  |
|
|
||||
|
||||||
| Journal of the New Zealand Medical Association,
20-August-2004, Vol 117 No 1200
|
||||||
|
Prevention of group B meningococcal disease by vaccination: a
difficult task
Mark Thomas
An epidemic of disease due to one strain of serogroup B
Neisseria meningitidis began in New
Zealand in 1991 and since then has caused almost 5,000 hospitalisations and over
200 deaths.1 A vaccine, based on a similar
vaccine developed in response to an epidemic in Norway, has been designed
specifically to control this New Zealand epidemic. To achieve this goal, the
vaccine will need to prevent disease, and perhaps also carriage—and will
need to be delivered to a large majority of the target population. Low vaccine
efficacy and or inadequate vaccine delivery will result in a disappointing
failure to prevent disease. A wider understanding of the difficulties associated
with the development of this vaccine and its delivery may improve the chances of
ultimate success in disease prevention.
N. meningitidis is
spread in secretions coughed or sneezed by an infected person. After
acquisition, by inhalation or by direct contact with infected secretions, the
organisms adhere firmly to the epithelial surface of nasopharyngeal cells.
Within a few days, the adherent bacteria may manipulate the epithelial cells to
transport the bacteria through the cell cytoplasm to then be released into the
sub-cellular space2 (Figure 1). From there, the
bacteria invade blood vessels and are disseminated in the bloodstream.
In most people, serum antibodies attach to the surface of
the bacteria and initiate immune responses, which ensure that the bacteria are
killed before they can cause disease. However in people who lack protective
antibodies to the invading strain of meningococcus, the organism may survive and
proliferate in the blood and from there may invade and multiply in the
cerebrospinal fluid. Furthermore, colonisation of the nasopharynx persists for
weeks to months providing an ongoing source of infection for others.
Figure 1. After
Neisseria meningitidis attaches to the
surface of nasopharyngeal epithelial cells (A), it is transported through the
cytoplasm of these cells to reach the sub-cellular space, from where it invades
the bloodstream (B). Persistent colonisation of the epithelial surface of
nasopharyngeal cells provides a source of infection for others (C). Eventually
the infection of the epithelial surface of the nasopharyngeal cells is
eradicated (D) and the person is no longer a source of infection for
others.
 Most people with N.
meningitidis colonisation of the nasopharynx do not develop
disease—because serum antibodies initiate the immune responses, which
rapidly clear the organism from the blood. Antibody bound to the surface of
N. meningitidis activates serum
complement proteins to create channels which disrupt the cytoplasmic membrane of
the bacteria and thus kill it. Antibody bound to the surface of the bacteria
also enhances phagocytosis by neutrophils and macrophages.
The epidemiology of disease due to
N. meningitidis is largely a reflection
of these central roles of antibody in protection against disease. Newborn
infants have high levels of antibody, which has been transported across the
placenta from their mother’s blood during the last 6 weeks of pregnancy.
This antibody is broken down during the first year of life and is slowly
replaced by antibody synthesised by the child’s lymphocytes stimulated by
mucosal infection with closely related non-pathogenic organisms. The lowest
levels of serum antibody are found in children aged 9 months to 5 years, and it
is children in this age group who are at highest risk of meningococcal disease
(Figure 2).
Figure 2. The incidence of disease due to
Neisseria meningitidis (solid line) is
greatest between the ages of about 6 months and 5 years when the titre of serum
bactericidal antibody (broken line) is lowest
 The meningococcus has evolved to evade immune
responses.4,5 It ‘hides’ within a
polysaccharide capsule, which is poorly immunogenic compared with the proteins
of the bacterial cell wall and outer membrane (Figure 3).
