Effectiveness of a vaccination programme for an epidemic of meningococcal B in New Zealand

New Zealand has experienced a prolonged epidemic of meningococcal B disease since 1991. The epidemic has waned significantly since its most recent peak in 2001. A strain-specific vaccine, MeNZB, was introduced to control the epidemic in 2004, achieving 81% coverage of people under the age of 20. The vaccine was rolled out in a staged manner allowing the comparison of disease rates in vaccinated and unvaccinated individuals in each year.Vaccine effectiveness in people aged under 20 years is estimated using a Poisson regression model in the years 2001-2008, including adjustments for year, season, age, ethnicity, region and socioeconomic status. Further analyses investigate the dose response relationship, waning of the vaccine effect after one year, and cross-protection against other strains of meningococcal disease.The primary analysis estimates MeNZB vaccine effectiveness to be 77% (95% CI 62-85) after 3 doses and a mean follow-up time of 3.2 years. There is evidence for a protective effect after 2 doses 47% (95% CI 16-67), and no evidence for a waning of effectiveness after one year. Simultaneous modelling of invasive pneumococcal disease and epidemic strain meningococcal B suggests a degree of residual confounding that reduces the effectiveness estimate to 68%. There is evidence for some cross-protection of MeNZB against non-epidemic strains.The MeNZB vaccine was effective against the New Zealand epidemic strain of meningococcal B disease. Between July 2004 and December 2008 an estimated 210 epidemic strain cases (95% CI 100-380), six deaths and 15-30 cases of severe sequelae were avoided in New Zealand due to the introduction of the MeNZB vaccine.     

MeNZB: a safe and highly immunogenic tailor-made vaccine against the New Zealand Neisseria meningitidis serogroup B disease epidemic strain

Clinical studies have been conducted in New Zealand evaluating the safety and immunogenicity of an outer membrane vesicle (OMV) vaccine, MeNZB, developed to control epidemic disease caused by group B meningococci, subtype P1.7b,4. MeNZB, administered in a three-dose regimen, was well tolerated and induced a seroresponse, defined as a four-fold rise (> or =titre 8) in serum bactericidal antibodies against the vaccine strain 4-6 weeks after the third vaccination, in 96% (95% confidence interval (CI): 79-100%) of adults, 76% (95% CI: 72-80%) of children, 75% (95% CI: 69-80%) of toddlers and 74% (95% CI: 67-80%) of infants receiving MeNZB. In conclusion, these findings suggest that MeNZB is safe and is likely to confer protection against systemic group B meningococcal disease caused by the epidemic strain.     

A prospective study of the effectiveness of the New Zealand meningococcal B vaccine

The effectiveness of a new group B strain-specific meningococcal vaccine referred to as "MeNZB," developed by Chiron Vaccines (Siena, Italy) in collaboration with the Norwegian Institute of Public Health, was assessed in a prospective observational study following a nationwide vaccination program in New Zealand. The vaccination program began in July 2004, and the study uses data from January 2001 to June 2006. A generalized estimating equation model was used to estimate vaccine effectiveness that included potential confounding variables, such as disease progression over time, age, ethnicity, socioeconomic status, seasonality, and geographic region. The model provides strong statistical evidence for a vaccine effect (p < 0.0001), with estimated disease rates 3.7 times higher in the unvaccinated group than in the vaccinated group (95% confidence interval: 2.1, 6.8) and a vaccine effectiveness of 73% (95% confidence interval: 52, 85). An estimated 54 epidemic strain meningococcal cases were prevented in the 2 years since the vaccination program began (95% confidence interval assuming a fixed population size: 22, 115). In a sensitivity analysis, these estimates proved to be robust to modeling assumptions, including population estimates, estimates of the numbers vaccinated, effects of partial vaccination, and temporal autocorrelation.     

