The development of a new heptavalent
diphtheria—tetanus—whole cell pertussis—hepatitis
B—Haemophilus influenzae type b—Neisseria
meningitidis serogroups A and C vaccine:
a randomized dose-ranging trial of the
conjugate vaccine components§
S. Gatchaliana,b, E. Palestroquea, I. De Vleeschauwerc,
H.H. Hand, J. Poolmanc, L. Schuermanc, K. Dobbelaerec, D. Boutriauc,*
aResearch Institute for Tropical Medicine, Alabang, Muntinlupa, Philippines
bUniversity of the Philippines College of Medicine, Manila, Philippines
cGlaxoSmithKline Biologicals, Rue de l’Institut, 89, Rixensart 1330, Belgium
dGlaxoSmithKline Biologicals, Singapore
Received 19 February 2007; received in revised form 13 July 2007; accepted 1 August 2007
Corresponding Editor: Dean A. Fergusson, Ottawa, Canada
International Journal of Infectious Diseases (2008) 12, 278—288
Objective: To assess immunogenicity, antibody persistence, immune memory, and reactogenicity
of a novel heptavalent DTPw—HBV/Hib—MenAC (diphtheria, tetanus, whole cell pertussis—hepa-
titis B virus/Haemophilus influenzae type b—Neisseria meningitidis serogroups A and C) vaccine.
Design: This was an open, randomized study in the Philippines, with DTPw—HBV/Hib—MenAC
administered at 6, 10, and 14 weeks of age. Three different polysaccharide contents of the
conjugate vaccine components were assessed with conjugated PRP (polyribosylribitol phosphate),
MenA, and MenC polysaccharides at the following doses: 2.5 mg of each, 5 mg of each, or 2.5 mg of
PRP and 5 mg each of MenA and MenC. Controls received licensed DTPw—HBV and Hib or DTPw—
HBV/Hib and MenC conjugate vaccines separately. Immune memory was evaluated via plain
polysaccharide challenge administered to half of the subjects at 10 months of age.
bactericidal antibody (SBA)—MenA and SBA—MenC titers ?1:8, and at least 99% had anti-PRP
§Data from primary and challenge phases of this study were presented as posters at the International Pathogenic Neisseria Conference,
Milwaukee, USA, 5—10 September, 2004.
* Corresponding author. Tel.: +32 2 656 9136; fax: +32 2 656 8044.
E-mail address: Dominique.Boutriau@gskbio.com (D. Boutriau).
1201-9712/$32.00 # 2008 International Society for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.
Neisseria meningitidis causes endemic and epidemic menin-
gococcal disease worldwide with at least 30 000 deaths esti-
mated to occur each year.1This figure does not consider the
numbers who die in rural areas of Africa and Asia before
reaching medical facilities. Mortality in some regions may
of victims left with long-term sequelae including limb loss
and neurological deficit.1,2Children under 5 years of age are
most often affected by endemic disease, while infants under
Although outbreaks due to serogroup C (MenC) and more
recently W-135 and serogroup X have been reported in Africa
and Asia, serogroup A (MenA) accounts for most meningo-
coccal epidemics and particularly affects countries within
the ‘meningitis belt’ of Africa.3—8In Asia, serogroup A has
been responsible for three pandemics since the 1960s: the
first began in China in the mid 1960s, the second one started
in China and Nepal in the 1980s, extending to India, Bhutan,
Saudi Arabia, and Yemen, and the third one began in China in
1994 and moved to Mongolia, Russia, and Africa.9,10In addi-
tion to these pandemics, epidemics have affected Mongolia
(1973—74) and Vietnam (1977). More recently, Taiwan
reported a re-emergence of MenA cases in 2001; MenA out-
breaks also occurred in India and the Philippines in 2005.9—11
Endemic disease rates in Africa may be as high as 20/
100 000, but during epidemics may reach more than 1000/
100 000.1,2,6To place this rate in perspective, an overall
disease incidence rate of approximately 10/100 000 was
observed during the 1999 MenC epidemic in England and
Meningococcal polysaccharide vaccines have been avail-
able since the 1980s and are effective in preventing disease.
