Pediatr Drugs (2013) 15:59–70
DOI 10.1007/s40272-013-0007-7
ADIS DRUG EVALUATION
DTaP-IPV-Hep B-Hib Vaccine (HexaximÒ)
A Review of its Use in Primary and Booster Vaccination
Paul L. McCormack
Published online: 22 January 2013
 Springer International Publishing Switzerland 2013
Abstract Hexaxim (DTaP-IPV-Hep B-Hib) is a new,
thiomersal-free, fully liquid, hexavalent combination pediatric
vaccine containing diphtheria and tetanus toxoids, acellular
pertussis, inactivated poliovirus, recombinant hepatitis B virus
surface antigen produced in the yeast Hansenula polymorpha,
and Haemophilus influenzae type b polysaccharide (polyribo-
sylribitol phosphate) conjugated to tetanus toxoid. It is cur-
rently registered in markets outside of the EU for primary
vaccination of infants from 6 weeks of age and for booster
vaccination up to 24 months of age. In randomized controlled
trials, primary vaccination of infants with Hexaxim using
various immunization schedules was highly immunogenic for
all vaccine component antigens regardless of the administration
schedule, producing high levels of seroprotection or serocon-
version for each antigen. Hexaxim was as immunogenic as the
comparator DTwP- or DTaP-based vaccines in these studies.
The serological responses were generally sustained at high
levels over a follow-up of &1 year, and booster vaccination at
15–18 months further enhanced the immune response. Hex-
axim was less reactogenic than a DTwP-based combination
vaccine, and displayed a tolerability profile similar to those of
the comparator DTaP-based combination vaccines. Thus,
Hexaxim provides effective seroprotection or seroconversion
against six major childhood diseases simultaneously, both as
The manuscript was reviewed by: G. Gabutti, Department of
Prevention, O.U. Hygiene and Public Health, LHU4 ‘‘Chiavarese’’ -
Regione Liguria, Chiavari, Italy; J.G. Liese, University Children’s
Hospital, Pediatric Infectious Diseases and Immunology, Würzburg,
Germany; M.E. Pichichero, Centre for Infectious Diseases and
Immunology, Rochester General Hospital, Rochester, NY, USA
P. L. McCormack (&)
Adis, 41 Centorian Drive, Private Bag 65901,
Mairangi Bay, North Shore 0754, Auckland, New Zealand
e-mail: pdd@adis.com
Key features and properties of preservative-free, fully liquid
diphtheria, tetanus, acellular pertussis, inactivated poliovirus,
hepatitis B, and Haemophilus influenzae type b conjugate vaccine
(DTaP-IPV-Hep B-Hib; HexaximÒ)
Indication
Primary vaccination against diphtheria, tetanus, pertussis,
poliomyelitis, hepatitis B, and invasive H. influenzae type b disease
in infants, and booster vaccination in toddlers
Vaccine composition per 0.5 mL
Diphtheria toxoid {C20 IU [30 limit of flocculation (Lf)]}
Tetanus toxoid (C40 IU [10 Lf])
Acellular pertussis antigens:
Pertussis toxoid (PT) [25 lg]
Filamentous hemagglutinin (FHA) [25 lg]
Inactivated type 1 (Mahoney strain) poliovirus, D antigen (40 units)
Inactivated type 2 (MEF-1 strain) poliovirus, D antigen (8 units)
Inactivated type 3 (Saukett strain) poliovirus, D antigen (32 units)
Recombinant hepatitis B virus surface antigen (10 lg) derived from
the yeast Hansenula polymorpha
H. influenzae type b (Hib) capsular polysaccharide (polyribosylribitol
phosphate) [12 lg] conjugated to tetanus toxoid (PRP-T)
Aluminum hydroxide adjuvant (0.6 mg)
Dosage and administration
Dose 0.5 mL
Route of Intramuscular
administration
Frequency of administration
Primary Three-dose series, commencing at C6 weeks of
vaccination age and with doses administered at C4 week
intervals
Booster Single dose administered at up to 24 months of
vaccination age
Most common (solicited) adverse events
Injection-site reactions (pain, erythema and swelling), irritability,
crying, pyrexia, somnolence, anorexia, vomiting
60
primary and booster vaccination, and offers the benefits and
convenience of a fully liquid, ready-to-use vaccine
1 Introduction
The WHO currently recommends routine immunization of
infants against a range of infectious diseases, including
diphtheria, tetanus, pertussis, hepatitis B, poliomyelitis,
and invasive Haemophilus influenzae type b infections [1].
Administering different vaccines at the same time simpli-
fies immunization schedules and maximizes coverage;
thus, WHO recommends administering the aforementioned
vaccines during the same visits [1].
Combination vaccines minimize the number of injec-
tions required, reduce costs, and potentially increase
compliance, and so have become standard in routine
pediatric practice [2]. The valences of combination
pediatric vaccines vary, with many being based on a
combination of diphtheria (D) and tetanus (T) toxoids,
and acellular pertussis (aP) as the core to which other
vaccines have been added [2]. These DTaP vaccines are
gradually replacing the equivalent whole-cell pertussis
vaccines (DTwP), since they are less reactogenic [3].
DTaP vaccines usually include between two and five
pertussis antigens (pertussis toxin [PT], filamentous
hemagglutinin [PHA], pertactin [PRN], and fimbriae type
2 and type 3) [3].
Despite the challenges involved in producing combina-
tion vaccines without any significant decrease in immu-
nogenicity or efficacy, or increase in reactogenicity, with
any component compared with the individual vaccines
administered separately, combination DTaP-based vac-
cines with up to six components (hexavalent vaccines)
have been developed successfully [2].
Hexaxim (DTaP-IPV-Hep B-Hib) is a new hexavalent
combination vaccine containing diphtheria and tetanus
toxoids, two acellular pertussis antigens (PT and PHA),
inactivated poliovirus vaccine (IPV; types 1, 2, and 3),
H. influenzae type b vaccine (Hib), consisting of H. influ-
enzae type b polysaccharide (polyribosylribitol phosphate)
conjugated to tetanus toxoid (PRP-T) and hepatitis B
vaccine (Hep B) consisting of recombinant hepatitis B
virus surface antigen (HBsAg) produced in the yeast
Hansenula polymorpha (see the Key Features and Proper-
ties table for details regarding the vaccine composition)
[4–6]. All of the valences of Hexaxim, other than the Hep
B vaccine, have been used extensively in other licensed
P. L. McCormack
monovalent and combination pediatric vaccines, such as
the pentavalent vaccine DTaP-IPV-Hib (PentaximTM or
PentavacTM), and have well established immunogenicity
and reactogenicity profiles [7, 8]. The immunogenicity and
safety of the H. polymorpha-derived recombinant HBsAg
included in Hexaxim have been confirmed previously in
adolescent and adult populations [9].
Concerns over the long-term protection against hepa-
titis B arose with an earlier fully liquid, hexavalent vac-
cine, HexavacTM. The license for HexavacTM, which
contained recombinant HBsAg (5 lg) from the yeast
Saccharomyces cerevisiae, was suspended in the EU as a
result of these concerns [10]. The concerns were related
to variability in the Hep B immunogenicity of HexavacTM
(with C5–20 % of subjects having low anti-HBsAg titers
