Pneumococcal polysaccharide conjugate vaccine, turbid liquid suspension for injection (0.5 mL) in pre-filled syringe or vial, Synflorix®
Public Summary Document for Pneumococcal polysaccharide conjugate vaccine, turbid liquid suspension for injection (0.5 mL) in pre-filled syringe or vial, Synflorix®
Page last updated: 30 October 2009
PDF printable version for Pneumococcal polysaccharide conjugate vaccine (PDF 103 KB)
Public Summary Document
Product: Pneumococcal polysaccharide conjugate
vaccine, turbid liquid suspension for injection (0.5 mL) in
pre-filled syringe or vial, Synflorix®
Sponsor: GlaxoSmithKline Australia Pty Ltd
Date of PBAC Consideration: July 2009
1. Purpose of Application
To request listing on the National Immunisation Program (NIP) for
immunisation of infants and children up to two years against
disease caused by Streptococcus pneumoniae.
2. Background
This vaccine had not previously been considered by the PBAC.
Pneumococcal vaccine has been available under the NIP since 1
January 2005. The vaccine is administered at two, four and six
months of age, with a fourth dose at 12 months of age for medically
at risk children.
3. Registration status
Pneumococcal polysaccharide conjugate vaccine, 10-valent adsorbed suspension for injection pre-filled syringe was TGA registered on 24 March 2009 for the indication:
Active immunisation of infants and children from the age of 6 weeks up to 2 years against disease caused by Streptococcus pneumoniae serotypes 1, 4, 5, 6B, 7F, 9V,14,18C, 19F and 23F (inclusding invasive disease, pneumonia and acute otitis media).
4. Listing requested and PBAC’s View:
The requested National Immunisation Program indication is:
For immunisation of all Australian infants and children from the
age of eight weeks to two years of age against disease caused by
Streptococcus pneumoniae serotypes 1, 4, 5, 6B, 7F, 9V,
14, 18C, 19F and 23F (including invasive disease, pneumonia, and
acute otitis media).
It is intended that the vaccine be administered as a three dose
primary series at 2, 4 and 6 months plus a fourth (booster)
dose.
See Recommendation and Reasons for PBAC’s
view.
5. Clinical place for the proposed therapy
This vaccine would provide an alternative vaccine for pneumococcal
disease compared to the 7 valent pneumococcal vaccine currently
listed on the NIP.
6. Comparator
The submission nominated 7 valent pneumococcal conjugate vaccine
(Prevenar®) as the comparator.
7. Clinical trials
The submission presented four randomised trials comparing Synflorix
with Prevenar in infants receiving primary pneumococcal vaccination
in a range of alternative 3 dose vaccination schedules (Trials 001,
003, 011, 012), two randomised extension trials in infants
receiving a booster dose of Synflorix or Prevenar (Trials 007 and
017: extensions of Trials 001 and 011, respectively), two
supportive trials (supplemental evidence) examining possible
benefits of Synflorix in reducing acute otitis media (AOM) and six
supportive trials (supplemental evidence) supporting the existence
of a pneumococcal conjugate vaccine class effect against
pneumococcal pneumonia.
8. Results of Trials
Comparative efficacy was assessed using three surrogate outcome
measures:
1. ELISA with 22F pre-adsorption for assessment of immunogenicity -
the difference in immune response (IgG antibody concentration)
between Synflorix and Prevenar was expressed in terms of the
percentage of subjects with pneumococcal antibody concentrations
≥0.2μg/mL.
2. Opsonophagocytic assay (OPA) - the difference between Synflorix
and Prevenar was expressed in terms of the percentage of subjects
achieving an OPA antibody titre ≥8 (surrogate measure of
protection against invasive pneumococcal disease).
3. Protein D - the difference between Synflorix and Prevenar was
expressed in terms of the percentage of subjects with antibody
responses against protein D (≥100 EL.U/mL). Protein D is a
highly conserved surface lipoprotein found in all Haemophilus
influenzae, including non-typeable H.influenzae
(NTHi). NTHi strains are rarely associated with invasive disease in
healthy children and adults, but they are associated with
respiratory tract infections in both populations.
Trial results were reported separately then pooled using standard
meta-analytical techniques. Non-inferiority was demonstrated if the
lower limit of the 2-sided 96.5% confidence interval of the
difference between groups (Synflorix minus Prevenar) was ≤-10%.