From secondary prevention to primary prevention: a unique strategy that gives hope to a country ravaged by meningococcal disease

New Zealand has been affected by an epidemic of group B meningococcal disease dominated by a strain defined as, B:4:P1.7b,4. Over 5550 cases and 222 deaths have been reported since 1991 in a population of 4 million people.Meningococcal disease cases notified on EpiServ database operated by Institute of Environmental Science and Research Limited through to 30 September 2004. Through the collaborative efforts of a government agency, vaccine company, university and laboratory institute, clinical trials of the Chiron produced outer membrane vesicle (OMV) strain-specific MeNZB vaccine were run in rapid succession. The delivery of MeNZB will be New Zealand's largest immunisation programme with three doses given at 6-week intervals to over 1 million people aged 6 weeks-19 year olds inclusive. Planning, co-ordinating and delivering the immunisation programme is a challenging project for the New Zealand Health Sector.     

Immunogenicity and safety of a strain-specific MenB OMV vaccine delivered to under 5-year olds in New Zealand

To control the devastating group B meningococcal epidemic in New Zealand a strain-specific OMV vaccine (MeNZB) was extensively tested before vaccination of >1,000,000 people under 20 years. After the three-dose course 75% of 6-8-month-old infants and 16-24-month-old toddlers showed four-fold increases in bactericidal antibodies. In 6-10-week-old infants a fourth dose was needed to obtain similar results. After primary vaccination, the antibody titre decline was most pronounced among the youngest but both young infants and toddlers showed a clear booster response to a fourth dose. MeNZB was safe and well tolerated. The comprehensive post-licensure safety surveillance revealed no safety concerns.     

Safety review: two outer membrane vesicle (OMV) vaccines against systemic Neisseria meningitidis serogroup B disease

MenBvac is an OMV vaccine against systemic serogroup B Neisseria meningitidis disease. MenBvac was developed for control of a B:15:P1.7,16 subtype epidemic in Norway and administered to 180,000 subjects in 28 clinical studies. MeNZB, a daughter vaccine of MenBvac, was developed for a clonal B:4:P1.7b,4 epidemic in New Zealand and administered to 1 million people <20 years. The vaccines were similar regarding reactogenicity profile. Serious adverse events (SAEs) in general and particularly neurologic SAEs were very rare. Despite frequently reported local reactions and fever in those under 5 years, these OMV-based vaccines containing 25 microg antigen can be considered safe for use in all age groups.     

Evaluación de la efectividad de los programas de vacunación

Vaccines have contributed enormously to reducing the incidence of many communicable diseases. The protective efficacy of a vaccine refers to the health effects of the vaccine applied in optimal, ideal conditions, whereas the effectiveness of a vaccination program refers to the health effects of vaccination in the vaccinated individuals in clinical practice or within public health programs, which may differ widely from optimal conditions. Vaccine efficacy is estimated by randomized clinical trials. In contrast, effectiveness can be measured by various types of epidemiological studies: randomized community trials, in which the target vaccine is randomly assigned to a group and disease incidence in this group is compared with that of an unvaccinated group; cohort studies, which are observational epidemiological studies in which the vaccination status is known in healthy vaccinated (vaccinated cohort) and unvaccinated (unvaccinated cohort) people and the occurrence of the disease in the two groups is studied; and observational case-control studies, in which two groups are selected; one with the disease under investigation (cases) and the other without (controls), and vaccination histories are investigated in the two groups. Vaccine effectiveness may also be estimated by comparing attack rates in epidemic outbreaks or secondary attack rates in the home, or by screening.     

Assessing the effectiveness of vaccination programs

Vaccines have contributed enormously to reducing the incidence of many communicable diseases. The protective efficacy of a vaccine refers to the health effects of the vaccine applied in optimal, ideal conditions, whereas the effectiveness of a vaccination program refers to the health effects of vaccination in the vaccinated individuals in clinical practice or within public health programs, which may differ widely from optimal conditions. Vaccine efficacy is estimated by randomized clinical trials. In contrast, effectiveness can be measured by various types of epidemiological studies: randomized community trials, in which the target vaccine is randomly assigned to a group and disease incidence in this group is compared with that of an unvaccinated group; cohort studies, which are observational epidemiological studies in which the vaccination status is known in healthy vaccinated (vaccinated cohort) and unvaccinated (unvaccinated cohort) people and the occurrence of the disease in the two groups is studied; and observational case-control studies, in which two groups are selected; one with the disease under investigation (cases) and the other without (controls), and vaccination histories are investigated in the two groups. Vaccine effectiveness may also be estimated by comparing attack rates in epidemic outbreaks or secondary attack rates in the home, or by screening.     

