Barbara Law

Epidemiology of varicella zoster virus infection in Canada and the United Kingdom

Many countries are currently studying the possibility of mass vaccination against varicella. The objective of this study was to provide a comprehensive picture of the pre-vaccine epidemiology of the varicella zoster virus (VZV) to aid in the design of immunization programs and to adequately measure the impact of vaccination. Population-based data including physician visit claims, sentinel surveillance and hospitalization data from Canada and the United Kingdom were analysed. The key epidemiological characteristics of varicella and zoster (age specific consultation rates, seasonality, force of infection, hospitalization rates and inpatient days) were compared. Results show that the overall epidemiology of varicella and zoster is remarkably similar between the two countries. The major difference being that, contrary to Canada, the epidemiology of varicella seems to be changing in the United Kingdom with an important decrease in the average age at infection that coincides with a significant increase in children attending preschool. Furthermore, differences exist in the seasonality between the United Kingdom and Canada, which seem to be primarily due to the school calendar. These results illustrate that school and preschool contact patterns play an important role in the dynamics of varicella. Finally, our results provide baseline estimates of varicella and zoster incidence and morbidity for VZV vaccine effectiveness and cost-effectiveness studies.

Importance of background rates of disease in assessment of vaccine safety during mass immunisation with pandemic H1N1 influenza vaccines.

Because of the advent of a new influenza A H1N1 strain, many countries have begun mass immunisation programmes. Awareness of the background rates of possible adverse events will be a crucial part of assessment of possible vaccine safety concerns and will help to separate legitimate safety concerns from events that are temporally associated with but not caused by vaccination. We identified background rates of selected medical events for several countries. Rates of disease events varied by age, sex, method of ascertainment, and geography. Highly visible health conditions, such as Guillain-Barré syndrome, spontaneous abortion, or even death, will occur in coincident temporal association with novel influenza vaccination. On the basis of the reviewed data, if a cohort of 10 million individuals was vaccinated in the UK, 21.5 cases of Guillain-Barré syndrome and 5.75 cases of sudden death would be expected to occur within 6 weeks of vaccination as coincident background cases. In female vaccinees in the USA, 86.3 cases of optic neuritis per 10 million population would be expected within 6 weeks of vaccination. 397 per 1 million vaccinated pregnant women would be predicted to have a spontaneous abortion within 1 day of vaccination.

Epidemiological Features of Pertussis in Hospitalized Patients in Canada, 1991- 1997: Report of the Immunization Monitoring Program—Active (IMPACT)

To assess the morbidity associated with the continued high levels of pertussis, we studied all children <2 years of age who were admitted to the 11 Immunization Monitoring Program--Active (IMPACT) centers, which constitute 85% of Canadas tertiary care pediatric beds. In the 7 years preceding implementation of acellular pertussis vaccine, a total of 1,082 pertussis cases were reported, of which 49.1% were culture-confirmed. The median age of the patients was 12.4 weeks; 78.9% of cases were in children <6 months of age. Complications of pertussis were common: pneumonia was reported in 9.4% of cases, new seizures in 2.3%, and encephalopathy in 0.5%. There were 10 deaths (0.9%), all in children < or =6 months of age. Duration of hospitalization was longer (9.3 days vs. 4.9 days; P = .001) and intensive care was required more frequently (19.2% vs. 4.9%; P = .001) in infants under <6 months of age than in those > or =6 months. Pertussis continues to cause significant morbidity and occasional mortality in Canada, particularly in young infants.

Predictors of death in infants hospitalized with pertussis: a case-control study of 16 pertussis deaths in Canada.

OBJECTIVESnTo describe the clinical course of fatal cases of pertussis and identify predictors of death at the time of presentation for medical care.nnnMETHODSnCase-control study of 16 deaths from pertussis identified by the Immunization Monitoring Program, Active (IMPACT) surveillance network (January 1991-December 2001) matched with 32 nonfatal cases by age, date, and geography. Differences were compared by Fisher exact test and logistic regression. A multivariate model was developed using stepwise logistic regression.nnnRESULTSnAll 16 fatal cases were < or =6 months old; 13 were <2 months old. Fatal cases were less likely to have had cough complications during pregnancy (48% vs 14%; P=.046) and more likely to have pneumonia (63% vs 16%; P=.0024) before hospital admission and more likely to have seizures, pneumonia, leukocytosis, and hypoxemia after admission (P<.001 for all comparisons). White blood cell count and pneumonia were independent predictors of fatal outcome in the multivariate model.nnnCONCLUSIONSnInfants too young to have begun their immunizations are at highest risk of fatal pertussis infection. Leukocytosis and pneumonia are predictors of a poor outcome; however, rapid progression of the disease may make interventions difficult.

