[Human Vaccines 3:5, 196-204, September/October 2007]; ©2007 Landes Bioscience
Research Paper
Post-Marketing Safety Monitoring of a New Group B Meningococcal Vaccine in New Zealand, 2004–2006 Anne McNicholas1,8,9,* Yvonne Galloway1,8 Paul Stehr-Green1,2,8 Stewart Reid1,3,8,9 Sarah Radke1,8 Kerry Sexton1,8 Charlotte Kieft1,8 Claire Macdonald1,8 Jocelyn Neutze4,10 Ross Drake5,10 Dorothy Isaac4 Mary O’Donnell5 Michael Tatley6,9 Philipp Oster7 Jane O’Hallahan1,9
Abstract
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NZ, New Zealand; AEFIs, adverse events following immunization; ISMB, Independent Safety Monitoring Board; CARM, Center for Adverse Reactions Monitoring; WHO, World Health Organization; IVMP, Intensive Vaccine Monitoring Program; ED, emergency department; AFP, acute flaccid paralysis; SFS, simple febrile seizure; HSP, HenochSchönlein Purpura
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Introduction
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4Middlemore Hospital; Manukau, New Zealand
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for Adverse Reactions Monitoring; University of Otago; Dunedin, New Zealand 7Novartis Vaccines and Diagnostics S.r.l.; Siena, Italy
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Management Group; 9Mortality Review Group; Committee
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*Correspondence to: Anne McNicholas; Meningococcal Vaccine Strategy; Ministry of Health; PO Box 5013; Wellington, New Zealand; Tel.: +64.4.816.4324; Fax: +64.4.460.4791; Email:
[email protected]
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Original manuscript submitted: 03/6/07 Manuscript accepted: 05/18/07
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Previously published online as a Human Vaccines E-publication: http://www.landesbioscience.com/journals/vaccines/article/4458
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3Ropata Medical Centre; Lower Hutt, New Zealand
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A new outer membrane vesicle vaccine, MeNZB™, was introduced in New Zealand (NZ) in 2004 to combat an epidemic of group B meningococcal disease.1 Group B meningococcal outer membrane protein vaccines have been used extensively worldwide, with efficacy shown to parallel immunogenicity.2‑7 Phase III clinical trials of the vaccine, which was tailor‑made for NZ,8 were not undertaken, with its licensure supported by the satisfactory immunogenicity and safety profile demonstrated in Phase I and II trials,9‑13 efficacy and safety data on similar vaccines,2‑8,13‑15 and planned intensive post‑licensure surveillance of adverse events following immunization (AEFIs).16 Under the Meningococcal B Immunization Program, the delivery of the three‑dose vaccine series* was staggered by region and age group. Other vaccinations, including those on the NZ immunization schedule,17 were co-administered if the child was of the appropriate age. The Meningococcal B Immunization Program started in July 2004 for children aged six months to 19 years in parts of Auckland, then gradually extended nationwide from late 2004. Vaccination of infants aged under six months began in the wider Auckland area in February 2005, then extended nationwide three months later. The graduated NZ‑wide vaccine delivery reflected historical meningococcal disease patterns, with regions at higher disease risk starting first.1,16 Strict safety monitoring requirements were established since Phase III trials were not undertaken for the vaccine. In addition, enhanced post‑marketing surveillance was necessary to provide an expanded safety profile. The safety strategy involved a measured approach to vaccine delivery, with a pre-defined number of vaccine recipients in each age group being observed before progressing to another region. Based on the absence of safety concerns from an expanding safety database, the Program extended across NZ. We designed the safety monitoring to rapidly identify AEFIs that were serious enough to cause the cessation of the Program and to maintain public and health professional confidence in the vaccine’s safety. Oversight by an Independent Safety Monitoring Board (ISMB) was integral to the vaccination campaign, especially in maintaining public and health professional confidence. The purpose of this paper is to describe the safety monitoring activities
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2University of Washington; Seattle, Washington USA
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Abbreviations
1Meningococcal Vaccine Strategy; Ministry of Health; Wellington, New Zealand
5Auckland City Hospital; Auckland, New Zealand
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New Zealand introduced a new outer membrane vesicle vaccine in 2004 to combat an epidemic of group B meningococcal disease. An Independent Safety Monitoring Board oversaw intensive safety monitoring, which included hospital surveillance, health professional reporting (passive and active) and mortality monitoring. With over three million doses administered to individuals aged under 20 years, the monitoring results provide consistent evidence supporting the vaccine’s safety.
