Catherine Jackson

New Zealand epidemic strain meningococcal B outer membrane vesicle vaccine in children aged 16-24 months

Background: New Zealand has experienced an epidemic of Neisseria meningitidis dominated by strain B:4:P1.7b,4 since 1991. Children younger than 5 years are at highest risk. Previous serogroup B outer membrane vesicle (OMV) strain specific vaccines have shown variable efficacy in this age group. Objective: To evaluate the immunogenicity, reactogenicity and safety in 16–24-month-old children of an OMV vaccine developed against the New Zealand epidemic strain. Methods: Children (332) aged 16–24 months were randomized to receive the New Zealand candidate vaccine made using strain NZ98/254 (B:4:P1.7b,4) or the Norwegian parent vaccine made using strain 44/76 (B:15:P1.7,16). Vaccines (25 μg/dose) were administered at 0, 6 and 12 weeks in this observer-blind trial. Immune response was measured by serum bactericidal assay and enzyme-linked immunosorbent assay. Sero-response was defined as a 4-fold or greater rise in serum bactericidal antibody titer compared with baseline, with titers <1:4 required to increase to ≥1:8 to be considered a sero-response. Local and systemic reactions were monitored for 7 days after vaccination. Results: Sero-response against NZ98/254 was achieved after 3 doses in 75% (95% CI: 69–80%) receiving the New Zealand candidate vaccine by both intention to treat (ITT) and per protocol (PP) analyses. In Norwegian parent vaccinees this was seen in 3% (0–12%) (ITT) and 4% (0–13%) (PP). Vaccines were well tolerated with no vaccine-related serious adverse events. Conclusion: The New Zealand candidate vaccine administered to these 16–24-month-old children in 3 doses was safe and elicited a promising immune response against the candidate vaccine strain NZ98/254 (N. meningitidis B:4:P1.7b,4) contributing to vaccine licensure for this age group.

Immunogenicity and tolerability in infants of a New Zealand epidemic strain meningococcal B outer membrane vesicle vaccine.

Background: An outer membrane vesicle meningococcal vaccine (MeNZB), was developed for the New Zealand epidemic strain of Neisseria meningitidis B:4:P1.7-2,4. Methods: A phase II, randomized, observer blind, controlled study evaluating the safety, reactogenicity, and immunogenicity of MeNZB administered with routine New Zealand immunizations at 6 weeks, 3 months, and 5 months of age (n = 375). Group 1 (n = 250) received 25 μg MeNZB and routine immunizations with a fourth MeNZB dose given at 10 months (n = 51). Group 2 (n = 125) received routine immunizations only. Sero-response was a ≥4-fold rise in vaccine strain serum bactericidal antibody titer compared with baseline or a titer of at least 1:8 for baselines <1:4. Reactogenicity was monitored for 7 days after vaccination. Results: Sero-response in Group 1 was achieved in 53% (95% Confidence interval [CI]: 46–59, n = 239) and 69% (95% CI: 54–80, n = 45) with geometric mean antibody titers of 9 (95% CI: 7–10) and 22 (95% CI: 12–39) after the third and fourth doses, respectively. No negative interference by MeNZB on routine immunizations was detected. There were no serious adverse events judged to be vaccine related. Conclusions: In this group of New Zealand infants, 4 MeNZB doses were required to demonstrate titers comparable with those achieved after 3 doses in older children. MeNZB was safe when used concomitantly with routine New Zealand immunizations to 5 months of age.

Fast Tracking the Vaccine Licensure Process to Control an Epidemic of Serogroup B Meningococcal Disease in New Zealand

Epidemics of serogroup B meningococcal disease are rare. Strain-specific outer membrane vesicle vaccines, which are not marketed, are the only current tool for control. A correlate of protection is ill defined, but published data suggest that measured serum bactericidal antibody levels parallel efficacy. Even infants can mount a strain-specific antibody response to a strain-specific vaccine. New Zealands epidemic (1991-2007; peak rate [in 2001], 17.4 cases per 100,000 persons) was dominated by a single strain. After a 5-year search (1996-2001) for a manufacturer for a strain-specific outer membrane vesicle vaccine, a fast-tracked research program (2002-2004) determined the safety and immunogenicity of vaccine in infants (2 age groups: 6-10 weeks and 6-8 months), children (age, 16-24 months), and school-aged children (age, 8-12 years) after an adult trial. The vaccine was reactogenic, compared with control vaccines (meningococcal C conjugate and routine infant vaccines), but retention was high. Three vaccine doses produced antibody levels (measured by serum bactericidal assay) that were considered to be adequate for public health intervention. However, in young infants, a fourth dose was required to achieve levels equivalent to those achieved by other age groups. Provisional licensure by New Zealands MedSafe was based on serological criteria strengthened by bridged safety data from studies of the parent outer membrane vesicle vaccine, independent assessment of manufacturing quality, and a clear plan for safety monitoring and effectiveness evaluation after licensure.