The effect of routine vaccination on invasive pneumococcal infections in Canadian children, Immunization Monitoring Program, Active 2000–2007

Active surveillance was conducted by the 12 centers of the Canadian Immunization Monitoring Program, Active from 2000-2007 in children 16 years of age and younger to determine the influence of 7-valent pneumococcal conjugate immunization programs on the prevalence, serotype and antibiotic resistance patterns of invasive pneumococcal disease (IPD) caused by Streptococcus pneumoniae. The absolute number of reported IPD cases decreased 48% (p<0.01) over the 8-year period and 56% (p<0.01) in children 0-4 years of age. The absolute number of reported IPD cases caused by serotypes in the conjugate vaccine decreased 87.5% (p<0.01) overall and 92% (p<0.01) in children 0-4 years. Although 6 non-vaccine serotypes increased over time, only serotype 19A increased significantly (p<0.01). Overall, the proportion of penicillin resistant isolates remained unchanged at 17%. Cefotaxime/ceftriaxone resistance remained unchanged at 2% of isolates annually. Universal pneumococcal conjugate infant immunization programs have dramatically decreased cases of invasive pneumococcal disease.

Invasive infections caused by haemophilus influenzae serotypes in twelve Canadian IMPACT centers, 1996-2001.

Background: Haemophilus influenzae type b (Hib) immunization has changed the epidemiology of pediatric bacterial invasive disease. We describe the epidemiology of H. influenzae invasive infections in 12 Canadian pediatric tertiary care [Immunization Monitoring Program, ACTive (IMPACT)] centers during the era of universal immunization against this pathogen. Methods: Children with positive cultures for H. influenzae serotypes a to f (Hia to Hif) and nontypable H. influenzae from sterile sites were identified from the laboratory records at 12 IMPACT centers from January 1, 1996 to December 31, 2001. Hospital records were retrospectively reviewed for demographic and clinical information. Results: Of 166 H. influenzae cases, 58 (35%) were caused by Hib, 89 (54%) by non-b serotypes, and 19 (11%) were not serotyped. The non-b serotypes included: 25 Hia (28%), 4 Hid (4%), 2 Hie (2%), 11 Hif (12%), and 47 were nontypable isolates (53%). For patients with Hib and Hia infection, meningitis was the most common presentation, accounting for 40% and 52% respectively, whereas the most common presentation for nontypable serotypes was pneumonia, seen in 43% of cases. Epiglottitis was associated mainly with Hib. Aboriginal ethnicity was an important risk factor for Hia cases, accounting for 76% of patients with infections caused by this serotype. Mean duration of hospitalization, need for admission to a pediatric intensive care unit, and case fatality rates were similar for the cases because of Hib, Hia, Hif, and nontypable serotypes. Conclusions: In 1996–2001, two-thirds of H. influenzae invasive disease in the 12 IMPACT centers was caused by non-b serotypes, which were associated with significant morbidity and mortality.

Analysis of varicella vaccine breakthrough rates: implications for the effectiveness of immunisation programmes.

The objective of this study was to quantify key parameters describing varicella zoster virus (VZV) vaccine efficacy. To do so a mathematical model was developed to represent breakthrough cases as a function of time after vaccination in vaccine efficacy trials. Efficacy parameter sets were identified by fitting the predicted annual number of breakthrough infections with that observed in three clinical trials chosen to represent the plausible range of vaccine efficacy. Results suggest that varicella vaccination seems to result in a high proportion of individuals who are initially totally protected (97% for the base-case). However, individuals lose full protection relatively rapidly (3% per year for the base-case). Once total protection has waned individuals have a high probability of developing a breakthrough infection if exposed to varicella (73% of the probability in unvaccinated susceptibles for the base-case). Results also highlight that vaccine efficacy parameters should be estimated concurrently to take into account dependencies between parameters.