Evaluation of serogroup A meningococcal vaccines in Africa: a demonstration project

Endemic and epidemic meningococcal disease constitutes a major public-health problem in African countries of the 'meningitis belt' where incidence rates of the disease are many-fold higher (up to 25 cases per 100,000 population) than those in industrialized countries, and epidemics of meningococcal disease occur with rates as high as 1,000 cases per 100,000 people. Using the precedent established during the licensing of conjugate vaccines against Haemophilus influenzae type b and serogroup C meningococci and components of currently-licensed meningococcal polysaccharide vaccines, new meningococcal conjugate vaccines will likely be licensed using immunological endpoints as surrogates for clinical protection. Post-licensure evaluation of vaccine effectiveness will, therefore, be of increased importance. One vaccine being developed is the serogroup A meningococcal (Men A) conjugate vaccine produced by the Meningitis Vaccine Project (MVP), a partnership between the World Health Organization and the Program for Applied Technology in Health. This vaccine will likely be the first meningococcal conjugate vaccine introduced on a large scale in Africa. This paper summarizes the general steps required for vaccine development, reviews the use of immunogenicity criteria as a licensing strategy for new meningococcal vaccines, and discusses plans for evaluating the impact of a meningococcal A conjugate vaccine in Africa. Impact of this vaccine will be measured during a vaccine-demonstration project that will primarily measure the effectiveness of vaccine. Other studies will include evaluations of safety, vaccine coverage, impact on carriage and herd immunity, and prevention-effectiveness studies.     

Combined administration of serogroup B meningococcal vaccine and conjugated serogroup C meningococcal vaccine is safe and immunogenic in college students

This study evaluated the first use of a combination of the lyophilized components of the conjugated group C vaccine Menjugate reconstituted with the liquid group B outer membrane vesicle (OMV) vaccine MeNZB. At 6-week intervals, healthy residential students received three doses of MeNZB alone or concomitantly with one dose of Menjugate (MeNZB+MenC). Short-lasting injection-site reactions of mild or moderate intensity were frequent in both groups. There were no vaccine-related serious adverse events. After three doses, the percentage of subjects with serum bactericidal assay (SBA) titres > or = 1:8 against the serogroup B strain NZ98/254 was 82% for MeNZB+MenC and 78% for MeNZB. All subjects in the MeNZB+MenC group achieved SBA titres > or = 1:8 against serogroup strain C11 and 67% in the MeNZB group. All SBA and ELISA responses of the combined vaccine were at least as good as for MeNZB alone. After vaccination, the pharyngeal carriage rate of any meningococcus in the vaccinated group had declined from 40% to 21%.     

Vaccine Preventability of Meningococcal Clone,Greater Aachen Region,Germany

Emergence of serogroup B meningococci of clonal complex sequence type (ST) 41/44 can cause high levels of disease, as exemplified by a recent epidemic in New Zealand. Multiplication of annual incidence rates (3.1 cases/100,000 population) of meningococcal disease in a defined German region, the city of Aachen and 3 neighboring countries (Greater Aachen) prompted us to investigate and determine the source and nature of this outbreak. Using molecular typing and geographic mapping, we analyzed 1,143 strains belonging to ST41/44 complex, isolated from persons with invasive meningococcal disease over 6 years (2001–2006) from 2 German federal states (total population 26 million) and the Netherlands. A spatially slowly moving clone with multiple-locus variable-number tandem repeat analysis type 19, ST42, and antigenic profile B:P1.7–2,4:F1–5 was responsible for the outbreak. Bactericidal activity in serum samples from the New Zealand MeNZB vaccination campaign confirmed vaccine preventability. Because this globally distributed epidemic strain spreads slowly, vaccination efforts could possibly eliminate meningococcal disease in this area.     

Observational methods in epidemiologic assessment of vaccine effectiveness.

