Vaccine 36 (2018) 698–706

Contents lists available at ScienceDirect

Vaccine
journal homepage: www.elsevier.com/locate/vaccine

Immunologic non-inferiority and safety of the investigational

pneumococcal non-typeable Haemophilus influenzae protein D-conjugate
vaccine (PHiD-CV) 4-dose vial presentation compared to the licensed
PHiD-CV 1-dose vial presentation in infants: A phase III randomized
study
Khalequ Zaman a,⇑, Sheikh Farzana Zaman a, Farzana Zaman a, Asma Aziz a, Sayeed-Bin Faisal a,
Magali Traskine b, Md Ahsan Habib b, Javier Ruiz-Guiñazú b, Dorota Borys b
a
International Centre for Diarrheal Disease Research, Bangladesh (icddr,b), 68 Shaheed Tajuddin Ahmed Sarani, Mohakhali, Dhaka 1212, Bangladesh
b
GSK, 20 Avenue Fleming, B-1300 Wavre, Belgium

a r t i c l e i n f o a b s t r a c t

Article history: Background: To support vaccination programs in developing countries, a 4-dose vial presentation of
Received 22 July 2017 pneumococcal non-typeable Haemophilus influenzae protein D-conjugate vaccine (PHiD-CV) was devel-
Received in revised form 11 December 2017 oped. This study assessed immunologic non-inferiority and safety of the investigational PHiD-CV 4-
Accepted 12 December 2017
dose versus licensed 1-dose vial presentation in infants.
Available online 23 December 2017
Methods: In this phase III, mono-center, observer-blind study in Bangladesh, 6–10-week-old infants were
randomized 1:1 to receive PHiD-CV primary vaccination (at ages 6, 10, 18 weeks) and a booster dose (at
Keywords:
age 9 months) with a 4-dose vial (with preservative, 4DV group) or 1-dose vial (preservative-free, 1DV
Pneumococcal non-typeable Haemophilus
influenzae protein D-conjugate vaccine
group). DTPw-HBV/Hib was (co)-administered per study protocol and polio, measles and rubella vaccines
(PHiD-CV) as part of the national immunization program. Non-inferiority of PHiD-CV 4-dose versus 1-dose vial for
1-dose vial presentation each vaccine pneumococcal serotype (VT) and vaccine-related serotype 19A in terms of antibody geomet-
4-dose vial presentation ric mean concentration (GMC) was assessed (criterion: upper limit of 2-sided 95% confidence interval of
Immunologic non-inferiority antibody GMC ratios [1DV/4DV] <2-fold). Immune responses were measured. Solicited, unsolicited and
Safety serious adverse events (AEs) were evaluated.
Infants Results: Of 320 infants (160 per group) vaccinated during the primary vaccination phase, 297 received a
booster. Non-inferiority was demonstrated for each VT and 19A. One month post-primary vaccination, for
most VT, 97.9% of infants in each group had antibody concentrations 0.2 lg/mL; for 19A  80.1%
reached this threshold. Pneumococcal antibody responses and opsonophagocytic activity for each VT
and 19A were within similar ranges between groups after primary and booster vaccination, as were
anti-protein D responses. Booster immune responses were observed in both groups. Reported AEs were
within similar ranges for both presentations.
Conclusion: Immunologic non-inferiority of PHiD-CV 4-dose vial (with preservative) versus PHiD-CV
1-dose vial (preservative-free) was demonstrated. Immune responses and reactogenicity following
primary/booster vaccination were within similar ranges for both presentations. PHiD-CV 4-dose vial
would help improve access and coverage in resource-limited countries.
Clinical Trial Registry: NCT02447432.
Ó 2017 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY license (http://
creativecommons.org/licenses/by/4.0/).

Abbreviations: AE, adverse event; ATP, according-to-protocol; CI, confidence interval; DTPw-HBV/Hib, diphtheria-tetanus-whole cell pertussis-hepatitis B and H.
influenzae type b conjugate vaccine; EPI, Expanded Program on Immunization; GAVI, Global Alliance for Vaccines and Immunization; GMC, geometric mean concentration;
GMTs, geometric mean titer; IgG, immunoglobulin G; IPD, invasive pneumococcal disease; LAR, legally acceptable representative; NIP, national immunization program; OPA,
opsonophagocytic activity; PCV, pneumococcal conjugate vaccine; PCV13, 13-valent pneumococcal conjugate vaccine; PHiD-CV, pneumococcal non-typeable Haemophilus
influenzae protein D-conjugate vaccine; SAE, serious AE; SBIR, central internet randomization system; TVC, total vaccinated cohort; UL, upper limit; VT, vaccine pneumococcal
serotypes; WHO, World Health Organization; 1DV group, infants that received vaccination with PHiD-CV 1-dose vial; 4DV group, infants that received vaccination with PHiD-
CV 4-dose vial; 22F-ELISA, enzyme linked immunosorbent assay with serotype 22F polysaccharide adsorption.
⇑ Corresponding author.
E-mail addresses: [email protected] (K. Zaman), [email protected] (S.F. Zaman), [email protected] (F. Zaman), [email protected] (A. Aziz), sayeed.
[email protected] (S.-B. Faisal), [email protected] (M. Traskine), [email protected] (M.A. Habib), [email protected] (J. Ruiz-Guiñazú), Dorota.D.
[email protected] (D. Borys).

https://doi.org/10.1016/j.vaccine.2017.12.034
0264-410X/Ó 2017 The Authors. Published by Elsevier Ltd.
This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
 K. Zaman et al. / Vaccine 36 (2018) 698–706 699