Safety and immunogenicity of Haemophilus influenzae-tetanus toxoid conjugate vaccine given separately or in combination with a three-component acellular pertussis vaccine combined with diphtheria and tetanus toxoids and inactivated poliovirus vaccine for the first four doses.

The purpose of this randomized, controlled trial was to assess the safety and immunogenicity of a three-component acellular pertussis vaccine combined with diphtheria and tetanus toxoids and inactivated poliovirus vaccine given either separately or combined as a single injection with a Haemophilus influenzae type b-tetanus toxoid conjugate vaccine. A total of 180 infants were immunized at 2, 4, and 6 months of age; 129 were given a booster dose at 16-19 months of age. Vaccine-associated adverse events were similar whether the vaccines were combined as a single injection or given separately. There were no differences in levels of antibodies to Bordetella pertussis antigens (pertussis toxoid, filamentous hemagglutinin, and pertactin), diphtheria toxoid, or the three poliovirus types. The tetanus antitoxin level after the primary three-dose series was higher in recipients of the combined vaccine (2.37 IU/mL) than in recipients of the separate injections (1.32 IU/mL; two-sided P = .0001). In contrast, combined vaccine recipients had lower levels of antibody to H. influenzae type b polysaccharide after the third dose (1.57 microg/mL) than did those given separate injections (3.22 microg/mL; two-sided P = .0026). The antibody levels were not significantly different before or 1 month after the booster dose (32.9 microg/mL vs. 47.8 microg/mL, respectively; two-sided P = .07). We conclude that the vaccines were immunogenic and well tolerated. Despite lower levels of antibody to the H. influenzae type b polysaccharide after the primary three-dose series, mixing of the vaccines in a single syringe likely induced immunologic priming, as suggested by the high antibody levels after the booster dose.

Benefits and costs of immunization of children with pneumococcal conjugate vaccine in Canada

To estimate cost-effectiveness of routine and catch-up vaccination of Canadian children with seven-valent pneumococcal conjugate vaccine, a simulation model was constructed. In base scenario (vaccination coverage: 80%, and vaccine price: 58 dollars per dose), pneumococcal disease incidence reduction would be superior to 60% for invasive infections, and to 30% for non-invasive infections, but the number of deaths prevented would be small. Annual costs of routine immunization would be 71 million dollars (98% borne by the health system). Societal benefit to cost ratio would be 0.57. Net societal costs per averted pneumococcal disease would be 389 dollars and 125,000 per life-year gained (LYG). Vaccine purchase cost is the most important variable in sensitivity analyses, and program costs would be superior to societal benefits in all likely scenarios. Vaccination would result in net savings for society, if vaccine cost is less than 30 dollars per dose. Economic indicators of catch-up programs are less favorable than for routine infant immunization.

Global safety of vaccines: strengthening systems for monitoring, management and the role of GACVS.

Vaccines have contributed enormously in reducing the impact of many infectious diseases, and the expanded use of new and existing vaccines provides unprecedented potential for further reducing the global burden of infectious diseases. Yet, as with the deployment of other technologies, their use may also sometimes be associated with undesirable effects that need to be identified rapidly, understood and minimized. In this article, we review the models and systems that have been developed to monitor and respond to concerns regarding vaccine safety and we give illustrative examples of real or perceived vaccine safety issues. The Global Advisory Committee on Vaccine Safety (GACVS) was set up 10 years ago and charged to provide the WHO with independent advice on vaccine safety issues. The role of the GACVS is both to analyze and to interpret reports of the adverse effects of vaccines that impact on global vaccination programs and strategies, and to foster the development of improved surveillance systems to detect any adverse effects of vaccines, particularly in low- and middle-income countries. It also monitors the development of new vaccines during clinical testing and advises on the safe use of vaccines in immunization programs. As success is achieved with reducing the burden of vaccine-preventable diseases, there will be increasing attention focused on potential adverse effects, on the development of effective surveillance systems to detect adverse effects, and on improved methods to manage and control any harmful consequences of vaccination.