in terms of reduced administration costs [2] and storage space requirements.

Coadministration with other vaccinesCombination vaccines that can be coadministered with other vaccines add convenience and are likely to increase compliance by reducing the number of clinic visits. The coadministration profile of a vaccine is therefore an important factor. A recent review examining the effects of the coadministration of conjugate pneumococcal or meningococcal vaccines with hexavalent vac-cines concluded that, while the number of published studies was small, coadministration had no ‘noteworthy negative effects’ on the safety and immunogenicity of the vaccines in question [72].

Here, we assess some of the documented evidence surrounding the concomitant administration of DTPa–HBV–IPV/Hib with other vaccines.

Table 5. Cumulative number of observed/expected cases of sudden unexpected death following vaccination with DTPa–HBV–IPV/Hib (Infanrix hexa™) in the first and second year of life, October 2000–October 2007.

First year of life Second year of life

Time since vaccination (days)

Observed* Expected O:E standardized incidence ratio (95% CI)

Observed* Expected O:E standardized incidence ratio (95% CI)

1 9 39.61 0.23 (0.10, 0.43) 2 0.59 3.41 (0.41, 12.25)

2 21 79.21 0.27 (0.16, 0.41) 3 1.17 2.56 (0.53, 7.49)

3 28 118.82 0.24 (0.16, 0.34) 3 1.76 1.71 (0.35, 4.98)

4 33 158.43 0.21 (0.14, 0.29) 3 2.34 1.28 (0.26, 3.75)

5 34 198.03 0.17 (0.12, 0.24) 3 2.93 1.02 (0.21, 2.99)

6 34 237.64 0.14 (0.10, 0.20) 3 3.52 0.85 (0.18, 2.49)

7 36 277.25 0.13 (0.09, 0.18) 3 4.10 0.73 (0.15, 2.14)

14 40 554.49 0.07 (0.05, 0.10) 5 8.21 0.61 (0.20, 1.42)*Data lock point: 23 October, 2007. CI: Confidence interval; DTPa–HBV–IPV/Hib: Diphtheria, tetanus, acellular pertussis–hepatitis B virus–inactivated poliovirus vaccine/Haemophilus influenzae type b vaccine; E: Expected; O: Observed.



Vaccine Profile

Pneumococcal & meningococcal vaccinesRecent studies have examined the efficacy and safety profiles of DTPa–HBV–IPV/Hib and a seven-valent pneumococcal vaccine when coadministered during primary vaccination at 2–3–4 months of age, and with the booster dose at 12–15 months of age [22] or 12–23 months of age [21]. Following primary vaccina-tion, comparable seroprotection or vaccine response rates against most antigens were obtained when DTPa–HBV–IPV/Hib was given alone and in combination with the seven-valent pneumo-coccal vaccine [21,22]. In one study, no significant reductions in geometric mean titer (GMT)/GMC values were observed with coadministration after primary vaccination [21]. After the fourth dose, GMT/GMC values for several of the antigens were lower in the coadministration group than in the separate-administration group. However, seroprotection/vaccine response rates after the booster were only moderately affected with regard to HBV and two of the three pertussis components (FHA and PRN), ranging from 96.8 to 99.1%. The other study confirmed the adequate immunogenicity of coadministration; small reductions in GMCs for some antigens were observed with coadministration after the third dose, but no clinically relevant impact on seroprotection or vaccine response rates were observed [22]. The two studies also showed that coadministration of the vaccines was well tolerated, with a similar frequency of local adverse reactions reported, com-pared with those subjects given the vaccines on separate occasions. The frequency of the systemic reactions (fever 38–39°C, antipy-retic use, sleepiness, fussiness or loss of appetite) was significantly greater in the coadministration group [22].

DTPa–HBV–IPV/Hib has also been shown to be well tolerated and immunogenic when coadministered with a number of menin-gococcal serogroup C vaccines: CRM

197-conjugated vaccines

(Meningitec™ [Wyeth Lederle Vaccines, Pearl River, NY, USA], Menjugate™ [Novartis Vaccines, Marburg, Germany]) [16,73,74] and a tetanus toxoid conjugate vaccine (NeisVac-C™ [Baxter Vaccines, Vienna, Austria]) [23]. In a study of infants in Spain receiving DTPa–HBV–IPV/Hib (2–4–6 months) and menin-gococcal C vaccine (2–4–6 or 3–5–7 months), coadministration of the two revealed a similar tolerability profile to that of sepa-rate administration [16]. There was a modest increase in titers of antibody against the meningococcal antigens when the vaccines were administered separately; however, this was attributed to the ‘priming’ effect of diphtheria toxoid in the DTPa–HBV–IPV/Hib vaccine, enhancing the immunogenicity of the meningococ-cal C vaccine [16]. No significant difference in seroprotection rates was detected between the two groups [16,72].