1. Introduction of 10 pneumococcal serotypes: 1, 4, 5, 6B, 7F, 9V, 14 and 23F con-

jugated to non-typeable H. influenzae protein D, 18C to tetanus tox-
The invasive pneumococcal disease (IPD) burden has been sub- oid and 19F to diphtheria toxoid as described previously [17].
stantially reduced worldwide since the introduction of pneumo- The investigational PHiD-CV 4-dose vial contained the same
coccal conjugate vaccines (PCVs) in national immunization conjugated capsular polysaccharides as the PHiD-CV 1-dose vial
programs (NIPs) [1,2]. Currently, PCVs are supplied to developing but with the preservative 2-phenoxyethanol. Consecutive vial-
countries via the Global Alliance for Vaccines and Immunization doses from the PHiD-CV 4-dose presentation were used for vacci-
(GAVI) in high volume at affordable prices [3]. nation of infants randomized to receive this vaccine (0.5 mL per
The efficacy and effectiveness/impact of pneumococcal non- dose).
typeable Haemophilus influenzae protein D-conjugate vaccine Composition of the (co)-administered DTPw-HBV/Hib vaccine
(PHiD-CV, GSK) against IPD have been demonstrated in clinical (Tritanrix HB and Hiberix, GSK) was previously published [18].
trials [4,5] and in post-marketing studies, including evidence for During primary vaccination, both PHiD-CV and DTPw-HBV/Hib
vaccine effectiveness against vaccine serotypes (VT) and vaccine- were administered as intramuscular injections into the anterolat-
related serotype 19A IPD [6–13]. PHiD-CV, as preservative-free eral thigh on the right and left sides, respectively.
1-dose or 2-dose vial presentations [13], is prequalified by the
World Health Organization (WHO). 2.3. Objectives
The previously licensed 2-dose vial improves logistics (delivery,
storage and cold chain capacity) compared to the 1-dose vial. The confirmatory objectives were to demonstrate non-
However, vaccine vials should be discarded within maximum 6 h inferiority of the investigational PHiD-CV 4-dose vial versus
after opening as this presentation is preservative-free. licensed PHiD-CV 1-dose vial in terms of antibody geometric mean
GSK has developed a 4-dose vial presentation of PHiD-CV with concentrations (GMCs) for each VT (primary objective) and
addition of a preservative (2-phenoxyethanol) to control potential vaccine-related serotype 19A (secondary objective) at 1 month
microbial contamination, allowing vaccine use up to 28 days after post-primary vaccination.
opening as per WHO multi-dose vial policy [14]. This would further Additional secondary objectives were to assess immune
enhance logistics and adherence to immunization programs in responses of PHiD-CV 4-dose vial against VT and vaccine-related
developing countries, as in place for other pediatric vaccines [15], serotypes 6A and 19A at 1 and 5 months post-primary vaccination
including the recently WHO-qualified 13-valent pneumococcal and 1 month post-booster vaccination, and against protein D at 1
conjugate vaccine (PCV13) 4-dose vial [16]. Here, we present the month post-primary and booster vaccinations. Reactogenicity and
immunologic non-inferiority of the PHiD-CV 4-dose vial in infants safety following PHiD-CV 4-dose vial vaccination were also
compared to the PHiD-CV 1-dose vial after primary vaccination. assessed.
The immunogenicity, reactogenicity and safety after primary and
booster vaccination with PHiD-CV 4-dose and 1-dose vials were
2.4. Immunogenicity assessment
also assessed.

Blood samples were collected 1 and 5 months post-primary

2. Methodology vaccination, and 1 month post-booster vaccination (Fig. S1).
Serotype-specific pneumococcal immunoglobulin G (IgG) anti-
2.1. Study design and population bodies against VT and vaccine-related serotypes 6A and 19A were
measured using the enzyme linked immunosorbent assay with ser-
This phase III, single-center, observer-blind, controlled study otype 22F polysaccharide adsorption (22F-ELISA) (at the laboratory
(ClinicalTrials.gov: NCT02447432) was conducted in Bangladesh Néomed-Labs Inc, Quebec, Canada), as previously described [19].
between June 2015 and May 2016. The percentage of children with antibody concentrations 0.2
Infants aged 6–10 weeks were randomized 1:1 to receive either lg/mL are presented here. This threshold is equivalent to an anti-
PHiD-CV 4-dose vial (4DV group) or PHiD-CV 1-dose vial (1DV body concentration 0.35 mg/mL as measured by the non-22F-
group) administered in a 3 + 1 schedule at ages 6, 10 and 18 weeks ELISA of the WHO reference laboratory [20].
(primary vaccination) and 9 months (booster vaccination) (Fig. S1). Functional immune responses (opsonophagocytic activity, OPA)
Children received diphtheria-tetanus-whole cell pertussis-hepatitis to each VT and vaccine-related serotypes 6A and 19A were mea-
B and H. influenzae type b conjugate vaccine (DTPw-HBV/Hib, GSK) sured in a selected subset (first 50% of infants recruited in each
and polio, measles and rubella vaccines as described in Fig. S1. month of enrolment throughout the study) by a validated multi-
Eligibility criteria for inclusion in the study, and reasons for plex OPA assay (at the University College of London, Institute of
exclusion of infants from the study are presented in supplementary Child Health, London, United Kingdom). The assay cut-off was an
text S1. A protocol summary is available at http://www.gsk-clini- opsonic titer of 8 as previously described [21].
calstudyregister.com (study ID 200799). Details regarding blinding Antibodies against the protein D carrier were measured at 1
and randomization are shown in supplementary text S2. month post-primary and 1 month post-booster vaccination in the
Overall, the study was conducted in accordance with the princi- same selected subset as OPA using an in-house ELISA (GSK, Bel-
ples of Good Clinical Practice, Declaration of Helsinki and all appli- gium). The assay cut-off was 153 ELISA units (EL.U)/mL.
cable regulatory requirements.
Signed/thumb-printed and witnessed informed consent was 2.5. Reactogenicity and safety assessment
obtained from the parent(s) or legally acceptable representative
(s) (LAR[s]) of each infant before enrolment. Solicited adverse events (AEs) at the injection site (pain, redness
and swelling) and general AEs (drowsiness, fever, irritability and
2.2. Study vaccines loss of appetite) were reported on diary cards within 4 days post-
vaccination. Unsolicited AEs were reported within 31 days post-
The licensed PHiD-CV 1-dose vial (Synflorix, GSK) was a vaccination, and serious AEs (SAEs) throughout the study. For the
preservative-free suspension containing capsular polysaccharides illiterate parents/LARs, fieldworkers visited each infant every day
700 K. Zaman et al. / Vaccine 36 (2018) 698–706

