Pertussis vaccine-acellular combined with diphtheria and tetanus toxoids (Adsorbed), 0.5 mL, Adacel® - November 2011
Page last updated: 16 March 2012
Public Summary Document
Product: Pertussis vaccine-acellular combined with
diphtheria and tetanus toxoids (Adsorbed), 0.5 mL,
Adacel®
Sponsor: Sanofi-Aventis Australia Pty Ltd
Date of PBAC Consideration: November 2011
1. Purpose of Application
To request listing on the National Immunisation Program (NIP) as a
single dose booster immunisation against tetanus, diphtheria and
pertussis to both parents of newborn infants, where there is no
documented evidence of a dTpa booster having been given in the
previous 10 years.
2. Background
The PBAC had not previously considered this vaccine for this
indication.
3. Registration Status
Adacel was registered by the TGA on 16 November 2005 for the indication:
Active immunisation against tetanus, diphtheria and pertussis in persons aged 10 years and over as a booster following primary immunisation.
4. Listing Requested and PBAC’s View
National Immunisation Program
As a single dose booster immunisation against tetanus, diphtheria
and pertussis to both parents of newborn infants where there is no
documented evidence of a dTpa booster having been given in the
previous 10 years.
For PBAC’s view, see Recommendation and
Reasons.
5. Clinical Place for the Proposed Therapy
Pertussis (whooping cough) is a respiratory infection caused by
Bordetella pertussis, a coccobacillus. Pertussis affects
people of all ages, and it can be particularly severe in infants,
sometimes leading to seizures, brain damage, hospitalisations and
even death. Despite the NIP providing a combined tetanus,
diphtheria and pertussis vaccine (DTPa) for free to children and
adolescents, Australia has recently experienced a sustained
pertussis outbreak, resulting in a large increase in the number of
pertussis notifications for infants of less than one year of age
(566 in 2008 compared to 156 in 2006).
It has been suggested that parents may be the source of pertussis
infection in their children in more than 50% of cases where an
infection source is known. This has led the National Health and
Medical Research Council (NHMRC) to recommend that both parents
should receive an adult booster dose of pertussis vaccine, either
when planning pregnancy or as soon as possible after giving birth,
the intention being to provide a “cocoon” of protection
around the infant.
The submission proposed that the place in therapy of dTpa for the
proposed indication was to reduce transmission of pertussis from
parents to newborn infants who are too young to have been fully
vaccinated against this disease under the infant NIP
schedule.
6. Comparator
Two main comparators were nominated by the submission; no routine
vaccination, and Boostrix (a dTpa vaccine containing three
pertussis antigens, whereas Adacel contains five pertussis
antigens).
The PBAC accepted that ‘no routine vaccine’ was the
appropriate comparator, given that the application to list the
Boostrix® brand of dTpa vaccine for this cocooning
indication was rejected at the July 2011 PBAC meeting.
7. Clinical Trials
The submission and the Australian Technical Advisory Group on
Immunisation (ATAGI) pre-PBAC submission advice acknowledged the
absence of empirical data supporting the effectiveness of a
cocooning strategy. Therefore, the submission presented the
clinical evidence supporting the proposed Adacel (dTpa5v)
vaccination strategy in two steps.
The submission first presented an indirect comparison of evidence
supporting the efficacy of the dTpa5v vaccine in preventing
pertussis infection in adults. The immunogenicity of the dTpa5v
vaccine was compared to the Boostrix (dTpa3v) vaccine, which was
compared to the three component acellular pertussis vaccine (pa3v)
vaccine. The submission then presented results from the APERT
randomised trial comparing the efficacy of the pa3v vaccine in
preventing pertussis infection and disease in a vaccinated
individual compared to an inactive control.
In the second step, the proportion of pertussis cases in infants
that are the result of contact with an infected parent was
estimated as a proxy for the rate of pertussis transmission from
infected parents to susceptible infants. The submission did not
provide evidence from randomised controlled trials on the efficacy
of dTpa vaccination on the transmission from an infected parent to
a susceptible infant.