Figure 3. Neisseria
meningitidis is surrounded by a polysaccharide capsule, an outer membrane
which has a variety of proteins including Por A and Por B inserted into it, a
peptidoglycan cell wall, and a cytoplasmic membrane
 Infants produce very weak antibody responses to
polysaccharide antigens, and neither infants nor adults generate either
immunological memory, or enhanced antibody responses following re-exposure to
polysaccharide antigens. The serogroup B meningococcus has further refined this
evasion of immune responses by synthesising a polysaccharide capsule, which is
composed of the same sugars as those found on the surface of immature neural
cells. Lymphocytes with the capacity to produce antibody to these sugars have
been deleted in foetal life to avoid the production of harmful auto-antibodies.
While infection with other serogroups of N.
meningitidis (eg, A,C,Y,W135) stimulates antibody responses (albeit weak)
against their polysaccharide capsules, infection with serogroup B
N. meningitidis fails to stimulate an
anti-capsular antibody response.
Antibodies to the proteins of the outer membrane, which lies
within the polysaccharide capsule, can facilitate complement activation and
phagocytosis. Two of these outer membrane proteins (OMPs) are the main
components of the serogroup B meningococcal vaccine which will be used in New
Zealand. Por A and Por B form clusters that span the outer membrane and provide
channels for molecules to gain access to and from the
bacterium6 (Figure 3). The structure of these
porin molecules can vary widely between different meningococcal strains. The
current New Zealand epidemic has been caused almost exclusively by a strain with
porin molecules classified as serotype 4 (based on the predominant Por B
molecule) and serosubtype P1.4 (based on the predominant Por A
molecule).7
The variation in the Por A and Por B molecules produced by
different strains of meningococci has the effect that antibodies which bind to
the Por A or Por B molecules of one strain may fail to bind to the Por A and Por
B molecules of an otherwise similar strain.4,5
Furthermore, the capsule surrounding the bacteria, and other molecules present
in the outer membrane, may mask the Por A and Por B molecules and reduce their
accessibility to serum antibodies.8
Despite these disadvantages, the
OMPs have been the principal antigens in vaccines created to control epidemics
of serogroup B meningococcal disease in Cuba, Norway, Brazil, and
Chile.9–13 While extensive use of a
locally produced vaccine appears to have contributed to the disappearance of
serogroup B meningococcal disease in Cuba,9 the
experience with similar vaccines in Norway, Brazil, and Chile has been less
dramatic, and in none of these latter countries has the vaccine progressed from
clinical trials to routine use.10–13
Results from clinical trials of these vaccines may help to predict the efficacy
of the New Zealand vaccine.
It is probable that the antibody responses to a vaccine
derived from the New Zealand epidemic strain will be broadly similar to those
found in people immunised with other serogroup B meningococcal vaccines.
Seroconversion, defined as a four-fold or greater rise in the titre of serum
bactericidal antibody, (ie, antibody which, in the presence of complement, leads
to killing of the bacteria) has been found to be a reasonably consistent marker
of protection against disease and thus has come to be accepted as a surrogate
marker of effective immune responses following vaccination.
Table 1 shows the proportion of vaccinees who seroconverted
following two or three doses of a serogroup B meningococcal vaccine and the
efficacy of the vaccine in protection against disease during epidemics largely
caused by the vaccine
strain.10–16
Table 1. Seroconversion rates and vaccine efficacy for
serogroup B meningococcal vaccines
Figure 4 illustrates the relationship between seroconversion
and vaccine efficacy in a more easily assimilated format.
Figure 4. Previous trials of serogroup B meningococcal
vaccines have shown a relationship between the proportion of vaccinees who had a
≥4X rise in serum bactericidal antibody titre following vaccination
(horizontal axis) and the protective efficacy of the vaccine (vertical axis).