within the 31 days after PHiD-CV vaccination and recorded their (Table S1). The elapsed time from PHiD-CV 4-dose vial opening
signs and symptoms on the diary cards. For literate parents/LARs, to use of the last vial-dose ranged between 0 and 7 days during
fieldworkers visited each infant every day within the 4 days after the primary vaccination and between 0 and 23 days during the
PHiD-CV vaccination, but the parents/LARs filled in the diary cards. booster vaccination.
Fever was defined as axillary temperature 37.5 °C. AE intensity
grades and SAE definitions are detailed in supplementary text S3. 3.3. Immunogenicity results
All solicited injection site reactions were considered as causally
related to vaccination. Causality of all other AEs was assessed by 3.3.1. Primary vaccination phase
the investigators. One month post-primary vaccination, non-inferiority of PHiD-
CV 4-dose versus 1-dose vial was demonstrated for each VT and
2.6. Statistical analyses vaccine-related serotype 19A (Fig. 2). For each VT, the percentage
of infants with antibody concentrations 0.2 lg/mL was at least
Except for the confirmatory objectives related to immunologic 97.9%, except for serotypes 6B and 23F. For vaccine-related sero-
non-inferiority, the other study objectives were descriptive. types 6A and 19A, at least 58.2% and 80.1% of infants in both
A total of 320 infants were planned to be enrolled, considering groups, respectively, had antibody concentrations 0.2 lg/mL.
that up to 12.5% could be eliminated from the according-to- Serotype-specific antibody GMCs were within similar ranges
protocol (ATP) cohort for immunogenicity. A resulting 140 evalu- between groups (Table 2).
able infants per group would provide at least 90.8% power (under The percentage of infants with OPA titers 8 was at least 83.8%
equal mean) to show non-inferiority of PHiD-CV 4-dose vial versus for each VT, and at least 54.5% and 80.6% for vaccine-related sero-
PHiD-CV 1-dose vial in terms of antibody GMC ratios. types 6A and 19A. For each serotype, OPA GMTs were within the
Immunogenicity analyses were performed on the ATP cohorts same ranges in both groups (Table 3).
for immunogenicity adapted for primary and booster vaccination. All infants had anti-protein D antibody concentrations 153 EL.
Details regarding infant eligibility for inclusion in these cohorts U/mL 1 month post-primary vaccination. Antibody GMCs were
are shown in supplementary text S4. within similar ranges between the 4DV and 1DV groups (Table S2).
The percentages of infants reaching pre-defined immunologic
cut-offs, antibody GMCs and OPA geometric mean titers (GMTs) 3.3.2. Booster vaccination phase
were calculated with 95% confidence intervals (CIs). Antibody Five months post-primary vaccination (pre-booster), the persis-
GMCs and OPA GMTs were calculated as described previously tence of the immune responses following PHiD-CV 4-dose vial vac-
[20,21]. cination was similar to that observed after PHiD-CV 1-dose vial
Comparison of the PHiD-CV 4-dose vial versus PHiD-CV 1-dose vaccination, for each VT and vaccine-related serotypes 6A and
vial in terms of non-inferiority was demonstrated if the upper limit 19A (Tables 2 and 3).
(UL) of the 2-sided 95% CI of the GMC ratios (1DV group/4DV One month post-booster, for each VT at least 98.6% of infants
group) was less than 2-fold for each VT (primary confirmatory had antibody concentrations 0.2 mg/mL, except serotypes 6B
objective) and vaccine-related serotype 19A (secondary confirma- and 23F. For serotypes 6A and 19A, at least 80.8% and 90.7% of
tory objective). The latter was only assessed if the primary objec- infants in both groups, respectively, had antibody concentrations
tive was met. 0.2 mg/mL. Antibody GMCs were higher 1 month poster-booster
Reactogenicity and safety analyses were performed on the total compared to post-primary vaccination, and within similar ranges
vaccinated cohort (TVC). Percentages of doses followed by solicited for each VT, 6A and 19A (Table 2).
or unsolicited AEs were tabulated with exact 95% CIs. SAE occur- One month post-booster, at least 90.5% of infants had OPA titers
rence was described. 8 for each VT. For serotypes 6A and 19A, at least 71.8% and 86.8%
Statistical Analysis System was used to perform statistical of infants in both groups, respectively, had OPA titers 8. For most
analyses. serotypes, OPA GMTs were higher post-booster compared to post-
primary vaccination, and within similar ranges between groups for
each VT, 6A and 19A (Table 3).
3. Results One month post-booster, all infants had anti-protein D antibody
concentrations 153 EL.U/mL and antibody GMCs were within
3.1. Study population similar ranges between the 4DV and 1DV groups (Table S2).