The following trials had been published at the time of
submission:
| Trial ID / First author | Protocol title / Publication title | Publication citation |
|---|---|---|
| Trials comparing dTpa5v with inactive control | ||
| Trials comparing dTpa5v with dTpa3v | ||
| Trials comparing pa3v with inactive control | ||
| Trials comparing dTpa5v with pa5v | ||
| Trials comparing dTpa3v with pa3v | ||
| Pichichero ME et al, 2005 | Combined tetanus, diphtheria and 5 component pertussis vaccine for use in adolescents and adults. | JAMA 2005; 293(24):3003-11. |
| Halperin SA et al, 2000a | An adult formulation of a five-component acellular pertussis vaccine combined with diphtheria and tetanus toxoids is safe and immunogenic in adolescents and adults. | Vaccine 2000; 18(14):1312-1319. |
| Blatter M et al, 2009 | Immunogenicity and safety of a tetanus toxoid, reduced diphtheria toxoid and three-component acellular pertussis vaccine in adults 19-64 years of age. | Vaccine 27(5):765-72 |
| APERT Ward JL et al, APERT study group (2007) | Bordetella pertussis infections in vaccinated and unvaccinated adolescents and adults, as assessed in a national prospective randomised Acellular Pertussis Vaccine Trial (APERT). | Clin Infect Dis 44(1):149-150. |
| Ward JI et al, 2005 | Efficacy of an acellular pertussis vaccine among adolescents and adults. | New Engl J Med 2005; 353(15):1555-1563. |
| Le T et al, 2004 | Immune responses and antibody decay after immunisation of adolescents and adults with an acellular pertussis vaccine: The APERT study. | J Infect Dis 2004; 190(3):535-544. |
| Halperin SA et al, 2000b | Adult formulation of a five component acellular pertussis vaccine combined with diphtheria and tetanus toxoids and inactivated poliovirus vaccine is safe and immunogenic in adolescents and adults. | Pediatr Infect Dis J, 2000;19:276–83 |
| Van der Wielen M et al, 2000 | A randomised controlled trial with a diphtheria-tetanus-acellular pertussis (dTpa) vaccine in adults. | (2000) Vaccine 18(20):2075-82. |
| Turnbull FM et al, 2001 | A randomised trial of two acellular pertussis vaccines (dTpa and pa) and a licensed diphtheria-tetanus vaccine (Td) in adults. | Vaccine. 2000 Nov 8;19(6):628-36 |
8. Results of Trials
Vaccine Efficacy In Adults:
The immunogenicity results were presented for geometric mean titres
(GMTs) or geometric mean concentrations (GMCs) of pertussis
antibodies for each vaccination group. The submission conducted a
post-hoc analysis to estimate the geometric mean fold rise (GMFR)
of pre-vaccination to post-vaccination GMTs or GMCs of pertussis
antibodies for each vaccination group.
In Blatter 2009, the GMFR of pertussis toxin (PT) and filamentous
haemagglutinin (FHA) antibodies were almost twice as high in the
dTpa3v vaccine compared to the dTpa5v vaccine and the submission
argued that this may be a result of the lower concentration of
these antigens in the dTpa5v vaccine. The relevance and impact of
this difference on overall clinical efficacy is uncertain. GMFR of
PT and pertactin (PRN) antibodies were lower for the dTpa5v vaccine
in Blatter 2009 than in Pichichero 2005 and Halperin 2000a.
Comparison of the GMFR of pertussis antibodies in the dTpa3v and
pa3v formulations (Van der Wielen 2000 and Turnbull 2001) suggested
these vaccines elicit a comparable immunologic response.
Based on an indirect comparison of relative immunogenicity for the
various vaccine formulations the submission asserted that the
dTpa5v vaccine elicits a comparable immunologic response to the
single component pa3v vaccine.
The submission presented pertussis booster response rates from the
randomised trials at approximately one month post-vaccination.
Pertussis booster response was defined as a specified increase in
antibodies after vaccination. The defined threshold for achieving
booster response varied across the trials from a two to four-fold
increase on pre-vaccination antibody levels.
The dTpa5v and dTpa3v booster response rate to PT in Blatter 2009
was below the defined primary endpoint of 80% in the lower
confidence interval, with the PT response in the dTpa5v group also
significantly lower than the PT response in the dTpa3v group. All
other trials and vaccine formulations had no significant
differences.
The submission also presented non-combination pertussis (pa3v)
vaccine efficacy in the APERT trial against the inactive control
(in this case Hepatitis A Vaccine, HAV). Vaccination with pa3v
reduced the primary cases of pertussis compared to HAV vaccination
for adults followed up to 2 years post-vaccination. Adjusted
vaccine efficacy of 92% (95% CI: 32% to 99%) was calculated using
the primary case definition including the serologic criteria.
