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| Journal of the New Zealand Medical Association,
20-August-2004, Vol 117 No 1200
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Proceedings of the Meningococcal Vaccine Strategy World
Health Organization Satellite Meeting, 10 March 2004, Auckland, New
Zealand
Kerry Sexton, Diana Lennon, Philipp Oster, Ingeborg Aaberge,
Diana Martin, Stewart Reid, Sharon Wong, Jane O’Hallahan
A significant milestone in the New Zealand Meningococcal
Vaccine Strategy (MVS) was reached when the first data from the clinical trial
in the toddler age group of the tailor-made New Zealand group B meningococcal
vaccine, MeNZB™, became available for public release.
To mark this occasion, the Ministry of Health invited New
Zealand infectious diseases specialists, paediatricians, public health
specialists, microbiologists, representatives from Medsafe (the New Zealand new
medicines regulatory authority), and other interested parties to a special
meeting on 10 March 2004 to hear presentations on the MVS and the first results
of the toddler age-group clinical trials. These proceedings summarise the key
points from the presentations, and highlight some of the important issues
considered in the discussion that followed. A companion
article1 summarises the scientific rationale
behind the MVS.
The epidemiology of meningococcal disease in New ZealandSurveillance data indicate that from
1991 to the end of 2003 there have been 5293 cases and 216 deaths from
meningococcal disease in New Zealand, with between 440 and 650 cases every year
since 1995. New Zealand’s epidemic is dominated by group B meningococci
with the class 1 outer membrane protein (OMP) PorA subtype
P1.7b,4.2 An estimated 71.6% of all cases in
2003 were caused by this ‘epidemic
strain’.3
The case fatality rate in New Zealand is comparatively low,
and was 2.4% (13 deaths) in 2003.3 However,
significant permanent morbidity is sustained. In a case review of 106 cases in
South Auckland patient morbidity was 16%
(14/89).4 More than 80% of cases occur in those
under 20 years of age, with children under 1 year of age at greatest risk. The
highest age-standardised rates are among Pacific peoples, followed by Maori.
Based on case numbers from 1997 through 2002, and using 2001
Census data as the denominator, a Pacific child has a 1 in 66 chance of
acquiring meningococcal disease by the age of 5, and a Maori child has a 1 in
117 chance—compared with a 1 in 438 chance for European and
‘Other’ children. European children make up almost one-third of
cases in under-20-year-olds based on absolute case
numbers.5
Using the Norwegian epidemic as a model, we can expect the
epidemic to persist for another 6 to 10 years, or
more.6
The New Zealand Meningococcal Vaccine StrategyThe New Zealand MVS aims to attain
rapid epidemic control through a mass immunisation programme to all aged less
than 20 years using a tailor-made vaccine, MeNZB™. The strategy to obtain
a licence to distribute MeNZB™ in New Zealand relies on its manufacture
being similar to, and the bridging of safety data from, the Norwegian parent
vaccine (MenBvac™), a series of clinical trials that demonstrate an immune
response to MeNZB™ in each age group to be vaccinated, and undertaking
enhanced surveillance for vaccine-associated adverse events during the
immunisation programme. Post-licensure vaccine effectiveness will be evaluated
in the absence of a randomised controlled trial through modelling. A
case-control study may also be undertaken (see companion
article1). This strategy has been supported by
wide consultation and national and international peer
review.1,7
A comprehensive system of safety surveillance has been put
in place for the immunisation programme, and access to identifiable data for
this purpose has been subject to ethics review. The safety monitoring system has
been designed, firstly, to detect serious adverse events following vaccination;
secondly, to enable assessment of a causal versus a temporal (coincidental)
relationship with vaccination; and thirdly, to increase public confidence in the
immunisation programme. An Independent Safety Monitoring Board, established by
the Health Research Council, will review all safety data.
The standard passive reporting system to the Centre for
Adverse Reactions Monitoring (CARM) will be stimulated by letters of
encouragement sent to primary care providers, and feedback on events reported.
This will be supplemented by an Intensive Vaccine Monitoring Programme using an
enrolled cohort of general practitioners (GPs) around the country (to cover 3000
to 5000 children). The clinical details of all visits for children in a
specified age range in the 6 weeks following a MeNZB™ vaccination will be
automatically sent from the GPs’ practice management systems to CARM for
review.