In total, 320 infants were enrolled. Informed consent was 3.4. Reactogenicity and safety results
obtained from 213 literate and 107 illiterate (83 by signing, 24
by thumb impression) parents/LARs. Of 160 vaccinated infants in 3.4.1. Primary vaccination phase
each group, 154 and 146 infants in the 4DV and 1DV groups, During the 4-day post-vaccination period, pain was the most
respectively, were included in the ATP cohort for immunogenicity frequently reported solicited PHiD-CV injection site reaction and
for primary vaccination (Fig. 1). irritability was the most frequently reported solicited general AE
During the booster vaccination phase, 297 infants were (Fig. 3A). No large swelling reactions were reported.
included in the TVC and completed the study (152 in the 4DV Solicited general AEs considered by the investigator as
group and 145 in the 1DV group). Of these, 295 were included in vaccination-related were reported after less than 23.3% (irritabil-
the ATP cohort for immunogenicity for booster vaccination: 151 ity) of doses in the 4DV group, and after less than 26.6% (irritabil-
in the 4DV group and 144 in the 1DV group (Fig. 1). ity) of doses in the 1DV group. Grade 3 solicited general AEs
Baseline demographic characteristics were similar between considered as vaccination-related were reported after 0.4%
groups (Table 1). (drowsiness) to 3.8% (irritability) of doses in the 4DV group and
after 1.1% (loss of appetite) to 3.1% (irritability) of doses in the
3.2. Use of the PHiD-CV 4-dose vial 1DV group. No vaccination-related grade 3 fever was reported.
During the 31-day post-vaccination period, at least 1 unso-
Each vial dose from the PHiD-CV 4-dose presentation was licited AE was reported after 2.1% of doses in the 4DV group and
evenly repartitioned between consecutive vaccinations 3.7% of doses in the 1DV group; grade 3 unsolicited AEs were
 K. Zaman et al. / Vaccine 36 (2018) 698–706 701

Primary vaccination phase (N=320)

Total vaccinated cohort 4DV group 1DV group

(N=320) N=160 N=160

Reason for exclusion: 5 Essential serological data missing 13 Essential serological data missing
1 Non-compliance with blood sampling 1 Protocol deviation**

ATP cohort for immunogenicity* 4DV group 1DV group

(N=300) N=154 N=146

3 Migrated/moved from study area 5 Migrated/moved from study area

Reason for discontinuation
1 SAE 4 Consent withdrawal
during primary vaccination:
1 Lost to follow-up (incomplete vaccination) 3 Lost to follow-up (incomplete vaccination)
1 SAE
Infants from total vaccinated
4DV group 1DV group
cohort who completed primary
N=155 N=147
vaccination phase
Reason for study 2 Consent withdrawal 1 Consent withdrawal
discontinuation: 1 Lost to follow-up 1 Lost to follow-up

Booster vaccination phase (N=297)

Total vaccinated cohort 4DV group 1DV group

(N=297) N=152 N=145

1 Non-compliance with vaccination 1 Protocol deviation**

Reason for exclusion: schedule

ATP cohort for immunogenicity 4DV group 1DV group

(N=295) N=151 N=144

Fig. 1. Flow diagram by vaccination phase. *Immunologic non-inferiority was assessed in this cohort; **Linked to inclusion/exclusion criteria; 4DV group, infants that received
PHiD-CV vaccination with 4-dose vial; 1DV group, infants that received PHiD-CV vaccination with 1-dose vial; N, number of infants; ATP, according-to-protocol; SAE, serious
adverse event.

Table 1
Demographic characteristics (total vaccinated cohort).
1
Category 4DV group 1DV group
4
Primary vaccination phase N = 160 N = 160
Age at dose 1 (weeks), mean ± SD 6.9 ± 1.3 6.8 ± 1.2 5
Pneumococcal serotypes

Female, n (%) 80 (50.0) 73 (45.6)

6B
Asian – South East Asian Heritage, n (%) 160 (100) 160 (100)
Booster vaccination phase N = 152 N = 145 7F
Age at booster dose (months), mean ± SD 8.1 ± 0.3 8.1 ± 0.3 9V
Female, n (%) 77 (50.7) 66 (45.5)
Asian – South East Asian Heritage, n (%) 152 (100) 145 (100) 14

N, number of infants; SD, standard deviation; n (%), number (percentage) of infants 18C
in a given category.
19F

23F

reported after 0.6% and 1.5% of doses, respectively. The most com- 19A
monly reported unsolicited AEs were diarrhea (0.8% of doses in the
0 0.5 1 1.5 2 2.5 3
4DV group; 0.7% of doses in the 1DV group), nasopharyngitis (0.9%
Antibody GMC ratio (1DV group over 4DV group) with 95% CI
of doses in the 1DV group) and pneumonia (0.7% of doses in the
1DV group). None of the unsolicited AEs were considered as Fig. 2. Antibody GMC ratios for each vaccine pneumococcal serotype and vaccine-
vaccination-related. related serotype 19A one month post-primary vaccination with PHiD-CV 4-dose
Following primary vaccination, SAEs were reported for 4 infants vial or 1-dose vial presentations (ATP cohort for immunogenicity). GMC, geometric
mean concentration; ATP, according-to-protocol; CI, confidence interval calculated
in the 4DV group and 9 in the 1DV group (for 3 of them SAEs
by ANOVA model on the logarithm 10 transformation – pooled variance. Note:
occurred between primary and booster), none being considered vertical dotted black line indicates the threshold used to define non-inferiority
as vaccination-related. Two SAEs were fatal, 1 in the 4DV group criterion.
702 K. Zaman et al. / Vaccine 36 (2018) 698–706

Table 2
Percentages of infants with serotype-specific pneumococcal antibody concentrations 0.2 mg/mL and antibody geometric mean concentrations (GMCs) (ATP cohort for
immunogenicity adapted for each vaccination phase).