Measles–mumps–rubella–varicella vaccineCoadministration of DTPa–HBV–IPV/Hib with a recently approved measles–mumps–rubella–varicella vaccine (MMR-V; Priorix tetra™, GSK Biologicals) has been assessed at the time of the DTPa booster dose at the age of 12–23 months [28]. A total of 6 weeks after coadministration of the vaccines, no impact on immune response was seen, and coadministration was well toler-ated with a low incidence of AEs [28]. The incidence of local and general symptoms was slightly higher in the group receiving the

DTPa–HBV–IPV/Hib and MMR-V concomitantly. No SAEs considered related to vaccination were reported. To determine whether the lack of negative impact of coadministration of DTPa–HBV–IPV/Hib and MMR-V on vaccine efficacy and tolerability persists in the long term, further studies are needed. Indeed long-term effects, especially with regard to the efficacy of the MMR-V vaccine, can only be evaluated by additional follow-up studies.

Rotavirus vaccineResearch has shown that coadministration of DTPa –HBV–IPV/Hib with rotavirus vaccine in infants does not impair the immune response to any of the coadministered antigens [75]. In this study, healthy infants 6–14 weeks of age were given two doses of RIX4414 rotavirus vaccine (Rotarix™, GSK Biologicals, Rixensart, Belgium) or placebo concomitantly with DTPa–HBV–IPV/Hib or DTPa–IPV–Hib (Infanrix™ IPV Hib, GSK Biologicals, Rixensart, Belgium) vaccine in six European coun-tries. The immune response to the various antigens contained in the DTPa-combined vaccines was similar between the placebo and rotavirus vaccine groups, with seroprotection or seropositivity rates varying from 92 to 99% in those given an Infanrix vaccine and the rotavirus vaccine, and from 91 to 100% in those given an Infanrix vaccine and placebo [75].

ConclusionAs this review has highlighted, DTPa–HBV–IPV/Hib, the currently available hexavalent combination vaccine, is a robust vaccine, displaying a profile of good immunogenicity and tol-erability in a variety of settings using different primary and booster vaccination strategies. It has efficacy and safety profiles comparable to those of vaccines where the antigens are admin-istered separately. Furthermore, since its launch, the cumulative postmarketing experiences of countries such as Germany have demonstrated its effectiveness in the field, with maintenance of low incidence of invasive Hib disease [48–50]. It is important to continue to monitor the potential impact of introducing new vaccines for coadministration as they are developed in the future; a summary of the topics discussed in this review is provided in Table 6.

Studies have also shown that DTPa–HBV–IPV/Hib can be co administered safely with newly recommended vaccines (pneu-mococcal, meningococcal, MMR-V and rotavirus). Currently available data show that vaccination with DTPa–HBV–IPV/Hib also affords adequate long-term protection against diphtheria, tetanus, pertussis, polio, hepatitis B and Hib in children. Initial follow-up research has determined that boosting with the vac-cine in the second year of life provides a persistent level of sero-protection or seropositivity against the six diseases, including hep-atitis B and Hib disease, for at least 3.5–4 years [26,31]. In addition, recent data show that 7–9-year-old children previously vaccinated in infancy with DTPa–HBV–IPV/Hib mount a response to an additional HBV vaccine dose, indicating that immune memory to HBV persists for more than 6 years after the fourth dose of DTPa–HBV–IPV/Hib [30].



Vaccine Profile

Table 6. DTPa–HBV–IPV/Hib (Infanrix hexa™): summary of topics.

Topic Evaluation Results/findings Ref.

Immunogenicity Clinical studies with DTPa–HBV–IPV/Hib, given to infants and young children across a range of primary vaccination schedules (6–10–14 weeks, 2–3–4 months, 2–4–6 months, 3–4–5 months, 3–5–11 and 3–5–12 months) and booster vaccine doses (12–23 months)

DTPa–HBV–IPV/Hib was shown to be highly immunogenic across a range of primary schedules and booster doses

[10,11,13,14,17,18,21,24–26]

Hepatitis B response Clinical studies with DTPa–HBV–IPV/Hib, given to infants and young children across a range of primary vaccination schedules and booster vaccine doses

DTPa–HBV–IPV/Hib was highly immunogenic for the hepatitis B antigen across a range of schedules

[10,13,14,17,21,24–26]

Hib response Clinical trial data German surveillance data (ESPED)

DTPa–HBV–IPV/Hib induces a good long-term response against Hib and is highly effective in reducing the incidence of Hib in the field

[26,47–49]

Safety Clinical studies with DTPa–HBV–IPV/Hib, given to infants and young children across a range of primary vaccination schedules and booster doses (see ‘Immunogenicity’ above) Safety monitoring – GSK postmarketing surveillance data