1. ELISA with 22F pre-adsorption for assessment of
immunogenicity
The percentage of subjects with pneumococcal antibody
concentrations ≥0.2μg/mL post dose-3 of the primary
vaccination course were below the pre-defined limit for
non-inferiority of 10% for eight out of ten serotypes (1, 4, 5, 7F,
9V, 14, 18C, and 19F). Although, non-inferiority was demonstrated
for five of the seven serotypes included in Prevenar (4, 9V, 14,
18C, 19F), non-inferiority was not demonstrated for serotypes 6B
and 23F.
Post-hoc sensitivity analyses of the percentage of subjects in the
ATP (According-to-protocol) cohort with antibody concentrations
≥0.2µg/mL compared to an ELISA threshold
≥0.35µg/mL showed that the percentage of responders
achieving the revised threshold of ≥0.35µg/mL was >90%
for all serotypes except for 6B and 23F which was consistent with
the original analysis conducted using the threshold of
≥0.2µg/mL.
One month after administration of the fourth dose (booster dose)
the percentage of subjects with antibody concentrations
≥0.2μg/mL was within the same range in both the Synflorix and
Prevenar groups for all common serotypes, and in the time period
after completion of the primary series and immediately before
booster vaccination (i.e. between PIII(M5) and “pre
booster” timepoints), a decline in antibody GMCs was observed
for all serotypes in both groups.
However, the data demonstrate, that Synflorix, induces a more
durable antibody response to serotype 6B over time, with more
subjects maintaining antibody concentrations of > 0.20 μg/mL
between post primary and pre-booster administration compared with
Prevenar; Synflorix [post dose 3 (PIII(M5): 88.1%, pre booster:
80%], Prevenar [post dose 3 (PIII(M5): 92.1%, pre booster:
58.9%].
Post-hoc sensitivity analyses of the percentage of subjects in the
ATP cohort of the booster trials (Trials 007 and 017) with antibody
concentrations ≥0.35µg/mL showed high levels of response
(i.e. ≥96%) to all serotypes for both vaccines, including
serotypes 6B and 23F.
2. Opsonophagocytic assay (OPA)
The results of the meta-analysis showed that the difference between
groups in terms of percentage of subjects with OPA ≥8 was below
the pre-defined limit for non-inferiority of 10% for seven out of
ten serotypes (4, 7F, 9V, 14, 18C, 19F, 23F). Although,
non-inferiority was demonstrated for six of the seven serotypes
included in Prevenar (4, 9V, 14, 18C, 19F, 23F), non-inferiority
was not demonstrated for serotype 6B.
In Trials 007 and 017, one month after administration of the
booster dose, the percentage of subjects with functional antibody
concentrations (OPA) ≥8 was within the same range in both groups
for all common serotypes. In study 017, Synflorix, induced a more
durable antibody response over time (between post dose 3 and pre
booster) for serotypes (6B, 23F and 18C) as compared with Prevenar
resulting in higher antibody levels prior to boosting for serotype
6B and antibody levels with overlapping CI for serotype 18C and
23F.
3. Protein D measured using ELISA
For Trial 001 the antibody responses (seropositivity rates and
GMCs) against protein D, one month post-vaccination dose three of
Synflorix (pooled production lots), showed that all subjects except
two had measurable antibodies against protein D (≥100 EL.U/mL).
For Trial 003 all subjects except one had measurable antibodies
against protein D (≥100 EL.U/mL). For Trial 011 all but one of
the subjects who received Synflorix had anti-PD antibody
concentrations ≥100 EL.U/mL. For Trial 012 all subjects in the
Synflorix group had measurable antibodies against protein D
(≥100 EL.U/mL).
For Trial 007(extension of Trial 001) following the booster dose,
99.4% of subjects in the Synflorix group had measurable antibodies
(≥100 EL.U/mL) against protein D compared to only 18.6% of
subjects in the Prevenar group. For Trial 017 (extension of Trial
011) following the booster dose, 100% of subjects in the Synflorix
group had measurable antibodies (≥100 EL.U/mL) against protein D
compared to only 44.6% of subjects in the Prevenar group.