in the range of 10–99 mIU/mL), lower than expected
seroconversion when administered concomitantly with
other meningococcal and pneumococcal vaccines, and less
efficient or absent booster responses in a small cohort of
7- to 9-year-old children initially immunized with Hexa-
vacTM who had initial anti-HBsAg antibody concentra-
tions between 10 and 99 mIU/mL compared with children
who had anti-HBsAg concentrations between 100 and
1000 mIU/mL [11–13]. However, there was no evidence
of breakthrough infection with hepatitis B. A later study
found that 92 % of children initially immunized with
HexavacTM produced an anamnestic response to mono-
valent HBsAg booster after 4.8 years (compared with 94
% of children primed with Infanrix hexa), despite having
significantly lower pre-booster seroprotection rates and
anti-HBsAg concentrations than children immunized with
Infanrix hexa [13].
Hexaxim is a thiomersal-free, fully liquid vaccine,
which does not require reconstitution of any component
prior to injection and, therefore, facilitates administration
and reduces the risk of medication error. It is intended for
use both for primary vaccination (three doses at least
4 weeks apart from 6 weeks of age) and for booster vac-
cination at up to 24 months of age [14]. The European
Medicines Agency’s Committee for Medicinal Products for
Human Use (CHMP) adopted a positive opinion in June
2012 recommending the granting of a scientific opinion for
Hexaxim in accordance with Article 58 of Regulation
(EC) No 726/2004 [14]. This positive opinion of the
CHMP, reached in cooperation with the WHO, recom-
mends and supports the use of Hexaxim in markets out-
side of the EU. A central procedure is ongoing for
registration of this vaccine within the EU.
DTaP-IPV-Hep B-Hib Vaccine (Hexaxim): A Review
Data sources: Medical literature (including published
and currently not fully published data) on Hexaxim
was identified by searching databases (including
MEDLINE and EMBASE) for articles published from
1996 to 7 January 2013, bibliographies from published
literature, clinical trial registries/databases and websites
(including those of regional regulatory agencies and the
manufacturer). No language restrictions were applied.
Additional information (including contributory data
currently not fully published) was also requested from
the company developing the vaccine.
Search terms: ‘Hexaxim’, ‘diphtheria’, ‘tetanus’,
‘pertussis’, ‘whooping cough’, ‘poliomyelitis’, ‘hepati-
tis B’, ‘haemophilus’, ‘DTP’, ‘DTaP’, ‘DTaP-IPV’,
‘DTaP-Hib’, ‘hexavalent’, ‘DTaP-IPV-Hep B-PRP-T’,
and ‘DTaP-IPV-Hep B-Hib’.
Study selection: Studies in infants and children who
received primary and/or booster vaccination with
DTaP-IPV-Hep B-Hib vaccine (Hexaxim). Inclusion
of studies was based mainly on the methods section of
the trials. When available, large, well-controlled trials
with appropriate statistical methodology were pre-
ferred. Relevant immunogenicity, efficacy and reac-
togenicity data are also included.
Keywords: Hexaxim, diphtheria, tetanus, acellular
pertussis, inactivated poliovirus, hepatitis B, Hae-
mophilus influenzae type b, DTaP-IPV-Hep B-Hib
vaccine, infants, immunogenicity, reactogenicity.
2 Immunogenicity
The immunogenicity of Hexaxim used for primary vac-
cination has been assessed in a number of phase II [6] and
III [5, 15–20] randomized, open-label [5, 6, 15] or obser-
ver-blind [16–20], comparative clinical trials conducted in
Argentina (A3L02) [6], Colombia and Costa Rica (A3L24)
[18], Peru and/or Mexico (A3L04, A3L11/A3L21, and
A3L17) [16, 19, 20], South Africa (A3L15) [5], Thailand
(A3L12) [17], and Turkey (A3L10/A3L22) [15]. Study
A3L04 was primarily a safety study [19]. Three follow-up
studies (two currently published only as abstracts [15, 21])
assessed booster vaccination with Hexaxim in toddlers
[15, 20, 21]. The majority of the primary vaccination
studies have been published in full, apart from two [15, 18]
that have currently been published only in abstract form.
Study A3L16 [22], which was a booster follow-up to study
A3L02, used a vaccine other than Hexaxim as the
booster, but did provide persistence data (i.e. pre-booster)
at 1 year after primary vaccination with Hexaxim (see
Sect. 2.2).
61
In the primary series trials, Hexaxim was compared
with standard doses of licensed vaccines, alone or in
combination, which provided prophylaxis against the same
six disease states (see Tables 1, 2, 3, 4). The comparator
vaccines consisted of:
• quadrivalent CombAct-HibTM containing DTwP liquid
suspension used to reconstitute freeze-dried Hib vac-
cine co-administered with monovalent Hep B vaccine
(Engerix BTM Pediatric) and oral poliovirus vaccine
(OPV);
• pentavalent Tritanrix-Hep BTM/Hib containing DTwP-
Hep B suspension used to reconstitute freeze-dried Hib
vaccine (HiberixTM);
• pentavalent Pentaxim containing DTaP-IPV liquid
suspension used to reconstitute freeze-dried Hib (DTaP-
IPV/Hib) co-administered with monovalent Hep B
vaccine (Engerix BTM or Engerix BTM Pediatrico);
• hexavalent Infanrix hexa containing DTaP, Hep B and
IPV in liquid suspension used to reconstitute freeze-
dried Hib (DTaP-HBV-IPV/Hib).
Where stated, the primary vaccination trials enrolled
healthy infants, born at full term of pregnancy
(C37 months) and with a birth weight of C2.5 kg, whose
mothers were not seropositive for HBsAg, HIV or hepatitis
C. According to local practice, participants had [17–19] or
had not [6, 15, 16, 19, 20] received hepatitis B vaccination
at birth; one trial randomized infants to receive hepatitis B
vaccination at birth or not [5]. In one trial, infants also
received bacillus Calmette–Guérin vaccination at birth
[18]. Eligible participants had not received any other vac-
cines before the test vaccine administration.
The three-dose primary vaccination administration
schedules for Hexaxim used in the trials complied with
the recommended immunization schedules for the coun-
tries in which they were conducted and consisted of vac-
cine doses at 6, 10, and 14 weeks of age (South Africa) [5],
2, 3, and 4 months of age (Turkey) [15], or 2, 4, and
6 months of age (Argentina, Colombia, Costa Rica, Mex-
ico, Peru, and Thailand) [6, 16–20, 22]. In trials assessing a
subsequent single booster dose of Hexaxim (A3L15,
A3L21 and A3L22), the booster was administered at
15–18 months of age [15, 20, 21].
In two primary vaccination trials [17, 18], Hexaxim
was administered concomitantly with seven-valent pneu-
mococcal conjugate vaccine (PCV7; PrevnarTM; Preve-
narTM). In one of these trials, oral rotavirus vaccine
(Rotarix) was also co-administered [18]. In South African
infants, the Hexaxim booster (A3L15) was co-administered
with measles/mumps/rubella (MMR) and varicella vac-
cines [21], which were also assessed.
In the immunogenicity trials, geometric mean concen-
trations (GMCs [anti-D, anti-T, anti-PT, anti-FHA, anti-Hep
62 P. L. McCormack