Clinical studies showed DTPa–HBV–IPV/Hib to be well tolerated across a range of primary schedules and booster dosesThe incidences of local and systemic adverse events following administration of DTPa–HBV–IPV/Hib are comparable to those seen with other DTPa-based vaccines

[10,11,13,14,17,18,21,24–26,54]

Sudden unexpected death in infants

Analysis of case reports in Germany (2000–2003) and meta-ana lysis of case–control studies

No causal relationship between hexavalent vaccines and sudden unexpected death identified

[109,65–67,78]

Coadministration with other vaccines

Clinical studies with DTPa–HBV–IPV/Hib coadministered with pneumococcal, meningococcal, MMR-V and rotavirus vaccines

DTPa–HBV–IPV/Hib can be safely and effectively coadministered with all of the vaccines mentioned

[16,22,28,43,71,74]

DTPa–HBV–IPV/Hib: Diphtheria, tetanus, acellular pertussis–hepatitis B virus–inactivated poliovirus vaccine/Haemophilus influenzae type b vaccine; ESPED: Die Erhebungseinheit für seltene Pädiatrische Erkrankungen in Deutschland; GSK: GlaxoSmithKline; MMR-V: Measles–mumps–rubella–varicella vaccine.

Expert commentaryCombination vaccines have become widely accepted and rou-tinely used in pediatric vaccination programs in recent years, and DTPa combination vaccines have been shown to contrib-ute to improved compliance with vaccination schedules [70,71]. However, research has revealed that a significant number of parents have general concerns about vaccine safety [76]. Many fear that infants given a combination vaccine may receive too many antigens simultan eously, and that this may weaken or overload their immune systems [77,78]. Such safety concerns are unwarranted and rarely based on scientific evidence [78]. The immune system, even in young infants, has the capac-ity to respond to an enormous number of antigens simultane-ously; it has been suggested that each infant could respond to ‘about 10,000 vaccines at any one time’ [77]. In a Summit of Independent European Vaccination Experts, a regular meeting established by the University of Mainz (Germany), experts met to discuss the perception of vaccines and vaccination by the general public and healthcare professionals in Europe, and ways of improving vaccine uptake [78]. The experts identified the need for positive communication about the benefits of vaccination to

the public, and the key role that healthcare professionals play in disseminating information about vaccines and vaccination to parents.

It is likely that in some parents, concerns about ‘weakening or overloading’ their child’s immune systems may also lead to the unsubstantiated belief that vaccines are responsible for cases of SUD. The EMEA continues to monitor the safety profile of hexavalent vaccines and, to date, has made no further changes to their conditions of use based on the risk of SUD (Hexavac was suspended from use in Europe, but based on a suboptimal anti-hepatitis B response rather than concerns over SUD). Indeed, the findings of the CHMP are echoed by the WHO Global Advisory Committee on Vaccine Safety, which emphasized that rates of SUD in young children had decreased in Germany and Italy over the period when hexavalent vaccines were introduced [79].

Five-year viewThe experiences of the previous 8 years have helped to demon-strate to healthcare professionals and parents alike that higher-valent vaccines are indeed effective at disease control, and that such vaccines can be relied upon for their safety and tolerability.



Vaccine Profile

These vaccines have become a cornerstone of routine pediatric vaccination, providing a safe and practical way to ensure high vaccination coverage and timely vaccination of infants and chil-dren. With increased reassurance of their safety, it is likely that the use of hexavalent vaccines will increase together with the spread of additional recommendations for infant vaccination, such as the pneumococcal and meningococcal vaccines. Indeed, in the context of current recommendations, the addition of new vaccines to already crowded pediatric schedules means that the use of large DTPa-based combinations has become a prerequisite.

Other hexavalent vaccines targeting the same diseases as the GSK vaccine discussed in this review may become available. These vaccines are called hexavalent on the basis of the number of diseases they target. If one considers the number of antigens included, the currently available hexavalent vaccine actually con-sists of ten antigens. Vaccines with a higher number of valences exist today, although they are not the ones that usually come to mind when one thinks of large combinations: these are the 23-valent pneumococcal polysaccharide vaccine or the next gen-eration of pneumococcal conjugate vaccines that may include up to 13 valences [80]. It is not impossible that DTPa-based combi-nations may evolve towards larger vaccines, targeting additional pathogens such as meningococcal serotypes, or towards different vaccines; for example, replacing some of the current valences

with new ones. However, this may be at a further horizon than 5 years away, as currently targeted diseases remain a priority for protection

Infanrix, Infanrix hexa, Priorix tetra and Rotarix are trade-marks of the GSK group of companies. NeisVac-C is a trademark of Baxter, Hexavac is a trademark of Sanofi Pasteur, Meningitec is a trademark of Wyeth and Menjugate is a trademark of Novartis.