Antibody persistence following MeNZB vaccination of adults and children and response to a fourth dose in toddlers

Background A New Zealand serogroup B meningococcal epidemic prompted trials of a strain-specific (B:4:P1.7-2,4) outer membrane vesicle vaccine (MeNZB). Methods Adults, school children, and infants provided serum after three MeNZB doses to evaluate antibody persistence via serum bactericidal assay. Toddler (16–24 months) non-responders and responders received a fourth MeNZB dose 11 and 17 months after dose three respectively. Response was a ≥4-fold rise in bactericidal titre to a titre of ≥8. Results Geometric mean bactericidal titres (GMTs), with 95% CI, after dose 3: adults: 27 (14–52), 5 (3–11), and 7 (3–15) at 1, 10, and 22 months; school children: 18 (13–25) and 4 (3–6) at 1 and 4 months; infants: 27 (19–39) and 2 (2–3) at 1 and 7 months. The titre achieved after priming significantly influenced persistence. Toddler non-responder GMTs were 4 (3–5) and 1 (1–1) at 1 and 11 months after dose 3 and 69 (46–106) 1 month after dose 4. Responder GMTs were 24 (19–30) and 3 (2–4) at 1 and 17 months after dose 3 and 259 (184–363) 1 month after dose 4. Dose 4 had no safety concerns. Conclusions Immune response to MeNZB was most sustained in adults. In infants, bactericidal titres decayed almost to baseline by 7 months after dose 3. Toddlers showed marked immune response following a fourth dose suggesting memory. Persisting antibody is likely to be necessary for ongoing protection, as seen with serogroup C meningococci.

Phase II Meningococcal B Vesicle Vaccine Trial in New Zealand Infants

Background: A tailor-made serogroup B outer membrane vesicle vaccine was evaluated in the context of a serogroup B meningococcal epidemic dominated by Neisseria meningitidis strain B:4:P1.7b,4. Objective: To determine the safety, reactogenicity and immunogenicity in infants aged 6–8 months of a meningococcal B vaccine developed against the New Zealand epidemic strain. Design, setting and participants: Observer-blind, randomised, controlled trial conducted in 296 healthy infants in Auckland, New Zealand. Intervention: Infants were randomised 4:1 to receive three doses of New Zealand candidate vaccine (epidemic strain NZ98/254, B:4:P1.7b,4) or meningococcal C conjugate vaccine at 6-weekly intervals. Main outcome measures: Immune response was determined by human complement mediated serum bactericidal assay. Sero-response was a fourfold or greater rise in titre compared to baseline, with baseline titres <4 required to increase to ⩾8. Blood samples were taken before vaccination, 6 weeks after dose two, and 4 weeks after dose three. Local and systemic reactions were recorded for 7 days following vaccination. Results: Sero-response to the candidate vaccine strain, NZ98/254, was demonstrated in 74% of vaccinees (95% CI: 68% to 80% intention-to-treat; 67% to 79% per protocol) after three doses of New Zealand candidate vaccine. No meningococcal C conjugate vaccine recipients were sero-responders to NZ98/254 after three doses. Both vaccines were well tolerated with no vaccine related serious adverse events. Conclusions: Our data indicate that the New Zealand candidate vaccine administered in three doses to this group of 6–8-month-old infants was safe and immunogenic against the candidate vaccine strain NZ98/254 (Neisseria meningitidis B:4:P1.7b,4).

Immunogenicity, Reactogenicity, and Safety of a P1.7b,4 Strain-Specific Serogroup B Meningococcal Vaccine Given to Preteens

ABSTRACT New Zealand (NZ) has experienced a Neisseria meningitidis serogroup B epidemic since 1991. MeNZB, a strain-specific outer membrane vesicle vaccine made using an NZ epidemic strain isolate, NZ98/254 (B:4:P1.7b,4), from two manufacturing sites, the Norwegian Institute of Public Health (NIPH) and Chiron Vaccines (CV; now Novartis), was evaluated for safety, immunogenicity, and reactogenicity in this observer-blind trial with 8- to 12-year-old children. In year 1, cohort A (n = 302) was randomized 4:1 for receipt of NIPH-MeNZB or MenBvac (Norwegian parent vaccine strain 44/76; B:15:P1.7,16). In year 2, cohort B (n = 313) was randomized 4:1 for receipt of CV-MeNZB or NIPH-MeNZB. Participants all received three vaccinations 6 weeks apart. Local and systemic reactions were monitored for 7 days. Seroresponse was defined as a fourfold or greater rise in the serum bactericidal antibody titer from the baseline titer as measured by a serum bactericidal assay. Those with baseline titers of <1:4 required titers of ≥1:8 to serorespond. Intention-to-treat (ITT) and per protocol (PP) analyses are presented. In cohort A, 74% (ITT) and 73% (PP) of NIPH-MeNZB recipients demonstrated seroresponses against NZ98/254 after three doses, versus 32% (ITT and PP) of MenBvac recipients. In cohort B, seroresponses against NZ98/254 after three doses occurred in 79% (ITT and PP) of CV-MeNZB versus 75% (ITT) and 76% (PP) of NIPH-MeNZB recipients. Vaccines were tolerable, with no vaccine-related serious adverse events. In conclusion, the NZ strain meningococcal B vaccine (MeNZB) from either manufacturing site was immunogenic against New Zealand epidemic vaccine strain meningococci with no safety concerns when given in three doses to these 8- to 12-year-old children.