Table 1 Seroprotection/seroconversion rates with respect to hepatitis B, Haemophilus influenzae type b and poliovirus antigens at 1 month after
three-dose primary or subsequent single-dose booster vaccination of infants with HexaximÒ (DTaP-IPV-Hep B-Hib)
Study Vaccine (no. of subjects) Seroprotection rate (%)a [pre-booster value]
Anti-Hep B Anti-Hib Anti-PV1 Anti-PV2 Anti-PV3
(C10 mIU/mL) (C0.15 lg/mL) (C8 1/dil) (C8 1/dil) (C8 1/dil)

Primary series: 6, 10, and 14 weeks of age

A3L15 [5] Hexaxim [without Hep B at birth] (220) 95.7 95.4 100 98.5 100
CombAct-HibTM ? Engerix BTM Pediatric ? OPV 95.4 100 93.0 100 98.3
[without Hep B at birth] (212)
Hexaxim [with Hep B at birth] (123) 99.0 97.5 99.0 98.2 100
Primary series: 2, 3, and 4 months of age (without Hep B at birth)
A3L10 [15] Hexaxim (145) 94.0 90.7 97.7 94.7 97.4
PentaximTM ? Engerix BTM (141) 96.1 97.8 97.9 94.0 100
Primary series: 2, 4, and 6 months of age (without Hep B at birth)
A3L02 [6] Hexaxim (260) 99.2 94.6 100 100 100
PentaximTM ? Engerix BTM Pediatrico (271) 100 97.4 100 100 100
A3L04 [19] Hexaxim (192) 100
Tritanrix-Hep BTM/Hib ? OPV (95) 100
A3L11 [20] Hexaxim (1,022) 98.3 98.8 99.9 100 99.9
Infanrix hexa (167) 100 99.2 100 100 100
A3L17 [16] Hexaxim (132) 99.2 100
Infanrix hexa (130) 100 99.2
Primary series: 2, 4, and 6 months of age – co-administered with PCV7 (with Hep B at birth)
A3L12 [17] Hexaxim (189) 99.5 97.9 100 100 100
Infanrix hexa (190) 99.5 96.3 100 100 99.5
Primary series: 2, 4, and 6 months of age – co-administered with PCV7 and Rotarix [2 and 4 months]s (with Hep B at birth)
A3L24 [18] Hexaxim (1,002) 99.7 94.6 100 100 100

Infanrix hexa (338) 100 95.9 100 100 99.7
Hexaxim booster at 15–18 months of ageb
A3L15 [21] Hexaxim [without Hep B at birth] (218) 98.5 [79.8] 100 [81.4] 100 [97.4] 100 [98.4] 100 [98.4]
Hexaxim [with Hep B at birth] (130) 100 [94.7] 100 [75.9] 100 [96.4] 100 [98.2] 100 [99.1]
A3L21 [20] Hexaxim (223) 99.4 [89.8] 100 [86.9] 100 [100] 100 [100] 100 [96.5]
Infanrix hexa (87) 100 [95.4] 100 [92.3] 100 [100] 100 [100] 100 [98.5]

A3L22 [15] Hexaxim (145) 97.3 [80.7] 100 [85.0] 100 [98.9] 100 [100] 100 [85.2]
PentaximTM ? Engerix BTM (141) 100 [99.0] 100 [83.3] 100 [98.8] 100 [97.7] 100 [96.5]
anti-Hep B antibody to recombinant hepatitis B surface antigen, anti-Hib antibody to H. influenzae type b capsular polysaccharide (polyribo-
sylribitol phosphate), anti-PV1 antibody to poliovirus type 1, anti-PV2 antibody to poliovirus type 2, anti-PV3 antibody to poliovirus type 3,
Hep B hepatitis B vaccination, OPV oral poliovirus vaccine, PCV7 seven-valent pneumococcal conjugate vaccine (PrevenarTM; PrevnarTM)
a
Assessed in the per-protocol [5, 6, 15–18, 20] or intent-to-treat [19] populations
b
Study A3L15 was a continuation of the core primary vaccination study and A3L21 and A3L22 were follow-up studies to A3L11 and A3L10,
respectively

B, and anti-Hib]) or geometric mean titers (GMTs [anti-PV1,
anti-PV2, and anti-PV3]) of serum antibodies to the vaccine
antigens were determined at 1 month after the third dose
(and sometimes prior to vaccination) for primary vaccina-
tion, and/or prior to and 1 month after the booster dose. Not
all antigens were assessed in all trials (depending on the trial
objectives). A key focus of most trials was the antibody
response and persistence of antibodies to the HBsAg
component of Hexaxim, which differentiates it from the
widely available pentavalent vaccine of the same family
(PentaximTM/PentavacTM) [7]. The primary immunogenic-
ity assessment following primary vaccination of infants was
a comparison (usually a demonstration of noninferiority
[5, 6, 15–18]) of Hexaxim with the comparator vac-
cine(s) with respect to rates of inducing seroprotective levels
of antibody against Hep B [15, 16, 19], or Hep B and Hib
DTaP-IPV-Hep B-Hib Vaccine (Hexaxim): A Review 63

Table 2 Geometric mean concentration of antibodies to hepatitis B, Haemophilus influenzae type b and poliovirus antigens at 1 month after
three-dose primary or subsequent single-dose booster vaccination of infants with HexaximÒ (DTaP-IPV-Hep B-Hib)
Study Vaccine (no. of subjects) GMC/GMTa [pre-primary or pre-booster value]
Anti-Hep B Anti-Hib Anti-PV1 Anti-PV2 Anti-PV3
(mIU/mL) (lg/mL) (1/dil) (1/dil) (1/dil)

Primary series: 6, 10, and 14 weeks of age

A3L15 [5] Hexaxim [without Hep B at birth] (220) 330 3.31 579 620 975
CombAct-HibTM ? Engerix BTM Pediatric ? OPV 148 5.18 198 446 228
[without Hep B at birth] (212)
Hexaxim [with Hep B at birth] (123) 1913 3.83 557 371 811
Primary series: 2, 4, and 6 months of age (without Hep B at birth)
A3L02 [6] Hexaxim (260) 1148 [0.3] 4.42 [0.10] 4091 [7] 3244 [12] 3839 [7]
PentaximTM ? Engerix BTM Pediatrico (271) 850 [0.3] 3.93 [0.11] 4198 [7] 3223 [11] 5502 [7]
A3L04 [19] Hexaxim (192) 1075
Tritanrix-Hep BTM/Hib ? OPV (95) 3376
A3L11 [20] Hexaxim (1,022) 1142 12.2 882 1655 1106
Infanrix hexa (167) 1576 6.68 1370 2337 2186
A3L17 [16] Hexaxim (132) 986 5.22
Infanrix hexa (130) 1139 3.93
Primary series: 2, 4, and 6 months of age – co-administered with PCV7 (with Hep B at birth)
A3L12 [17] Hexaxim (189) 2477 5.07 765 1489 837
Infanrix hexa (190) 2442 2.41 1566 2277 2029

Primary series: 2, 4, and 6 months of age – co-administered with PCV7 and Rotarix [2 and 4 months] (with Hep B at birth)
A3L24 [18] Hexaxim (1,002) 3013 3.56 680 1180 1106
Infanrix hexa (338) 2766 2.24 1298 1981 1944
Hexaxim booster at 15–18 months of ageb
A3L15 [21] Hexaxim [without Hep B at birth] (218) 4630 [51] 68.5 [0.76] 7298 [127] 6637 [210] 6411 [161]

Hexaxim [with Hep B at birth] (130) 44893 [228] 63.1 [0.63] 5346 [142] 4190 [191] 5144 [127]
A3L21 [20] Hexaxim (223) 2553 [93] 67.5 [1.09] 8572 [608] 10046 [751] 6971 [339]
Infanrix hexa (87) 4757 [127] 102 [1.33] 10173 [887] 13482 [1267] 13337 [896]
anti-Hep B antibody to recombinant hepatitis B surface antigen, anti-Hib antibody to H. influenzae tye b capsular polysaccharide (polyribo-
sylribitol phosphate), anti-PV1 antibody to poliovirus type 1, anti-PV2 antibody to poliovirus type 2, anti-PV3 antibody to poliovirus type 3,
GMC geometric mean concentration of antibody, GMT geometric mean titer of antibody, Hep B hepatitis B vaccination, OPV oral poliovirus
vaccine, PCV7 seven-valent pneumococcal conjugate vaccine (PrevenarTM; PrevnarTM)
a
Assessed in the per-protocol [5, 6, 15–18, 20] or intent-to-treat [19] populations
b
Study A3L15 was a continuation of the core primary vaccination study and A3L21 was a follow-up to study A3L11