Financial & competing interests disclosureFred Zepp has received reimbursements from GlaxoSmithKline Biologicals for conference attendance; Fred Zepp and the Johannes Gutenberg University have also received, respectively, consulting fees and research funds from GlaxoSmithKline Biologicals. Heinz-Josef Schmitt has received research funds and consulting fees from GlaxoSmithKline Biologicals, Sanofi Pasteur-MSD and Wyeth, and is currently an employee of Novartis Vaccines. Jan Cleerbout, Thomas Verstraeten, Lode Schuerman and Jeanne-Marie Jacquet are employees of GlaxoSmithKline Biologicals. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Writing assistance was utilized in the production of this manuscript. Assistance in preparing the manuscript was provided by Alpharmaxim Healthcare Communications (UK). Funding for the preparation of the manuscript was provided by GlaxoSmithKline Biologicals.

Key issues

• The current hexavalent diphtheria, tetanus, acellular pertussis–hepatitis B virus-inactivated poliovirus vaccine/Haemophilus influenzae type b vaccine (DTPa–HBV–IPV/Hib) vaccine has been shown to be a robust vaccine that is well tolerated and highly immunogenic in a variety of settings and infant vaccination schedules.

• The persistence of vaccine-induced antibodies has been evaluated in children up to 5 years of age: antipolyribosylribitol phosphate and anti-hepatitis B surface antigen antibodies persist in more than 90% of vaccinees.

• Immune memory to hepatitis B has been demonstrated in 98% of 8-year-old children who have received a full primary and booster vaccination course with this vaccine.

• The field effectiveness of DTPa–HBV–IPV/Hib in protecting against Hib disease has been demonstrated in Germany over a follow-up of 5 years after introduction, showing protective efficacy of 100% in recipients of the complete four-dose vaccination course.

• The safety of DTPa–HBV–IPV/Hib has been demonstrated over 8 years of routine use and through more than 28 million doses distributed.

• DTPa–HBV–IPV/Hib can be effectively and safely coadministered at the same visit with other routinely recommended childhood vaccines, such as pneumococcal, meningococcal, measles–mumps–rubella–varicella and rotavirus vaccines.

ReferencesPapers of special note have been highlighted as:• of interest•• of considerable interest

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107 European Agency for the Evaluation of Medicinal Products (EMEA). Procedural steps taken and scientific information after the authorization: changes made after 01/11/2002 (Infanrix hexa) (2008) www.emea.europa.eu/humandocs/pdfs/epar/infanrixhexa/200500en8b.pdf (Accessed September 2008)

108 European Agency for the Evaluation of Medicinal Products (EMEA). Public statement. EMEA reviews hexavalent vaccines: Hexavac and Infanrix hexa. (2003) www.emea.europa.eu/pdfs/human/press/pus/851903en.pdf (Accessed September 2008)

109 European Agency for the Evaluation of Medicinal Products (EMEA). Public statement. EMEA update on hexavalent vaccines: Hexavac and Infanrix hexa. (2003) www.emea.europa.eu/pdfs/human/press/pus/588903en.pdf (Accessed September 2008)

Affiliations• Fred Zepp, Prof.

University Hospital, Department of Pediatrics, Johannes Gutenberg University, Langenbeckstrasse 1, 55131 Mainz, Germany Tel.: +49 6131 177 326 Fax: +49 6131 173 918 [email protected]

• Heinz-Josef Schmitt, Prof. Novartis Vaccines, Emil von Behring Strasse, 35041 Marburg, Germany Tel.: +49 6421 396 475 Fax: +49 6421 392 826 [email protected]

• Jan Cleerbout GlaxoSmithKline Biologicals, Rue de l’Institut 89, B-1330 Rixensart, Belgium Tel.: +32 2656 6758 Fax: +32 2656 9072 [email protected]

• Thomas Verstraeten GlaxoSmithKline Biologicals, Rue de l’Institut 89, B-1330 Rixensart, Belgium Tel.: +32 2656 6758 Fax: +32 2656 9072 [email protected]

• Lode Schuerman GlaxoSmithKline Biologicals, Rue de l’Institut 89, B-1330 Rixensart, Belgium Tel.: +32 2656 6758 Fax: +32 2656 9072 [email protected]

• Jeanne-Marie Jacquet GlaxoSmithKline Biologicals, Rue de l’Institut 89, B-1330 Rixensart, Belgium Tel.: +32 2656 6758 Fax: +32 2656 9072 [email protected]


review of 8 years of experience with infanrix hexa™ (dtpa–hbv–ipv/hib hexavalent vaccine)

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