The points shown are for: the Norwegian vaccine given to children aged
14–16yrs (1); the Cuban vaccine given to children in Sao Paulo, Brazil,
aged <2yrs (2), 2-4yrs (3), 4–7yrs (4); the Cuban vaccine given to
children in Rio de Janeiro, Brazil, aged <2yrs (5), 2-4yrs (6), 4–9yrs
(7); and an American vaccine given to children in Iquique, Chile, aged
1–4yrs (8) and 5–21yrs
(9).10–15
Tapperro et al found that a high proportion of vaccinees
(including those aged less than 1 year) seroconverted following three doses of
either the Cuban or the Norwegian vaccine16
(Table 1). This suggested that a three dose immunisation program would provide
protection against disease for a high proportion of vaccinees. The initial
results from the New Zealand immunogenicity studies are similar to those from
the Tapperro study. Seroconversion rates increased with each dose of vaccine and
were 100% in adults and 75% in toddlers after three vaccine doses. These results
suggest that the New Zealand vaccine should be effective in these age
groups.
Unfortunately immunisation with serogroup B meningococcal
vaccines does not lead to high levels of serum bactericidal antibody, and the
overall effect of giving more doses of vaccine is to increase the proportion of
vaccinees who seroconvert rather than to dramatically increase the titres of
serum bactericidal antibodies in seroconverters.
Thus, geometric mean titres of serum bactericidal antibody
were 1.2–4.6 pre-immunisation and 2.8–30.2 and 9.2–64.6 after
the second and third doses of a serogroup B meningococcal
vaccine.13–15 In contrast, the geometric
mean titres of serum bactericidal antibody rose from being undetectable
pre-immunisation to 13, 302, and 629 after the first, second, and third doses of
a conjugated serogroup C meningococcal vaccine.
17
The relatively low geometric mean titres of serum
bactericidal antibody in people given two or three doses of serogroup B
meningococcal vaccines are the probable explanation for the decline in vaccine
efficacy which occurs within a year or two of immunisation with these
vaccines.10,12 Careful observation will be
necessary to determine whether initial immunisation will need to be followed by
repeat doses at intervals of a year or two.
Vaccines, which produce very high levels of antibody
following immunisation, such as the conjugated vaccines against
Haemophilus influenzae type b,
serogroup C meningococcus, and Streptococcus
pneumoniae reduce asymptomatic nasopharyngeal colonisation as well as
invasive disease.18–20 Not surprisingly,
given the relatively low titres of antibody produced, immunisation with
serogroup B meningococcal vaccines does not appear to reduce nasopharyngeal
colonisation by the organism13,14,21 and
therefore a successful vaccination program may not reduce transmission of
infection.
This has important implications for vaccine delivery.
Vaccines which prevent carriage reduce the exposure of susceptible persons to
the organism and can virtually eliminate disease despite vaccine uptake rates of
‘only’ 90%. In contrast, vaccines which do not prevent carriage do
not reduce the exposure of susceptible persons to the organism and therefore
disease prevention requires very high levels of vaccine uptake.
The effect of the meningococcal vaccination campaign on the
incidence of meningococcal disease in New Zealand largely will depend on the
average vaccine efficacy in a fully immunised person and the proportion of the
population who are fully immunised. Thus, a vaccine which provides protection
against disease in 90% of fully immunised people might be expected to reduce the
incidence of disease by about 81% if 90% of the target population are fully
immunised.
However, as the vaccine is likely to be less effective in
protecting against meningococcal disease due to strains other than the vaccine
strain (which comprise about 20% of current New Zealand isolates), and as the
vaccine will not be given to people over the age of 20 years (who comprise about
17.6% of notified cases of disease),1 the
overall reduction in disease incidence may be correspondingly less.