Supplemental evidence of effectiveness – acute
otitis media (AOM)
The results of POET (Phase III trial of the Synflorix prototype
formulation: 11-valent pneumococcal D conjugate vaccine) showed
that during the ATP efficacy follow-up (i.e. from 2 weeks post-dose
3 to 24-27 months of age), in fully vaccinated children less than 2
years of age, 333 clinical AOM episodes were recorded in the
Synflorix prototype group (N=2455) and 499 in the HAV control group
(N=2452) giving a significant reduction in the overall incidence of
AOM of 33.6% (95% CI 20.8% to 44.3%). Vaccine efficacy was
demonstrated for AOM episodes due to non-typeable Haemophilus
influenzae (NTHi) with a 35.3% (95% CI 1.8% to 57.4%; p=0.041)
reduction in episodes. Significant protective efficacy was also
demonstrated against bacterial AOM episodes confirmed by culture
(42.1%; 95% CI 27.7% to 53.7%) and culture confirmed pneumococcal
AOM regardless of the serotype (51.5%; 95% CI 36.8% to
62.9%).
Supplemental evidence of effectiveness –
pneumococcal pneumonia
The submission presented the results of a further six studies as
supplemental evidence to support the existence of a pneumococcal
conjugate vaccine class effect against pneumonia, similar to the
class effect previously reported for Hib conjugate vaccines. The
submission claimed that given these results it was reasonable to
conclude that Synflorix will provide protection against
pneumococcal pneumonia at least to a similar extent to that of
Prevenar used in Australia, albeit that this had not been well
studied to date.
The reactogenicity profiles of the two vaccines showed that
Synflorix was non-inferior to Prevenar with respect to solicited
local and general adverse events. The most frequently reported
solicited local adverse event was redness in both Synflorix and
Prevenar groups. The incidences of febrile reactions post-primary
and post-booster vaccination were similar between Synflorix and
Prevenar (fever all events; RD=0.88%, 95%CI -5.57% to 7.33%: all
fever; RD=-1.46%, 95%CI -7.12% to 4.21%, respectively), when both
were co-administered with DTPa-based combined vaccines.
The safety profile of the primary vaccination schedule (3 doses) of
Synflorix was similar to that of Prevenar with the results of the
meta-analysis of safety data demonstrating non-inferiority of
Synflorix to Prevenar. No statistically significant differences
were observed between the two vaccines (primary course) with the
exception of pain (RD=5.81%, 95%CI 1.91% to 9.71%), swelling
(RD=5.33%, 95%CI 1.41% to 9.26%) and loss of appetite (RD=3.94%,
95%CI 0.02% to 7.86%). The meta-analysis of safety outcomes for
Trials 007 and 017 indicates there was no statistically significant
difference between Synflorix and Prevenar (given as a booster dose)
with the exception of pain; where pain (all) was reported more
frequently in infants receiving Synflorix: RD 8.16% (95% CI 2.08%
to 14.23%; p=0.009).
9. Clinical claim
The submission described Synflorix as non-inferior in terms of
comparative effectiveness and non-inferior in terms of comparative
safety over Prevenar.
For PBAC’s views see Recommendation and
Reasons.
10. Economic analysis
The submission presented a cost minimisation analysis on the basis
that Synflorix 0.5mL injection and Prevenar 0.5mL injection were
equi-effective. This relativity was based on the immunogenicity
results of the comparative trials of Synflorix and Prevenar.
11. Estimated PBS usage and Financial Implications
The likely number of patients vaccinated per year was between
100,000 and 200,000. The net cost of listing Synflorix was assumed
not to be higher than the current cost of Prevenar on the NIP as
the price was the same.
12. Recommendation and Reasons
The PBAC recommended the listing of the 10-valent pneumococcal polysaccharide and
non-typeable Haemophilus influenzae (NTHi) protein D conjugate vaccine (10Pn-PD-DiT – “Synflorix”) on the NIP on a cost-minimisation
basis against the 7-valent pneumococcal conjugate vaccine (7vPCV – “Prevenar’’), with
the cost of four doses of Synflorix (2, 4, 6 months and a booster) plus an additional
administration cost of the booster dose at an existing vaccination point being equivalent
to the effective cost of three doses of Prevenar (2, 4 and 6 months) on NIP.
The submission presented four randomised trials comparing Synflorix with Prevenar
in infants receiving primary pneumococcal vaccination (3 dose vaccination schedule:
Trials 001, 003, 011, 012), two randomised extension trials in infants receiving a
booster dose of Synflorix or Prevenar (Trials 007 and 017: extensions of Trials 001
and 011, respectively), two supportive trials (supplemental evidence) examining possible
benefits of Synflorix in reducing acute otitis media (AOM) and six supportive trials
(supplemental evidence) supporting the existence of a pneumococcal conjugate vaccine
class effect against pneumococcal pneumonia.