Key words
group B meningococcal vaccine, outer membrane vesicle, vaccine safety, postmarketing surveillance, AEFI Acknowledgements See page 202. 196
*In January 2006, a fourth vaccine dose was recommended for infants who had started their vaccination series before the age of six months.
Human Vaccines
2007; Vol. 3 Issue 5
Safety of a New Meningococcal Group B Vaccine
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The Ministry of Health established a dedicated Data Management Group to design and lead the safety monitoring activities. As part of these activities it undertook routine analyses and provided regular reports via a secure webpage to the ISMB. The ISMB consisted of two international and three NZ members with expertise in infectious diseases, biostatistics, epidemiology, vaccinology and pediatrics. It provided regular feedback and advised the Ministry of Health regarding extensions of vaccinations to other age groups and regions as pre-determined vaccine dose numbers were delivered. In order to increase our ability to identify and evaluate a broad range of AEFIs in as close to real time as possible, we collected data through a variety of complementary surveillance activities. Spontaneous reporting program. The Center for Adverse Reactions Monitoring (CARM) operates NZ’s routine Spontaneous Reporting Program whereby health professionals voluntarily report AEFIs.18 CARM staff assigned event terms for each reported AEFI using the standard World Health Organization (WHO) Adverse Reaction Terminology Dictionary and assessed events using WHO coding for causality, seriousness, severity and outcome. CARM staff also categorised reports into groups of related clinical symptoms and signs to facilitate recognition of event patterns. Where other vaccines were co-administered, causality was attributed to all vaccines unless the report described a localized event, in which case causality was attributed to the specific vaccine administered at that site. Intensive Vaccine Monitoring Program (IVMP). CARM staff also implemented a new active surveillance system, the IVMP, to overcome shortcomings (e.g., under‑reporting) common with passive surveillance systems such as the Spontaneous Reporting Program.19,20 They prospectively collected data on a cohort from 35 medical centers NZ‑wide, enrolling children aged six weeks to four years when they received any immunization at participating medical centers. Vaccinators advised parents/guardians about the IVMP, provided an information pamphlet and offered a choice to “opt out.” Routinely recorded data on all immunizations administered, and health consultations at the child’s own medical center in the subsequent six weeks, were electronically transferred to CARM and assessed similarly to the Spontaneous Reporting Program. The IVMP received multi‑region approval through the Otago Ethics Committee. Hospital surveillance. The hospital surveillance was the key safety monitoring activity, its primary aim being to rapidly identify AEFIs of sufficient severity to require hospital admission and, for some conditions, emergency department (ED) consultation. It operated at three hospitals (Auckland City, Middlemore and Whangarei) serving the four regions where the Program started, and through it we aimed to monitor 100,000 recipients of the three‑dose vaccine series under the age of five years and 100,000 aged five to 19 years. It was modelled on Canada’s IMPACT system for AEFIs21 but was expanded in a number of ways. We undertook more frequent (often weekly) analyses of the data, monitored ED consults as well as admissions, included “other serious or unusual” events in vaccine recipients as well as pre-selected events in both vaccinated and unvaccinated individuals, and matched hospital admission and ED databases against a newly established National Immunization Register to establish vaccination status. We established the hospital surveillance over 18 months, and it was fully operational three months prior to
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commencement of the vaccination campaign. The hospital surveillance received Auckland Ethics Committee approval. We identified AEFIs through the hospital surveillance in two ways: Pre-selected events. We identified pre-selected events, regardless of the patient’s vaccination status, which allowed comparison of observed events against historical levels, and between vaccinated and unvaccinated individuals. Dedicated pediatric nurses identified events by daily review of admission databases, medical charts, discharge letters and laboratory records. We established the individual’s immunization status by weekly electronic matches against the immunization register and, for serious events, the nurses independently verified immunization status (e.g., from the patient’s medical records). The pre-selected events under surveillance were similar to those monitored by the IMPACT system21 and included anaphylaxis, acute flaccid paralysis (AFP), encephalopathy, hypotonic‑hyporesponsive episodes, thrombocytopenia (platelet count