Hospital-based monitoring will be the key system providing
reassurance of safety of the vaccine. In as close to real time as possible,
there will be daily screening of hospital admissions at Middlemore Hospital
including Kidz First Children’s Hospital, Auckland City Hospital including
Starship Children’s Health, and Whangarei Hospital for specified rare
events that have historically been linked to vaccination, such as acute flaccid
paralysis, encephalopathy, seizure, anaphylaxis, hypotonic-hyporesponsive
episodes, and thrombocytopaenia. These particular hospitals have been selected
to be monitored as they service the DHBs where MeNZB™ immunisations will
first be administered as part of the staged roll out of the Programme.
The aim of this aspect of the hospital monitoring is to look
for clusters which may require further assessment, and/or which may be
sufficiently severe to stop vaccine use. After a pre-determined number of doses
have been given to specified age groups the real-time hospital-based
surveillance will be suspended, but the safety monitoring via CARM will continue
throughout all phases of the mass immunisation programme.
In addition, on a national basis, all events occurring
within 7 days of vaccination will be monitored retrospectively by matching the
hospital discharge data with the National Immunisation Register. Background
hospitalisation rates over the last 5 to 10 years have been determined for
certain conditions and will be used as alerts for rate increases following the
introduction of MeNZB™ vaccine. Database matching similar to that used in
the North Thames region of London to look for vaccine-associated adverse events
will be used much later in the roll out by means of linking the National
Immunisation Register with the hospital discharge
database.8
The Meningococcal B Immunisation ProgrammeThe goal is to deliver an effective
immunisation programme that reduces health inequalities for Maori and Pacific
peoples and achieves 90% coverage in all children and young people aged
0–19 years. The roll out of the Meningococcal B Immunisation Programme
(the Programme) will roughly progress from north to south in the North Island,
then from south to north in the South Island, reflecting disease incidence
patterns and taking into account inequalities of disease burden, logistical
issues, ease of communication, and the need to monitor and evaluate the
Programme. The key limiting factors for the Programme are regulatory approval,
vaccine availability, and readiness of the National Immunisation Register as a
tool to track MeNZB™ immunisations.
Initial licensure has authorised use only in children 6
months of age and over. A catch-up programme may be required for those children
aged between 6 weeks and 6 months if licensure to vaccinate this youngest age
group is granted at a later date following the clinical trials in young infants
(currently in progress).
The first stage of the Programme begins with Counties
Manukau District Health Board (DHB) and a geographically defined ‘eastern
corridor’ of Auckland DHB (Glen Innes to Otahuhu) in mid-2004 for the
school-attending population and those aged 6-months to 5-years. The Programme
will then be progressively rolled out around the country to all aged less than
20 years—prioritising delivery to under-5s from late 2004 and through
2005.
More than 80% of the disease burden is experienced by those
aged less than 20 years. As a result, the Programme has been targeted at this
age group. There have been some clusters of meningococcal disease in adults
living in residential facilities, especially in the Otago region, but this has
predominantly been group C disease rather than group B disease, and this has
been addressed separately.
The immunisation scheduleMeNZB™ is given by
intramuscular injection with the course of immunisations comprising three doses
given at 6-week intervals. It is essential that children complete the three-dose
course. However, in the initial stages of the Programme before vaccine is
available in all regions, if it is known that a child will be moving it will be
especially important to ensure that the child receives at least the first two
doses. In this situation, the time interval between the first and second doses
can be reduced to 4 weeks.
A decision on whether a fourth booster dose will be required
is dependent on clinical trial results concerning antibody decay, and the
occurrence of disease following widespread use of the vaccine.
It is recommended that those who have been diagnosed with
meningococcal disease still receive MeNZB™, as the duration of immunity
following disease is unknown.
Challenges for the ProgrammeThere are many challenges facing the
Programme. Child population groups, that past mass immunisation programmes have
failed to reach, are the very same groups that the current programme will need
to reach in order to be successful.
Benchmarking national telephone research recently contracted
by the Ministry of Health regarding MeNZB™ immunisation found that of the
501 parents of children under 20 years old (who were interviewed after being
randomly selected from the electoral roll), 76% will immunise their children,
12% will be cautious abstainers who will require prompting, and 12% will refuse
the MeNZB™ vaccine. The research also showed that although awareness of
the disease is very high, perceived personal relevance of the disease was much
lower. Disconcertingly, this was especially so for the Pacific participants
(n=100). Despite Pacific peoples having the highest rates of meningococcal
disease, only 32% of the Pacific parents felt that this disease was personally
relevant.