[17], or with respect to seroprotection or seroconversion 2.1 Antibody Response

rates against all vaccine antigens [5, 6, 18, 20].
The established threshold levels of antibody considered
to be indicative of seroprotection in these trials were
C10 mIU/mL for anti-Hep B, C0.15 lg/mL for anti-Hib,
C0.01 IU/mL for anti-D and anti-T, and C8 1/dil for anti-
poliovirus 1, 2, and 3 [5, 6, 15–22]. In the absence of
defined serological correlates of protection for anti-per-
tussis antibodies, a C4-fold increase from baseline in anti-
pertussis antibody concentrations (ELISA units [EU]/mL)
was predefined as the surrogate measure of seroconversion.
The principal immunogenicity analyses, where stated,
were based on the per-protocol [5, 6, 15–18] or intent-to-
treat [19] populations.
Hexaxim, administered as a 3-dose primary vaccination
series in healthy infants beginning at age 6 weeks or
2 months, or as a single-dose booster at age 15–18 months,
was highly immunogenic for all component toxoids and
antigens at 1 month after the third primary dose or 1 month
after the booster dose regardless of the administration
schedule used in randomized controlled trials [5, 6, 15–21].
2.1.1 Response to Hepatitis B Virus Surface Antigen
As primary vaccination Primary vaccination with Hexax-
im induced seroprotective levels of antibodies to Hep B
64 P. L. McCormack

Table 3 Seroprotection/seroconversion rates with respect to diphtheria, tetanus and acellular pertussis antigens at 1 month after three-dose
primary or subsequent single-dose booster vaccination of infants with HexaximÒ (DTaP-IPV-Hep B-Hib)
Study Vaccine (no. of subjects) Seroprotection/seroconversion rate (%)a [pre-primary or pre-booster value]
Anti-D Anti-T Anti-PT Anti-FHA
(C0.01 IU/mL) (C0.01 IU/mL) (C4-fold increase) (C4-fold increase)

Primary series: 6, 10, and 14 weeks of age

A3L15 [5] Hexaxim [without Hep B at birth] (220) 97.6 100 93.6 93.1
CombAct-HibTM ? Engerix BTM 96.1 100 83.2 57.7
Pediatric ? OPV (212)
Hexaxim [with Hep B at birth] (123) 95.1 100 95.1 90.0
Primary series: 2, 3, and 4 months of age
A3L10 [15] Hexaxim (145) 99.3 100 93.6 81.9
PentaximTM ? Engerix BTM (141) 97.1 100 94.2 83.1
Primary series: 2, 4, and 6 months of age
A3L02 [6] Hexaxim (260) 100 100 91.8 93.2
PentaximTM ? Engerix BTM Pediatrico (271) 99.6 100 92.9 90.0
A3L11 [20] Hexaxim (1,022) 96.4 100 97.4 98.4
Infanrix hexa (167) 99.2 100 95.8 96.5
A3L17 [16] Hexaxim (132) 95.5 [82.6]
Infanrix hexa (130) 100 [84.6]
Primary series: 2, 4, and 6 months of age – co-administered with PCV7
A3L12 [17] Hexaxim (189) 97.4 100 93.7 94.7

Infanrix hexa (190) 100 100 93.7 95.2
Primary series: 2, 4, and 6 months of age – co-administered with PCV7 and Rotarix [2 and 4 months]
A3L24 [18] Hexaxim (1,002) 100 100 89.6 94.7
Infanrix hexa (338) 100 100 89.7 91.0
Hexaxim booster at 15–18 months of ageb
A3L15 [21] Hexaxim [without Hep B at birth] (218) 100 [93.4] 100 [100] 94.8 91.2
Hexaxim [with Hep B at birth] (130) 100 [84.5] 100 [100] 93.9 94.7
A3L21 [20] Hexaxim (223) 99.4 [92.0] 100 [100] 91.8 86.7
Infanrix hexa (87) 98.5 [96.9] 100 [100] 88.9 87.3
A3L22 [15] Hexaxim (145) 100 [90.4] 100 [100] 96.5 91.8
PentaximTM ? Engerix BTM (141) 100 [88.3] 100 [100] 96.2 97.4
anti-D antibody to diphtheria toxoid, anti-FHA antibody to filamentous hemagglutinin, anti-PT antibody to pertussis toxoid, anti-T antibody to
tetanus toxoid, Hep B hepatitis B vaccination, OPV oral poliovirus vaccine, PCV7 seven-valent pneumococcal conjugate vaccine (PrevenarTM;
PrevnarTM)
a
Assessed in the per-protocol population
b
Study A3L15 was a continuation of the core primary vaccination study, and A3L21 and A3L22 were follow-up studies to A3L11 and A3L10,
respectively

(C10 mIU/mL) in 94–100 % of infants across studies
irrespective of the vaccination schedule used (Tables 1 and
2) [5, 6, 15–20]. While longer intervals between vaccine
doses may increase final anti-Hep B titers, they do not
appear to increase seroconversion rates [23]. The sero-
protection rate was high regardless of whether infants had
(99.0–99.7 %) or had not (94.0–100 %) received Hep B
vaccination at birth (Table 1).
Where reported, the proportions of subjects having anti-
Hep B GMCs C100 mIU/mL at 1 month after primary
immunization with Hexaxim were generally in the range
of 91.7–96.2 % in those not receiving Hep B at birth
[16, 19, 20], and 96.9 % and 98.4 % in those given Hep B
at birth [5, 17], compared with 99.2–99.5 % for Infanrix
hexa [16, 17, 20] and 98.9 % for Tritanrix-Hep BTM/Hib
[19], although, in one study [5], 78.8 % of Hexaxim
recipients (not receiving Hep B at birth) achieved this titer
compared with 65.5 % of CombAct-HibTM plus Engerix
BTM Pediatric recipients.
In the study that randomized infants to receive Hep B
vaccination at birth or not, the respective seroprotection
rates for anti-Hep B after primary vaccination with
DTaP-IPV-Hep B-Hib Vaccine (Hexaxim): A Review 65

Table 4 Geometric mean concentration of antibodies to diphtheria, tetanus and acellular pertussis antigens at 1 month after three-dose primary
or subsequent single-dose booster vaccination of infants with Hexaxim (DTaP-IPV-Hep B-Hib)
Study Vaccine (no. of subjects) GMCa [pre-primary or pre-booster value]
Anti-D Anti-T Anti-PT Anti-FHA
(IU/mL) (IU/mL) (EU/mL) (EU/mL)

Primary series: 6, 10, and 14 weeks of age

A3L15 [5] Hexaxim [without Hep B at birth] (220) 0.074 1.51 332 207
CombAct-HibTM ? Engerix BTM Pediatric ? OPV (212) 0.040 1.88 191 37
Hexaxim [with Hep B at birth] (123) 0.074 1.33 288 188
Primary series: 2, 4, and 6 months of age
A3L02 [6] Hexaxim (260) 0.211 [0.13] 2.29 [1.14] 155 [4] 189 [6]
PentaximTM ? Engerix BTM Pediatrico (271) 0.175 [0.14] 1.79 [1.16] 184 [4] 156 [6]
A3L11 [20] Hexaxim (1,022) 0.196 [0.196] 1.84 240 [3] 239 [4]

Infanrix hexa (167) 0.173 [0.167] 2.20 228 [3] 182 [4]
A3L17 [16] Hexaxim (132) 0.156 [0.183]
Infanrix hexa (130) 0.192 [0.276]
Primary series: 2, 4, and 6 months of age – co-administered with PCV7
A3L12 [17] Hexaxim (189) 0.297 1.38 168 148

