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The Strategy to Control New Zealand's Epidemic of Group B Meningococcal Disease

O'Hallahan, Jane MBChB*; Lennon, Diana MBChB, FRACP; Oster, Philipp MD

The Pediatric Infectious Disease Journal: December 2004 - Volume 23 - Issue 12 - p S293-S298
doi: 10.1097/01.inf.0000147645.53942.00
Supplement Article

Background: In New Zealand today, babies of Pacific ethnicity born in South Auckland have a 1-in-48 chance of contracting meningococcal disease by the time they are 5 years of age.

Methods: The New Zealand government, Chiron Vaccines and the University of Auckland have collaborated to develop and investigate a group B meningococcal vaccine to allow a mass-immunization program to control a prolonged and intense epidemic. Within 3 years, a strain-specific meningococcal outer membrane vesicle vaccine has been developed, and overlapping clinical trials have been undertaken; a report was submitted for regulatory approval within 2 years. An important aspect of the project's strategy was to apply, with physicochemical data, the results of the New Zealand outer membrane vesicle vaccine trials to the parent vaccine produced and evaluated by the Norwegian National Institute of Public Health. Immunogenicity results for the New Zealand vaccine are promising, with the vaccine showing a reactogenicity profile similar to that of the parent vaccine.

Conclusions: Controlling the epidemic depends on delivering an effective vaccine to the individuals at greatest risk, ie, mainly Maori and Pacific populations that previous health programs have struggled to reach. Participation of and partnership with these communities in public health decision-making and vaccine delivery will be critical to a successful immunization program.

From the *New Zealand Ministry of Health, Wellington, New Zealand; †Department of Population Health of Children and Youth, University of Auckland, Auckland, New Zealand; and ‡Chiron Vaccines, Siena, Italy.

Supported by the Ministry of Health, New Zealand and by Chiron Vaccines.

Address for reprints: Jane O'Hallahan, MD, New Zealand Ministry of Health, 133 Molesworth Street, PO Box 5013, Wellington, New Zealand. Fax 6404-496-2340; E-mail Jane_O'

Since 1991, New Zealand has experienced an epidemic of serogroup B meningococcal disease, caused predominantly by a single strain of Neisseria meningitidis for which there is no vaccine.1 Meningococcal disease, caused by N. meningitidis infection, can result in meningitis, bacteremia, or pneumonia and is a serious health threat, especially among children <5 years of age.2 The average case fatality rate for serogroup B meningococcal disease in New Zealand since 1991 is 4.3%.3 Because of the high rate of morbidity associated with this disease, a vaccination strategy is needed to prevent serogroup B meningococcal disease among high risk groups in New Zealand.

N. meningitidis is composed of an outer membrane and a polysaccharide envelope. It is classified into 12 serogroups on the basis of the capsular polysaccharide.4,5 Five serogroups of N. meningitidis, ie, A, B, C, Y, and W135, are responsible for the majority of meningococcal disease worldwide.2 The capsular polysaccharides of serogroups A and C have been used to develop vaccines that have been shown to be effective among adolescents and adults,6 but these vaccines have poor immunogenicity among infants and young children and may result in hyporesponsiveness.5,7–12

To improve immunogenicity and memory, polysaccharides have been chemically conjugated to carrier proteins.4,5 Clinical studies of a serogroup C conjugate vaccine demonstrated improved immunogenicity, compared with plain polysaccharide vaccines, among infants and children.13–22 Vaccine manufacturers are developing conjugate vaccine combinations incorporating group A, C, Y, and W135 polysaccharides.4 Multivalent meningococcal conjugate vaccines that could significantly reduce the disease burden of meningococcal disease attributable to serogroups A, C, Y, and W135 are expected to be available in the United States and Europe within a few years.5 However, serogroup B vaccines appear to lack immunogenicity, and vaccines developed with N. meningitidis outer membrane proteins are serotype specific and do not appear to confer protection against a broad range of circulating serogroup B serotypes.23,24

As a vaccine against the strain of meningococcal serogroup B in New Zealand is not available, there has been a combined effort by the New Zealand Ministry of Health, Chiron Vaccines, and a research team led by the University of Auckland to conduct immunogenicity and safety trials and to offer a specially prepared outer membrane vesicle (OMV) vaccine to control this epidemic. A 6-point plan has been developed to control meningococcal disease in New Zealand. The 6 points include (1) intensified epidemiologic surveillance, (2) promotion of public awareness, (3) promotion of professional awareness, (4) prevention of secondary cases, (5) identification of modifiable risk factors, and (6) vaccination strategy. This article focuses on the vaccination strategy that will be implemented as part of the plan to control the epidemic. Data from this project can help advance understanding of meningococcal disease and vaccine development and may help similarly affected countries.