ST Time point % of infants with IgG concentration 0.2 mg/mL Antibody GMCs (mg/mL)
4DV group 1DV group 4DV group 1DV group
N % (95% CI) N % (95% CI) Value (95% CI) Value (95% CI)
1 Post-primary 154 99.4 (96.4; 100) 146 100 (97.5; 100) 2.78 (2.43; 3.18) 3.03 (2.60; 3.54)
Pre-booster 151 96.7 (92.4; 98.9) 144 93.1 (87.6; 96.6) 0.93 (0.79; 1.10) 0.99 (0.81; 1.19)
Post-booster 151 100 (97.6; 100) 144 100 (97.5; 100) 6.37 (5.48; 7.41) 7.50 (6.28; 8.97)
4 Post-primary 154 100 (97.6; 100) 146 100 (97.5; 100) 4.23 (3.69; 4.84) 3.87 (3.33; 4.51)
Pre-booster 151 100 (97.6; 100) 144 100 (97.5; 100) 1.90 (1.65; 2.19) 1.71 (1.45; 2.01)
Post-booster 151 100 (97.6; 100) 143 100 (97.5; 100) 9.68 (8.47; 11.06) 9.41 (8.16; 10.86)
5 Post-primary 154 100 (97.6; 100) 146 100 (97.5; 100) 5.12 (4.46; 5.88) 5.30 (4.59; 6.12)
Pre-booster 151 98.0 (94.3; 99.6) 144 98.6 (95.1; 99.8) 1.75 (1.50; 2.05) 1.75 (1.48; 2.08)
Post-booster 151 100 (97.6; 100) 144 100 (97.5; 100) 11.53 (10.14; 13.12) 12.24 (10.65; 14.05)
6B Post-primary 154 84.4 (77.7; 89.8) 146 84.9 (78.1; 90.3) 1.23 (0.95; 1.57) 1.37 (1.05; 1.79)
Pre-booster 151 92.1 (86.5; 95.8) 144 88.9 (82.6; 93.5) 1.14 (0.93; 1.40) 1.06 (0.84; 1.32)
Post-booster 151 95.4 (90.7; 98.1) 144 94.4 (89.3; 97.6) 3.76 (3.01; 4.69) 4.11 (3.21; 5.25)
7F Post-primary 154 100 (97.6; 100) 146 100 (97.5; 100) 5.52 (4.90; 6.22) 5.79 (5.06; 6.62)
Pre-booster 151 100 (97.6; 100) 144 100 (97.5; 100) 2.86 (2.50; 3.27) 2.75 (2.40; 3.16)
Post-booster 151 100 (97.6; 100) 144 100 (97.5; 100) 12.84 (11.38; 14.48) 13.71 (12.01; 15.65)
9V Post-primary 154 98.7 (95.4; 99.8) 146 97.9 (94.1; 99.6) 4.60 (3.98; 5.32) 4.07 (3.34; 4.95)
Pre-booster 151 99.3 (96.4; 100) 144 97.2 (93.0; 99.2) 2.32 (1.96; 2.75) 2.25 (1.83; 2.76)
Post-booster 151 99.3 (96.4; 100) 144 98.6 (95.1; 99.8) 12.07 (10.42; 13.98) 12.43 (10.22; 15.13)
14 Post-primary 154 99.4 (96.4; 100) 146 100 (97.5; 100) 4.97 (4.05; 6.10) 4.84 (3.91; 5.99)
Pre-booster 151 94.7 (89.8; 97.7) 144 95.1 (90.2; 98.0) 2.98 (2.39; 3.72) 2.40 (1.90; 3.04)
Post-booster 151 99.3 (96.4; 100) 143 99.3 (96.2; 100) 9.84 (8.02; 12.08) 9.72 (7.92; 11.93)
18C Post-primary 154 100 (97.6; 100) 146 100 (97.5; 100) 19.58 (16.65; 23.03) 21.18 (17.9; 25.06)
Pre-booster 151 100 (97.6; 100) 144 100 (97.5; 100) 8.37 (7.14; 9.82) 9.23 (7.82; 10.90)
Post-booster 151 100 (97.6; 100) 144 100 (97.5; 100) 41.64 (36.87; 47.02) 47.06 (41.88; 52.88)
19F Post-primary 154 98.7 (95.4; 99.8) 146 99.3 (96.2; 100) 13.24 (11.17; 15.68) 13.11 (11.16; 15.41)
Pre-booster 151 98.7 (95.3; 99.8) 144 98.6 (95.1; 99.8) 6.36 (5.36; 7.55) 6.45 (5.50; 7.57)
Post-booster 151 99.3 (96.4; 100) 144 98.6 (95.1; 99.8) 23.43 (19.48; 28.19) 24.96 (21.07; 29.57)
23F Post-primary 154 89.0 (82.9; 93.4) 146 94.5 (89.5; 97.6) 1.59 (1.25; 2.01) 2.04 (1.61; 2.58)
Pre-booster 151 89.4 (83.4; 93.8) 144 87.5 (81.0; 92.4) 1.09 (0.89; 1.33) 1.21 (0.96; 1.53)
Post-booster 151 98.7 (95.3; 99.8) 144 95.8 (91.2; 98.5) 6.69 (5.66; 7.90) 6.69 (5.33; 8.41)
6Aa Post-primary 154 61.7 (53.5; 69.4) 146 58.2 (49.8; 66.3) 0.31 (0.25; 0.38) 0.29 (0.23; 0.36)
Pre-booster 151 62.3 (54.0; 70.0) 144 63.9 (55.5; 71.7) 0.31 (0.24; 0.39) 0.30 (0.24; 0.38)
Post-booster 151 80.8 (73.6; 86.7) 144 82.6 (75.4; 88.4) 0.97 (0.74; 1.26) 1.11 (0.83; 1.49)
19Aa Post-primary 154 81.8 (74.8; 87.6) 146 80.1 (72.7; 86.3) 0.76 (0.60; 0.96) 0.68 (0.54; 0.86)
Pre-booster 151 76.2 (68.6; 82.7) 144 80.6 (73.1; 86.7) 0.70 (0.55; 0.89) 0.69 (0.54; 0.88)
Post-booster 151 90.7 (84.9; 94.8) 144 93.8 (88.5; 97.1) 3.03 (2.26; 4.05) 3.63 (2.73; 4.82)
a
Vaccine-related serotypes; ATP, according-to-protocol; IgG, immunoglobulin G; ST, serotype; post-primary, 1 month after dose 3; pre-booster, 5 months post-dose 3;
post-booster, 1 month after the booster dose; N, number of infants with available results; CI, confidence interval.