Observational methods are important in the measurement of vaccine effectiveness (VE) as experimental designs cannot be used for measurement of vaccines already on the vaccination schedule. Furthermore, efficacy measured in clinical trials under ideal conditions may differ to effectiveness in the field under non-ideal conditions and in different populations. In addition to post-licensure surveillance, observational VE studies are particularly important when disease incidence does not predictably decrease with increased vaccine coverage, when high proportions of vaccine failure among reported cases suggest a problem with the vaccine or when issues arise that were not predicted in pre-licensure evaluations. Commonly used study types for evaluating VE include cohort studies, household contact studies, case-control studies, the screening method and case-cohort studies. There are many potential biases in all observational VE studies which should be considered in the study design and analysis stage. Of the five observational study types reviewed, cohort studies undertaken during an outbreak investigation offer the simplest means of VE estimation and is the preferred study design where the situation permits. Where this is not possible the screening method is the most economical and rapid method. It is essential that the effectiveness of all vaccination programs be evaluated. As new vaccines are introduced to the schedule, booster doses are added and the timing of doses changed, the role of observational methods in the evaluation of VE will become even more important. To date, few observational VE studies have been undertaken in Australia, suggesting the under-utilisation of these methods.     

Real-time monitoring of the influenza vaccine field effectiveness

Twice a year, the World Health Organization recommends the composition of the influenza vaccine depending on the strains which circulate several months before the beginning of the epidemic. Therefore, it is important to assess the field vaccine effectiveness (FVE) yearly. Thanks to data on vaccine coverage and data on influenza like illness cases collected by the French Sentinel Network, we are able to estimate the FVE few weeks after the beginning of the yearly influenza epidemic. In this paper, we have analysed the estimates obtained for the last 10 epidemic seasons for people over and under 65. Making the assumption that the vaccine coverage is stable from 1 year to another, we are able to assess the level of the FVE few weeks after the beginning of the epidemic and we should detect a lack of effectiveness of the vaccine.     

Methods of outbreak investigation in the "era of bacteriology" 1880-1920

The advent of bacteriological methods in the later 19th century has been seen, on the examples of America and Germany, to have been followed by a new laboratory-based, contact-tracing method of investigating outbreaks of epidemic disease. In Britain, however, this new approach never took firm root, and practising epidemiologists continued to follow an observational and deductive tradition in field investigations, rejecting any primary dependence on bacteriological methods. Alongside this persistent observational practice, there emerged a new statistical approach, based in Pearsonian biometrics, which allied itself with experimental laboratory techniques to develop a more systematic, theoretical trajectory for explaining disease outbreaks in the years after World War I.     

Selection bias in evaluating of influenza vaccine effectiveness: a lesson from an observational study of elderly nursing home residents

Selection bias is of critical concern in the study of influenza vaccine effectiveness when using an observational study design. This bias is attributable to the inherently different characteristics between vaccinees and non-vaccinees. The differences, which are related both to vaccination and signs of clinical disease as an outcome, may lead to erroneous estimation of the effectiveness. In this report, we describe how selection bias among elderly nursing home residents may lead to a spurious interpretation of the protective effect of influenza vaccine. Our results should be a lesson in the importance of regarding selection bias when assessing influenza vaccine effectiveness.     

New strategies are needed to improve the accuracy of influenza vaccine effectiveness estimates among seniors

ObjectiveThe magnitude of the benefit of influenza vaccine among elderly individuals has been recently debated. Existing vaccine effectiveness estimates derive primarily from observational studies, which may be biased. In this paper, we provide a methodological examination of the potential sources of bias in observational studies of influenza vaccine effectiveness in seniors and propose design and analysis strategies to reduce bias in future studies.Study Design and SettingWe draw parallels to bias documented in observational studies of therapies in other areas of medical research including pharmacoepidemiology, discuss reasons why existing adjustment methods in influenza studies may not adequately control for the bias, and evaluate statistical approaches that may yield more accurate estimation of influenza vaccine effectiveness.ResultsThere is strong evidence for the presence of bias in existing observational estimates of influenza vaccine effectiveness in the elderly and the failure of current adjustment methods to reduce bias.ConclusionPromising approaches for reducing bias include obtaining more accurate information on confounders, such as functional status, avoiding all-cause death in favor of outcomes, such as pneumonia or influenza-related pneumonia, and evaluating the extent to which bias is reduced by these and other methods using the ‘control’ period before influenza season.     