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New Zealand (population of ∼4 million) has experienced an epidemic of serogroup B meningococcal infection for 13 years, and disease rates are likely to remain elevated.3 Combined notification and laboratory data show that >5300 cases and >200 deaths can be attributed to the epidemic. Probable and culture-confirmed cases reached a peak of approximately 600 in 2001, and >500 cases were estimated to occur in 2003 (Fig. 1). 3 This is an increase from the 50 probable and confirmed cases that were estimated to have occurred in 1990. Approximately 85% of all culture-confirmed cases tested were found to be attributable to a specific serosubtype of serogroup B meningococci (B:4:P1.7b,4).1



There is a geographic pattern in the rates of meningococcal disease in New Zealand that has remained relatively constant during the course of the epidemic (Fig. 2). 3 The highest rates per 100,000 people have been observed on the North Island, in the regions of Rotorua, eastern Bay of Plenty, and Taupo.3 Approximately 70% of cases occur in the northern region of the North Island; in contrast, only 15% of cases occur on the South Island. This is most likely because the South Island is much more sparsely populated than the North Island (populations of 960,900 and 3,048,300, respectively).



A relatively constant temporal pattern has also been noted with surveillance data. Approximately two-thirds of cases occur during the winter/spring peak, which, in New Zealand, is between the months of June and November.3 In 2002, 65.7% of cases occurred between these months. The patterns of seasonal variations may differ geographically.3 In 2002, the peak number of cases in the northern region of the North Island of New Zealand occurred in June, but the peaks in the midland, central, and southern regions occurred in August. During the peak season, as many as 15–25 cases of serogroup B meningococcal disease are reported each week, which highlights the urgent need for a meningococcal serogroup B vaccine.

Disease incidences also exhibit a fairly constant pattern of ethnicity. The population of New Zealand (as of 2001) is composed of European/Pakeha (79.6%), Maori (indigenous people of New Zealand), 14.5%. Pacific (5.6%), Chinese (2.2%), and Indian (1.2%) individuals. Pacific and Maori individuals are the most greatly affected by meningococcal disease. The highest incidence of disease occurs among Pacific children <5 years of age (Fig. 3). 3 By the age of 5 years, 1 of 66 Pacific children and 1 of 117 Maori children are affected by meningococcal disease, compared with 1 of 438 European or Pakeha children.3 Furthermore, although Pacific individuals represent only 9% of the population <20 years of age and Maori individuals represent only 23%, these groups account for 24% and 37% of cases, respectively, among individuals <20 years of age. Europeans, who represent 59% of the population <20 years of age, account for 36% of cases in this population.



The disproportionate distribution of meningococcal disease among Pacific and Maori individuals may be attributable to their low socioeconomic status, compared with European New Zealanders. Results of a case-control study that controlled for age, ethnicity, season, and socioeconomic factors showed that the risk of disease was strongly linked to overcrowding (as measured by the number of adolescent and adult household members per room).25 Other factors that increased risk included analgesic use (thought to be a marker of recent illness), number of days at substantial social gatherings, and number of smokers in the household.