(sepsis) and 1 in the 1DV group (septic shock), but their microbio- chain and increasing the storage time, especially in developing
logical etiology could not be confirmed. countries. While PHiD-CV is currently licensed as a pre-filled syr-
inge, a 1-dose or a 2-dose vial, all preservative-free, this is the first
3.4.2. Booster vaccination phase study that evaluated a 4-dose vial presentation of PHiD-CV con-
During the 4-day post-vaccination period, the most frequently taining preservative. We compared the immunogenicity, reacto-
reported solicited PHiD-CV injection site reactions and general genicity and safety of the 4-dose vial to the 1-dose vial.
AEs were swelling and irritability, respectively (Fig. 3B). No large This study demonstrated non-inferiority of the PHiD-CV 4-dose
swelling reactions were reported. vial versus the PHiD-CV 1-dose vial in terms of antibody GMCs for
Solicited general AEs considered as vaccination-related were each VT and 19A after completion of a 3-dose primary vaccination
reported after less than 7.2% (irritability) of doses in the 4DV in infants at ages 6, 10 and 18 weeks. Due to the lack of a clear cor-
group, and after less than 3.4% (irritability) of doses in the 1DV relate of protection against IPD, the WHO recognizes immunologic
group. Grade 3 irritability considered as vaccination-related was non-inferiority post-primary vaccination as one of the serological
reported for 1 infant (after 0.7% of doses) in the 4DV group. criteria for assessment of new PCVs for licensure and prequalifica-
During the 31-days post-booster dose, no unsolicited AEs were tion [22]. We have applied the non-inferiority criteria in terms of
reported. No SAEs were reported post-booster vaccination. anti-pneumococcal antibody GMCs measured by ELISA as previ-
ously used to demonstrate PHiD-CV lot-to-lot consistency [23].
4. Discussion The 2-fold non-inferiority margin for the antibody GMC ratio was
chosen because different PHiD-CV lots were previously shown to
The use of a multi-dose vial would improve the logistics of PCV be within a 2-fold range [23]. Similarly, the criteria used for licen-
immunization programs, by reducing the required volume of cold sure and prequalification of the 4-dose presentation of PCV13 con-
 K. Zaman et al. / Vaccine 36 (2018) 698–706 703

Table 3
Percentages of infants with pneumococcal serotype-specific opsonophagocytic activity (OPA) titers 8 and antibody geometric mean titers (GMTs) (ATP cohort for
immunogenicity adapted for each vaccination phase).