黑龙江省双价肾综合征出血热疫苗免疫效果观察

目的分析黑龙江省大规模接种双价肾综合征出血热(hemorrhagic fever with renal syndrome,HFRS)疫苗免疫效果,为以疫苗接种为主的新防控对策在省内推广和应用提供科学依据。方法在黑龙江省出血热高发病地区的重点人群中实施浙江天元生物药业股份有限公司生产的双价HFRS疫苗接种,之后分析出血热疫情变化。结果全省2008年出血热发病数与2007年同期相比下降37.78%。27个市(县)区出血热疫苗接种点2008年出血热发病数与2007年同期相比下降40.81%。2008年1-9月发病数与2007年同期相比下降24.41%。2008年10-12月出血热发病数与2007年同期相比下降60.70%,接种疫苗者无一例发病。结论疫苗接种后出血热发病率下降幅度显著增加,事实证明在出血热高发病疫区采取疫苗接种是见效最快、最安全、效果最显著的防病措施。     

Mumps vaccination coverage and vaccine effectiveness in a large outbreak among college students--Iowa, 2006

Following implementation of a routine childhood two-dose measles-mumps-rubella vaccination strategy, mumps disease levels dropped dramatically in the US and an elimination goal was set for 2010. However, a 2006 epidemic involved >5700 cases nationwide, with many reported among fully vaccinated college students. In an outbreak in two Iowa colleges, we investigated: (1) vaccination coverage using electronic records verified by provider records and (2) vaccine effectiveness assessed by comparison of dose-specific attack rates. Mumps was classified as typical (parotitis/orchitis) or atypical (parotid tenderness or submandibular/sublingual adenitis). Two-dose mumps vaccination coverage was 90% both for the student population (2128/2363) and case-students (97/108). Two-dose vaccine effectiveness was 76-88% with no significant difference for attack rates between one and two doses. Among two-dose vaccine recipients, 74% of the population (1482/2009) and 79% of the case-students (75/95) had received the second dose >10 years before. A large mumps outbreak occurred despite high two-dose vaccination coverage in a population most of whom had received the second dose >10 years before. Two-dose vaccine effectiveness was similar to previous one-dose estimates. Further studies are needed to examine the persistence of two-dose mumps vaccine-induced immunity and to determine whether US mumps elimination can be achieved with the current vaccination strategy.     

Validation of the serum bactericidal assay for measurement of functional antibodies against group B meningococci associated with vaccine trials

Provisional licensure of the trial vaccine, MeNZB, required demonstration of immune responses in vaccines, as measured by a validated Serum Bactericidal Assay (SBA). Reported are the investigations undertaken to define test parameters, lower limits of quantitation and measurement of SBA reproducibility. Results helped to formulate the operating procedure for the measurement of serum bactericidal antibodies during six age-group MeNZB vaccine trials. The lower limit of quantitation was determined as a titre of 4. A four-fold rise in antibody (sero-conversion) from a pre-vaccination titre of 2 (<4) required a minimum post-vaccination titre of 8, a more stringent measurement than has been used in other published studies.     

Using observational epidemiology to evaluate COVID-19 vaccines: integrating traditional methods with new data sources and tools

Although clinical trials are necessary for vaccine approval, observational epidemiology will be required to evaluate the long-term effectiveness, safety, and population impacts of newly approved COVID-19 vaccines under real-world field conditions. In this commentary, I argue that a hybrid approach that combines new data sources and tools, including COVID-19 vaccine registries, with traditional epidemiological methods will be needed to evaluate COVID-19 vaccines using observational epidemiology. Wherever possible, primary data collection, active surveillance, and linkage with existing population-based cohorts should be leveraged to supplement secondary data sources and passive surveillance systems. Evidence-informed public health decision making around provincial COVID-19 immunization programs will need to account for potential biases, incomplete or conflicting information, and heterogeneity across subpopulations.