Infanrix hexa (190) 0.209 1.83 200 123
Primary series: 2, 4, and 6 months of age – co-administered with PCV7 and Rotarix [2 and 4 months]
A3L24 [18] Hexaxim (1,002) 0.252 1.55 102 182
Infanrix hexa (338) 0.240 1.80 98.9 100
Hexaxim booster at 15–18 months of ageb
A3L15 [21] Hexaxim [without Hep B at birth] (218) 9.37 [0.06] 10.0 [0.22] 288 [12] 570 [31]

Hexaxim [with Hep B at birth] (130) 7.00 [0.05] 8.1 [0.17] 235 [12] 472 [25]
A3L21 [20] Hexaxim (223) 10.4 [0.13] 6.3 [0.29] 185 [15] 402 [34]
Infanrix hexa (87) 6.0 [0.08] 7.0 [0.30] 162 [15] 291 [26]
anti-D antibody to diphtheria toxoid, anti-FHA antibody to filamentous hemagglutinin, anti-PT antibody to pertussis toxoid, anti-T antibody to
tetanus toxoid, GMC geometric mean concentration of antibody, Hep B hepatitis B vaccination, OPV oral poliovirus vaccine, PCV7 seven-valent
pneumococcal conjugate vaccine (PrevenarTM; PrevnarTM)
a
Assessed in the per-protocol population
b
Study A3L15 was a continuation of the core primary vaccination study and A3L21 was a follow-up study to A3L11