Initially, Maori were consulted about the MVS at several key
hui (meetings). Subsequently, a National Roll Out Advisory Group, which is
predominantly Maori, has been established. This group meets regularly to provide
advice on implementation of the MVS. Each DHB will be funded to provide
awareness-raising activities and outreach immunisation services that support a
whanau ora (family wellbeing) approach. Similarly, Pacific targeted strategies
have been developed in association with advice from Pacific health and community
leaders. Appropriate communication strategies (including appropriate media
channels and appropriate messengers) will be essential.
Young adults have been identified as a group that will be
difficult to reach. The one-dose meningococcal C vaccine campaign in the UK
achieved less than 30% coverage in this group.9
A strategy for DHBs to reach youth has been prepared by the Immunisation
Advisory Centre (IMAC).10 The youth strategy
highlights what is known not to work in this age group, and that mass media and
community mobilisation appear to be the most effective strategies. However,
priority should be given to reaching those aged less than five years in whom the
disease burden is greatest.
Group B meningococci and measuring immune response to vaccinesThe polysaccharide capsule
determines the group of the meningococcus. Disease caused by group B
meningococci accounts for around 30–40% of cases in the United
States11 and just under 70% of cases in
Europe.12 In New Zealand, the impact of group B
disease is overwhelming, with 80 to 90% of cases attributed to group B
meningococci.5 Meningococcal type and sub-type
are based on proteins on the organism’s surface called outer membrane
proteins (OMPs). Type is based on the PorB OMP and the subtype on the PorA OMP.
The New Zealand strain is defined as group B, type 4, and PorA subtype
P1.7b,4.2
The polysaccharide capsule of group B meningococci is poorly
immunogenic. In group B infections, antibodies are largely directed against the
OMPs, particularly the PorA proteins.13
Therefore, vaccines targeting strain-specific OMPs are currently the only
response available against group B meningococcal disease epidemics. For that
reason, development of a tailor-made vaccine targeting the New Zealand epidemic
strain PorA type was considered to be the best approach as there are no
currently licensed vaccines that contain the New Zealand PorA type.
The method used for evaluating the immune response to
meningococcal vaccines is to measure serum bactericidal antibody (SBAb) levels
using the serum bactericidal assay (SBA), a laboratory test which mimics the
complement-mediated response to infection that occurs naturally following
infection. The SBA has been used to measure immune responses following natural
infection,14,15 vaccination with polysaccharide
antigens,16 and (most recently) vaccination
with group C conjugate vaccine in the UK.17
A ‘protective’ level of SBAb has not been
established for outer membrane vesicle (OMV) group B vaccines such as
MeNZB™. It may never be possible to ascertain a protective level because
OMV vaccines comprise multiple antigens and the SBA measures SBAb responses to
an unknown quantity of these antigens. In addition, individuals may respond
differently to the various antigens.
For the New Zealand MeNZB™ clinical trials (described
below) the Institute of Environmental Science and Research Limited (ESR)
validated the SBA, in association with three international
laboratories.18 A four-fold rise in SBAb titre
following vaccination was set as the criterion for seroresponse. However,
because a specific correlate of protection has not been determined, the success
of the vaccine in halting the epidemic will be monitored through the effect on
disease incidence.1
The parent vaccineNorway experienced an epidemic of
group B meningococcal disease from the 1970s to the 1990s. The Norwegian
Institute of Public Health (NIPH) consequently began developing a vaccine
against the Norwegian strain in 1983 using a clinical isolate representative of
the epidemic. The production process involves growth of the bacteria in a
fermentor, inactivation of the organism and extraction of the OMVs with
detergent (sodium deoxycholate), purification of the OMVs, and adsorption of the
vesicles on to aluminium hydroxide adjuvant.19
The resulting vaccine, MenBvac™ (the parent vaccine to
MeNZB™), underwent a series of phase I, II, and III clinical trials (25 in
total) from 1987 to 2003 but was never used for epidemic control. This is
because MenBvac™ was not available for a certain time period due to a lack
of Good Manufacturing Practice production facilities and the epidemic waned
through the 1990s. Since 1998, there have been too few cases to justify a mass
immunisation programme in Norway.20
However, results from the clinical trials of MenBvac™
have guided the New Zealand MVS. A large (n = 171, 800) efficacy trial in
teenagers21,22 demonstrated that two doses 6 to
14 weeks apart (usually around 6 weeks) was not enough to provide long-term
protection against meningococcal disease—as efficacy (when measured at 29
months) was 57%, whilst at 10 months the point estimate was
87%.23 A subsequent smaller (n = 373)
immunogenicity trial23 demonstrated that a
higher and longer response was possible using a third dose given 1 year after
dose two. In this study, a total of 81% of the MenBvac™ recipients were
still exhibiting a four-fold rise in SBAb 1 year following the third dose.