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It was recently shown that broadly protective, immunogenic vaccines could be produced through chemical conjugation of the capsular polysaccharides of 4 of the 5 most pathogenic meningococcal serogroups to a carrier protein.4,5 A conjugate vaccine for serogroup C was shown to have a major impact on the incidence of serogroup C meningococcal disease in the United Kingdom and was effective in a mass-immunization campaign in Canada.13,26

N. meningitidis serogroup B polysaccharide appears to be unable to be used for vaccine development because it is nonimmunogenic and is structurally similar to a neural cell adhesion molecule found in humans.4,5 Another method of vaccine development is the use of OMVs as antigens.5 OMVs are blebs of outer membrane that are constantly released by N. meningitidis and contain outer membrane proteins, including PorA (immunodominant antigen), PorB, and lipopolysaccharide.4 OMV vaccines can offer protection in epidemic situations, such as in New Zealand, when the majority of disease is caused by a single strain of meningococcus B.1

One OMV vaccine was developed by the Finlay Institute in Cuba27 and another by the National Institute of Public Health (NIPH) in Norway,28 for use in clonal outbreaks in Cuba and Norway27,28 and then Chile and Brazil.29–32 Clinical studies conducted in concert with OMV vaccination campaigns during these outbreaks showed that OMV vaccines can elicit protective antibodies, that infants can mount an immune response to PorA, and that OMV vaccines have acceptable safety profiles. On the basis of this information, it was decided that vaccine manufacturers would be approached and asked to develop a specially made vaccine against the meningococcus B strain responsible for the epidemic in New Zealand.33

Four manufacturers expressed interest in developing a specially made vaccine for New Zealand. In 2001, the New Zealand Ministry of Health decided to work with Chiron Vaccines in collaboration with the NIPH.34 The New Zealand strain-specific vaccine (MeNZB) was developed by using the Norwegian vaccine (MenBvac) as the parent vaccine.35 The vaccine was prepared from a B:4:P1.7b,4 New Zealand strain through fermenter growth and detergent extraction of OMVs, which were adsorbed to aluminum hydroxide.35

Clinical trials with MeNZB began in Auckland, under the direction of the University of Auckland, in May 2002 and have continued through 2004.33 For rapid implementation of the vaccine, phase I and II clinical trials among adults, 8-12-year-old children, toddlers, and infants were conducted in rapid succession (Table 1). In all trials, 3 doses of vaccine were administered, with 6 weeks between doses. The phase I trial, which included 75 adults recruited from the health care sector in Auckland, showed the vaccine to be immunogenic and safe at 2 different dosages. An additional trial among 6- to 10-week-old infants was started in January 2004. For this age group, MeNZB was administered concurrently with routine immunizations, to facilitate the immune response to MeNZB and to establish whether there was clinically significant interference among vaccines.



On the basis of the immunogenicity and safety data for previously used OMV vaccines and the data generated in New Zealand clinical trials, Medsafe, the division of the New Zealand Ministry of Health responsible for approving vaccines for supply, granted provisional consent for staging of a vaccination effort with MeNZB. Additional data collected during the vaccine introduction will allow full licensure of the vaccine.

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Vaccine introduction began in July 2004. The goal of the vaccination strategy is to implement an effective national immunization program for group B meningococcal disease that reduces health care inequalities for Maori and Pacific individuals and achieves 90% coverage for the New Zealand population <20 years of age.33 It is especially important to reach 90% of the Pacific population <20 years of age with the complete MeNZB dose schedule, particularly those <5 years of age. The goal is a 70% reduction in cases involving the New Zealand epidemic strain among adults and children 0–19 years of age. Although the program is designed to target all those 0–19 years of age, delivery to any age group is dependent on regulatory approval, which is dependent on the results of the clinical trials outlined in Table 1.

The development of an appropriate vaccine introduction strategy is important because an effective strategy can prevent a significant number of cases of serogroup B meningococcal disease. There are many factors that must be considered in the development of a vaccination strategy. The epidemiologic features of the New Zealand epidemic appear to involve 3 major variables, ie, age, geography, and ethnicity. To achieve the greatest reduction in disease burden, it is important to quickly administer the vaccine to those at highest risk. Therefore, the introduction strategy will be implemented according to age and geographic region, and steps will be taken to ensure that the plan avoids ethnic inequalities. Vaccine introduction began with those 6 months to 19 years of age living at the top of the North Island, where disease rates are highest, and will proceed to the bottom of the North Island and then from the bottom of the South Island to the top.33 It will probably require up to 1 year for all regions to begin vaccination. The first stage will begin in the Counties-Manukau District Health Board and the eastern corridor of the Auckland District Health Board. Primary health care providers will vaccinate children <5 years of age and children outside the school system. Public health nurses will vaccinate school students in a school-based program. A variety of health care providers will vaccinate young people who no longer attend school. Three doses will be administered, at 6-week intervals.

