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Supplemental Digital Content 1. Antibodies to Coadministered Vaccine Antigens
Methods
Antibodies to the coadministered DTPw-HBV/Hib, IPV, and OPV vaccine antigens were
analyzed in 2 independent random subsets of 100 subjects from each country (each
equaled half of the coadministration immunogenicity subset defined in the primary study).
Immune responses against hepatitis B surface antigen (HBs) and polio 1, 2, and 3 were
measured in the first subset and responses against Bordetella pertussis, H. influenzae
type b (Hib) polysaccharide PRP, diphtheria, and tetanus were measured in the second.
Antibodies were analyzed according to standard techniques (ELISA for all antigens except
for polio where a microneutralization assay was used), as described previously,1 with the
following cut-off values: diphtheria and tetanus, 0.1 IU/mL; anti-B. pertussis, 15 EL.U/mL;
HBs antigen, 10 mIU/mL; anti-Hib polysaccharide PRP, 0.15 µg/mL; polio types 1, 2, 3, 1/8
dilution.
Results
One month after booster vaccination, seropositivity/seroprotection/booster vaccine
response rates for antibodies against the antigens contained in the coadministered DTPwHBV/Hib and IPV/OPV vaccines (Table) were in line with previous observations.2–5
Antibody concentrations or titers were within the same range for the PHiD-CV and 7vCRM
groups, apart from anti-diphtheria and anti-tetanus antibody GMCs in the PHiD-CV groups,
which were higher than those in 7vCRM recipients. As observed in the primary vaccination
study,1 higher responses to anti-polio 3 antibodies were measured after booster
vaccination with IPV in Poland compared to OPV vaccination in the Philippines. In both
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Filipino groups, GMCs for anti-HBs antibodies tended to be lower and GMCs for anti-PRP
antibodies were higher than in the groups in Poland (Table).
Discussion
In both countries, good booster immune responses were observed against the
coadministered DTPw-HBV/Hib and poliovirus vaccines, indicating effective priming, and
seroprotection/seropositivity rates and antibody concentrations were within the same range
between both countries for most of the coadministered vaccine antigens. However,
seroprotection rates and GMCs for anti-HBs antibodies before and after booster vaccination
tended to be lower in the Philippines than in Poland, although the post-booster differences
were less striking than after primary vaccination.1 In addition to the difference in immunization
schedule, all infants in Poland received a dose of hepatitis B vaccine at birth compared with
only 6 subjects in the immunogenicity subset for coadministered vaccines in the Philippines.
It is known that the early and accelerated schedule, without previous HBV at birth, may lead
to lower anti-HBs immune responses, since the same trend was observed previously with
DTPw-HBV/Hib vaccines,1,6–8 as well as with DTPa-based, HBV-containing combination
vaccines,3 when administered at 6, 10, and 14 weeks to children in the Philippines and
Myanmar. Interference of maternal antibodies might also have contributed to lower anti-HBs
responses in the Philippines.9 This illustrates the importance of neonatal vaccination against
hepatitis B,3,10 which is now recommended in the Philippines.
Higher anti-PRP antibody concentrations were observed before and after booster vaccination
in the Philippines compared to Poland, as previously observed following primary vaccination1
or following booster vaccination with other Hib-containing vaccines in Filipino children.3,8 Latin
American studies of DTPw-based, Hib-containing vaccines have also reported high anti-PRP
antibody GMCs.11–13 This suggests that differences in the anti-PRP antibody response in the
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current study could potentially be due to early exposure to Hib or cross-reacting antigens in
the nasopharynx or the gastrointestinal tract, or to genetic, environmental, or other yet
unidentified differences between populations. The higher anti-tetanus responses in the
Philippines could also have contributed to the difference in Hib responses since a PRPtetanus toxoid-conjugate vaccine was used.
Although the number of subjects in the 7vCRM groups was low, there appeared to be a trend
for higher post-booster anti-tetanus antibody GMCs in the PHiD-CV groups compared to the
7vCRM groups, suggesting enhancement of the immune response by the tetanus toxoid
carrier protein used for serotype 18C in PHiD-CV, as reported previously.1 Anti-diphtheria
antibody GMCs also tended to be higher in PHiD-CV recipients, despite the use of diphtheria
toxoid as carrier protein for serotype 19F only in PHiD-CV and the use of the CRM carrier
protein (which is closely related to diphtheria toxoid) for all 7 serotypes in 7vCRM.
References (SDC 1: Coadministered Vaccines)
1.
Knuf M, Szenborn L, Moro M, et al. Immunogenicity of routinely used childhood
vaccines when coadministered with the 10-valent pneumococcal non-typeable
Haemophilus influenzae protein D conjugate vaccine (PHiD-CV). Pediatr Infect Dis J.
2009;28(Suppl):S97–S108.
2.
Prymula R, Plisek S. Clinical experience with DTPw-HBV and DTPw-HBV/Hib
combination vaccines. Expert Opin Biol Ther. 2008;8:503–513.
3.
Gatchalian S, Bravo L, Cadrona-Carlos J, et al. A hexavalent DTPa-HBV-IPV/Hib
vaccine administered to Filipino infants at 6, 10 and 14 weeks and 12-15 months of
age; importance of the birth dose of HBV. Philipp J Pediatr. 2007;56:153–160.
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4.
Plotkin SA, Vidor E. Poliovirus vaccine - inactivated. In: Plotkin SA, Orenstein WA,
Offit PA, eds. Vaccines. 5th ed. New York: Elsevier; 2008:605–630.
5.
Sutter RW, Kew OM, Cochi SL. Poliovirus vaccine - live. In: Plotkin SA, Orenstein
WA, Offit PA, eds. Vaccines. 5th ed. New York: Elsevier; 2008:631–686.