There is relatively sparse information about the uptake of
childhood immunisations in New Zealand—a situation which should be
improved by the introduction (this year) of a national childhood vaccination
register. A national survey conducted in 1992 found that less than 60% of all
children, and only 42% of Maori children, had been fully immunised by their
second birthday.22
A subsequent survey, conducted in 1996 in Auckland and
Northland, found that 44.6% of Maori children, 53.1% of Pacific children, and
72.3% of ‘other’ children were fully immunised by their second
birthday.23 In contrast, a school and public
health system-based immunisation program intended to control an epidemic of
serogroup A meningococcal disease in Auckland in 1987 and 1988 had an overall
uptake of approximately 90%.24
The uptake of any public health intervention is dependent on
the perceived benefits and risks of the intervention and on the organisational
skill of the health system. The widespread, prolonged epidemic of meningococcal
disease in New Zealand over the last 14 years has provided many with close
experience of its unpredictable occurrence and often terrifying severity. Fear
of the disease, together with parochial support for a local initiative are
likely to enhance vaccine uptake, while concerns about less than complete
protection and adverse effects following immunisation are likely to reduce
vaccine uptake. The need for three doses of vaccine to achieve seroconversion in
a high proportion of vaccinees and the goal of immunising all those aged less
than 20 years, during a relatively short period, will provide significant tests
of the organisational skills of the health system.
The unequal incidence of meningococcal disease (with rates
of 28.9, 20.5, 12.1, and 6.8 per 105 population
respectively in Pacific, Maori, European and ‘other’ ethnic
groups)1 will make high rates of vaccine uptake
particularly important in Pacific and Maori children. Unfortunately, these
groups have had lower rates of vaccine uptake for routine childhood
immunisations22,23 and, with some exceptions,
also had disappointingly low rates of participation in the recent hepatitis B
screening program.25 Hopefully, lessons learnt
from previous public health initiatives will ensure that the vaccine does get
delivered to those who might gain the most benefit from it.
Concerns about vaccine safety can have dramatic effects on
vaccine uptake. In general, serogroup B meningococcal vaccines cause local
symptoms at the injection site—but are safe. Substantial safety data exist
for the Norwegian vaccine, on which the New Zealand vaccine is based, and for
other similar vaccines. Approximately 345,000 doses of the Norwegian vaccine
have been administered in Norway, with approximately 226,000 doses given in
controlled trials, mainly to
teenagers,10—with no serious adverse
events related to the vaccine.26
Further evidence of vaccine safety comes from experience
with the Cuban vaccine, of which over 65 million doses have been administered,
the American vaccine,13 and the Dutch vaccine,
which contains six PorA OMPs including that present in the New Zealand strain
(P1.4), and which has been given to 103 infants in an English
trial.27 Although there are excellent reasons
to expect that the New Zealand vaccine will be safe, comprehensive
post-licensure safety monitoring both by the Centre for Adverse Reaction
Monitoring (CARM) and a specifically developed ‘real-time’, hospital
based monitoring system will be in place during the epidemic campaign.
Furthermore, all safety data will be assessed by an independent safety
monitoring board established by the Health Research Council.
The New Zealand meningococcal vaccination program is the
culmination of years of effort by many in New Zealand and overseas. It is to be
hoped that it will dramatically reduce the incidence of meningococcal disease
and thus repay the approximately NZ$200 million which the Ministry of Health has
committed to this project over the next 5 years. It is also likely to advance
our understanding of this disease and its prevention in ways that may prove
useful to other countries afflicted by similar epidemics.
Author information:
Mark G Thomas, Associate Professor of Infectious Diseases, Department of
Molecular Medicine and Pathology, Faculty of Medical and Health Sciences,
University of Auckland, Auckland.
Acknowledgements: I
am grateful for helpful comments from Stewart Reid, Diana Martin, Diana Lennon,
Jane O’Hallahan, Philipp Oster, and Michael Baker during the preparation
of the manuscript. The illustrations were provided by Val Grey.
Correspondence: Mark
Thomas, Department of Molecular Medicine and Pathology, Faculty of Medical and
Health Sciences, University of Auckland, Private Bag 92019, Auckland. Fax: (09)
373 7492; email: mg.thomas@auckland.ac.nz
References:
|
|
||||
| | Current
issue | Search journal |
Archived issues | Classifieds
| Hotline (free ads) Subscribe | Contribute | Advertise | Contact Us | Copyright | Other Journals |
|