their effect on carriage is minimal, and their use is therefore
restricted to epidemic situations.1,2Except for serogroup A
polysaccharide that induces an immune response in infants
under 1 year of age with some evidence of efficacy, menin-
gococcal polysaccharide vaccines are poorly immunogenic in
young children under 2 years of age. Furthermore, adminis-
tration of the MenC polysaccharide is found to cause hypor-
esponsiveness to subsequent doses of MenC vaccine.13
tally altered the epidemiology of MenC disease in countries
where vaccination has been widely implemented.12,14The
immunization would enlarge endemic and epidemic invasive
Organization (WHO) Expanded Program on Immunization (EPI)
tetanus, pertussis, hepatitis B virus (HBV), polio, and Haemo-
philus influenzae type b (Hib) for all infants.15Whole-cell
pertussis vaccines are most commonly used in less industria-
recent acellular pertussis vaccines. In endemic areas where
poliomyelitis has not been eradicated yet, WHO recommends
the use of oral polio vaccine (OPV).16Combined diphtheria—
tetanus—whole-cell pertussis—hepatitis B (DTPw—HBV) and
these existing vaccines will promote rapid uptake and high
coverage of the new components, while minimizing cost and
logistical problems in vaccine delivery.
This study evaluated three novel heptavalent DTPw—
HBV/Hib—MenAC combination vaccines that differed in
the dose of the Hib—MenAC conjugate component, for use
in a three-dose primary schedule during the first year of life.
Study design and subjects
The study was an open, randomized study in the Philippines,
conducted in two phases: primary vaccination (study
number: 759346/001) and polysaccharide challenge (study
number: 759346/002). The study protocols (NCT00317174)
were reviewed and approved by the relevant ethics commit-
tee and were conducted according to Good Clinical Practice
Guidelines and the Declaration of Helsinki. Written informed
consent was obtained from the parent/guardian of every
child prior to enrolment in the study.
Healthy infants aged between 6 and 10 weeks at the time
of the first vaccination were eligible for inclusion. Subjects
were excluded if they had a major congenital defect or
serious chronic illness, any confirmed or suspected immuno-
suppressive or immunodeficient condition, evidence of pre-
vious diphtheria, tetanus, pertussis, hepatitis B, Hib, MenA
and/or MenC vaccination or disease, any history of allergic
reactions to any vaccine component, receipt of any investi-
gational or non-registered drug or vaccine within 30 days
before or during the study, or receipt of immunosuppressive
or immunoglobulin therapy or blood products before enrol-
ment or during the study. Subjects were also excluded if they
had received hepatitis B or Bacille Calmette—Gue ´rin vaccine
after the first two weeks of life.
Intheprimary phaseofthestudy,525eligibleinfants were
randomized to one of five groups (1:1:1:1:1). Three groups
evaluated different doses of the novel heptavalent vaccine:
group 2.5/2.5 received DTPw—HBV/Hib—MenAC containing
2.5 mg each of conjugated PRP (polyribosylribitol phos-
phate), MenA, and MenC polysaccharides, group 2.5/5
DTP—wHBV/Hib—MenAC vaccines: randomized dose-ranging trial
antibody concentrations ?0.15 mg/ml. Immune responses to DTPw—HBV components were not
impaired by the lowest dose of Hib—MenAC vaccine. Plain polysaccharide challenge induced marked
increases in Hib, MenA, and MenC antibodies in primed subjects, indicative of immune memory. All of
the experimental vaccines were well tolerated.
Conclusion: The lowest dose of DTPw—HBV/Hib—MenAC polysaccharide conjugate vaccine was well
tolerated, immunogenic, had good persistence of antibodies, and demonstrated immune memory, and
consequently was selected for further development.
# 2008 International Society for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.
37. Trotter CL, Andrews NJ, Kaczmarski EB, Miller E, Ramsay ME.
Effectiveness of meningococcal serogroup C conjugate vaccine 4
years after introduction. Lancet 2004;364:365—7.
38. Ismail AA, Harris SL, Granoff DM. Serum group A anticapsular
antibodies in a Sudanese population immunized with meningo-
coccal polysaccharide vaccine during a group A epidemic. Ped-
riatr Infect Dis J 2004;23:7488—555.
39. Hassan-King MK, Wall RA, Greenwood BM. Meningococcal car-
riage, meningococcal disease
40. Chippaux JP, Dallio A, Marra A, E ´tard JF. Impact of previous
immunization on the incidence of meningococcal disease during
an outbreak in a Sahelian area of Senegal. Vaccine 2007;25:
and vaccination.J Infect
288 S. Gatchalian et al.