The PBAC noted that comparative immunogenicity was assessed using ELISA with 22F pre-adsorption
(IgG antibody concentration) and expressed in terms of the percentage of subjects
with pneumococcal antibody concentrations ≥ 0.2 μg/mL. Based on this outcome, non-inferiority
was not demonstrated for serotypes 6B and 23F. However, the PBAC accepted the advice
from ATAGI that the WHO (2005) recommendation which stated that non-inferiority to
antibody response for each of the serotypes was desirable, but not an absolute requirement,
as being reasonable. In addition, PBAC also noted the post-hoc analyses of the percentage
of subjects in the ATP (According-to-protocol) cohort with antibody concentrations
≥ 0.2 µg/mL compared to the more stringent non-inferiority threshold of ≥ 0.35 µg/mL,
which was recommended by the WHO with respect to an alternative assay (ELISA without
pre-adsorption with serotype 22F. The results of this analysis confirmed that the
percentage of responders achieving the revised threshold of ≥ 0.35 µg/mL was > 90
% for all serotypes except for 6B and 23F which was consistent with the original analysis
conducted using the threshold of ≥ 0.2 µg/mL.
Using opsonophagocytic assay (OPA - the difference between Synflorix and Prevenar
was expressed in terms of the percentage of subjects achieving an OPA antibody titre
≥ 8, a surrogate measure of protection against invasive pneumococcal disease and which,
in ATAGI’s opinion, correlated better with clinical protection than ELISA antibodies),
non-inferiority was not demonstrated for serotype 6B.
However, ATAGI advised that the majority of current vaccines failures in Australia
were caused by serotype 19F (55 %), for which non-inferiority between Synflorix and
Prevenar had been demonstrated using the comparison of the 3 dose schedule. Serotypes
6B and 23F contributed to 19 % and 11 % respectively of vaccines failures.
The PBAC also noted the post-hoc analyses of the percentage of subjects in the ATP
cohort of the booster trials (Trials 007 and 017) with antibody concentrations ≥ 0.35
µg/mL showed high levels of response (i.e. ≥ 96 %) to all serotypes for both vaccines,
including serotypes 6B and 23F.
Overall, the PBAC accepted the advice from ATAGI that the addition of a booster dose
of Synflorix removed almost all uncertainties regarding the comparability of protection
of all vaccines serotypes after the primary course of Synflorix compared with Prevenar,
in particular serotype 6B. Higher antibody titres after the booster dose may also
be important for the persistence of immunity.
With respect to the implementation of the booster dose, the PBAC noted that there
were existing vaccination points at 12 months and 18 months. ATAGI advised the PBAC
that from a disease prevention perspective, there were likely to be some modest benefits
from a Synflorix booster at 12 months rather than 18 months, but that must be balanced
against the potential for improved program delivery and avoiding splitting of the
scheduled vaccines into two visits. The choice will be between a Hib vaccine or a
pneumococcal conjugate vaccine booster at 12 versus 18 months. Overall, the PBAC considered
that the availability of a Synflorix booster dose on the NIP either at 12 or 18 months
was unlikely to require a separate GP visit. Therefore, the usual $7 administration
fee of an additional vaccine given at an established vaccination point would apply
as an additional cost to the costs of the four-dose course of Synflorix.
Recommendation
PNEUMOCOCCAL POLYSACCHARIDE CONJUGATE VACCINE, turbid liquid suspension for injection
(0.5 mL) in pre-filled syringe or vial
Restriction: National Immunisation Program
For immunisation of all Australian infants and children from the age of eight weeks to two years of age against disease caused by Streptococcus pneumoniae serotypes 1, 4, 5, 6B, 7F, 9V, 14, 18C, 19F and 23F (including invasive disease, pneumonia, and acute otitis media).
13. Context for Decision
The PBAC helps decide whether and, if so, how medicines should be
subsidised in Australia. It considers submissions in this context.
A PBAC decision not to recommend listing or not to recommend
changing a listing does not represent a final PBAC view about the
merits of the medicine. A company can resubmit to the PBAC or seek
independent review of the PBAC decision.