6.
Gatchalian S, Reyes M, Bernal N, et al. A new DTPw-HBV/Hib vaccine is
immunogenic and safe when administered according to the EPI (Expanded
Programme for Immunization) schedule and following hepatitis B vaccination at birth.
Hum Vaccin. 2005;1:198–203.
7.
Hla KH, Thein SA, Aye A, et al. Reactogenicity and immunogenicity profiles of a
novel
pentavalent
diphtheria-tetanus-whole
cell
pertussis-hepatitis
B
and
Haemophilus influenzae type B vaccine: a randomized dose-ranging trial of the Hib
tetanus-conjugate content. Pediatr Infect Dis J. 2006;25:706–712.
8.
Gatchalian S, Reyes M, Bermal N, et al. A new DTPw-HBV/Hib vaccine: immune
memory after primary vaccination and booster dosing in the second year of life. Hum
Vaccin. 2008;4:60–66.
9.
Bravo L, Carlos J, Gatchalian S, et al. The new DTPw-HBV-Hib combination vaccine
can be used at the who schedule with a monovalent dose of hepatitis B vaccine at
birth. Southeast Asian J Trop Med Public Health. 1998;29:772–778.
10.
Bavdekar SB, Maiya PP, Subba Rao SD, Datta SK, Bock HL. Immunogenicity and
safety of combined diphtheria tetanus whole cell pertussis hepatitis B/ Haemophilus
influenzae type b vaccine in Indian infants. Indian Pediatr. 2007;44:505–510.
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11.
Hoppenbrouwers K, Lagos R, Swennen B, et al. Safety and immunogenicity of an
Haemophilus influenzae type b-tetanus toxoid conjugate (PRP-T) and diphtheriatetanus-pertussis (DTP) combination vaccine administered in a dual-chamber syringe
to infants in Belgium and Chile. Vaccine. 1998;16:921–927.
12.
Santos JI, Martin A, De LT, et al. DTPw-HB and Hib primary and booster vaccination:
combined versus separate administration to Latin American children. Vaccine.
2002;20:1887–1893.
13.
Tregnaghi M, Lopez P, Rocha C, et al. A new DTPw-HB/Hib combination vaccine for
primary and booster vaccination of infants in Latin America. Rev Panam Salud
Publica. 2006;19:179–188.
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Table (SDC 1). Seroprotection/seropositivity rates and antibody concentrations against DTPw-HBV/Hib and poliovirus vaccine components
1 month after booster vaccination (ATP immunogenicity cohort)
Philippines
Poland
Antibody
(cut-off)
Group
N
% (95% CI)
GMC or GMT† (95% CI)
N
% (95% CI)
GMC or GMT† (95% CI)
Diphtheria
(≥0.1 IU/mL)
PHiD-CV
65
100 (94.5–100)
7.83 (6.34–9.67)
59
100 (93.9–100)
8.46 (7.11–10.07)
7vCRM
25
100 (86.3–100)
4.77 (3.70–6.15)
24
100 (85.8–100)
4.88 (3.50–6.79)
PHiD-CV
65
100 (94.5–100)
20.98 (18.36–23.97)
59
98.3 (90.9–100)
12.17 (9.77–15.16)
7vCRM
25
100 (86.3–100)
9.70 (8.17–11.52)
24
100 (85.8–100)
6.72 (4.60–9.82)
Bordetella
pertussis
(≥15 EL.U/mL)
PHiD-CV
65
100 (94.5–100)
139.51 (123.26–157.89)
59
100 (93.9–100)
121.73 (103.16–143.64)
7vCRM
25
100 (86.3–100)
133.45 (110.33–161.40)
24
100 (85.8–100)
121.76 (91.81–161.47)
HBs
(≥10 mIU/mL)
PHiD-CV
69
98.6 (92.2–100)
1220.5 (790.6–1884.0)
62
100 (94.2–100)
4428.7 (2980.3–6581.0)
7vCRM
21
90.5 (69.6–98.8)
1098.1 (358.4–3364.9)
19
100 (82.4–100)
3188.6 (1171.7–8677.1)
PHiD-CV
65
100 (94.5–100)
106.00 (79.94–140.57)
59
100 (93.9–100)
53.39 (34.82–81.86)
7vCRM
25
100 (86.3–100)
89.38 (55.13–144.89)
24
100 (85.8–100)
33.66 (19.46–58.20)
PHiD-CV
69
98.6 (92.2–100)
854.6 (573.5–1273.5)
63
100 (94.3–100)
932.5 (770.5–1128.6)
7vCRM
21
90.5 (69.6–98.8)
426.9 (166.2–1096.7)
19
100 (82.4–100)
737.3 (512.9–1059.9)
PHiD-CV
69
100 (94.8–100)
716.9 (487.6–1054.1)
63
100 (94.3–100)
1195.7 (977.8–1462.2)
7vCRM
21
100 (83.9–100)
689.1 (304.8–1557.9)
19
100 (82.4–100)
1206.6 (737.0–1975.4)
Tetanus
(≥0.1 IU/mL)
PRP
(≥0.15 µg/mL)
Polio 1 (≥8)
Polio 2 (≥8)
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Polio 3 (≥8)
PHiD-CV
69
95.7 (87.8–99.1)
232.7 (159.6–339.4)
63
100 (94.3–100)
1464.2 (1128.0–1900.6)
7vCRM
21
95.2 (76.2–99.9)
190.4 (78.2–463.6)
19
100 (82.4–100)
1346.2 (857.6–2113.2)
†
Polio types 1, 2, 3
GMC = geometric mean antibody concentration; GMT = geometric mean titer; HBs = hepatitis B surface antigen; PRP = Haemophilus influenzae type
b polyribosylribitol phosphate. N indicates number of subjects with available results
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