Reducing inequalities with vaccines: New Zealand’s MeNZB vaccine initiative to control an epidemic

Disadvantaged children of Māori and Pacific origin in New Zealand carry an inequitable burden of infectious diseases, many of which are preventable, some by vaccine. Immunisation is recognised in the developing world as a cheap, effective and efficient means of reducing inequalities. The MeNZB immunisation programme delivered in 2004–2006 towards the expected natural end of a projected 15‐year epidemic appears to have had an effect (difficult to prove conclusively) on reducing the disproportionate burden of meningococcal disease carried by this group of children. It was delayed by the late engagement of the New Zealand Ministry of Health, fully briefed from 1996, leading to unnecessary and potentially avoidable deaths and sequelae, many lifelong. Further, failure to adequately assess vaccine effectiveness means that the contribution of MeNZB to the observed reduction in disease, particularly in those aged less than five years, will never be reliably known. However, the MeNZB campaign has at least left a legacy: the National Immunisation Register, which should enable New Zealand to minimise the ‘vaccine inverse care law’ and contribute to reducing ethnic inequity in the burden of vaccine preventable diseases.

Factors associated with reported pain on injection and reactogenicity to an OMV meningococcal B vaccine in children and adolescents.

Pain on vaccine injection and subsequent site reactions of pain and swelling may influence confidence in vaccines and their uptake. This study aimed to identify factors associated with reported pain on injection and reactogenicity following administration of a strain specific meningococcal B outer membrane vesicle vaccine. A retrospective analysis of data was conducted from a phase II single center randomized observer-blind study that evaluated the safety, reactogenicity and immunogenicity of this vaccine in 2 cohorts of healthy 8 to 12 y old children. Vaccine administration technique was observed by an unblinded team member and the vaccine administrator instructed on standardized administration. Participants kept a daily diary to record local reactions (erythema, induration and swelling) and pain for 7 d following receipt of the vaccine. Explanatory variables were cohort, vaccine, age, gender, ethnicity, body mass index, atopic history, history of frequent infections, history of drug reactions, pain on injection, vaccinator, school population socioeconomic status, serum bactericidal antibody titer against the vaccine strain NZ98/254, and total IgG. Univariate and multivariable analyses were conducted using ordinal logistic regression for factors relating to pain on injection and reactogenicity. Perceived pain on injection was related to vaccine formulation, vaccine administrator and ethnicity. Reactogenicity outcomes varied with ethnicity and vaccine administrator. Maintaining community and parental confidence in vaccine safety without drawing attention to differences between individuals and groups is likely to become increasingly difficult. Vaccine administration technique alone has the potential to significantly reduce pain experienced on injection and local vaccine reactions.

Linking trauma registry injury data with national injury compensation data – opportunities for public health action in New Zealand

Background Trauma registries can play a key role in quality assurance and planning of trauma care. This study aimed to explore the feasibility and utility of linking data from a trauma registry to the national injury compensation scheme to estimate the impact of major trauma beyond the hospitalisation. Methods Using a deterministic linkage approach that included the unique national master patient index number, trauma registry data from adult patients admitted for acute care to Auckland City Hospital over a 22 month period (1 April 2006 to 31 January 2008) was linked to Accident Compensation Corporation data. Descriptive analysis investigated the quality, potential biases and the utility of this approach to achieve the study aims. Results A successful link was achieved for 72.4% (n=1520/2099) of trauma patients meeting the study criteria. Factors affecting the success of linkage included: ethnicity, TRISS scores, admission duration, and survival to discharge. Eighty-three percent of patients with linked data had returned to work within 12 months of injury. Those most likely to receive compensated time off work included machinery operators/drivers, and those injured due to land transport accidents. Cases least likely to have returned to work at 3 months were labourers, those injured in land transport incidents, and cases with ISS >15. Conclusions High quality, robust data linkage that, in the future, also includes probabilistic approaches, have the potential to inform priority setting in injury prevention, and aid in evaluating the quality and effectiveness of acute trauma care and rehabilitation services.