For safety assessment during the vaccine introduction, New Zealand's passive adverse event reporting system will be enhanced and supplemented. Data will be collected from several sources, including hospitals, select general practitioners, and the newly implemented National Immunization Register.33 Adverse event information will be assessed by an independent safety monitoring board (independent of the Ministry of Health and Chiron), which will advise the Ministry regarding cessation of vaccination because of possible safety risks or the need for additional investigation of possible safety risks. This robust structure should bolster public confidence. At this time, there is no system in place for evaluation of ethnic differences in safety; however, such a system may be implemented at a later time.

The efficacy of the vaccine will also be evaluated throughout the vaccine introduction. Methods to evaluate efficacy will include public health surveillance, data modeling, and a case-control study. Public health surveillance will closely monitor the epidemic and vaccine coverage. Although previous studies were too small for evaluation of clear differences in immunogenicity among Maori and Pacific individuals, compared with European New Zealanders, it may be possible to detect differences with surveillance conducted during the vaccine introduction.

New Zealand's past vaccination coverage rates suggest that current immunization strategies best serve those whose parents and caregivers are well motivated, understand the need for immunization, and require little or no prompting to take their children for immunization. Achieving high coverage rates among groups with poor access to health care will be critical for achieving epidemic control. Systems will be in place to ensure that every measure is taken to reduce inequalities in the national immunization program. There has been much consultation with the Maori and Pacific communities, and a national advisory group composed predominantly of Maori health care professionals has been assembled. In addition, a steering committee in each of the local areas will have Maori representation, and Maori health care providers will provide outreach services, through mobile vaccination clinics, to reach children without access to normal primary health care services.

Strategies are also in place to reach the Pacific New Zealanders. New Zealand's near neighbors are Pacific Island nations. There are 10 key groups of Pacific peoples in New Zealand, and all have distinct cultures and languages, which makes communication challenging. Pacific people-specific research and evaluation have been conducted to increase understanding of the issues for Pacific communities, and community awareness will be increased through the appropriate channels for each culture. Pacific community leaders and health officials will be used to increase community awareness of the national immunization program, and mobile vaccination teams will be used to ensure broad coverage.

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New Zealand has been affected by a devastating group B meningococcal disease epidemic since 1991, and disease rates are likely to remain high. The New Zealanders most affected by the epidemic are Maori and Pacific individuals, who account for a minority of the total population, with children <5 years of age accounting for most of these cases. No broadly protective serogroup B vaccine exists; however, an OMV-based vaccine approach appears to have been successful in controlling a serogroup B clonal epidemic in Cuba and has shown efficacy in large-scale, randomized, controlled trials among older children in Norway, Cuba, and Chile.

Chiron Vaccines, in conjunction with the NIPH, has developed a specially made OMV vaccine for New Zealand. Clinical trials have demonstrated vaccine safety and immunogenicity among adults and children and, on the basis of these results and safety and efficacy data for previously used OMV vaccines, MeNZB was granted licensure with provisional consent. This licensure allowed initiation of the largest immunization campaign ever attempted in New Zealand. Immunization began in July 2004.

This immunization program has the potential to prevent significant illness and numerous deaths in New Zealand; >5300 cases and 200 deaths have been reported since the epidemic began in 1991. Safety and efficacy data that will be collected and analyzed by an independent safety monitoring board will advance knowledge of serogroup B meningococcal disease and vaccine development. What is learned should lead to advances in eradication of the disease and may help similarly affected countries in the future. It will be important to note whether, after widespread implementation of the immunization program, another strain of N. meningitidis increases in incidence, although such a phenomenon has not been observed after implementation of immunization programs in other epidemic situations. In addition, it will be important to determine whether there are any differences in vaccine safety or efficacy among the different ethnic populations in New Zealand.

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serogroup B meningococcal disease; outer membrane vesicle vaccines; New Zealand; Neisseria meningitidis; epidemic

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