Haemophilus influenzae type b and group c meningococcal polysaccharide conjugate vaccine, lyophilised powder for injection, 1 vial with 0.5 mL pre-filled syringe diluent, 10 vials with 10 0.5 mL pre-filled syringe diluent, Menitorix®
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polysaccharide conjugate vaccine, lyophilised powder for injection, 1 vial with 0.5
mL pre-filled syringe diluent, 10 vials with 10 0.5 mL pre-filled syringe diluent,
Product: Haemophilus influenzae type b and group c meningococcal polysaccharide conjugate vaccine, lyophilised powder for injection, 1 vial with 0.5 mL pre-filled syringe diluent, 10 vials with 10 0.5 mL pre-filled syringe diluent, Menitorix®
Sponsor: GlaxoSmithKline Australia Pty Ltd
Date of PBAC Consideration: November 2010
1. Purpose of Application
The submission sought listing on the National Immunisation Program
(NIP) for the active immunisation of all Australian children, at 12
months of age, for the prevention of diseases caused by
Haemophilus influenzae and Neisseria meningitis
This combination vaccine had not previously been considered by the
The NIP schedule currently indicates the monovalent Haemophilus influenzae type b vaccine (Hib) be given at 2 months, 4 months, 6 months and a booster at 12 months of age. The monovalent Neisseria meningitides serogroup C (Men C) vaccine is listed on the NIP for children 12 months of age only.
Advice from the Australian Technical Advisory Group on Immunisation (ATAGI) received in November 2009 states that the Hib-Men C combination vaccine is suitable for use on the NIP as an alternative to the current individual monovalent Hib and Men C vaccines at the 12 month age point following any primary Hib schedule.
3. Registration Status
On 5 August 2010, the combined Hib-Men C vaccine was TGA registered
for prevention of invasive diseases caused by Haemophilus
influenzae type b and Neisseria meningitides serogroup
4. Listing Requested and PBAC’s View
Listing on the NIP Schedule for administration at 12 months of
For PBAC’s view, see Recommendation and Reasons.
5. Clinical Place for the Proposed Therapy
The combined Hib-Men C vaccine is intended to serve as an
alternative to the concurrent administration of existing single
antigen Hib and Men C vaccines currently used in the NIP.
The submission nominated Haemophilus influenzae type b and
meningococcal serogroup C vaccines administered at 12 months of
age, given as separate injections, as the comparator. The PBAC
considered this appropriate.
7. Clinical Trials
The submission presented one randomised trial (study 016) comparing
a single dose of Menitorix with concurrent doses of
Hiberix® (a Hib vaccine) and
Meningitec® (a Men C vaccine) given to children 12
months of age. The trial had multiple follow-up periods, although
only one month and one year data were provided in the
Study 016 was not published at the time of consideration.
8. Results of Trials
The results from study 016 demonstrated that Menitorix is
non-inferior to the concurrent administration of separate Hib and
Men C vaccines, in terms of immunological outcomes (percentage of
subjects with serum bactericidal antibody assay using rabbit
complement (rSBA)-MenC titres >1:8 and percentage of subjects
with anti- polyribosylribitol phosphate (PRP) concentration >
0.15 micrograms/ml one month after vaccination)for both invasive
Haemophilus influenzae type b and invasive meningococcal
serogroup C disease.
Whilst not statistically significant, higher geometric mean titre (GMT) and geometric mean concentration (GMC) were achieved with the separate vaccines than with the conjugate Hib/MenC vaccine. For GMC, anti-PRP (Hib) levels were higher with the separate vaccines. For GMT, the rSBA-MenC levels were also higher with the separate vaccines.
The sponsor’s Pre-Sub-Committee Response provided the abstract of a non-inferiority study (Vesikari et al. 2008) comparing Menitorix to NeisVac-C® (a Men C vaccine) in a primary vaccination setting. The study was an open randomised (1:1) trial in 690 infants vaccinated with Menitorix plus Infanrix penta® (a vaccine covering diphtheria, tetanus, pertussis, hepatitis B and poliomyelitis versus) NeisVac-C plus Hib containing Infanrix hexa® (a vaccine covering diphtheria, tetanus, pertussis, hepatitis B, poliomyelitis and haemophilus influenzae type b) at 3, 5, and 11 months. Data from this study were supportive of Menitorix being non-inferior to Men C vaccines other than Meningitec. However, only limited efficacy data and no safety data were presented. Also, it was noted that this study was conducted in the UK where the infants received 3-doses of MenC vaccine. Consequently the applicability to the Australian population was uncertain.