ST Time point % of infants with OPA titers 8 OPA GMTs

4DV group 1DV group 4DV group 1DV group
N % (95% CI) N % (95% CI) Value (95% CI) Value (95% CI)
1 Post-primary 74 90.5 (81.5; 96.1) 74 83.8 (73.4; 91.3) 48.3 (34.9; 67) 52.8 (36.0; 77.5)
Pre-booster 72 47.2 (35.3; 59.3) 70 50.0 (37.8; 62.2) 11.5 (8.2; 16.1) 12.8 (9.1; 17.9)
Post-booster 73 98.6 (92.6; 100) 71 98.6 (92.4; 100) 227.7 (170.6; 303.9) 326.7 (238.7; 447.0)
4 Post-primary 75 100 (95.2; 100) 74 98.6 (92.7; 100) 823.1 (670.9; 1009.8) 836.8 (644.5; 1086.6)
Pre-booster 72 97.2 (90.3; 99.7) 70 95.7 (88.0; 99.1) 248.1 (178.6; 344.7) 280.5 (193.4; 406.6)
Post-booster 76 100 (95.3; 100) 73 100 (95.1; 100) 2025.4 (1641.6; 2498.8) 2888.7 (2221.6; 3756.1)
5 Post-primary 73 97.3 (90.5; 99.7) 74 98.6 (92.7; 100) 179.0 (140.7; 227.8) 211.0 (162.9; 273.2)
Pre-booster 73 90.4 (81.2; 96.1) 71 94.4 (86.2; 98.4) 51.3 (37.0; 71.3) 62.7 (44.4; 88.7)
Post-booster 76 100 (95.3; 100) 73 100 (95.1; 100) 550.6 (437.8; 692.4) 801.2 (633.2; 1013.6)
6B Post-primary 73 86.3 (76.2; 93.2) 73 89.0 (79.5; 95.1) 560.6 (336.9; 932.8) 759.6 (470.2; 1227.3)
Pre-booster 73 90.4 (81.2; 96.1) 70 91.4 (82.3; 96.8) 290.3 (177.1; 475.7) 286.8 (183.5; 448.0)
Post-booster 74 90.5 (81.5; 96.1) 72 94.4 (86.4; 98.5) 851.3 (533.4; 1358.6) 1352.0 (913.9; 1999.9)
7F Post-primary 74 100 (95.1; 100) 73 100 (95.1; 100) 2044.0 (1669.3; 2502.9) 2076.8 (1627.0; 2650.9)
Pre-booster 74 100 (95.1; 100) 73 100 (95.1; 100) 1112.8 (864.8; 1431.8) 1181.7 (933.4; 1495.9)
Post-booster 76 100 (95.3; 100) 73 100 (95.1; 100) 4574.7 (3756.1; 5571.6) 5635.8 (4561.7; 6962.9)
9V Post-primary 75 96.0 (88.8; 99.2) 74 97.3 (90.6; 99.7) 613.3 (444.9; 845.4) 821.1 (602.5; 1119.2)
Pre-booster 69 95.7 (87.8; 99.1) 72 97.2 (90.3; 99.7) 415.8 (280.6; 616.3) 570.6 (408.4; 797.3)
Post-booster 76 100 (95.3; 100) 73 98.6 (92.6; 100) 2308.4 (1903.3; 2799.7) 3181.9 (2376.9; 4259.6)
14 Post-primary 73 100 (95.1; 100) 74 97.3 (90.6; 99.7) 1563.9 (1105.1; 2213.2) 1655.8 (1141.1; 2402.7)
Pre-booster 73 93.2 (84.7; 97.7) 72 97.2 (90.3; 99.7) 660.1 (432.4; 1007.6) 745.0 (513.9; 1080.0)
Post-booster 76 100 (95.3; 100) 73 100 (95.1; 100) 3345.6 (2585.0; 4330.1) 3649.1 (2808.6; 4741.2)
18C Post-primary 75 100 (95.2; 100) 74 100 (95.1; 100) 3965.4 (3288.6; 4781.5) 3809.7 (3067.0; 4732.3)
Pre-booster 74 100 (95.1; 100) 73 100 (95.1; 100) 1505.4 (1196.4; 1894.1) 1735.2 (1373.8; 2191.7)
Post-booster 76 100 (95.3; 100) 73 100 (95.1; 100) 7316.1 (6137.6; 8720.8) 7181.6 (6003.6; 8590.7)
19F Post-primary 75 97.3 (90.7; 99.7) 74 100 (95.1; 100) 2151.3 (1573.5; 2941.4) 2879.2 (2348.4; 3529.9)
Pre-booster 74 95.9 (88.6; 99.2) 72 100 (95.0; 100) 770.1 (536.6; 1105.3) 1254.3 (990.8; 1587.9)
Post-booster 76 97.4 (90.8; 99.7) 73 100 (95.1; 100) 3197.3 (2271.1; 4501.2) 4757.7 (3772.3; 6000.4)
23F Post-primary 75 89.3 (80.1; 95.3) 74 93.2 (84.9; 97.8) 524.8 (338.5; 813.9) 730.2 (495.6; 1075.7)
Pre-booster 70 90.0 (80.5; 95.9) 69 87.0 (76.7; 93.9) 267.7 (168.7; 424.9) 252.7 (154.8; 412.4)
Post-booster 76 97.4 (90.8; 99.7) 73 95.9 (88.5; 99.1) 1250.8 (931.3; 1679.8) 1465.6 (1002.9; 2141.7)
6Aa Post-primary 66 54.5 (41.8; 66.9) 69 58.0 (45.5; 69.8) 50.3 (26.9; 94.0) 68.5 (36.8; 127.7)
Pre-booster 72 50.0 (38.0; 62.0) 68 48.5 (36.2; 61.0) 52.4 (27.4; 100.1) 45.5 (24.0; 86.5)
Post-booster 71 71.8 (59.9; 81.9) 68 80.9 (69.5; 89.4) 192.0 (102.9; 358.4) 284.4 (158.4; 510.6)
19Aa Post-primary 72 80.6 (69.5; 88.9) 71 81.7 (70.7; 89.9) 98.6 (60.9; 159.6) 117.1 (71.9; 190.6)
Pre-booster 73 60.3 (48.1; 71.5) 71 69.0 (56.9; 79.5) 42.7 (25.1; 72.7) 43.6 (26.6; 71.3)
Post-booster 76 86.8 (77.1; 93.5) 72 90.3 (81.0; 96.0) 410.4 (246.7; 682.8) 591.7 (356.9; 980.9)
a
Vaccine-related serotypes; ATP, according-to-protocol; ST, serotype; post-primary, 1 month after dose 3; pre-booster, 5 months post-dose 3; post-booster, 1 month after
the booster dose; N, number of infants with available results; CI, confidence interval.

taining preservative included non-inferiority in terms of a 2-fold recommendation to assess new PCVs for licensure and prequalifi-
limit for anti-pneumococcal antibody GMCs after 3-dose primary cation [22].
vaccination [16,24]. The PHiD-CV 4-dose vial (with preservative) had an acceptable
Demonstration of immunologic non-inferiority of the PHiD-CV reactogenicity profile, similar to the one of the PHiD-CV 1-dose vial
4-dose versus the PHiD-CV 1-dose vial supports the inference of (preservative-free) in infants following a 3-dose primary vaccina-
efficacy/effectiveness in clinical trials [4,5] and effectiveness/ tion at 6, 10 and 18 weeks (given with DTPw-HBV/Hib at 6 and
impact in post-marketing studies [6–12]. This suggests that the 10 weeks) and following booster vaccination at 9 months. No
PHiD-CV 4-dose vial can provide a similar protection against pneu- safety concerns were raised. Overall, incidences of solicited AEs
mococcal infections as the licensed 1-dose vial. seemed to be generally lower than in previous studies conducted
In addition, this study also assessed immunogenicity of the in India [25,26], Mali and Nigeria [27,28].
PHiD-CV 4-dose in terms of percentage of infants with antibody Rates of reported unsolicited AEs were in line with other studies
concentrations 0.2 mg/mL, percentage of infants with OPA titers with PHiD-CV conducted in India [25,26] and the Gambia [29], and
8 and OPA GMTs 1 month post-primary vaccination, following generally lower than in other developing countries [30,31].
WHO recommendations [22]. No differences were observed for Overall, these data suggest that the preservative included in the
these parameters for each VT and 19A between 4DV and 1DV PHiD-CV 4-dose vial does not interfere with either the immune
groups. response to or the reactogenicity profile of PHiD-CV. This is in line
Post-booster vaccination with PHiD-CV 4-dose at 9 months old, with the findings observed with the 4-dose presentation of PCV13
increases in antibody GMCs (for all VT, and 19A) were observed, containing preservative [16,24].
indicating effective priming. For most serotypes, post-booster In addition, as outlined in the WHO multi-dose vial policy and
increases in OPA GMTs were also observed. These findings support as required for WHO prequalification [14], the time limit for keep-
the PHiD-CV 4-dose vial boostability, which is also part of WHO ing the opened 4-dose vial with preservative was 28 days per pro-
704 K. Zaman et al. / Vaccine 36 (2018) 698–706