Although tenderness at the injection site was relatively
common, and transient systemic symptoms occurred following vaccination, no
serious adverse events have been attributed to MenBvac™. In the efficacy
trials four cases of serious neurological disease occurred in vaccine
recipients, and two in placebo recipients. However a large cohort study
(covering a period of time during which 345, 000 doses of MenBvac™ were
administered) found no statistically significant increased risk of serious
neurological events at 30 and 56 days following receipt of
MenBvac™.24
The MeNZB™ clinical trialsPhase I and Phase II clinical trials
of MeNZB™ vaccine are being led by the University of Auckland, under
contract to the Ministry of Health. Most of these trials have been completed.
There have been no serious safety concerns regarding the vaccine to date, and
the immune response to the vaccine has been good in all age groups for which
results are available.
Results from the adult clinical trials were released at the
New Zealand Paediatric Society’s Annual Scientific Meeting in August
2003.25 In summary, 100% (95% CI 85–100%)
of the adults who received 3 doses of 25 micrograms of MeNZB™ (n=23) were
seroresponders against the New Zealand vaccine strain after three doses, and
there were no serious vaccine-related adverse events. Results from the completed
trials in 8- to 12-year olds, and in 6- to 8-month olds are yet to be released.
The first results from the toddler age group trial are presented
below.
The early infant trial in the 6- to 10-week age group is
currently enrolling participants. MeNZB™ is being given with the routine
childhood immunisation schedule to assess immunogenicity and safety in that age
group, and interference with the immune response to routine childhood
immunisations (DTaP-IPV and Hib-HepB at 6 weeks and 3 months, and DTaP-IPV and
HepB at 5 months). Each child in the trial, whether they are the test or a
control, is having two injections in one leg separated by 2.5 cm, and one in the
other leg. The controls are receiving DTaP and IPV separately. Reactogenicity
data will be collected on all three injection sites.
Other studiesA study has started in Otago
assessing a combination of group B and group C meningococcal vaccines in which
the lyophilised group C conjugate vaccine (Menjugate™) will be dissolved
in the liquid MeNZB™ vaccine for one of the three doses of MeNZB™.
The benefit of this approach, rather than using Menjugate™ separately in
vulnerable populations, is that the total number of injections required to cover
both group B and group C disease could be reduced by one. Furthermore, there is
evidence to suggest that the group B response might be enhanced when vaccine is
administered in this way as was seen when MenBvac™ was administered with
Menjugate™.26
A study funded by the UK Meningitis Foundation to assess the
effect of MeNZB™ vaccine on meningococcal carriage has been completed
pre-vaccination. A meningococcal carriage study post-vaccine delivery is
planned. Evidence in the literature is inconclusive in relation to whether OMV
vaccines lead to a reduction in carriage. It is unlikely that herd immunity will
play a role in controlling the epidemic.
Toddler clinical trial resultsThe toddler age group clinical trial
was led by Dr Sharon Wong and team at the University of Auckland and was
co-sponsored by the Ministry of Health and Chiron Vaccines. A total of 332 16-
to 24-month old toddlers were enrolled in the observer-blind randomised
controlled trial. A total of 265 were randomised to receive the candidate
vaccine (MeNZB™) and 67 (the control group) to receive the parent vaccine
(MenBvac™). Three doses of vaccine were given 6 weeks apart. Very high
completion rates were achieved (96% in the MeNZB™ group and 90% in the
control group). SBA, performed by ESR, was used to measure immune (SBAb)
response at baseline, 6 weeks following dose 2, and four weeks following dose 3.
Local and systemic reactions were monitored for 7 days after each dose. A brief
summary of the trial results is presented below.
Table 1. Percentage of recipients with a four-fold rise
in SBAb titre (‘seroresponse’) to the New Zealand epidemic
strain
Table 1 shows the percentage of participants who met the
evaluability criteria in the study protocol, that exhibited a seroresponse
(defined as a fourfold rise in SBAb titre compared with baseline) to the New
Zealand epidemic strain following dose 3 of the vaccines. A total of 75% of the
MeNZB™ recipients were seroresponders after three doses. As expected,
there was a lower SBAb response to the New Zealand epidemic strain following
three doses of MenBvac™ (the Norwegian strain vaccine).