In the clinical trials, serious adverse events or severe
reactogenicity were generally rare following dTpa5v vaccination and
there were no major differences in safety outcomes between the dTpa
formulations.
For PBAC’s view, see Recommendation and
Reasons.
9. Clinical Claim
Step one – efficacy of vaccination in
adults
The submission described the dTpa5v vaccine as superior in terms of
comparative effectiveness over no vaccine in preventing pertussis
in adults. Some mild adverse events are expected to occur with
vaccination with dTpa5v but without significant difference to other
immunisations.
Based on the supporting data, the PBAC considered this description
of superior efficacy may be reasonable for adults vaccinated with
dTpa. However, these conclusions form only the first part of the
stepped evaluation and did not demonstrate a reduced transmission
of pertussis to infants.
The PBAC noted that no evidence was presented in the submission
regarding vaccine efficacy in preventing subclinical pertussis
infection, as opposed to preventing symptomatic pertussis illness
in adults. The PBAC considered that the potential for adults with
subclinical infection to transmit pertussis to vulnerable infants
increases uncertainty associated with vaccine efficacy and the
effectiveness of a cocooning strategy.
Step two – transmission from infected parent to
susceptible infants
The submission did not provide clinical evidence on the comparative
efficacy in preventing pertussis in susceptible infants when the
vaccine is provided to parents shortly after birth.
10. Economic Analysis
The submission presented a cost-minimisation with Boostrix
(dTpa3v). This comparison was not considered by the PBAC, as
Boostrix was rejected at the July 2011 PBAC meeting.
The submission also presented two modelled economic evaluations
using no parental vaccination as the comparator – a
single-year static model, and a 20-year population-based
transmission dynamic model (TDM).
Static model
The static model calculated the expected effect of the cocooning
strategy on the birth cohort from 2009 compared to no vaccination.
The submission also presented the expected outcomes from
vaccinating mothers only.
The number of eligible fathers was calculated as a proportion of
the eligible mothers, however no vaccine administration costs were
expected for fathers or mothers.
The results of the static model for the cocooning strategy resulted
in an incremental cost-effectiveness ratio (ICER) per life year
gained (LYG) between $105,000 – $200,000 for vaccinating both
parents and between $45,000 – $75,000 for mothers only.
The re-specified base case presented in the sponsor’s
Pre-Sub-Committee Response produced a lower ICER also between
$45,000 – $75,000 per quality adjusted life year for
vaccination of mothers only, when cost savings and quality of life
gains to the mother due to a potentially reduced pertussis disease
burden were included.
However, the submission proposed that the static model was not
adequate, as it did not consider herd immunity, population effects,
different rates of pertussis in age groups other than infants, and
temporal effects and therefore considered the results of the TDM
were more appropriate.
Transmission dynamic model (TDM)
The TDM incorporated the herd immunity effects from the vaccine ie
reduced transmission rates of pertussis in the total population due
to the increased number vaccinated. Pre-PBAC submission advice from
ATAGI in December 2010 suggested that under an optimally delivered
cocooning strategy (i.e. 100% of eligible mothers and fathers
receive the vaccine) approximately 25% population coverage of the
vaccine may be achieved.
Extrapolating for 20 years including herd immunity, but only
counting the cost savings in children aged 0-1 year produced an
ICER of less than $15,000 per life year gained. It was not clear
what the ICER would be if herd immunity was excluded from the
model.
The PBAC agreed that both the incremental costs and incremental
effects presented in the submission from the TDM are highly
uncertain
Key results of the univariate sensitivity analyses performed on the
TDM presented by the submission and additional analyses conducted
during the evaluation showed that the cocooning strategy was more
effective and less costly in most one-way sensitivity analyses,
with the exception of changes in duration of the model and costs of
pertussis infections.
As the TDM was unable to be adjusted to exclude the effects of herd
immunity or reduce the predicted incidence of pertussis, a
multivariate sensitivity analysis was conducted during the
evaluation. The results indicated that by adjusting some of the
costing parameters and uptake, a cocooning strategy would result in
an ICER between $45,000 – $75,000 per LYG, and that if the
projected incidence was adjusted to more realistic levels or the
herd immunity effect removed, then the ICER is likely to increase
substantially.
For PBAC’s view, see Recommendation and
Reasons.
