A 'tailor made' vaccine trialled as part of public health response
to group B meningococcal epidemic in New Zealand
New Zealand has experienced an epidemic of serogroup B meningococcal
infection since 1991 (1), which has so far been responsible for more than
4700 cases and over 200 deaths (2). The overall incidence reached a high of
17.4 cases per 100 000 population in 2001. In 2002, incidence rates for Maori
and Pacific Islands children <1 year of age were 286 and 368 per 100 000
respectively (2). The New Zealand Health authorities asked the World Health
Organization (WHO) for assistance, and in 1993 an international advisory group
was established. Various options were evaluated, and in 2000 a proposal for
vaccine development and manufacture, followed by performance of clinical trials,
from the Norwegian Institute of Public Health (NIPH) and Chiron Vaccines (Siena,
Italy) (CV), was accepted (3). The proposal was to prepare a protein based,
outer membrane vesicle (OMV) vaccine from a wild-type strain typical of that
causing the epidemic in New Zealand.
Conventional capsular polysaccharide (PS) meningococcal vaccines against
serogroup A, C, Y, and W135 disease have existed since the late 1960s (3,
4). Recently successful attempts have shown that it is possible to formulate
conjugate vaccines with the respective capsular polysaccharides (3). The
major impact on disease following introduction of the C-conjugate vaccine
in the United Kingdom (UK) has led to licensure of this vaccine in several
countries and gives hope for the development of improved formulations of
other meningococcal vaccines (3). The group B polysaccharide, however, is
not suitable as a vaccine, mainly because it is non-immunogenic in humans.
Thus, most approaches for vaccine development against group B meningococcal
disease have focused on various outer membrane proteins as vaccine candidates
Group B meningococcal strains show substantial variation at the pheno-
and genotypical level (3, 6, 7). During an epidemic, however, the strains
causing the outbreak normally belong to the same clonal population. This
was the case during the epidemics in Cuba and Norway in the 1980s (8, 9),
in Chile from the mid 1990s (10) and currently in New Zealand (1). In New
Zealand the outbreak is caused by the hyper-virulent lineage III-clone,
characterised as B:4:P1.7-2,4 and ST42 or ST154 which are subclones of the
ST44 complex (1, 11).
The OMV vaccine was developed with reference to the Norwegian meningococcal
group B vaccine, MenBvac (12, 13). The vaccine was prepared from a B:4:P1.7-2,4
New Zealand strain by fermenter growth and extraction with the detergent
deoxycholate to yield OMVs which were adsorbed to aluminium hydroxide. Manufacture
and preclinical testing of such OMV vaccines have recently been described
For evaluation of safety, reactogenicity, and immunogenicity, phase I/II
trials in adults, 8-12 year-old children, toddlers (18-24 months), and infants
are being performed in rapid succession (15). Three doses of the vaccine
are being given six weeks apart. The first step of the successive trials
included 75 adult subjects. Preliminary results suggest that the vaccine
is safe and similar reactogenicity was observed as for the parent vaccine,
MenBvac. The remaining trials are each expected to include about 300 subjects.
Clinical trials in 8-12 year-old children and in toddlers are ongoing, and
further vaccination in larger groups of children and infants are planned.
Based on data from a clinical trial using MenBvac in Chile, a good immune
response in younger children and in infants is expected against the homologous
strain (10). After rollout of vaccine to all New Zealanders under 20 years
of age (expected to begin in 2004) the vaccine may be included in the national
immunisation schedule at least until the epidemic is controlled. The serum
immune responses of vaccinees are being evaluated by measuring antibodies
specific to OMV in enzyme-linked immunosorbent assay (ELISA), and by testing
for serum bactericidal activity (SBA) in sera from vaccinees. The SBA test
is a functional assay, considered to correlate with protection against meningococcal
disease (4, 16). Collaboration between four laboratories (in New Zealand,
USA, the UK, and Norway) has been established for standardisation and comparison
of SBA for the meningococcal group B.
In 1996 polymerase chain reaction (PCR) tests for meningococcal deoxyribonucleic
acid (DNA) became available and the use of this method has increased. In
2002, 557 cases of meningococcal disease were reported in New Zealand, of
which 413 (74.1%) were laboratory confirmed (2) and 31.8% of the cases,
unconfirmed by culture, were confirmed by PCR. Of the 384 cases for which
this could be measured, either by serotyping of an isolate or genotyping
of DNA from patient specimens, 297 (77.3%) were caused by the serogroup
B epidemic strain expressing the PorA P1.7-2,4 subtype (2).
The group B meningococcal epidemic in Norway in the 1980s persisted for
more than 10 years. In an attempt to predict the progress of the epidemic
in New Zealand, the number of cases in Norway (population 4.5 million) and
the registered cases in New Zealand (population 3.3 million) have been shown
together in the figure below.
Figure. Meningococcal disease cases by number of years
from pre-epidemic period (equivalent year) for Norway and New Zealand. Graphical
illustration of the two different group B meningococcal epidemics in Norway
[1970/80's] and in New Zealand [at present] (2).
Vaccine will be offered to each age group of the wider population depending
on the ability to mount a homologous immunologic response to the 'tailor
made' vaccine. A large body of safety data with the NIPH Norwegian strain
vaccine and similar vaccines is available and surveillance of adverse events
in 'real time' is planned. Public Health legislation in New Zealand allows
rapid evaluation for provisional vaccine licence in response to an epidemic.
A collaborative alliance between two governmental organisations located
on the opposite side of the globe and a vaccine manufacturer in Italy has
resulted in a 'tailor made' vaccine for controlling the ongoing epidemic
in New Zealand. The collaboration has managed to design and perform a public
health intervention in New Zealand for evaluation of vaccine efficacy, rather
than undertaking a traditional randomised controlled clinical trial. Provided
that the remaining trials produce positive results, and anticipating a population
rollout starting from early 2004, a preventive effect in the population
might be noticeable late 2004 or during the first half of 2005. If successful,
the concept of using 'tailor made' OMV vaccines might enable rapid response
to similar epidemic scenarios that are likely to surface in other parts
of the world in the coming years.
The New Zealand 'tailor made' vaccine is designed for the current situation,
but the same lineage III-clone (B:4:P1.7-2,4) is the predominant group B
meningococcus causing disease in several industrialised countries (17).
From a global perspective, however, a more sustainable solution might be
found in vaccine formulations using protein antigens with conserved epitopes,
which induce functional immune responses that cross-react with the majority
of the circulating group B strains (6).