Hexaxim were 99.0 % and 95.7 % [5]. However, the
proportion of infants with an anti-Hep B GMC C100 mIU/mL
was numerically higher in those receiving Hep B vacci-
nation at birth compared with those not receiving Hep B
vaccination at birth (97 % vs. 79 %) [5]. The GMC of anti-
Hep B was &6-fold higher in those receiving Hep B at
birth than in those not receiving Hep B at birth (Table 2)
[5]. Although higher post-immunization anti-Hep B titers
generally increase the time it takes for titers to decrease
below the seroprotective threshold (B10 mIU/mL), low
titers or even undetectable antibody levels do not neces-
sarily equate to loss of immunity [13, 23, 24].
Hexaxim produced anti-Hep B seroprotection rates that
were noninferior to those with monovalent Hep B vaccines
[5, 6, 15], and descriptively similar [19, 20] or noninferior
[16–18] to those with other combination vaccines contain-
ing Hep B. GMCs were generally not markedly different
between Hexaxim and the comparators (Table 2),
although Tritanrix-Hep BTM/Hib induced &3-fold higher
anti-Hep B GMCs than Hexaxim in one study [19], while
Hexaxim induced 1.4- to 2.2-fold higher anti-Hep B
GMCs than monovalent Hep B vaccine in two studies [5, 6].
In a pooled analysis of 1279 patients from four studies
conducted in Argentina, Mexico, or Peru (A3L02, A3L04,
A3L11, and A3L17) using an administration schedule of 2,
4, and 6 months, and without Hep B at birth, the proportion
of patients with seroprotective levels (C10 mIU/mL) of
anti-Hep B antibody 1 month after primary series vacci-
nation with Hexaxim was 98.8 % [25].
In studies using less favorable administration schedules
(either 6, 10, and 14 weeks or 2, 3, and 4 months, and
without Hep B at birth), seroprotection rates following
primary vaccination were still high at 95.7 % and 94 %,
respectively (Table 1) [5, 15].
66
As booster vaccination Seroprotection rates for anti-Hep
B at 1 month after a booster dose of Hexaxim at
15–18 months of age were C97 % regardless of the vaccine
used for primary vaccination of infants (Hexaxim,
Infanrix hexa, or PentaximTM ? Engerix BTM), the vac-
cine administration schedule, or whether or not infants
received Hep B vaccination at birth [15, 20, 21] (Table 1).
However, the GMC of anti-Hep B after the booster dose of
Hexaxim was nearly 10-fold higher in those who had
received Hep B vaccination at birth than in those who had
not received Hep B vaccination at birth (Table 2), which is
consistent with the 6-fold difference seen following pri-
mary vaccination [21].
2.1.2 Response to Poliovirus and Haemophilus influenzae
type b Antigens
As primary vaccination Primary vaccination with Hexax-
im induced seroprotective levels of antibody in C98 % of
infants for anti-PV1, C95 % for anti-PV2, C97 % for anti-
PV3, and C91 % for anti-Hib (Table 1) [5, 6, 15–18, 20].
Hexaxim was noninferior [5, 6, 17, 18] or descriptively
similar [15, 16, 20] to CombAct-HibTM [5], PentaximTM
[6, 15], or Infanrix hexa [16–18, 20] with respect to
seroprotection rates for anti-PV1, anti-PV2, anti-PV3, and
anti-Hib at 1 month after the third dose.
The GMC/GMT values are shown in Table 2. In par-
ticular studies, the rates for attaining anti-Hib titers
C1.0 lg/mL were descriptively higher for CombAct-
HibTM than Hexaxim (92.5 vs. 79.5 %) [5] and descrip-
tively higher for Hexaxim than Infanrix hexa (85.2 vs.
71.1 %) [17].
As booster vaccination In all three studies assessing
booster vaccination at 15–18 months of age, seroprotection
rates with Hexaxim or the comparator (PentaximTM or
Infanrix hexa) were consistently 100 % for PV1, PV2,
PV3, and Hib (Table 1) [15, 20, 21]. GMC/GMT values
following booster administration were generally descrip-
tively higher than those following primary vaccination
(Table 2).
2.1.3 Response to Diphtheria, Tetanus, and Pertussis
Antigens
As primary vaccination Following primary vaccination
with Hexaxim, seroprotection rates (GMC C0.01 IU/mL)
for anti-T were consistently 100 % in all studies assessing
the response to this toxoid, while those for anti-D were
C95 % (Table 3) [5, 6, 15–18, 20]. Seroconversion rates
for acellular pertussis antigens (C4-fold increases in anti-
body levels), where assessed, were C90 % for anti-PT and
C82 % for anti-FHA (Table 3).
P. L. McCormack
Hexaxim was noninferior [5, 6, 18] or descriptively
similar [15–17, 20] to the comparator vaccines with respect
to seroprotection rates for anti-D and anti-T. For anti-D
C0.1 IU/mL, Hexaxim had numerically higher rates than
CombAct-HibTM (39.8 % vs. 13.6 %) [5], as well as
numerically higher rates than PentaximTM (15.0 % vs.
5.9 %) [6] and Infanrix hexa (26.5 % vs. 12.1 %) for anti-
D C1.0 IU/mL [17]. However, for anti-T C0.1 IU/mL,
Infanrix hexa had a numerically higher rate than Hexax-
im (87.9 % vs. 70.9 %) [17].
With respect to seroconversion rates for anti-PT and
anti-FHA, studies found no differences between Hexaxim
and PentaximTM or Infanrix hexa [6, 15, 18, 20]. How-
ever, the seroconversion rates for anti-PT and anti-FHA
were numerically higher with Hexaxim than with
CombAct-HibTM (Table 3) [5].
GMCs for each of the antigens are shown in Table 4 and
were generally descriptively similar between Hexaxim
and the comparators.
As booster vaccination A single booster dose of Hexax-
im at 15–18 months of age produced anti-D and anti-T
seroprotection rates C99 % in all instances [15, 20, 21].
The seroconversion rates for anti-PT and anti-FHA were
high at C92 % and C87 %, respectively (Table 3). All four
of these antigens produced robust fold-increases in anti-
body levels over pre-booster values (Table 4) [20, 21]. The
GMCs for anti-D and anti-T after the booster were gener-
ally considerably higher than after primary vaccination,
while those for anti-FHA and anti-PT tended to be similar
to or moderately higher than post-primary values (Table 4).
2.2 Persistence of Antibody Response
The persistence of antibody titers against Hexaxim tox-
oids/antigens has been assessed from 1 month after the
completion of Hexaxim three-dose primary vaccination
(i.e. from 18 weeks of age [21], 5 months of age [15], or
7 months of age [20, 22]) until just prior to booster vac-
cination at 15–18 months of age in four studies. Two of
these studies [20, 21] are shown in Tables 2 and 4, since
they also assessed immunogenicity; another study [15] also
assessed immunogenicity, but is currently only published
as an abstract/poster, which did not report antibody GMC
values for this interval.
Across the four studies, pre-booster seroprotection rates
were consistently 100 % for anti-T, 96–100 % for anti-
PV1, 98–100 % for anti-PV2, 85–99 % for anti-PV3, 80–95
% for anti-Hep B, 74–93 % for anti-D, and 76–87 % for
anti-Hib [15, 20–22]. With respect to pertussis antigens,
pre-booster GMCs were lower than post-primary vaccina-
tion GMCs for both anti-PT (12 vs. 288–332 EU/mL [21];
15 vs. 240 EU/mL [20]; 11 vs. 155 EU/mL [22]) and anti-
DTaP-IPV-Hep B-Hib Vaccine (Hexaxim): A Review
FHA (25–31 vs. 188–207 EU/mL [21]; 34 vs. 239 EU/mL
[20]; 28 vs. 189 EU/mL [22]), although the clinical sig-
nificance of these differences in antibody levels is
unknown in the absence of serological correlates of pro-
tection against pertussis.
In the study comparing infants who received primary
vaccination with Hexaxim and did or did not receive
vaccination against hepatitis B at birth, the pre-booster
anti-Hep B seroprotection rate was 80 % in those not
receiving vaccination against hepatitis B at birth compared
with 95 % in those who did receive hepatitis B vaccination
at birth [21]. Similarly, the pre-booster anti-Hep B GMC
was descriptively higher in those who received vaccination
against hepatitis B at birth than in those who did not
(Table 2). By way of comparison, the pre-booster sero-
protection rate for anti-Hep B was 92 % in the third
treatment arm of this study in which infants received
primary vaccination with CombAct-HibTM ? OPV ?
Engerix BTM Pediatric, without hepatitis B vaccination at
birth (booster results not shown in Tables 1, 2, 3, 4 since
the subjects received a booster dose of CombAct-HibTM ?
OPV, rather than Hexaxim) [21].
The proportions of subjects having anti-Hep B GMCs of
C100 mIU/mL (indicative of long-term persistence of
anti-Hep B antibodies) just prior to receiving the booster
were 52.8 % after primary vaccination with Hexaxim
compared with 58.5 % after Infanrix hexa [20]. The
respective proportions of subjects achieving a titer of
C100 mIU/mL after a booster dose of Hexaxim were
93.2 % and 96.9 %.
The persistence of antibodies to all antigens after
&1 year did not differ between those receiving primary
vaccination at 2, 4 and 6 months with Hexaxim or In-
fanrix hexa [20]. In study A3L22, the pre-booster anti-
Hep B seroprotection rate was descriptively lower in
infants receiving primary vaccination at 2, 3, and 4 months
with Hexaxim compared with those receiving primary
vaccination with PentaximTM plus Engerix BTM (81 % vs.
99 %) [15]. In the follow-up to study A3L02 [22], the anti-
Hep B seroprotection rate 1 year after the third primary
vaccination dose was descriptively higher for infants
receiving primary vaccination (2, 4, and 6 months) with
PentaximTM plus Engerix BTM Pediatrico than in those