A. Primary vaccination
4DV group (N=472) 1DV group (N=455) Grade 3
100
90
80
% of dosses (95% CI)

70
60
50
40
30
20
10
0
PHiD-CV DTPw- PHiD-CV DTPw- PHiD-CV DTPw-
HBV/Hib HBV/Hib HBV/Hib
Pain Redness Swelling Drowsiness Irritability Loss of Fever
appetite

Local General

B. Booster vaccination
4DV group (N=152) 1DV group (N=145) Grade 3
100
90
80
(95% CI)

70
60
50
% of doses

40
d

30
20
10
0
Pain Redness Swelling Drowsiness Irritability Loss of Fever
appetite

Local General

Fig. 3. Percentage of doses followed by solicited local (at each injection site) and general symptoms by vaccination phase (total vaccinated cohort). N, number of documented
PHiD-CV doses; grade 3, crying when limb was moved/limb was spontaneously painful (pain), diameter >30 mm (redness/swelling), preventing everyday activity
(drowsiness/irritability), crying that cannot be comforted (irritability), not eating at all (loss of appetite), axillary temperature >39.5 °C (fever); any fever, axillary temperature
37.5 °C; CI, confidence intervals. Notes: The number of documented DTPw-HBV/Hib doses (co-administered with PHiD-CV at 6 and 10 weeks of age) was 317 in the 4DV
group and 308 in the 1DV group.

tocol. At study end, we have recorded a maximum time after open- received common childhood vaccines as in a real-life setting and
ing and until use of the last vial-dose of 23 days, which is close to per Expanded Program on Immunization (EPI) schedule at 6–10–
the WHO allowed maximum after opening. The faster use observed 14 weeks. PHiD-CV is administered in Bangladesh per local EPI
during primary vaccination is expected in the settings and condi- schedule for pneumococcal vaccination at 6–10–18 weeks [32].
tions of mass vaccination in developing countries for which this This non-classical EPI schedule might be followed by other coun-
presentation is intended. tries to allow additional vaccinations such as IPV at 14 weeks.
The strengths of this study include the confirmatory objective Although booster vaccination is not included in the EPI schedule,
with appropriate design: well-recognized, predefined non- infants received a PHiD-CV booster dose as per current recommen-
inferiority criteria in a two-arm trial design comparing PHiD-CV dations [13]. The booster dose was given at 9 months of age to
4-dose vial with the 1-dose vial. Furthermore, use of each dose allow co-administration with the routine measles vaccination,
from the 4-dose vial was evenly repartitioned among primary which is earlier than the usual PCV booster vaccination in the sec-
and booster vaccine doses. Therefore, safety and immunogenicity ond year of life. A clinical study in India did not suggest differences
data generated in this study are representative of a 4-dose vial in terms of antibody GMCs between children receiving a PHiD-CV
used up to the last dose, and any vial dose can be given at any vac- booster dose at 9–12 or 15–18 months of age following primary
cination visit. Another strength was that this study was conducted vaccination [26].
in a GAVI-eligible country in which the 4-dose presentation is The study also had limitations. The assessment of the functional
planned to be used. In addition to PHiD-CV 4-dose vial, infants also OPA responses and immune responses to booster vaccination were
 K. Zaman et al. / Vaccine 36 (2018) 698–706 705

descriptive and comparisons should be interpreted with caution authors participated in the development of this manuscript. All
due to multiple comparisons without adjustment for multiplicity. authors had full access to the data, gave final approval before sub-
Furthermore, the OPA and protein D responses were assessed in mission and agree to be accountable for all aspects of the work. The
a subset (50%) of subjects. corresponding author was responsible for submission of the
publication.
5. Conclusion
Appendix A. Supplementary material
This study demonstrated immunologic non-inferiority of the
PHiD-CV 4-dose vial presentation (with preservative) compared A summary of the manuscript has been included in the supple-
to the PHiD-CV 1-dose vial presentation (preservative-free). Fol- mentary material as focus on the patient section. This is intended
lowing primary vaccination at 6, 10 and 18 weeks of age and boos- to highlight the main contents for health care provider readers.
ter vaccination at 9 months of age, immune responses elicited by Supplementary data associated with this article can be found, in
PHiD-CV 4-dose and 1-dose vial were in similar ranges. PHiD-CV the online version, at https://doi.org/10.1016/j.vaccine.2017.12.
4-dose vial also showed an acceptable reactogenicity profile. The 034.
PHiD-CV 4-dose vial would help improve access and coverage in
resource-limited countries, and may enable more children to References
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