11. Estimated PBS Usage and Financial Implications
The net financial cost to the NIP was estimated by the submission
to be less than $10 million in Year 5. There is potential for the
net cost/year for the NIP to be greater as the submission assumed
no vaccine administration costs for either parent.
12. Recommendation and Reasons
The PBAC accepted that ‘no routine vaccine’ was the
appropriate comparator, given that the application to list Boostrix
brand of dTpa vaccine for this cocooning indication was rejected at
the July 2011 PBAC meeting.
The PBAC noted that the Adacel vaccine contains five pertussis
antigens (dTpa5v), as compared with Boostrix, which contains three
(dTpa3v). The PBAC considered that the results of the indirect
comparison of the relative immunogenicity of dTpa5v, dTpa3v and
three component acellular pertussis vaccine (pa3v) using the APERT
trial, provided reasonable support for the efficacy of the dTpa5v
vaccine in preventing pertussis infection and disease in adults.
However, the indirect comparison used surrogate immunogenicity
outcomes for pertussis (geometric mean titres, geometric mean
concentrations and a post-hoc analysis to estimate geometric mean
fold rise (GMFR) of pre-vaccination to post-vaccination GMTs or
GMCs of pertussis antibodies for each vaccination group. The PBAC
acknowledged that there are significant limitations with the
comparison between the dTpa5v and pa3v vaccines that limit the
conclusions, such as different assay methods and booster response
definitions. There is also no commonly agreed serological surrogate
for protection against pertussis, noted in the ATAGI advice, which
suggests that IgG markers are at least partially correlated with
vaccine protection against infection with pertussis.
The PBAC considered that the clinical effectiveness of the
requested listing - to reduce transmission of pertussis from an
infected parent to a susceptible infant - was uncertain as no
evidence from randomised controlled trials was presented in the
submission for this indication. Rather, the submission provided an
estimate of the proportion of infant cases of pertussis that are
the result of contact with an infected parent as a proxy for rate
of transmission.
The PBAC noted that no evidence was presented in the submission
regarding vaccine efficacy in preventing subclinical pertussis
infection, as opposed to preventing symptomatic pertussis illness
in adults. The PBAC considered that the potential for adults with
subclinical infection to transmit pertussis to vulnerable infants
increases uncertainty associated with vaccine efficacy and the
effectiveness of a cocooning strategy.
In terms of safety, the PBAC noted that there were no major
differences in safety outcomes between the dTpa formulations.
However, the PBAC considered that should a cocooning strategy be
approved, it would likely result in an expansion of the immunising
population, which may be associated with an increase in adverse
events due to differing levels of experience in injection
technique.
The submission presented two modelled economic evaluations using no
parental vaccination as the comparator – a single-year static
model, and a 20-year population-based transmission dynamic model
(TDM).
The static model calculated the number of eligible fathers as a
proportion of eligible mothers and no vaccine administration costs
are included. The PBAC noted the results of the static model for
the cocooning strategy resulted in an incremental
cost-effectiveness ratio (ICER) per life year gained (LYG) between
$105,000 – $200,000 for vaccinating both parents and between
$45,000 – $75,000 for mothers only. A re-specified base case
presented in the sponsor’s Pre-Sub-Committee Response
produced a lower ICER between $45,000 – $75,000 per quality
adjusted life year for vaccination of mothers only, when cost
savings and quality of life gains to the mother due to a
potentially reduced pertussis disease burden are included.
The results of the economic evaluation using the TDM, extrapolating
for 20 years, including herd immunity, but only counting the cost
savings in children aged 0-1 year produced an ICER of less than
$15,000 per LYG. The PBAC agreed that both the incremental costs
and incremental effects presented in the submission from the TDM
are highly uncertain due to a number of factors as identified in
the ESC Advice.
The PBAC noted that the results of the multivariate sensitivity
analysis of the TDM indicate that by adjusting some of the costing
parameters and uptake, a cocooning strategy would result in an ICER
between $45,000 – $75,000 per LYG, and that if the projected
incidence was adjusted to more realistic levels or the herd
immunity effect removed, then the ICER is likely to increase
substantially.
The PBAC therefore rejected the submission on the basis of
uncertain clinical effectiveness of the cocooning strategy and
likely high and highly uncertain cost effectiveness.
Recommendation:
Reject
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
Sanofi Pasteur is disappointed by the decision and will be considering its position regarding any further action.