receiving Hexaxim (99.5 % vs. 85.5 %). Likewise, the
anti-Hep B GMC was descriptively higher 1 year after
PentaximTM plus Engerix BTM Pediatrico than after Hex-
axim (197 vs. 87.6 mIU/mL) [22].
2.3 Co-Administration with Other Vaccines
Co-administration of Hexaxim with PCV7 and rotavirus
vaccine during primary series vaccination did not materi-
ally affect the immune response to any of the vaccines [18].
67
The proportions of infants achieving antibody levels
C0.35 lg/mL for each of the seven pneumococcal antigens
were 95–100 % when both PCV7 and rotavirus vaccine
were co-administered with either Hexaxim or Infanrix
hexa as primary vaccination [18]. The proportions of
infants achieving anti-rotavirus IgA levels C20 U/mL were
84.0 % when co-administered with Hexaxim and 86.9 %
when co-administered with Infanrix hexa; the respective
GMCs were 110 and 155 U/mL [18].
In the other study comparing primary vaccination with
Hexaxim and Infanrix hexa, when each was co-admin-
istered with PCV7, the immune responses to antigens in
Hexaxim and Infanrix hexa did not appear to be affected
by PCV7 co-administration and were similar to responses
observed in other studies (Tables 1, 2, 3, 4) [17].
Anti-Hep B GMCs following primary vaccination with
Hexaxim co-administered with PCV7, with or without
rotavirus vaccine, in infants who had received Hep B
vaccination at birth [17, 18] were similar to or better than
those in equivalent infants who received primary vaccina-
tion with Hexaxim alone [5] (Table 2).
Co-administration of MMR and varicella vaccines with
a booster dose of Hexaxim or CombAct-HibTM plus OPV
did not alter the expected immunogenicity of the booster
vaccines [21].
3 Reactogenicity
The reactogenicity data for Hexaxim when used for pri-
mary or booster vaccination are derived from the ran-
domized controlled trials discussed in Sect. 2. Of particular
note is the large-scale, observer-blind, safety study
(A3L04), which compared the reactogenicity and safety of
Hexaxim (n = 1,422) with that of the DTwP-based vac-
cine Tritanrix-Hep BTM/Hib ? OPV (n = 711) for pri-
mary series vaccination at 2, 4, and 6 months of age [19].
In all studies, solicited adverse events were considered to
be related to the vaccination, while unsolicited adverse
events could be considered related or not related to
vaccination.
The primary assessment in the safety study was the
incidence of severe fever (rectal temperature C39.6 C)
within 7 days after any vaccine injection (body tempera-
ture was measured twice daily for 7 days after each
injection) [19]. Solicited adverse events recorded on diary
cards during the first 7 days following each vaccination
included injection-site reactions (erythema, swelling, and
pain) and systemic reactions (pyrexia, vomiting, crying,
somnolence, anorexia, and irritability) [19].
The incidence of severe fever after any dose of Hex-
axim was neither superior nor inferior to that with Trit-
anrix-Hep BTM/Hib ? OPV (3.97 % vs. 5.55 %; risk ratio
68
0.715; 95 % CI 0.48–1.066), since the upper bound of the
95 % CI was \3 (predefined nonsuperiority criterion) and
not\1 (predefined inferiority criterion) [19]. Descriptively,
there were no notable differences between groups in the
incidence of severe fever for each of the three individual
vaccine doses.
However, the incidence of fever of any grade following
any vaccine dose was lower following Hexaxim than
following Tritanrix-Hep BTM/Hib ? OPV (74.8 % vs. 92.7
%) (Fig. 1); the 95 % CI for the difference between treat-
ments (Hexaxim minus Tritanrix-Hep BTM/Hib ? OPV
= -17.9, 95 % CI -20.79 to -14.83) did not include zero
(the point of no difference).
Apart from vomiting (which was descriptively similar
between groups), all other solicited local and systemic
adverse events in the safety study were descriptively lower
with Hexaxim than with Tritanrix-Hep BTM/Hib ? OPV
(Fig. 1) [19]. Severe events were also descriptively lower
with Hexaxim than with Tritanrix-Hep BTM/Hib ? OPV,
except for pyrexia (as mentioned), vomiting, and somno-
lence, which were descriptively similar between groups
[19].
There were no immediate vaccine-related events in the
30 min after vaccine administration [19]. Serious adverse
events occurring within 30 days after the third vaccine dose
were experienced by 3.4 % of Hexaxim and 3.7 % of
Tritanrix-Hep BTM/Hib ? OPV recipients. Of the seven
serious adverse events resulting in subjects being withdrawn
Fig. 1 Incidence of solicited
adverse events within 7 days
after any vaccine dose in a
safety study (A3L04) in which
infants received primary
vaccination at 2, 4, and
6 months of age with Hexaxim
(n = 1,422) or Tritanrix-Hep
BTM/Hib ? OPV (n = 711)
[19]. Severe (grade 3) local
reactions had a diameter C5 cm.
OPV oral poliovirus vaccine
P. L. McCormack
from the study, only one event (a hypotonic-hyporesponsive
episode 7 h after the first dose of Hexaxim) was considered
possibly related to vaccine administration [19].
Unsolicited adverse events were reported in 10.8 % of
Hexaxim recipients and 23.2 % of Tritanrix-Hep BTM/
Hib ? OPV recipients, the most frequent of which was
injection-site nodule (5.7 % vs. 11.2 %) [19].
In comparisons of Hexaxim with similar vaccines
containing acellular pertussis and inactivated poliovirus
(Infanrix hexa or PentaximTM ? Hep B vaccine) [see
Sect. 2.1], the incidences of solicited injection-site and
systemic adverse events were generally similar between
Hexaxim and the comparator vaccine, both for all events
and for severe (grade 3) events [6, 15–18, 20]. Small
differences noted in some studies were generally consid-
ered not to be clinically significant [6, 15, 17, 20]. In
these studies, there were no immediate vaccine-related
adverse events in the 30 min following injection and no
vaccine-related serious adverse events within 30 days.
Unsolicited adverse events were similar between groups
and most were not considered related to vaccine admin-
istration.
Adverse events following Hexaxim booster adminis-
tration were similar to those during primary series vacci-
nation in two studies [15, 21] and were noted to occur with
a lower incidence with the booster than the primary series
in one study [20]. One episode of extensive limb swelling
was reported in one booster study, but was not verified by
DTaP-IPV-Hep B-Hib Vaccine (Hexaxim): A Review
the investigator [20]. Adverse events following Hexaxim
booster did not vary according to the primary vaccine
received (Hexaxim, Infanrix hexa, or PentaximTM plus
Engerix BTM) [15, 20, 21]. Hexaxim booster was similarly
well tolerated when co-administered with MMR and vari-
cella vaccine [21].
4 Dosage and Administration
Hexaxim is available as a fully liquid 0.5 mL suspension
(prefilled syringe) for intramuscular injection intended for
primary vaccination (three doses administered at least
4 weeks apart) of infants from 6 weeks of age and single-
dose booster vaccination of toddlers at up to 24 months of
age [14]. Reconstitution of any component of the vaccine is
not required.
In clinical trials (see Sect. 2.1), Hexaxim was administered
as a three-dose primary vaccination course using one of three
schedules: 6, 10, and 14 weeks of age; 2, 3, and 4 months of
age; or 2, 4, and 6 months of age. A single booster dose of
Hexaxim was administered at 15–18 months of age.
All doses of Hexaxim should be administered in
accordance with applicable official recommendations.
Local prescribing information should be consulted for
full details of administration, contraindications, warnings,
and precautions.
5 HexaximÒ: Current Status
Hexaxim is indicated, initially outside of the EU, for
primary and booster vaccination of infants and toddlers
against diphtheria, tetanus, pertussis (whooping cough),
poliomyelitis, hepatitis B and invasive infections caused by
H. influenzae type b [14]. A central procedure for the
licensing of Hexaxim within the EU is currently underway.
Coverage against the broadest possible range of infec-
tious diseases is key to effective childhood vaccination
programs. High vaccine coverage rates are important to
prevent the resurgence of preventable infections in indus-
trialized countries and to further suppress or eradicate
disease, particularly in developing countries where the
prevalence of many vaccine-preventable diseases remains
high, and where diseases such as diphtheria, tetanus, per-
tussis, invasive H. influenzae type b disease, hepatitis B,
and poliomyelitis are still the cause of high morbidity and
mortality among children [26].
In line with WHO recommendations [1], primary vac-
cination with Hexaxim is indicated from 6 weeks of age
and consists of three doses administered C4 weeks apart
(Sect. 4). In clinical trials, it displayed high immunoge-
nicity when administered according to several different
69
schedules (Sect. 2). Hexaxim booster is indicated for
administration at up to 24 months of age (Sect. 4). WHO
recommends that booster vaccination against pertussis be
given during the second year of life [1], and in clinical
trials discussed in Sect. 2, Hexaxim booster was admin-
istered at 15–18 months of age.
WHO also recommends that monovalent Hep B vaccine
be administered as soon as possible after birth (within
24 h) [1]. While Hexaxim, either as a primary vaccina-