The PBAC noted the summary of evidence from the sixth and nineteenth Periodic Safety Update for Menitorix and Hiberix, respectively. During the review period 667,601 children were vaccinated with Menitorix and between 989,840 and 3,959,359 children were vaccinated with Hiberix.
During the review period, 101 reports were received for Menitorix that fulfilled the international conference on harmonisation (ICH) E2C criteria compared to 65 reports for Hiberix. The PBAC noted that a much higher proportion of events related to injury, poisoning and procedural complications for Menitorix than for Hiberix.
For Menitorix, no fatal outcomes or anaphylactic reactions were reported during the period. Although it should be noted that two fatalities and two anaphylactic reactions occurred in the previous reporting period. There was one case of status epilepticus.
For Hiberix, eight fatal outcomes were reported. Five of these occurred in a published clinical trial conducted in Ghana, where vitamin A supplements were administered concurrently with EPI (expanded program on immunisation) vaccinations.
The submission concluded that in general the outcomes reported for Hiberix were of a more serious nature that than for Menitorix, although the circumstances in which the two vaccines were administered differed significantly during the review period.
9. Clinical Claim
The submission claimed that Menitorix is non-inferior to the
separate administration of Hib plus Men C vaccines, in terms of
immunological response. It also claimed that Menitorix is generally
better tolerated and has a similar overall safety profile compared
to the separate administration of Hib plus Men C vaccines. The PBAC
accepted that the combined Hib/Men C vaccine was non-inferior to
the separate vaccines and offered equivalent protection compared to
the monovalent vaccines. See Recommendation and
10. Economic Analysis
The submission presented a cost minimisation analysis. The
equi-effective doses were estimated as 1 dose of Menitorix (0.5 mL
containing 5 micrograms of Hib PRP and 5 micrograms of Men C
polysaccharide) at the routine 12 month vaccination time-point is
equivalent to the concurrent administration of 1 dose of Hiberix
(0.5 mL containing 10 micrograms of purified capsular
polysaccharide of Hib) and 1 dose of Meningitec (0.5 mL containing
10 micrograms of Men C oligosaccharide). The PBAC agreed these
equi-effective doses are reasonable.
11. Estimated PBS Usage and Financial Implications
The submission estimated the likely number of patients per year to
be greater than 200,000 in 2011. Over the next 5 years, the
eligible population for this vaccination is likely to be greater
than 200,000 each year. The submission derived these estimates from
the Australian Bureau of Statistics population projections.
The estimated incremental cost of Menitorix was less than $10 million in 2016. The uptake rate of Menitorix was estimated to be equal to the current uptake rate of Hib vaccine, which is slightly higher than the Men C uptake rate. Therefore the incremental cost is due to a higher uptake rate for Menitorix compared to the monovalent Men C vaccine. The PBAC considered the submission’s estimates reasonable.
12. Recommendations and Reasons
The PBAC recommended inclusion in the NIP of this new presentation
of Hib – Men C vaccine under the same conditions as the
existing single antigen Hib and Men C vaccines, at the price
proposed in the submission.
The PBAC noted the results of a randomised controlled trial (study 016) comparing a single dose of the combination Hib with Men C (Hib/Men C) vaccine with concurrent separate doses of Hib and Men C given at 12 months of age. The PBAC noted that, whilst not statistically significant, higher GMT and GMC were achieved with the separate vaccines than with the conjugate Hib/Men C vaccine. For GMC, anti-PRP (Hib) levels were higher with the separate vaccines. For GMT, the rSBA-Men C levels were also higher with the separate vaccines. The PBAC accepted ATAGI’s view that the combined Hib/Men C vaccine was non-inferior to the separate vaccines and offered equivalent protection compared to the monovalent vaccines. However, committee members noted that the comparative durability of effect was uncertain.
The PBAC noted that there appeared to be fewer local and systemic adverse reactions with the combination than with the separate vaccines.
The PBAC noted that combination vaccines can interfere with the response to other vaccines, while recognising that there was no evidence of interference with measles mumps and rubella or Synflorix® (a pneumococcal vaccine) vaccines. This would be a consideration for vaccines that may be listed on the NIP in the future.
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.
14. Sponsor’s Comment
The sponsor is happy with the outcome.