Tenderness at the injection site was the most common local
reaction, and was similar in the MeNZB™ group and the MenBvac™
group. Most tenderness reactions were mild (minor reaction to touch) or moderate
(cried or protested to touch). Severe reactions (cried when injected limb moved)
occurred in 10-23% of MeNZB™ recipients with each dose. In general,
tenderness reactions peaked by day two and had reduced by day three. Systemic
reactions were very similar between the MeNZB™ and the MenBvac™
groups. Irritability was most common, occurring in around 40% of participants
with each dose. Approximately 10% of children receiving MeNZB™ had a
temperature greater than 38°C with each dose.
Key issues from the discussion
The use
of a four-fold rise in SBAb from baseline to denote seroresponse following
vaccination, the standard used to measure an immune response, has been used in
other trials.23,27–29 The complexity of
the SBA, in terms of measuring the immune response to the cocktail of antigens
in group B OMV vaccines, makes interpretation of the seroresponse rates from the
MeNZB™ clinical trials complicated. The actual efficacy of the vaccine
could be higher or lower. Extra efficacy gained through cross-protection against
other meningococcal strains is difficult to factor in, and immunological memory
and ‘late-responders’ also need to be taken into account.
Direct comparison cannot be made
with SBAb titres from group C vaccine studies because in group C studies the SBA
measures the immune response to a single antigen, whereas in group B studies the
SBA measures variable immune responses to multiple antigens.
Health professionals,
community awareness-raisers, and communication through the media should be
straightforward about the reactogenicity of MeNZB™ vaccine. Ways to manage
the side-effects should be presented to parents and young people such as the use
of ice packs and paracetamol.
Preliminary data from the
infant, toddler, and 8–12 year old MeNZB™ clinical trials suggest
that clinically significant differences in response to the vaccine are
unlikely.
The
comprehensive safety monitoring system has been designed to enable the
Independent Safety Monitoring Board to assess whether an event which follows
MeNZB™ could be caused by the vaccine and if so, how often. Published data
and the extensive use of similar vaccines are
reassuring.30
There is no
international evidence to support the likelihood that this will happen. It may
be possible to assess for attenuation of disease through notification data on
EpiSurv (the national notifiable disease surveillance database), but both
treatment and notification patterns will need to remain the same. Otherwise,
comparison of notification data from before and subsequent to the immunisation
programme will not be valid.
ConclusionsThe Meningococcal B Immunisation
Programme will be the biggest mass immunisation programme ever attempted in New
Zealand, and it needs to reach those who historically are less likely to be
reached by immunisation programmes. A tailor-made vaccine has been developed for
the Programme and the clinical trials are progressing well. In the toddler age
group 75% of MeNZB™ recipients exhibited a four-fold or greater rise in
SBAb after three doses. Interpretation of SBA results, however, is complex
because the assay measures the response to multiple antigens.
Overseas studies have shown a correlation between higher
SBAb titre levels and efficacy, but a ‘protective’ SBAb level has
not been determined. Local reactions to MeNZB™ are common, especially
injection site tenderness, but should be manageable if health professionals
inform parents and young people what to expect and how to manage the reaction. A
comprehensive safety monitoring programme will be in place to monitor for
adverse reactions following immunisation.
Author information:
Kerry Sexton, Public Health Medicine Registrar, Meningococcal Vaccine Strategy,
Ministry of Health, Wellington; Diana Lennon, Professor of Population Health of
Children and Youth, University of Auckland, Auckland; Philipp Oster, Associate
Director, Clinical Research and Medical Affairs, Chiron Vaccines, Siena, Italy;
Ingeborg Aaberge, Department Director, Department of Airborne Infections,
Division of Infectious Disease Control, Norwegian Institute of Public Health,
Oslo, Norway; Diana Martin, Principal Scientist, Institute of Environmental
Science and Research Limited (ESR), Porirua; Stewart Reid, General Practitioner,
Ropata Medical Centre, Lower Hutt; Sharon Wong, Clinical Research Fellow,
University of Auckland, Auckland; Jane O’Hallahan, Director, Meningococcal
Vaccine Strategy, Ministry of Health, Wellington
Acknowledgements: We
thank Kim Mulholland, Professorial Fellow, Centre for International Child
Health; Teuila Percival, Paediatrician, South Auckland Health; and Joanna
Stewart, Biostatistician, University of Auckland.
Correspondence: Jane
O’Hallahan, Meningococcal Vaccine Strategy, Ministry of Health, PO Box
5013, Wellington; Fax: (04) 495 4401; email: Jane_OHallahan@moh.govt.nz
References:
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