tion series or a booster dose, did produce substantially
higher anti-HBsAg antibody levels in infants who had
received Hep B vaccination at birth compared with those
who had not, seroprotection rates were similarly high in
both groups (Sect. 2.1.1). The seroprotection rate at
&1 year after primary vaccination was slightly lower in
those who had not received Hep B vaccination at birth
compared with those who had, although the clinical sig-
nificance of such a difference in terms of disease immunity
is not known.
Randomized controlled clinical trials of Hexaxim were
conducted in Mexico, Costa Rica, Colombia, Peru,
Argentina, South Africa, Thailand, and Turkey according
to local immunization schedules using as comparators
licensed DTaP- or DTwP-based vaccines providing the
same disease prophylaxis coverage. Primary vaccination of
infants with Hexaxim was highly immunogenic for all
vaccine components irrespective of the administration
schedule, producing high levels of seroprotection or sero-
conversion for each toxoid/antigen. The proportions of
infants achieving anti-Hep B titers C100 mIU/mL, which
are likely to confer longer-term seroprotection, were only
slightly below those achieving the nominal seroprotective
titer of C10 mIU/mL. Hexaxim was as immunogenic as
the comparator vaccines in all studies, including the other
available hexavalent vaccine Infanrix hexa, with respect
to seroprotection/seroconversion rates. Hexaxim was
co-administered with pneumococcal, rotavirus, MMR and
varicella vaccines in certain trials without any detected
interference with the immune responses to any of the
antigens. Overall, the serological responses to vaccine
antigens were generally sustained at &1 year after the
primary series, with slight decreases noted in sero-
protection rates for anti-D, anti-Hib and anti-Hep B. A
slightly lower decrease in the anti-Hep B seroprotection
rate was observed &1 year after primary vaccination with
three doses of monovalent Hep B vaccine compared with
Hexaxim.
Single-dose booster vaccination with Hexaxim at
15–18 months of age was also highly immunogenic, pro-
ducing high seroprotection or seroconversion rates for all
antigens at 1 month after administration.
Hexaxim was less reactogenic than a DTwP-based
combination vaccine and had a tolerability profile generally
70
similar to those of comparator DTaP-based combination
vaccines. Since Hexaxim is a fully liquid formulation and
does not require reconstitution of any vaccine component,
it may reduce the risk of medication errors and simplify
administration by healthcare professionals.
Thus, Hexaxim provides effective seroprotection or
seroconversion against six major childhood diseases
simultaneously, both as primary and booster vaccination,
and offers the benefits and convenience of a fully liquid,
ready-to-use vaccine.
Disclosure The preparation of this review was not supported by any
external funding. During the peer review process, the manufacturer of
the agent under review was offered an opportunity to comment on this
article. Changes based on any comments received were made by the
author on the basis of scientific and editorial merit.
References
1. World Health Organization. WHO recommendations for routine
immunization - summary tables. 2012. http://www.who.int/
immunization/policy/immunization_tables/en/. Accessed 27 Nov
2012.
2. Skibinski DAG, Baudner BC, Singh M, et al. Combination vac-
cines. J Glob Infect Dis. 2011;3(1):63–72.
3. World Health Organization. Pertussis vaccines: WHO position
paper. Wkly Epidemiol Rec. 2010;85(40):385–400.
4. Kitchin NRE. Review of diphtheria, tetanus and pertussis vac-
cines in clinical development. Expert Rev Vaccines. 2011;10(5):
605–15.
5. Madhi SA, Mitha I, Cutland C, et al. Immunogenicity and safety
of an investigational fully liquid hexavalent combination vaccine
versus licensed combination vaccines at 6, 10, and 14 weeks of
age in healthy South African infants. Pediatr Infect Dis J.
2011;30(4):e68–74.
6. Tregnaghi MW, Zambrano B, Santos-Lima E. Immunogenicity
and safety of an investigational hexavalent diphtheria-tetanus-
acellular pertussis-inactivated poliovirus-hepatitis B-Haemophi-
lus influenzae B conjugate combined vaccine in healthy 2-, 4-,
and 6-month-old Argentinean infants. Pediatr Infect Dis J. 2011;
30(6):e88–96.
7. Plotkin SA, Liese J, Madhi SA, et al. A DTaP-IPV//PRP-T
vaccine (PentaximTM): a review of 16 years’ clinical experience.
Expert Rev Vaccines. 2011;10(7):981–1005.
8. Vidor E, Plotkin SA. Immunogenicity of a two-component (PT &
FHA) acellular pertussis vaccine in various combinations. Hum
Vaccin. 2008;4(5):328–40.
9. Tregnaghi MW, Voelker R, Santos-Lima E, et al. Immunoge-
nicity and safety of a novel yeast Hansenula polymorpha-
derived recombinant Hepatitis B candidate vaccine in healthy
adolescents and adults aged 10–45 years. Vaccine. 2010;28(20):
3595–601.
10. European Medicines Agency. European Medicines Agency rec-
ommends suspension of Hexavac. 2005. http://www.ema.europa.
eu/docs/en_GB/document_library/Press_release/2009/12/WC50
0017695.pdf. Accessed 27 Nov 2012.
11. European Medicines Agency. Scientific conclusions and grounds
for the suspension of the marketing authorisation of Hexavac
presented by the EMEA. http://www.ema.europa.eu/docs/en_
GB/document_library/EPAR_-_Scientific_Conclusion/human/
000298/WC500074684.pdf. Accessed 22 Nov 2012.
P. L. McCormack
12. Jorgensen P, Poethko-Muller C, Hellenbrand W, et al. Low hepa-
titis B immunogenicity of a hexavalent vaccine widely used in
Germany: results of the German Health Survey for Children and
Adolescents, 2003–2006. Epidemiol Infect. 2010;138(11):1621–9.
13. Zanetti AR, Romano L, Giambi C, et al. Hepatitis B immune
memory in children primed with hexavalent vaccines and given
monovalent booster vaccines: an open-label, randomised, con-
trolled, multicentre study. Lancet Infect Dis. 2010;10(11):755–61.
14. European Medicines Agency. Hexaxim: summary of opinion.
2012. http://www.ema.europa.eu/docs/en_GB/document_library/
Other/2012/06/WC500129095.pdf. Accessed 27 Nov 2012.
15. Ceyhan M, Santos-Lima E. Immunogenicity and safety of an
investigational hexavalent fully liquid DTaP-IPV-Hep B-PRP-T
vaccine given at 2, 3, 4 months of age with a booster at
15–18 months compared to licensed vaccines in Turkish infants
[abstract plus poster]. Presented at 5th Asian Congress of Pedi-
atric Infectious Diseases, 23–26 Sep 2010, Taipei.
16. Lanata C, Zambrano B, Ecker L, et al. Immunogenicity and
safety of a fully liquid DTaP-IPV-Hep B-PRP-T vaccine at 2–4–
6 months of age in Peru. J Vaccines Vaccin. 2012;3(1):1000128.
17. Kosalaraksa P, Thisyakorn U, Benjaponpitak S, et al. Immuno-
genicity and safety study of a new DTaP-IPV-Hep B-PRP-T
combined vaccine compared to a licensed DTaP-IPV-Hep
B//PRP-T comparator, both concomitantly administered with a
7-valent pneumococcal conjugate vaccine at 2, 4, and 6 months
of age in Thai infants. Int J Infect Dis. 2011;15(4):e249–56.
18. Lopez P, Arguedas A, Consuelo-Miranda M, et al. Immunoge-
nicity and safety of a primary series of a new fully liquid
DTaP-IPV-Hep B-PRP-T hexavalent vaccine (HexaximTM)
co-administered with PrevenarTM and RotarixTM in healthy
children in Latin America. Presented at 15th International Con-
gress on Infectious Diseases, 13–16 Jun 2012, Bangkok.
19. Macias M, Lanata CF, Zambrano B, et al. Safety and immuno-
genicity of an investigational fully liquid hexavalent DTaP-
IPV-Hep B-PRP-T vaccine at two, four and six months of age
compared with licensed vaccines in Latin America. Pediatr Infect
Dis J. 2012;31(8):e126–32.
20. Becerra Aquino AG, Gutierrez Brito M, Aranza Doniz CE, et al.
A fully liquid DTaP-IPV-Hep B-PRP-T hexavalent vaccine for
primary and booster vaccination of healthy Mexican children.
Vaccine. 2012;30(45):6492–500.
21. Madhi SA, Mitha I, Koen A, et al. Post-primary antibody per-
sistence and immunogenicity/safety of an investigational DTaP-
IPV-Hep B-PRP-T (HexaximTM) booster vaccine compared to
licensed vaccines in South Africa [abstract plus poster]. Presented
at 7th Congress of the World Society for Pediatric Infectious
Diseases, 16–19 Nov 2011, Melbourne.
22. Tregnaghi M, Zambrano B, Santos-Lima E. Antibody persistence
after a primary series of a new DTaP-IPV-Hep B-PRP-T com-
bined vaccine or separate DTaP-IPV//PRP-T and hepatitis B
vaccines at 2, 4, and 6 months of age and the effect of a sub-
sequent DTaP-IPV//PRP-T booster vaccination at 18 months of
age in healthy Argentinean infants. Pediatr Infect Dis J. 2012;
31(1):e24–30.
23. World Health Organization. Hepatitis B vaccines: WHO position
paper. Wkly Epidemiol Rec. 2009;84(40):405–19.
24. Floreani A, Baldo V, Cristofoletti M, et al. Long-term persistence
of anti-HBs after vaccination against HBV: an 18 year experience
in health care workers. Vaccine. 2004;22(5–6):607–10.
25. Santos-Lima E, B’Chir S, Lane A. Combined immunogenicity
data for a new DTaP-IPV-Hep B-PRP-T vaccine (HexaximTM)
following primary series administration at 2, 4, 6 months of age
in Latin America. Vaccine. doi:10.1016/j.vaccine.2012.11.087
26. UNICEF. Immunization: why are children dying? 2012.
http://www.unicef.org/immunization/index_why.html. Accessed
28 Nov 2012.